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CAS No. : | 480-66-0 | MDL No. : | MFCD00002287 |
Formula : | C8H8O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XLEYFDVVXLMULC-UHFFFAOYSA-N |
M.W : | 168.15 | Pubchem ID : | 68073 |
Synonyms : |
2,4,6-trihydroxyacetophenone;1-(2,4,6-Trihydroxyphenyl)ethanone;THAP Monohydrate
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 42.71 |
TPSA : | 77.76 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.55 cm/s |
Log Po/w (iLOGP) : | 0.74 |
Log Po/w (XLOGP3) : | 1.09 |
Log Po/w (WLOGP) : | 1.01 |
Log Po/w (MLOGP) : | -0.07 |
Log Po/w (SILICOS-IT) : | 0.72 |
Consensus Log Po/w : | 0.7 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.87 |
Solubility : | 2.25 mg/ml ; 0.0134 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.32 |
Solubility : | 0.814 mg/ml ; 0.00484 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.0 |
Solubility : | 16.7 mg/ml ; 0.0995 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.1 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | at 180℃; for 0.666667 h; Microwave irradiation | 5,7-dihydro-2-methyl-4H-chromen-4-one: A mixture of 1 -(2,4,6-trihydroxyphenyl)ethan-1-one (2.02 g, 12.0 mmcl), AcONa (0.984 g, 12.0 mmol) in Ac20 (6.0 mL) was heated at 180 °C for 40 mm in a microwave reactor. The reaction mixture was poured into water, extracted with ethyl acetate (EA) , washed with sat’d NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was treated with a solution of K2003 (4.98 g, 36 mmol) in H20 (90 mL) and refluxed for 3 h. Acidified with 3 N HCI. The precipitate was collected by vacuum filtration to afford 1 .09 g (47percent) of 5,7-dihydro-2-methyl-4H-chromen-4-one as a yellow solid. Rff 0.45 (hexanes: EA = 1: 1); LC-MS (ESI): mlz 193 [M+1]’H NMR (400 MHz, DMSO-d6) ö (ppm) 2.35 (s, 3H), 6.17 (d, J=2.0 Hz, 2H), 6.33 (d, J=2.0 Hz, 1H), 10.78 (s, IH), 12.82 (s, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In acetone for 3 h; Reflux | To a refluxing solution of 2,4,6-trihydroacetophenone-monohydrate (10 g, 53.7 mmol) and K2CO3 (15 g, 108.7 mmol) in acetone (150 mL), (CH3)2SO4 was added at three hour intervals (3 x 3.5 mL, 40.0 mmol). The solution was filtered and the solvent was evaporated to afford 2,4-dimethoxy-6-hydroxyacetophenone as a yellow solid (98percent). |
99% | With potassium carbonate In acetone at 0 - 20℃; Inert atmosphere | Example 14 synthesis of 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (11) To a solution of commercial 2',4',6'-trihydroxyacetophenone dihydrate (15.0 g, 80.57 mmol, 1eq) in acetone (170 mL), potassium carbonate (23.4 g, 169.20 mmol, 2.1 eq) and dimethylsulfate (15.6 mL, 165.17 mmol, 2.05 eq) were added under argon at 0°C. After vigorous stirring at room temperature for 17h, the resulting mixture was filtered and the filtrate concentrated in vacuo. The resulting product 5 was recristallized from ethyl acetate / heptanes (3/97) to give 15.80 g (99percent) of a pale yellow solid. Molecular Weight: 196.20 (C10H12O4). 1H-NMR δ (CDCl3, 300 MHz) ppm (J in Hz): 2.61 (s, 3H, CH3CO), 3.82 (s, 3H, MeO), 3.85 (s, 3H, MeO), 5.91 (d, 1H, J=2.4, H- 3'), 6.05 (d, 1H, J=2.4, H-5'), 14.03 (s, 1H, OH). |
99% | With potassium carbonate In acetone | 2,4,6-trihydroxy-acetophenone (2) and the reaction wasdissolved in a dimethyl sulfate to potassium carbonate in acetone to synthesize4,6-dimethoxy-2-hydroxy acetophenone (3) |
95.8% | With potassium carbonate In acetone at 10 - 15℃; | A mixtureof phloroacetophenone (1) (300 g, 1.78 mol), acetone (1.5 L)and potassium carbonate (739.2 g, 5.35 mol) was chargedunder stirring at room temperature. Dimethyl sulphate (494.9g, 3.92 mol) was charged drop wise with the help of the additionfunnel at 10-15 °C for 3 h. TLC (20 percent EtOAc in hexane)showed no traces of starting material but observed traces oftrimethoxyacetophenone. After completion of the reaction, thereaction mixture was poured into ice cold water and stirredfor 3 h. A crude solid material was obtained on filtration andwashed with cold water and drained thoroughly. The yieldwas 84 percent with a purity of 95.8 percent obtained. |
94% | With potassium carbonate In acetone for 2 h; Reflux | A mixture of 2,4,6-trihydroxyacetophenone (1) (1.0 g, 5.95 mmol) anhydrous K2CO3 (1.64 g, 11.88 mmol) and (CH3)2SO4 (1.08 mL, 11.22 mmol) was stirred and refluxed in acetone (60 mL) for 2 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated and the residue subjected to silica gel column chromatography with PE/AcOEt 2:1 as an eluent to afford white solids 1.1 g, yield: 94percent. m.p. 77-79 °C (Lit.1: 79~80°C ). |
93.5% | Stage #1: With potassium carbonate In acetone at 25℃; for 0.5 h; Stage #2: at 25℃; |
To a solution of 1-(2,4,6-trihydroxyphenyl)ethanone (11.16 g, 0.06 mol) in dry acetone (150 mL), potassium carbonate (24.84 g, 0.18 mol) was added and stirred for 30 min at room temperature. Then dimethyl sulphate (12 mL, 0.12 mol) was added drop-wise, the reaction solution was stirred for 4-5 h at room temperature and monitored by thin-layer chromatograph (TLC). Poured the reaction solution to ice-water (1000 mL) and the precipitate was filtered, washed with water, dried to afford 1 (11.0 g) as white solid in 93.5percent yield. 1H NMR (400 MHz, DMSO‑d6) δ: 13.79 (s, 1H, OH), 6.11 (d, 1H, J = 2.3 Hz), 6.08 (d, 1H, J = 2.3 Hz), 3.86 (s, 1H), 3.81 (s, 1H), 2.55 (s, 1H). 13C NMR (100 MHz, DMSO‑d6) δ: 203.2, 166.7, 166.4, 163.2, 105.9, 94.1, 91.2, 56.5, 56.1, 33.1. |
87% | With potassium carbonate In acetoneReflux | (1 g, 5.95 mmol) was dissolved in 30 ml of acetone followed by the addition of potassium carbonate (4.11 g, 5 eq.), And dimethylsulfate (4 eq) was added dropwise. The suspension was refluxed for 5 to 8 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered and washed with acetone. The filtrate was evaporated under reduced pressure to give intermediate 5a (2-hydroxy-4,6-dimethoxyacetophenone) , 6a (2-hydroxy-4,6-diethoxyacetophenone) (5a, 1.01 g, yield 87percent; 6a, 1.15 g, 79percent yield); intermediate 5a, 6a, (4-hydroxy-5,7-dimethoxycoumarin), 6b (4-hydroxy-5,7-diethoxy coumarin) obtained by Method B of Method 9, (44 mg), 6b (50 mg) were each obtained by the method A of Example 9 to obtain the compound of the formula (5b, 1.00 g, yield 93percent; 6b, 1.07 g, yield 91percent 6,6 (Derivative 5, 60 mg, yield 74percent; derivative 6,63 mg, 64percent); nitration was carried out using Intermediate 6b (500 mg, 2 mmol) (see reaction of compound 2 (68 mg, yield 85percent) was obtained from Intermediate 6c (59 mg, 0.2 mmol) followed by Method A of Example 9 to give the intermediate 6c (484 mg, yield 82percent |
84.2% | With potassium carbonate In acetone for 5 h; Reflux | 4.1.5 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethanone (16) To a mixture of 1-(2,4,6-trihydroxyphenyl)ethanone 15 (4.5 g, 24.2 mmol) and anhydrous K2CO3 (8.29 g, 55.6 mmol) in acetone (90 mL), Me2SO4 (6.84 mL, 72.5 mmol) was added dropwise with stirring. The resulting mixture was refluxed for 5 h and then filtered and concentrated under reduced pressure. The residue was purified on a silica gel chromatography using CH2Cl2 as eluent, obtaining compound 16; 84.2percent yield; white solid; mp 78-79 °C (lit. 38 79-80 °C). |
84% | With potassium carbonate In acetone at 0 - 20℃; for 3 h; Inert atmosphere | To a stirred solution of ketone 1 (1.18 g, 10 mmol) and K2CO3 (3.45 g 25 mmol) in acetone (20 mL), (CH3)2SO4 (2.37 mL, 25 mmol) was added dropwise at 0 °C. After stirring at room temperature for 3 h, the solvent was then removed under reduced pressure. The residue was dissolved in water (30 mL) and the solution was extracted three times with EtOAc. The combined organics were washed with water and brine, then dried over anhydrous MgSO4 and concentrated in vacuo to give compound 11 (1.65 g, 84percent). 1H NMR (500 MHz, CDCl3) δ 14.03 (s, 1H), 6.08 (d, J = 2.4 Hz, 1H), 5.94 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.63 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 203.19, 167.58, 166.09, 162.91, 105.97, 93.45, 90.71, 55.55, 32.96; ESIMS: m/z = 197.2 [M+H]+. |
82% | With potassium carbonate In acetone at 20℃; | 1 -(2,4,6- trihydroxyphenyl)ethanone, 4, (16.8 g, 0.10 mol), anhydrous potassium carbonate (41.50 g, 0.30 mol) and anhydrous acetone (168 mL) were combined and stirred at room temperature after which dimethyl sulfate (26.9 g, 0.21 mol) was slowly added. Once the addition was complete, the reaction was stirred for 1 hour. The pH of the solution was adjusted to neutral using 2N HCl. The resulting yellow solid was collected by filtration and washed with water then dried to afford 16 g (82percent yield) of the desired product as a white solid. M.p. 76-78 0C. |
82% | With potassium carbonate In acetone for 0.333333 h; Reflux; Inert atmosphere | K2CO3 (7.23 g, 52.32 mmol) and Me2SO4 (2.48 mL, 26.16 mmol) were added to a solution of 2′,4′,6′-trihydroxyacetophenone (1, 2.00 g, 11.89 mmol) in acetone (50 mL). The reaction mixture was refluxed for 20 min under nitrogen atmosphere. After that, K2CO3 was filtered off, the acetone evaporated, and the residue recrystallized in EtOH affording the 2′-hydroxy-4′,6′-dimethoxyacetophenonein good yield (82percent, 1.91 g). |
82.5% | With potassium carbonate In acetone at 20℃; | This compound was prepared from a mixture of 1 (17.85 mmol, 3 g), K2CO3 (43.47 mmol, 6 g), Me2SO4 (19.67 mmol, 3.85 g), and 50 ml acetone, which was stirred at RT for 5–6 h, and then, the mixture was poured into water (300 ml). The precipitated solid was filtered, washed with water, and crystallized from 95 percent ethanol to give 2 as white powder, yield: 82.5 percent; IR (KBr) νmax 2,960 (OH),1,620 (C=O) cm-1; 1H NMR (DMSO-d6, 400 MHz): δ = 14.15 (1H, s, OH), 6.36 (1H, d, J = 2.5 Hz, H-3), 5.97(1H, d, J = 2.7 Hz, H-5), 3.89 (3H, s, OCH3-4), 3.83 (3H,s, OCH3-6), 2.7 (3H, s, COCH3). 13C NMR (DMSO-d6,100 MHz): δ = 203.1 (C, C=O), 167.6 (C, C-4), 166.1(C,C-6), 162.9 (C, C-2), 106.0 (C, C-1), 92.9 (CH, C-3), 90.1(CH, C-5), 55.4 (2CH3, OCH3), 32.1(CH3, COCH3); ESI–MS: m/z 197.09 [M+H]+. Anal. Calcd. for C10H12O41 96.07: C, 61.22; H, 6.16. Found: C, 61.27; H, 6.19. |
81.36% | With potassium carbonate In acetone at 50℃; for 6 h; | Anhydrous operation, 5 g of Intermediate 6 (26.85 mmol) was put in 80 ml of acetone, and 7.5 g of potassium carbonate was added(54.35 mmol) and 5.25 ml of dimethyl sulfate (20 mmol) were added, and the reaction solution was heated to 50 ° C, After the reaction was completed for 6 hours, the excess acetone was removed by distillation under reduced pressure, Purification by column chromatography gave a white solid in a yield of 81.36percent. |
78% | With potassium carbonate In acetone for 20 h; Reflux | The 9g compound (1) is dissolved in 30 ml of acetone, is added under stirring 14g potassium carbonate, then using the constant voltage dropping funnel slowly add sulfuric acid dimethyl ester 15g, reflux stirring 20h, cooling to room temperature, adding ice water precipitating a large amount of white solid, filtered, methanol recrystallization to obtain 7.5g white solid (2), yield 78percent. Compound mp: 74.4-75.1 °C. |
78% | With potassium carbonate In acetone for 20 h; Reflux | The compound 1 (9g ) dissolved in 30ml of acetone, 14g of potassium carbonate was added under stirring, then added slowly with constant pressure dropping funnel dimethyl sulfate 15g, was stirred at reflux for 20h, cooled to at room temperature, ice water was added to precipitate large amount of white solid was suction filtered, and recrystallized from methanol to give a white solid 7. 5g (2), a yield of 78percent. Compound mp 74. 4-75. 1 ° C. The product structure was confirmed by IR, NMR and MS analysis |
75% | With potassium carbonate In acetone at 20℃; for 4 h; | The 2,4,6-trihydroxyacetophenone monohydrate (3.72g, 20mmol) added to acetone (60 ml), then adding potassium carbonate (6.06g, 40mmol)with stirring, undissolved, then slowly dropping dimethyl sulfate (4 ml, 42mmol), after completion of dropwise addition the reaction was stirred at the room temperature 4 hours and degree of reaction was monitored by TLC monitoring. The end of the to be reacted, filtering off the solid insoluble materials, ten slowly adding water (100 ml), repeated oscillation, allowed to stand for half an for white solid precipitation. Filtering, drying to obtain the white solid (3.0g), yield 75percent. |
74% | With potassium carbonate In acetone for 5 h; Reflux | To a solution of 2’,4’,6’-trihydroxyacetophenone (3) (10.0 g, 59.5 mmol) in acetone (350 mL)was added K2CO3 (16.45 g, 119 mmol, 2.0 equiv) while stirring with a KPG stirrer at room temperature. Dimethyl sulfate (14.15 g, 112.2 mmol, 10.6 mL) was added dropwise to the suspension under vigorous stirring and then the reaction mixture was refluxed for 5 h. Then the reaction mixture was allowed to cool down and was stirred overnight. Afterwards, the reaction mixture was filtered, the solvent was evaporated under vacuum and the residue was recrystallized from methanol (15 mL). The crystals were filtered, washed with water to yield 8.65 g (44.1 mmol, 74percent) off-white solid; mp 74-75 °C [Lit. 73-76 °C]. Spectroscopic data is in accordance with the literature. |
54% | With potassium carbonate In acetone for 10 h; Reflux | A mixture of 1-(2,4,6-trihydroxyphenyl)ethan-1-one (2.50 g, 15 mmol), (CH3)2SO4 (2.85 mL, 30 mmol) and anhydrous K2CO3 (4.56 g, 33 mmol) in dry acetone (60 mL) was refluxed for 10 h. The reaction mixture was concentrated and poured on to ice-water (100 mL). The resulting precipitate was filtered off and washed with cold water. The obtained residue was purified by silica gel column chromatography with hexane: ethyl acetate (95: 5) as eluent. White solid, Yield: 54percent, M.P: 78-80 °C; 1H NMR (CDCl3, 400 MHz, ppm) δ: 14.03 (s, 1H,-OH), 6.06-6.05 (d, J = 2.20 Hz, 1H, Ar-H), 5.93-5.92 (d, J = 2.20 Hz, 1H, Ar-H), 3.86, 3.82 (s, each 3H, 2 * -OCH3), 2.61 (s, 3H, -COCH3); 13C NMR (CDCl3, 100 MHz, ppm) δ: 203.17 (-C=O); 167.56; 166.06; 162.88; 105.97; 93.43; 90.72; 55.53 (-OCH3); 50.86 (-OCH3); 32.91 (-CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.4% | With potassium carbonate; dimethyl sulfate In acetone | Production Example 7 To 50.1 g of 2',4',6'-trihydroxyacetophenone and 123.5 g of anhydrous potassium carbonate was added 500 ml of anhydrous acetone, and the mixture was stirred at room temperature for 30 minutes. Then, 78.9 g of dimethyl sulfate was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours to effect a reaction. After the reaction, the reaction mixture was neutralized with dilute hydrochloric acid, extracted with diethyl ether and filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was recrystallized from n-hexane to obtain 55.2 g (yield=94.4percent) of 2'-hydroxy-4',6'-dimethoxyacetophenone in the form of a colorless prism. Melting point: 77° to 78° C. Infrared absorption spectrum νmaxKBr cm-1: 1622, 1596, 1574, 1460, 1440, 1424, 1368, 1272, 1222, 1206, 1156, 1110, 1080, 894, 834, 596. Proton nuclear magnetic resonance (δ ppm in CDCl3): 2.61 (3H, s), 3.82 (3H, s), 3.85 (3H, s), 5.92 (1H, d, J=2.4 Hz), 6.05 (1H, d, J=2.4 Hz), 14.03 (1H, s, disappeared by addition of D2 O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium carbonate In dimethyl sulfoxide at 120℃; | Compound 4 (2.5 g, 0.015 mol), K2CO3 (1.7 g, 0.01 mol), and DMC (7.5 mL, 0.09 mol) in DMSO (20 mL) were heated at 120 °C until TLC showed that compound 4 had disappeared. Then the mixture was cooled to room temperature and H2O (30 mL) was added. The reaction mixture was neutralised to pH 3–4 with 10percent aqueous HCl and the precipitate was filtered and recrystallised from methanol to give compound 3 (2.0 g), yield 69percent, white crystals, m.p. 81–82 °C (lit.22 80–81 °C) 1H NMR (500 MHz, DMSO-d6) (δ, ppm): 2.60 (s, 3H,COCH3), 3.81 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.92 (s, 1H, ArH), 6.05 (s, 1H, ArH), 14.02 (s, 1H, OH). IR νmax (KBr/cm−1): 3461 (OH), 1619 (C=O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With potassium carbonate In acetone for 24 h; Reflux; Darkness | 4.1.1 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethan-1-one 21 2,4,6-Trihydroxyacetophenone (2 g, 10.7 mmol), methyl iodide (2.70 mL, 42.9 mmol) and K2CO3 (2.96 g, 21.4 mmol) were dissolved in 50 mL of acetone. The mixture was heated to reflux for 24 h in the dark. The reaction mixture was filtered under vacuum, and the filtrate was evaporated under reduced pressure. The crude product was purified by flash chromatography using cyclohexane/ethyl acetate 95:5 as eluting system; 1.13 g of title compound 21 were obtained. Yield: 36percent. 1H NMR (CDCl3) δ: 6.05 (d, J = 2.4 Hz, 1H, CH arom.); 5.92 (d, J = 2.4 Hz, 1H, CH arom.); 3.85 (s, 3H, OCH3); 3.81 (s, 3H, OCH3); 2.60 (s, 3H, CH3) ppm. |
1.2 g | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 48 h; | Heating 2, 4, 6-tri-hydroxy acetophenone 2g (12mmol), added to the 15mlDMF in, then adding CH 3 I1.72g (12.1mmol), K 2 CO 3 5 g. Stir at room temperature reaction 48h, is poured into the reaction liquid to the ice water, stirring 1h, then filter. Drying the obtained solid, recrystallized with ethanol, to obtain 2-hydroxy -4,6-di-methoxy acetophenone 1.2 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | at 90℃; for 3 h; | To a solution of 1-(2,4,6-trihydroxyphenyl)ethanone (1) (60 g, 0.36 mol) in HMPA (300 mL) was added K2CO3 (148 g, 1.07 mol) and BnCl (86.3 mL, 0.75 mol), and the suspension was stirred at 90 °C for 3 h. The solid was filtered, and the filtrate was poured into ice-water. The pH of the solution was adjusted to 2 by adding diluted hydrochloric acid. The resulting solid was filtered and recrystallized in CH2Cl2/MeOH to give 1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)ethanone (2). Yield: 75percent; 1H NMR (CDCl3, 300 MHz) δ: 2.56 (3H, s) 5.06 (4H, s), 6.11 (1H, s), 6.17 (1H, s), 7.41 (10H, m), 14.04 (1H, s). |
66.5% | With potassium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide at 90 - 93℃; for 1.5 h; | [0165] A mixture of 2',4',6'-trihydroxyacetophenone (20 g, 0.12 mol, dried in the oven at 140° C.) and anhydrous potassium carbonate (50 g, 0.36 mol) in hexamnethylphosphoramide (160 mL) was treated with benzyl chloride (30 mL, 0.26 mol), and the suspension heated at 90-93° C., under an argon atmosphere, for 1.5 h. The mixture was then cooled and filtered. The filtrate was added to 300 mL ice-cold water and acidified to pH 4 with 6N hydrochloric acid. The resulting suspension was heated to 70° C. for 1 h, and then cooled at 4° C. for 16 h. The deposited sticky solid was filtered off and washed with water. This solid was air-dried, and recrystallized from boiling methanol/acetone (2:1). Cooling the solution afforded the product 8 as off-white crystals (27.55 g, 66.5percent yield). 1H NMR (300 MHz, CDCl3): δ2.56 (s, 3H, CH3), 5.06 (s, 4H, CH2), 6.10 and 6.16 (2s, 2H, 3',5'-Ar-H), 7.40 (m, 10H, Ar-H), 14.01 (s, 1H, OH). |
66.5% | With potassium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide; water | (b) Preparation of 4',6'-bisbenzyloxy-2'-hydroxyacetophenone (8) from 2',4',6'-trihydroxyacetophenone 7: A mixture of 2',4',6'-trihydroxyacetophenone (20 g, 0.12 mol, dried in the oven at 140° C.) and anhydrous potassium carbonate (50 g, 0.36 mol) in hexamethylphosphoramide (160 mL) was treated with benzyl chloride (30 mL, 0.26 mol), and the suspension heated at 90-93° C., under an argon atmosphere, for 1.5 h. The mixture was then cooled and filtered. The filtrate was added to 300 mL ice-cold water and acidified to pH 4 with 6N hydrochloric acid. The resulting suspension was heated to 70° C. for 1 h, and then cooled at 4° C. for 16 h. The deposited sticky solid was filtered off and washed with water. This solid was air-dried, and recrystallized from boiling methanol/acetone (2:1). Cooling the solution afforded the product 8 as off-white crystals (27.55 g, 66.5percent yield). 1H NMR (300 MHz, CDCl3): δ 2.56 (s, 3H, CH3), 5.06 (s, 4H, CH2), 6.10 and 6.16 (2s, 2H, 3',5'-Ar-H), 7.40 (m, 10H, Ar-H), 14.01 (s, 1H, OH). |
66.5% | With potassium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide at 90 - 93℃; for 1.5 h; | A mixture of 2',4',6'-trihydroxyacetophenone (20 g, 0.12 mol, dried in the oven at 140° C.) and anhydrous potassium carbonate (50 g, 0.36 mol) in hexamethylphosphoramide (160 mL) was treated with benzyl chloride (30 mL, 0.26 mol), and the suspension heated at 90-93° C., under an argon atmosphere, for 1.5 h. The mixture was then cooled and filtered. The filtrate was added to 300 mL ice-cold water and acidified to pH 4 with 6N HCl. The resulting suspension was heated to 70° C. for 1 h, and then cooled at 4° C. for 16 h. The deposited sticky solid was filtered off and washed with water. This solid was air dried, and recrystallized from boiling methanol/acetone (2:1). Cooling the solution afforded the product 8 as off-white crystals (27.55 g, 66.5percent yield). 1H NMR (300 MHz, CDCl3): δ 2.56 (s, 3H, CH3), 5.06 (s, 4H, CH2), 6.10 and 6.16 (2s, 2H, 3',5'-Ar-H), 7.40 (m, 10H, Ar-H), 14.01 (s, 1H, OH). |
62% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 70℃; Inert atmosphere | To a mixture of ketone 1 (3.36 g, 20 mmol) and K2CO3 (7 g) in DMF (28 mL), benzyl chloride (4.5 mL) was slowly added at 0 °C. After stirring at 70 °C over night, the reaction mixture was diluted with water (30 mL), and the resulting mixture was extracted with EtOAc. The organic layer was washed with water and brine, then dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc (4:1) to afford compound 2 (4.31 g, 62percent) as white solid. 1H NMR (500 MHz, CDCl3) δ 14.02 (s, 1H), 7.44 – 7.31 (m, 10H), 6.17 (d, J = 2.3 Hz, 1H), 6.10 (d, J = 2.3 Hz, 1H), 5.06 (s, 2H), 5.06 (s, 2H), 2.56 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 203.21, 167.58, 165.11, 162.01, 135.88, 135.63, 128.77, 128.74, 128.49, 128.38, 127.99, 127.66, 106.37, 94.76, 92.38, 71.13, 70.28, 33.32; ESIMS: m/z = 349.3 [M+H]+. |
46% | Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 35 - 65℃; Inert atmosphere Stage #2: at 65 - 70℃; for 3 h; Inert atmosphere |
A 1 L 3-neck flask was charged with N,N-dimethylformamide (180 mL) under nitrogen, heated to 35 °C, then phloroglycinol hydrate (37.23 g, 0.20 mol) was added in one portion, followed by more DMF (120 mL). Potassium carbonate (60.8 g, 0.44 mol) was added and the mixture was heated to 65 °C. Benzyl chloride (50.6 mL, 0.44 mol) was introduced in one portion, and the mixture was heated to 70 °C for 3 h, cooled to room temperature, and filtered. The filter cake was then rinsed with methylene chloride. The combined filtrates were concentrated in vacuo and the residual orange oil was taken up in dichloromethane (400 mL), stirred for a few minutes, filtered, and the filtrate added to a pad of silica gel and eluted with dichloromethane. The filtrate volume was reduced to 150 mL, after which heptane (200 mL) was added, and the mixture was stirred for 20 min. The resultant white crystalline solid was collected by filtration, washed with heptane and air dried. The filtrate solution was loaded directly onto a silica gel column (700 mL) and eluted with 1:1 dichloromethane/heptane, then with 2:1 dichloromethane/heptane to yield additional product. The two batches were combined to afford 32.22 g (46percent) of 2,4-dibenzyloxy-6-hydroxyacetophenone 6a as a white crystalline solid: mp 103.5–105.5 °C (lit.33 103 °C); LC/MS m/z 349 [M+H]; 1H NMR (CDCl3, 400 MHz) δ 2.56 (s, 3H), 5.07 (m, 4H), 6.10 (d, J = 2.3, 1H), 6.17 (d, J = 2.3, 1H), 7.31–7.45 (m, 10H), 14.02 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 33.4, 70.4, 71.3, 92.5, 95.0, 106.6, 127.8, 128.1, 128.5, 128.6, 128.86, 128.9, 135.8, 136.1, 162.2, 165.3, 167.7, 203.3. Anal. Calcd for C22H20O4: C, 75.84; H, 5.79. Found: C, 75.88; H, 5.79. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 6 h; | 2,4,6-trihydroxyacetophenone (4.2 g, 25 mmol), bromobenzyl (9 mL,75 mmol), K2C03 (10.35 g, 75 mmol), DMF 50 ml, stirred at room temperature for 6 h, and monitored by TLC. After the reaction was completed, the reaction solution was poured into 200 mL of water, extracted three times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: (Eluent: DCM / MeOH (v / v) = 40: 1) to give 8.26 g of a white solid, intermediate 5 in 95percent yield. |
85% | Stage #1: With potassium carbonate In acetone at 65℃; for 1 h; Stage #2: for 16 h; |
The solution of 2,4,6-trihydroxyacetophenone (5 g,29.76 mmol) and anhydrous K2CO3 (15 g, 108.6 mmol) in120 mL dry acetone was refluxed at 65 °C for 1 h. Then BnBr (7.5 mL, 63.05 mmol) was added dropwise. After stirring for 16 h, the organic phase was separated. The solvent was removed, and the residue was purified by column chromatography on silica gel (petroleum ether-EtOAc, v/v, 30:1) to give 2 (8.8 g, 85percent) as white solids, mp 95-96 °C; |
70% | Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 0.25 h; Inert atmosphere Stage #2: at 0 - 23℃; |
Step 1: Synthesis of 1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)-ethanone: To a stirred solution of [50] (3.0 g, 16.19 mmol) in DMF, anhydrous K2CO3 (5.56 g, 40.32 mmol) was added at 0° C. under nitrogen atmosphere. After an additional stirring at this for 15 minutes at same temperature, benzyl bromide (4.92 ml, 40.32 mmol) was added drop-wise. The reaction temperature was allowed to increase up to 23° C. and stirring was continued for overnight. Consumption of [50] was monitored by TLC. After complete consumption of [50], water (50 ml) was added and organic layer was extracted with ethyl acetate (2*100 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light brown sticky material which was further purified using silica gel column chromatography using 5percent ethyl acetate/hexane as eluent to afford [51] as white powder (3.2 g, 70percent). ESIMS: 349[M+1] |
69% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 1 h; | To a solution of 5 (59.6 mmol) in DMF was added K2CO3 (2.2. equiv.). After stirring for 10 min at 0° C., BnBr (2.2. equiv.) was added and the mixture stirred for 1 h at room temperature. [0081] HCl 2M was added and the mixture was poured into water and extracted with EtOAc. Organic layers were combined, washed with brine, dried over MgSO4 and concentrated. Compound 6 was purified by CC (10:1 hexane/EtOAc) in 69percent yield. Rf=0.73 (4:1 P. Ether/EtOAc); pf. 103.5-104.0° C. (Lit. [66] p.f.=108-109° C.); 1H RMN (CDCl3) δ 14.17 (s, 1H, OH-8); 7.47-7.40 (m, 20H, CH, Ph); 6.22 (d, 1H, J5,7=2.32 Hz, H-7); 6.15 (d, 1H. J5,7=2.32 Hz, H-5); 5.09 (s, CH2Ph-4); 5.08 (s, CH2Ph-6); 2.61 (s, 3H, H-1); 13C RMN (CDCl3) δ 203.2 (C-2); 167.6 (C-6 e C-8); 162.1 (C-4); 135.9 (Cq-4); 135.7 (Cq-6); 128.8; 128.7; 128.5; 128.4; 128.1; 127.7 (CH, Ph); 106.3 (C-3); 94.8 (C-7); 92.4 (C-5); 71.2 (CH2Ph-6); 70.3 (CH2Ph-4); 33.4 (C−1). |
38.5% | Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 21 - 24 h; Stage #2: With hydrogenchloride; water In N,N-dimethyl-formamide |
Examples; Example 1 - Preparation of 2-Hydroxy-4,6-bis(benzyloxy)- acetophenone.; [0042] This example describes the preparation and purification of the title compound from commercially available 2,4,6-trihydroxy acetophenone. A stirred suspension of 2,4,6-trihydroxyacetophenone (10 g, 0.054 mol, 1 eq) and potassium carbonate (16.3 g, 0.118 mol, 2.2 eq) in N1N- dimethylformamide (100 mL, 10 vol, 1 g/10 ml_) was heated at 8O0C. To this suspension was added benzyl chloride (13.6 mL, 0.118 mol, 2.2 eq) in one portion. The suspension was kept at 809C for about 1 h. The reaction mixture was cooled to RT and carefully acidified with 1 M hydrochloric acid (200 mL). The aqueous layer was extracted twice with ethyl acetate (100 mL) The combined organic layers were washed twice with water (100 mL) and twice with brine (100 mL), dried over sodium sulfate, and filtered. The solvent was removed under vacuum to afford a red viscous oil. The oil was dissolved in dichloromethane and passed through a 200 g plug of silica gel. The silica gel was eluted with 1 L of dichloromethane. The combined solvent was evaporated under reduced pressure to produce an oil which solidified upon standing at RT. The yield was 18.7 g. HPLC purity was 69percent purity. The product contained 19.7percent of a tribenzyl impurity. EPO <DP n="23"/>[0043] The crude solid was dissolved in hot dichloromethane (15 mL) and methanol (20 ml_) was added slowly. The solids started to appear immediately. The suspension was allowed to cool to RT with agitation. The solids were suction filtered, washed with methanol (75 mL), and dried under high vacuum to produce 9.1 g of an off-white solid. The yield was 49percent. HPLC purity was 96.9percent. The product contained about 2.54percent of the tribenzyl impurity.; A number of reaction conditions and various benzylating reagents (benzyl bromide (BnBr) and benzyl chloride (BnCI) were screened to optimize the selective benzylation. The results are set out in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.5% | With potassium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide; water | (a) Preparation of 4',6'-bisbenzyloxy-2'-hydroxyacetophenone (2) from 2',4',6'-trihydroxyacetophenone (1): A mixture of 2',4',6'-trihydroxyacetophenone (20 g, 0.12 mol, dried in the oven at 140° C.) and anhydrous potassium carbonate (50 g, 0.36 mol) in hexamethylphosphoramide (160 mL) was treated with benzyl chloride (30 mL, 0.26 mol), and the suspension heated at 90-93° C., under an argon atmosphere, for 1.5 h. The mixture was then cooled and filtered. The filtrate was added to 300 mL ice-cold water and acidified to pH 4 with 6N HCl. The resulting suspension was heated to 70 ° C. for 1 h, and then cooled at 4° C. for 16 h. The deposited sticky solid was filtered off and washed with water. This solid was air dried, and recrystallized from boiling methanol/acetone (2:1). Cooling the solution afforded the product 8 as off-white crystals (27.55 g, 66.5percent yield). 1H NMR (300 MHz, CDCl3): δ 2.56 (s, 3H, CH3), 5.06 (s, 4H, CH2), 6.10 and 6.16 (2s, 2H, 3',5'-Ar-H), 7.40 (m, 10H, Ar-H), 14.01 (s, 1H, OH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20 - 80℃; for 1 - 7 h; Stage #2: With hydrogenchloride; water In N,N-dimethyl-formamide |
Examples; Example 1 - Preparation of 2-Hydroxy-4,6-bis(benzyloxy)- acetophenone.; [0042] This example describes the preparation and purification of the title compound from commercially available 2,4,6-trihydroxy acetophenone. A stirred suspension of 2,4,6-trihydroxyacetophenone (10 g, 0.054 mol, 1 eq) and potassium carbonate (16.3 g, 0.118 mol, 2.2 eq) in N1N- dimethylformamide (100 mL, 10 vol, 1 g/10 ml_) was heated at 8O0C. To this suspension was added benzyl chloride (13.6 mL, 0.118 mol, 2.2 eq) in one portion. The suspension was kept at 809C for about 1 h. The reaction mixture was cooled to RT and carefully acidified with 1 M hydrochloric acid (200 mL). The aqueous layer was extracted twice with ethyl acetate (100 mL) The combined organic layers were washed twice with water (100 mL) and twice with brine (100 mL), dried over sodium sulfate, and filtered. The solvent was removed under vacuum to afford a red viscous oil. The oil was dissolved in dichloromethane and passed through a 200 g plug of silica gel. The silica gel was eluted with 1 L of dichloromethane. The combined solvent was evaporated under reduced pressure to produce an oil which solidified upon standing at RT. The yield was 18.7 g. HPLC purity was 69percent purity. The product contained 19.7percent of a tribenzyl impurity. EPO <DP n="23"/>[0043] The crude solid was dissolved in hot dichloromethane (15 mL) and methanol (20 ml_) was added slowly. The solids started to appear immediately. The suspension was allowed to cool to RT with agitation. The solids were suction filtered, washed with methanol (75 mL), and dried under high vacuum to produce 9.1 g of an off-white solid. The yield was 49percent. HPLC purity was 96.9percent. The product contained about 2.54percent of the tribenzyl impurity.; A number of reaction conditions and various benzylating reagents (benzyl bromide (BnBr) and benzyl chloride (BnCI) were screened to optimize the selective benzylation. The results are set out in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In potassium hydroxide at 20℃; for 1h; | |
46% | With potassium hydroxide In dichloromethane; water at 20℃; for 1.5h; | |
20% | With potassium hydroxide In water at 0 - 20℃; for 2.5h; | 85.3 Step 3: preparing 1-[2,4,6-trihydroxy-3,5-di(3-methyl-2-buten-1-yl)phenyl]ethanone Step 3: preparing 1-[2,4,6-trihydroxy-3,5-di(3-methyl-2-buten-1-yl)phenyl]ethanone 1-(2,4,6-trihydroxyphenyl]ethanone (2.0 mg, 11.9 mmol) was dissolved in a 5% potassium hydroxide aqueous solution (20mL). After the mixture was cooled below 0°C, isopentenyl bromide (3.6 g, 24 mmol) was slowly added dropwise within 30 min. The reaction mixture was stirred at room temperature for 2 hours, then poured into an ice water and acidified to pH 2. The reaction mixture was extracted with ethyl acetate. The extract was collected and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography (dichloromethane as eluent) to give the desired compound (0.7g, yield 20%). |
With methanol; potassium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
ueber mehrere Stufen; | ||
Multi-step reaction with 2 steps 1: 92 percent / K2CO3 / acetone / 3 h / 65 °C 2: 60 percent / aluminium chloride / chlorobenzene / 1 h / Heating | ||
Multi-step reaction with 3 steps 1: 1.) K2CO3; 2.) dil. HCl / 1.) HMPA, 90-93 deg C, 70 min; 2.) HMPA, 60-70 deg C, 1 h 2: 91 percent 3: 89 percent / H2 / 10percent Pd/C |
Multi-step reaction with 2 steps 1: 17.4 percent / aq. 30percent sodium hydroxide / acetone / Zemplen's procedure | ||
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / Inert atmosphere; Reflux 2: potassium carbonate / acetone / Inert atmosphere; Reflux 3: potassium carbonate / methanol / Reflux; Inert atmosphere | ||
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 6 h / 65 °C / Schlenk technique; Sealed tube 2: aluminum (III) chloride / chlorobenzene / 1 h / Reflux; Sealed tube; Schlenk technique | ||
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 3 h / Reflux 2: aluminum (III) chloride / chlorobenzene / 1 h / Reflux | ||
Multi-step reaction with 2 steps 1.1: potassium carbonate / ethanol / 80 °C 2.1: aluminum (III) chloride / chlorobenzene / 130 °C 2.2: 20 °C | ||
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 3.33 h / 60 °C 2: tetrabutyl-ammonium chloride; sodium hydroxide 3: hydrogenchloride / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.7% | Stage #1: 2,4,6-trihydroxyacetophenone; acetic anhydride With sodium acetate for 2h; Reflux; Stage #2: With sodium carbonate In water for 3h; Reflux; | 117 5,7-dihydroxy-2-methyl-4H-chroman-4-one (122) Intermediate 121 (12.5 mmol) was dissolved in 10 mL of acetic anhydride.Then sodium acetate (37.5 mmol) was added and refluxed for 2 h.Cooled, 30 mL of water was added and extracted with ethyl acetate.Concentrate under reduced pressure.The concentrated solid was dissolved in sodium carbonate (62.5 mmol)In aqueous solution (30 mL), reflux for 3 h,Concentrated under reduced pressure, silica gel column chromatography (ethyl acetate / petroleum ether = 1:4)After getting a pale yellow solid 122,Yield: 66.7%, |
With sodium acetate Erwaermen des Reaktionsprodukts mit wss.-aethanol. Natriumcarbonat-Loesung; | ||
1.8 g | With sodium acetate; sodium carbonate for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sulfuric acid In water at 20℃; for 48h; | 6-Acetyl-5,7-dihydroxy-4-methylchromen-2-one (1). A mixture of 1(2,4,6-trihydroxyphenyl)ethanone (4) (8.4 g, 50 mmol)and ethyl acetoacetate (6.83 g, 52.mmol) in 70% sulfuric acid(60 mL) was stirred at room temperature for 48 h and then treated with water (200 mL) for 5 h. The precipitate formed was collected by filtration, washed with water (3×200 mL), and recrystallized from ethanol. Yield 69%, m.p. 235-237 °C.1H NMR (DMSOd6), δ: 2.47 (s, 3 H, CH3); 2.65 (s, 3 H, CH3);5.89 (s, 1 H, CH); 6.21 (s, 1 H, CH); 11.81 (br.s, 1 H, OH);15.23 (br.s, 1 H, OH). 13C NMR (DMSOd6), δ: 23.48, 33.00,94.52, 102.02, 106.46, 109.84, 154.88, 159.02, 159.68, 163.68,165.65, 205.11. MS (ESI), m/z: found 235.0601 [M + H]+.C12H10O5. Calculated: [M + H] = 235.0607. |
With aluminium trichloride; nitrobenzene | ||
With hydrogenchloride; acetic acid |
With sulfuric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 1h; | |
81% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 1.5h; | 1-(2, 4-bis(benzyloxy)-6-hydroxyphenyl)ethanone, 4 A mixture of 2’4’6’-trihydroxyacetophenone trihydrate (3.00 g, 16.12 mmol) and potassium carbonate (5.12 g, 37.06 mmol) in DMF (160 mL) was treated with benzyl chloride (4.1 mL, 35.45 mmol), and the suspension heated to 80°C. After 1.5 h, the mixture was cooled and filtered, then the organic solvent was removed under vacuum. The residue was dissolved in CH2Cl2, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/acetone = 3:1) to give 4 as white solids (4.56 g, 81%). 1HNMR (CDCl3, 400MHz) δ 2.54 (3H, s, CH3), 5.04 (4H, s, CH2 of Bn), 6.08 (1H, s, H-3), 6.15 (1H, s, H-5), 7.29-7.46 (10H, m, H of Bn); 13CNMR (CDCl3, 75MHz) δ 203.27, 167.67, 165.19, 162.09, 135.96, 135.71, 128.85(2C), 128.82(2C), 128.58, 128.46, 128.08(2C), 127.75(2C), 106.44, 94.85, 92.46, 71.22, 70.36, 33.43. MS (ESI): m/z 349.2 (M + H)+, 371.2 (M + Na)+. The spectroscopic data of 4 were consistent with the reference |
77% | With potassium carbonate In N,N-dimethyl-formamide at 40 - 50℃; for 0.833333h; |
76% | With potassium carbonate In N,N-dimethyl-formamide for 6h; Reflux; | |
75% | With potassium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide at 90℃; for 3h; | |
75% | With N,N,N,N,N,N-hexamethylphosphoric triamide; potassium carbonate at 90℃; for 3h; | Synthesis of neochromine S5 To a solution of 1-(2,4,6-trihydroxyphenyl)ethanone (1) (60 g, 0.36 mol) in HMPA (300 mL) was added K2CO3 (148 g, 1.07 mol) and BnCl (86.3 mL, 0.75 mol), and the suspension was stirred at 90 °C for 3 h. The solid was filtered, and the filtrate was poured into ice-water. The pH of the solution was adjusted to 2 by adding diluted hydrochloric acid. The resulting solid was filtered and recrystallized in CH2Cl2/MeOH to give 1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)ethanone (2). Yield: 75%; 1H NMR (CDCl3, 300 MHz) δ: 2.56 (3H, s) 5.06 (4H, s), 6.11 (1H, s), 6.17 (1H, s), 7.41 (10H, m), 14.04 (1H, s). |
66.5% | With potassium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide at 90 - 93℃; for 1.5h; | 4; b [0164] (b) Preparation of 4',6'-bisbenzyloxy-2'-hydroxyacetophenone (8) from 2',4',6'-trihydroxyacetophenone 7: [0165] A mixture of 2',4',6'-trihydroxyacetophenone (20 g, 0.12 mol, dried in the oven at 140° C.) and anhydrous potassium carbonate (50 g, 0.36 mol) in hexamnethylphosphoramide (160 mL) was treated with benzyl chloride (30 mL, 0.26 mol), and the suspension heated at 90-93° C., under an argon atmosphere, for 1.5 h. The mixture was then cooled and filtered. The filtrate was added to 300 mL ice-cold water and acidified to pH 4 with 6N hydrochloric acid. The resulting suspension was heated to 70° C. for 1 h, and then cooled at 4° C. for 16 h. The deposited sticky solid was filtered off and washed with water. This solid was air-dried, and recrystallized from boiling methanol/acetone (2:1). Cooling the solution afforded the product 8 as off-white crystals (27.55 g, 66.5% yield). 1H NMR (300 MHz, CDCl3): δ2.56 (s, 3H, CH3), 5.06 (s, 4H, CH2), 6.10 and 6.16 (2s, 2H, 3',5'-Ar-H), 7.40 (m, 10H, Ar-H), 14.01 (s, 1H, OH). |
66.5% | With potassium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide; water | 4.b (b) (b) Preparation of 4',6'-bisbenzyloxy-2'-hydroxyacetophenone (8) from 2',4',6'-trihydroxyacetophenone 7: A mixture of 2',4',6'-trihydroxyacetophenone (20 g, 0.12 mol, dried in the oven at 140° C.) and anhydrous potassium carbonate (50 g, 0.36 mol) in hexamethylphosphoramide (160 mL) was treated with benzyl chloride (30 mL, 0.26 mol), and the suspension heated at 90-93° C., under an argon atmosphere, for 1.5 h. The mixture was then cooled and filtered. The filtrate was added to 300 mL ice-cold water and acidified to pH 4 with 6N hydrochloric acid. The resulting suspension was heated to 70° C. for 1 h, and then cooled at 4° C. for 16 h. The deposited sticky solid was filtered off and washed with water. This solid was air-dried, and recrystallized from boiling methanol/acetone (2:1). Cooling the solution afforded the product 8 as off-white crystals (27.55 g, 66.5% yield). 1H NMR (300 MHz, CDCl3): δ 2.56 (s, 3H, CH3), 5.06 (s, 4H, CH2), 6.10 and 6.16 (2s, 2H, 3',5'-Ar-H), 7.40 (m, 10H, Ar-H), 14.01 (s, 1H, OH). |
66.5% | With potassium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide at 90 - 93℃; for 1.5h; | 1.a (a) Preparation of 4',6'-bisbenzyloxy-2'-hydroxyacetophenone (2) from 2',4',6'-trihydroxyacetophenone (1) A mixture of 2',4',6'-trihydroxyacetophenone (20 g, 0.12 mol, dried in the oven at 140° C.) and anhydrous potassium carbonate (50 g, 0.36 mol) in hexamethylphosphoramide (160 mL) was treated with benzyl chloride (30 mL, 0.26 mol), and the suspension heated at 90-93° C., under an argon atmosphere, for 1.5 h. The mixture was then cooled and filtered. The filtrate was added to 300 mL ice-cold water and acidified to pH 4 with 6N HCl. The resulting suspension was heated to 70° C. for 1 h, and then cooled at 4° C. for 16 h. The deposited sticky solid was filtered off and washed with water. This solid was air dried, and recrystallized from boiling methanol/acetone (2:1). Cooling the solution afforded the product 8 as off-white crystals (27.55 g, 66.5% yield). 1H NMR (300 MHz, CDCl3): δ 2.56 (s, 3H, CH3), 5.06 (s, 4H, CH2), 6.10 and 6.16 (2s, 2H, 3',5'-Ar-H), 7.40 (m, 10H, Ar-H), 14.01 (s, 1H, OH). |
62% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 70℃; Inert atmosphere; | Procedure for synthesis of ketone 2 To a mixture of ketone 1 (3.36 g, 20 mmol) and K2CO3 (7 g) in DMF (28 mL), benzyl chloride (4.5 mL) was slowly added at 0 °C. After stirring at 70 °C over night, the reaction mixture was diluted with water (30 mL), and the resulting mixture was extracted with EtOAc. The organic layer was washed with water and brine, then dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc (4:1) to afford compound 2 (4.31 g, 62%) as white solid. 1H NMR (500 MHz, CDCl3) δ 14.02 (s, 1H), 7.44 - 7.31 (m, 10H), 6.17 (d, J = 2.3 Hz, 1H), 6.10 (d, J = 2.3 Hz, 1H), 5.06 (s, 2H), 5.06 (s, 2H), 2.56 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 203.21, 167.58, 165.11, 162.01, 135.88, 135.63, 128.77, 128.74, 128.49, 128.38, 127.99, 127.66, 106.37, 94.76, 92.38, 71.13, 70.28, 33.32; ESIMS: m/z = 349.3 [M+H]+. |
62% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 12h; | |
46% | Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In N,N-dimethyl-formamide at 35 - 65℃; Inert atmosphere; Stage #2: benzyl chloride In N,N-dimethyl-formamide at 65 - 70℃; for 3h; Inert atmosphere; | 4.2 Preparation of 2,4-dibenzyloxy-6-hydroxyacetophenone 6a A 1 L 3-neck flask was charged with N,N-dimethylformamide (180 mL) under nitrogen, heated to 35 °C, then phloroglycinol hydrate (37.23 g, 0.20 mol) was added in one portion, followed by more DMF (120 mL). Potassium carbonate (60.8 g, 0.44 mol) was added and the mixture was heated to 65 °C. Benzyl chloride (50.6 mL, 0.44 mol) was introduced in one portion, and the mixture was heated to 70 °C for 3 h, cooled to room temperature, and filtered. The filter cake was then rinsed with methylene chloride. The combined filtrates were concentrated in vacuo and the residual orange oil was taken up in dichloromethane (400 mL), stirred for a few minutes, filtered, and the filtrate added to a pad of silica gel and eluted with dichloromethane. The filtrate volume was reduced to 150 mL, after which heptane (200 mL) was added, and the mixture was stirred for 20 min. The resultant white crystalline solid was collected by filtration, washed with heptane and air dried. The filtrate solution was loaded directly onto a silica gel column (700 mL) and eluted with 1:1 dichloromethane/heptane, then with 2:1 dichloromethane/heptane to yield additional product. The two batches were combined to afford 32.22 g (46%) of 2,4-dibenzyloxy-6-hydroxyacetophenone 6a as a white crystalline solid: mp 103.5-105.5 °C (lit.33 103 °C); LC/MS m/z 349 [M+H]; 1H NMR (CDCl3, 400 MHz) δ 2.56 (s, 3H), 5.07 (m, 4H), 6.10 (d, J = 2.3, 1H), 6.17 (d, J = 2.3, 1H), 7.31-7.45 (m, 10H), 14.02 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 33.4, 70.4, 71.3, 92.5, 95.0, 106.6, 127.8, 128.1, 128.5, 128.6, 128.86, 128.9, 135.8, 136.1, 162.2, 165.3, 167.7, 203.3. Anal. Calcd for C22H20O4: C, 75.84; H, 5.79. Found: C, 75.88; H, 5.79. |
18% | With potassium carbonate In acetone Heating; | |
With potassium carbonate; acetone | ||
6.8 g | With potassium carbonate In acetone for 4h; Heating; | |
With hydrogenchloride; potassium carbonate 1.) HMPA, 90-93 deg C, 70 min; 2.) HMPA, 60-70 deg C, 1 h; Yield given. Multistep reaction; | ||
With potassium carbonate In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.7% | With carbon disulfide; aluminum (III) chloride In nitrobenzene at 20 - 50℃; for 1h; | 1.1 1) Take phloroglucinol 5.0g (40mmol),Dissolved in 50ml of carbon disulfide and15 ml of nitrobenzene,15.6 g (120 mmol) of anhydrous aluminum trichloride was added,Stirred at room temperature for 10 minutes,To the reaction solution was added dropwise 10 ml of acetyl chloride 4.23 ml (60 mmol)Of carbon disulfide solution,Followed by heating under reflux at 50 ° C for 1 hour to complete the reaction.The carbon disulfide was distilled off under reduced pressure,To the residue was added 10 ml of a mixture of hydrochloric acid and 50 ml of ice water,Ethyl acetate was extracted three times (50 ml x 3) and the organic layer was saturated with chlorinationSodium, dried over anhydrous sodium sulfate, evaporated under reduced pressure, ethyl acetate, silica gel and silica gel column separation. Petroleum ether: ethyl acetate (2: 1)Obtained 5.71 g as a pale yellow solid in 85.7% yield. |
85% | Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride In dichloromethane; nitrobenzene at 0℃; Inert atmosphere; Stage #2: acetyl chloride In dichloromethane; nitrobenzene at 0 - 90℃; for 4h; Inert atmosphere; | Synthesis of 1-(2,4,6-Trihydroxy-phenyl)-ethanone (2) To the cooled (0oC) solution of phloroglucinol (1) (25 mmol) in dichloromethane: nitrobenzene (1:1, 50 mL), AlCl3 (100 mmol) was added carefully in portion, and the reaction mixture was allowed to stir for 10-15 min under nitrogen atmosphere. Acetyl chloride (30 mmol) was added dropwise in the reaction mixture with constant stirring, and the mixture was heated to 80-90 °C for 4h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was cooled at room temperature and quenched with ice. The aqueous layer was extracted with ethyl acetate (20 x 3), further the combined organic layer was washed with brine solution and dried over Na2SO4. The solvent was removed under vacuum, and the residue was purified by silica gel chromatography (hexane/ ethyl acetate 2:1) to afford 1-(2,4,6-trihydroxyphenyl)-ethanone (2) in 85% yield. 1H-NMR [DMSO-d6, 400 MHz] δ: 12.21 (s, 2H, -OH), 10.34 (s, 1H, -OH), 5.79 (s, 2H, Ar-H), 2.54 (s, 3H, CH3). |
82.5% | Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride In nitrobenzene; 1,2-dichloro-ethane at 0℃; for 0.166667h; Inert atmosphere; Stage #2: acetyl chloride In nitrobenzene; 1,2-dichloro-ethane for 5h; Inert atmosphere; | 1-(2,4,6-Trihydroxyphenyl)ethan-1-one (22) Aluminum trichloride (42.30g, 317.2mmol) was slowly added to a solution of phloroglucinol 21 (10.00g, 79.30mmol) in 1,2-dichloroethane/nitrobenzene (1:1, 150.0mL) at 0°C. After stirring at this temperature for 10min under a nitrogen atmosphere, acetyl chloride (9.300g, 119.0mmol) was added dropwise. The ice bath was removed and the mixture was reflux for 5h. The crude reaction mixture was cooled to rt and then quenched with water (100.0mL). The mixture was extracted with EtOAc (300.0mL), washed with saturated solution of NaCl, and concentrated in vacuum. Recrystallization by EtOAc to afford compound 22 (11.00g, 82.5%). mp 212.1-214.1°C; IR (KBr): 3287, 1630, 1522, 1171, 818cm -1. 1H NMR (400MHz, DMSO-d6) δ 12.22 (d, J=2.1Hz, 2H), 10.35 (d, J=2.0Hz, 1H), 5.80 (d, J=2.1Hz, 2H), 2.54 (d, J=2.0Hz, 3H). 13C NMR (100MHz, DMSO-d6) δ 202.5, 164.8, 164.3, 104.0, 94.5, 32.4. HRMS (ESI) calculated for C8H8NaO4+[M+Na]+ 191.0315, found 191.0317. |
79% | Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride In nitrobenzene; 1,2-dichloro-ethane at 0℃; for 0.166667h; Inert atmosphere; Stage #2: acetyl chloride In nitrobenzene; ethylene dibromide at 80℃; for 3h; Inert atmosphere; | Aluminum trichloride (13.3 g, 100 mmol) was slowly and carefully added to a solutionof phloroglucinol 12 (3.15 g, 25 mmol) in CH2ClCH2Cl/PhNO2(1:1, 50 mL) at 0 C. After stirring at this temperature for 10 min under nitrogen, acetyl chloride (2.38 mg, 30 mmol) was added. Theice bath was removed, and the mixture was stirred at 80 C for 3 h.The crude reaction mixture was cooled to room temperature and quenched with water (150 mL). The mixture was extracted withEtOAc (5 150 mL), washed with brine, and concentrated in vacuum.The crude product was purified by flash chromatography (silicagel, hexane/EtOAc = 2:l) to afford acetylphloroglucinol (3.32 g,79% yield). 1H NMR (500 MHz, DMSO-d6): d 5.81 (s, 2H), 2.54 (s,3H); 13C NMR (125 MHz, DMSO-d6): d 203.9, 166.2, 164.7, 105.9,96.3, 33.5. |
79% | Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride; nitrobenzene In 1,2-dichloro-ethane at 0℃; for 0.166667h; Inert atmosphere; Stage #2: acetyl chloride at 80℃; for 3h; | |
79% | Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride In 1,2-dichloro-ethane for 0.166667h; Cooling with ice; Stage #2: acetyl chloride In 1,2-dichloro-ethane at 80℃; for 3h; Cooling with ice; | 6 Synthesis of Acetyl-phloroglucinol Compound 35 Under ice-cooling, aluminum trichloride (13.3 g, 100 mmol) was slowly added to the phloroglucinol compound 19 (3.15 g, 25 mmol) of 1,2-dichloroethane/nitrotoluene mixed solution (1:1, 50 mL). After uniformly stirring for 10 minutes, acetyl chloride 34 (2.38 mg, 30 mmol) was slowly added dropwise to the reaction system. The ice bath conditions were removed and the reaction mixture was heated to 80 degrees Celsius and stirred for 3 hours. Then 150 mL of water was added to stop the reaction. The mixture was extracted 5 times with ethyl acetate (150 mL) and the organic phases were combined. The resulting organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate and filtered. The residue was further purified by flash column chromatography (n-hexane:ethyl acetate=2:1) to give a pale yellow solid compound 35 (3.32 g, 79% yield). |
77% | Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride In nitromethane; dichloromethane at 0℃; for 0.5h; Stage #2: acetyl chloride In nitromethane; dichloromethane for 3.5h; Reflux; | |
75% | Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride In carbon disulfide; nitrobenzene at 55℃; for 1h; Stage #2: acetyl chloride In carbon disulfide; nitrobenzene at 55℃; for 1h; | 4.2 General procedure for the synthesis of 3a-e General procedure: AlCl3 (4 equiv) was added to a stirred phloroglucinol suspension (1 equiv) in CS2. Nitrobenzene was added to the solution over 30min. The solution was refluxed at 55°C for 30min. Acyl chloride (1equiv) dissolved in nitrobenzene was added to the reaction mixture over 30min before heating for another 30min. The reaction mixture was allowed to cool with stirring and then poured into an ice-water bath. Afterwards, 3M HCl was added. The organic solvents were removed under a reduced pressure, and the oily residue containing the acylphloroglucinol was extracted with Et2O. After removing the Et2O, the crude product was purified via flash chromatography (PE (bp. 50-70°C)/EtOAc 5:1→3:1) [21]. |
72% | Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride In carbon disulfide at 20℃; for 0.333333h; Stage #2: acetyl chloride In carbon disulfide; nitrobenzene at 50℃; for 0.5h; | |
72% | Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride In nitromethane; dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: acetyl chloride In nitromethane; dichloromethane for 3h; Inert atmosphere; Reflux; | 4.1. Acylphloroglucinol12 (7) To a stirred suspension of phloroglucinol (8) (30.0 g, 0.238 mol) in a mixture of CH2Cl2 (240 mL) and nitromethane (240 mL), aluminium trichloride (127.0 g, 0.952 mol, 4 equiv) was added and the mixture was stirred at room temperature for 30 min. To this dark suspension acetyl chloride (17 mL, 0.238 mol, 1 equiv) was added slowly by syringe (HCl outgassing). After complete addition, the mixture was refluxed for 3 h, while checking the progress of the reaction by TLC. Thereafter, the mixture was cooled down to room temperature and poured into ice-water (about 400 mL) followed by evaporation of most of the volatiles under reduced pressure. This was followed by extraction of the mixture with ethyl acetate (3500 mL). The combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by flash chromatography (petroleum ether/ethyl acetate, 2:1) provided acylphloroglucinol (7)(28.93 g, 72%) as yellowish crystals. Compound 7 could also be recrystallized from toluene. |
71.36% | With aluminum (III) chloride; nitromethane In dichloromethane at 40℃; for 0.666667h; | 19 Example 19 Preparation of 2,4,6-trihydroxyacetophenone (9) Anhydrous operation, 12.603 g of phloroglucinol (100 mmol) and 26 g of aluminum chloride (200 mmol) were dissolved in 200 ml of DCM, After the reaction solution was dissolved, 12 g nitromethane (200 mmol) and acetyl chloride (8.63 g, 110 mmol) were added successively, After the addition was complete, the temperature of the reaction solution was raised to 40 ° C and stirred for 40 minutes. After completion of the reaction, The reaction solution was slowly poured into ice water, the pH of the mixture was adjusted to about 4 with dilute hydrochloric acid, the organic phase was discarded, the aqueous phase was extracted with ethyl acetate, washed with water,Dried over anhydrous sodium sulfate for 30 min. Ethyl acetate was removed by distillation under reduced pressure, and 15 g of a white solid were isolated by column chromatography in a yield of 71.36%. |
70% | With aluminium trichloride at 50℃; | |
70% | With aluminium trichloride In carbon disulfide at 50℃; for 0.5h; | |
70% | With aluminum (III) chloride In carbon disulfide; nitrobenzene Reflux; | |
61% | Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride In nitromethane; dichloromethane at 20℃; for 0.5h; Stage #2: acetyl chloride In nitromethane; dichloromethane for 10h; Reflux; | Acylphloroglucinol (4) To a stirred suspension of phloroglucinol (3) (25.0 g, 0.198 mol) in a mixture of CH2Cl2(200 mL) and nitromethane (200 mL), aluminiumtrichloride (105.8 g, 0.793 mol, 4 equiv) was added and the mixture was stirred at room temperature for 30 min. To this dark suspension acetyl chloride (14.1 mL,0.198 mol, 1 equiv) was added slowly by syringe. After complete addition, the mixture was refluxed for 10 h, while checking the progress of the reaction by TLC. Thereafter, the mixture was cooled down to room temperature and poured into ice-water (about 500 mL) followed by evaporation of most of the volatiles under reduced pressure. This was followed by extraction of the mixture with ethyl acetate (3 × 500 mL). The combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by a silica gel column (petroleum ether/ethyl acetate, 2:1) provided acylphloroglucinol (4) (20.4 g, 61%) as yellowish crystals. 1H NMR (500 MHz, DMSO-d6): δ 2.54 (s, 3H, CH3),5.80 (s, 2H, Ar), 10.35 (br s, 1H, OH), 12.18 (br s, 2H, OH); 13CNMR (125 MHz, DMSO-d6): δ 32.2 (CH3),94.5 (C-3, C-5), 104.0 (C-1), 164.2 (C-2, C-6), 164.7 (C-4), 202.3 (C=O);HRESIMS m/z 167.0349 [M-H]- (calcd for C8H7O4,167.0350) |
61% | Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride In nitromethane; dichloromethane at 20℃; for 0.5h; Stage #2: acetyl chloride In nitromethane; dichloromethane for 3h; Reflux; | |
60% | Stage #1: 3,5-dihydroxyphenol With carbon disulfide; aluminum (III) chloride at 20℃; for 0.333333h; Inert atmosphere; Stage #2: acetyl chloride In nitrobenzene at 50℃; for 0.5h; Inert atmosphere; | |
60% | With aluminum (III) chloride In nitromethane; dichloromethane at 20℃; | 4.2.1 2,4,6-Trihydroxyacetophenone (3) 1,3,5-Trihydroxybenzene (200.0 g, 1.59 mol) and AlCl3 (845.1 g, 6.34 mol) was dissolved in dichloromethane (1000.0 ml), followed by drop addition of nitromethane (1000.0 ml) in 30 min. After the reaction mixture was stirred at room temperature for 6 h, acetyl chloride (149.2 g, 1.90 mol) was added dropwise and then poured into water (4000.0 ml). The mixture was extracted with ethyl acetate (2000.0 ml × 3). The organic layer was concentrated to dryness and recrystallized with water to get faint yellow solid 3 (161.3 g, 60%). 1H NMR (600 MHz, DMSO-d6) δ: 12.20 (s, 2H, OH), 10.34 (s, 1H, OH), 5.79 (s, 2H, ArH), 2.53 (s, 3H, COCH3); 13C NMR (150 MHz, DMSO-d6) δ: 202.92, 165.22, 164.76, 104.50, 94.99, 32.79. HRMS calcd for C8H8O4 m/z [M+H]+ 169.0495, found 169.0490. |
53% | With aluminum (III) chloride In nitromethane; dichloromethane at 40℃; | |
42% | With boron trifluoride diethyl etherate at 80℃; for 2h; | |
40% | With aluminium trichloride In nitrobenzene at 20 - 60℃; for 2h; | |
With aluminium trichloride; diethyl ether; nitrobenzene dann in Nitrobenzol auf dem Wasserbad; | ||
With aluminium trichloride | ||
With aluminum (III) chloride In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | ||
Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride; nitromethane In dichloromethane at 40 - 50℃; Stage #2: acetyl chloride In dichloromethane Heating; | 4.1.1. General procedure A for the synthesis of acylphloroglucinols (AP) General procedure: A mixture of phloroglucinol (17) (100 mmol) and aluminium chloride (2 eq.) was suspended in dichloromethane (200 ml) and 2eq. nitromethane were added dropwise. The mixture was heated to 40-50 °C until no more HCl was formed. 1.1 eq. of the appropriate acid chloride were added dropwise and the reaction mixture heated for further 10 min. After cooling the reaction mixture was hydrolyzed with diluted ice-cold HCl. The organic solvents were removed in vacuo and the aqueous phase was extracted with diethyl ether. The organic extract was dried over magnesium sulphate, filtered and concentrated. The crude product was purified by flash chromatography using mixtures of acetone and petroleum ether (PE) as eluents. | |
With aluminum (III) chloride In nitrobenzene Inert atmosphere; | ||
Stage #1: 3,5-dihydroxyphenol; acetyl chloride at 60 - 80℃; for 0.166667h; Stage #2: With methanesulfonic acid at 20℃; for 0.5h; | Synthesis of compound 6b-6k Phloroglucinol (315 mg, 2.5 mmol) and acid chloride (3.75 mmol) were placed in a 10 mL dry round bottom flask,Heating to 60-80 ° C. After stirring for 10 minutes,Methanesulfonic acid (25 mmol, 1.6 mL) was slowly added dropwise to the reaction system.The reaction was continued at room temperature for 30 minutes and then allowed to cool to room temperature.The reaction mixture was poured into 25 mL of ice water and extracted three times with ethyl acetate (25 mL). The organic phases were combined,And washed with 25 mL of saturated sodium bicarbonate and brine, respectively. The organic phase was dried over anhydrous sodium sulfate and filtered,The resulting filtrate was dried under reduced pressure. The remaining oily mixture was subjected to flash column chromatography(N-hexane: ethyl acetate = 5: 1)To obtain the corresponding acyl phloroglucinol compound. | |
12.8 g | With aluminum (III) chloride In dichloromethane at -15 - 20℃; for 2h; | 1.1 Between 1L three-necked flask phloroglucinol material (12.6g, 0.1mol), was added 100mL of dichloromethane solvent dissolved. At a temperature of -15 and under stirring, was added anhydrous aluminum chloride (16g, 0.12mol) catalyst was added dropwise acetyl chloride (8.6g, 0.11mol), after the completion of the dropwise addition the reaction was stirred for 2 hours at room temperature. After stopping the reaction, hydrolysis 200mL water and partitioned. After the aqueous phase was washed with 50mL dichloromethane and the combined organic phase; solvent was removed by rotary evaporation to give 2,4,6-hydroxyacetophenone (12.8g, 0.076 mol). |
With aluminum (III) chloride In carbon disulfide; nitrobenzene at 20℃; for 1h; | ||
Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride In dichloromethane at 40℃; for 1h; Stage #2: acetyl chloride In dichloromethane Reflux; | 3.1.2. Two-Step Reaction: Friedel-Crafts Acylation and Direct C-Alkylation (3d, 4a-g) General procedure: Friedel-Crafts acylation: Small amounts of phloroglucinol (0.05 mol) and anhydrous aluminumchloride (0.1 mol) were first dissolved in dichloromethane (50 mL) and kept heated for 1 h at 40 °C.Acyl chloride (0.05 mole) was added dropwise into the reaction mixture, reuxed for 8 h, and quenchedwith 0.05 mole of HCl upon completion of the reaction. After the reaction was completed, the reactionmixture was extracted with ethyl acetate and concentrated under reduced pressure. The residueswere subjected to column chromatography using silica gel eluted with hexane/ethyl acetate (10:1) [25].Direct C-alkylation: A well-mixed mixture of acylphloroglucinol (1 mmol), geranyl bromide or prenylbromide (1 mmol), and anhydrous potassium carbonate (0.5 mmol) in dry methanol (3 mL) wasrefluxed for 8 h. After completion of the reaction, excess methanol was removed through high vacuumand the residues were extracted with ethyl acetate. The organic layers were combined, dried, andconcentrated. Column chromatography over silica gel eluted with petroleum ether/ethyl acetate (10:1)gave geranylated/prenylated compounds [11]. | |
With aluminum (III) chloride In 1,2-dichloro-ethane at 50℃; | ||
Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride In nitromethane; dichloromethane at 20℃; for 0.5h; Stage #2: acetyl chloride In nitromethane; dichloromethane for 3h; Reflux; | 2.2.2 2.2 Synthesis of Acylphloroglucinol (6) With 240mL dichloromethaneAdd 30.0g compound phloroglucinol(5) (0.238mol) to the suspension stirrer with 240mL nitromethane mixture, then add 127.0g aluminum trichloride (0.952mol, 4 times equivalent) to the mixture, and stir at room temperature for 30 minutes .Then use a syringe to add 17 mL of acetyl chloride (0.238 mol, 1 equivalent) to the black reaction flask.After the addition is complete, the reaction is refluxed for three hours, and the progress of the reaction is detected by a thin layer at the same time.Subsequently, the reactant was cooled to room temperature, volatile components were evaporated under reduced pressure, and 400 mL of ice water was added.Extract three times with 500 mL ethyl acetate.The mixture solution was washed once with saturated sodium chloride solution, absorbed water with anhydrous sodium sulfate, filtered, and concentrated in vacuo.Petroleum ether: ethyl acetate (2:1) flash column chromatography to obtain compound 6,Compound 6 is a pale yellow crystal, which can be recrystallized in toluene. | |
Stage #1: 3,5-dihydroxyphenol With aluminum (III) chloride In nitromethane; dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: acetyl chloride In nitromethane; dichloromethane for 3h; Inert atmosphere; Reflux; | 2.2.2 2.2 Synthesis of Acylphloroglucinol (6) Add 30.0 g of compound phloroglucinol (5) (0.238 mol) to a suspension stirrer containing 240 mL of dichloromethane and 240 mL of nitromethane mixture, and then add 127.0 g of aluminum trichloride (0.952 mol, 4 times equivalent) to the mixture , and stirred at room temperature for thirty minutes. Then, 17 mL of acetyl chloride (0.238 mol, 1 equiv.) was added to the black reaction flask with a syringe. After the addition was complete, the reaction was refluxed for three hours while monitoring the progress of the reaction with a thin layer. Subsequently, the reactant was cooled to room temperature, volatile components were evaporated under reduced pressure, 400 mL of ice water was added, and the mixture was extracted three times with 500 mL of ethyl acetate. The mixture solution was washed once with saturated sodium chloride solution, absorbed with anhydrous sodium sulfate, filtered and concentrated in vacuo. Petroleum ether:ethyl acetate (2:1) flash column chromatography to obtain compound 6, compound 6 is light yellow crystals, which can be recrystallized in toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In acetone Inert atmosphere; | |
100% | With potassium carbonate In acetone for 3h; Reflux; | To a refluxing solution of 2,4,6-trihydroacetophenone-monohydrate (10 g, 53.7 mmol) and K2CO3 (15 g, 108.7 mmol) in acetone (150 mL), (CH3)2SO4 was added at three hour intervals (3 x 3.5 mL, 40.0 mmol). The solution was filtered and the solvent was evaporated to afford 2,4-dimethoxy-6-hydroxyacetophenone as a yellow solid (98%). |
100% | With potassium carbonate In acetone at 66℃; for 2h; Inert atmosphere; | 4.1.2. 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethanone (2) A mixture of 2',4',6'-trihydroacetophenone hydrate (2.0 g, 11.89 mmol), potassium carbonate(3.62 g, 26.17 mmol) and dimethylsulfate (2.32 mL, 24.38 mmol) in acetone (30 mL) was stirred underargon at 66 °C for 2 h. The resulting mixture was cooled to room temperature, filtered, and washedwith acetone. The filtrate was extracted with ethyl acetate. The organic layer was washed three timeswith saturated NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure toproduce compound 2 with 100% yield (Rf = 0.34 (1:9 ethyl acetate: hexane); 1H NMR (400 MHz, CDCl3) δ 14.06 (s, 1H), 6.05 (d, J = 2.0 Hz, 1H), 5.81 (d, J = 2.4 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 2.61 (s, 3H)). |
99% | With potassium carbonate In acetone at 0 - 20℃; Inert atmosphere; | 14 Example 14 synthesis of 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (11) To a solution of commercial 2',4',6'-trihydroxyacetophenone dihydrate (15.0 g, 80.57 mmol, 1eq) in acetone (170 mL), potassium carbonate (23.4 g, 169.20 mmol, 2.1 eq) and dimethylsulfate (15.6 mL, 165.17 mmol, 2.05 eq) were added under argon at 0°C. After vigorous stirring at room temperature for 17h, the resulting mixture was filtered and the filtrate concentrated in vacuo. The resulting product 5 was recristallized from ethyl acetate / heptanes (3/97) to give 15.80 g (99%) of a pale yellow solid. Molecular Weight: 196.20 (C10H12O4). 1H-NMR δ (CDCl3, 300 MHz) ppm (J in Hz): 2.61 (s, 3H, CH3CO), 3.82 (s, 3H, MeO), 3.85 (s, 3H, MeO), 5.91 (d, 1H, J=2.4, H- 3'), 6.05 (d, 1H, J=2.4, H-5'), 14.03 (s, 1H, OH). |
99% | With potassium carbonate In acetone | |
99% | With potassium carbonate In acetone | 1 Example1 2,4,6-trihydroxy-acetophenone (2) and the reaction wasdissolved in a dimethyl sulfate to potassium carbonate in acetone to synthesize4,6-dimethoxy-2-hydroxy acetophenone (3) |
98% | With potassium carbonate In acetone at 65℃; for 6h; | |
98% | Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In acetone Inert atmosphere; Stage #2: dimethyl sulfate In acetone for 0.4h; Inert atmosphere; | 3.2.1. Synthesis of 2,4-Dimethoxy-3-hydroxyacetophenone 1a After K2CO3 (10.0 mmol, 2.0 eq) was added to a solution of 2,4,6-trihydroxyacetophenone 1(5.0 mmol, 1.0 eq), the resulting solution was stirred in acetone at room temperature under argon.Then, Me2SO4 (10.0 mmol, 2.0 eq) was added dropwise and the temperature was slowly increased to 40 °C. The reaction was monitored by thin layer chromatography (TLC) after about 4 h. The mixturewas then filtered and washed with acetone three times. The organic phase was evaporated to provide1a (white powder; yield 98%). Other data can be found in Reference [11]. |
98% | With potassium carbonate In acetone at 40℃; for 4h; Inert atmosphere; | 1.1 (1) Synthesis of compound 1a: At room temperature, 2,4,6-trihydroxyacetophenone 1 (1.0 equivalent) and K2CO3 (2.0 equivalent) were dissolved in acetone and dropped into Me2SO4 (2.0eq) under the protection of nitrogen. The reaction was monitored by TLC for about 4 hours.The reaction was filtered and washed 3 times with acetone. Evaporation of the organic phase gave 1a in 98% yield. |
95.8% | With potassium carbonate In acetone at 10 - 15℃; | 2-Hydroxy-4,6-dimethoxyacetophenone (2) A mixtureof phloroacetophenone (1) (300 g, 1.78 mol), acetone (1.5 L)and potassium carbonate (739.2 g, 5.35 mol) was chargedunder stirring at room temperature. Dimethyl sulphate (494.9g, 3.92 mol) was charged drop wise with the help of the additionfunnel at 10-15 °C for 3 h. TLC (20 % EtOAc in hexane)showed no traces of starting material but observed traces oftrimethoxyacetophenone. After completion of the reaction, thereaction mixture was poured into ice cold water and stirredfor 3 h. A crude solid material was obtained on filtration andwashed with cold water and drained thoroughly. The yieldwas 84 % with a purity of 95.8 % obtained. |
95% | With potassium carbonate In acetone for 4h; Inert atmosphere; Reflux; | 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethan-1-one (Int. IX) 1-(2,4,6-Trihydroxyphenyl)ethan-1-one (0.50 g, 3.00 mmol), potassium carbonate (0.86 g, 6.25mmol) were suspended in dry acetone (7 mL) and dimethyl sulfate (0.60 mL, 6.00 mmol) wasadded. The reaction mixture was refluxed for 4 h under inert atmosphere. The reaction mixturewas quenched by addition of 5% HCl aqueous solution (40 mL) and extracted with diethyl ether(3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4and evaporated to dryness under reduced pressure. The residue was purified by columnchromatography (DCM) to furnished the alcohol derivative IX (0.56 g, 95%). |
95% | With potassium carbonate In acetone for 2.5h; Reflux; | 1 Synthesis of intermediate f Combine 2,4,6-trihydroxyacetophenone (55.8g, 0.3mol), anhydrous potassium carbonate (104.0g, 0.75mol), acetone(500mL) was added to the three-necked flask in turn, under reflux and stirring,Slowly add dimethyl sulfate (75.6 g, 0.6 mol) dropwise. Dripping,carry on React for 2.5 hours. TLC monitoring, the reaction is over. Cool to room temperature,Filter, concentrate the filtrate, and homogenize the residue with 5% hydrochloric acid solution The slurry is filtered and the filter cake is washed with water to neutrality.The filter cake was collected and recrystallized with methanol to obtain a white solid, the product, with a yield of 95%. |
95% | With potassium carbonate In acetone at 56℃; for 8h; | |
94% | With potassium carbonate In acetone for 2h; Reflux; regioselective reaction; | 1.1. General Method for synthesis of 2-hydroxy-4,6-dimethoxyacetophenone (2) A mixture of 2,4,6-trihydroxyacetophenone (1) (1.0 g, 5.95 mmol) anhydrous K2CO3 (1.64 g, 11.88 mmol) and (CH3)2SO4 (1.08 mL, 11.22 mmol) was stirred and refluxed in acetone (60 mL) for 2 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated and the residue subjected to silica gel column chromatography with PE/AcOEt 2:1 as an eluent to afford white solids 1.1 g, yield: 94%. m.p. 77-79 °C (Lit.1: 79~80°C ). |
94.3% | With potassium carbonate In acetone at 20℃; for 16h; | 1.1 (1) Synthesis of Compound 3 2,4,6-Trihydroxyacetophenone (2) (10 g, 59.47 mmol) was added to a 250 mL round bottom flask, which was then dissolved in acetone 20 mL, followed by K2CO3 (16.5 g, 119.38 mmol), Me2SO4 (15 g) , 118.92), after the addition, the reaction at room temperature, after 16h, by TLC detection, the basic reaction of the starting material is complete. 100 mL of water was added, and K2CO3 was dissolved by stirring, and a white solid was gradually precipitated, filtered, washed with water (100 mL × 3), and dried under vacuum.A white solid of 3 11 g was obtained in a yield of 94.3%. |
93.5% | Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In acetone at 25℃; for 0.5h; Stage #2: dimethyl sulfate In acetone at 25℃; | 1 4.1.1.1 Preparation of 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone To a solution of 1-(2,4,6-trihydroxyphenyl)ethanone (11.16 g, 0.06 mol) in dry acetone (150 mL), potassium carbonate (24.84 g, 0.18 mol) was added and stirred for 30 min at room temperature. Then dimethyl sulphate (12 mL, 0.12 mol) was added drop-wise, the reaction solution was stirred for 4-5 h at room temperature and monitored by thin-layer chromatograph (TLC). Poured the reaction solution to ice-water (1000 mL) and the precipitate was filtered, washed with water, dried to afford 1 (11.0 g) as white solid in 93.5% yield. 1H NMR (400 MHz, DMSO-d6) δ: 13.79 (s, 1H, OH), 6.11 (d, 1H, J = 2.3 Hz), 6.08 (d, 1H, J = 2.3 Hz), 3.86 (s, 1H), 3.81 (s, 1H), 2.55 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 203.2, 166.7, 166.4, 163.2, 105.9, 94.1, 91.2, 56.5, 56.1, 33.1. |
93% | With potassium carbonate In acetone at 50℃; for 24h; | 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethanone (17) A solution of 2,4,6-trihydroxyacetophenone (16; 100 mg, 0.54 mmol) and K2CO3 (238 mg, 1.7 mmol) in anhydrous acetone (1.5 mL) was warmed at 50 °C and treated with a solution of Me2SO4 (156 mg, 1.24 mmol) in acetone (1 mL), delivered dropwise (1.0 mL/h) with a syringe pump. The system was further heated at 50 °C for 24 h, when completion of the reaction was checked by TLC. Then the solvent was evaporated, brine (10 mL) added, and the product was extracted with EtOAc (3 × 20 mL). The combined extracts were concentrated under reduced pressure and the residue was chromatographed to afford 17 as a light brown solid; yield: 109 mg (93 %); mp 74-75 °C (Lit.22e mp 73-76 °C). IR (KBr): 2943, 1614, 1593, 1568, 1456, 1440, 1423, 1367, 1271, 1220, 1205, 1157, 1113, 895 and 835 cm-1. 1H NMR (300 MHz, CDCl3/TMS): δ = 14.02 (s, 1 H, OH), 6.04 (d, J = 2.4 Hz, 1 H, H-3′), 5.90 (d, J = 2.4 Hz, 1 H, H-5′), 3.84* (s, 3 H, OCH3-6′), 3.80* (s, 3 H, OCH3-4′), 2.59 (s, 3 H, CH3-2). 13C NMR (75 MHz, CDCl3): δ = 203.1 (C-1), 167.6 (C-4′), 166.1 (C-2′), 162.9 (C-6′), 106.0 (C-1′), 93.5 (C-3′), 90.7 (C-5′), 55.5 (2 C, OCH3-3′ and OCH3-5′), 32.9 (CH3-2). EI-MS: m/z (%) = 196 (M+, 33), 181 [(M - 15)+, 100], 178 181 [(M -18)+, 7], 166 (11), 138 (9), 95 (11). |
92% | With potassium carbonate In acetone | |
92% | With potassium carbonate In acetone at 65℃; for 3h; | |
90% | With potassium carbonate In acetone at 20℃; | |
90% | With potassium carbonate In acetone for 5h; Heating; | |
90% | With potassium carbonate In acetone at 20℃; for 4h; | |
90% | With potassium carbonate In acetone for 5h; Reflux; | |
90% | With potassium carbonate In acetone at 65℃; for 6h; Schlenk technique; Sealed tube; | |
90% | With potassium carbonate In acetone for 7h; Inert atmosphere; Reflux; | |
90% | Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In acetone at 20℃; for 0.25h; Stage #2: dimethyl sulfate In acetone for 8h; Reflux; | Synthesis of 4, 6-Dimethoxy 2-hydroxyacetophenone (3) To the solution of 1-(2,4,6-trihydroxyphenyl)-ethanone (40 mmol) (2) in anhydrous acetone (100 mL), K2CO3 (119 mmol) was added. The mixture was allowed to stir at roomtemperature for 15 min, then dimethyl sulfate (119 mmol) was added dropwise and refluxed for 8h. The progress of the reaction was noticed by TLC. After completion of the reaction, the solution was cooled at room temperature, filtered, and concentrated under vacuum to get the residue, which was purified by silica gel chromatography (hexane: ethyl acetate 5:1) to afford (3) in 90% yield. [Mp 75°C (lit. 73-76°C)] 1H-NMR [DMSO-d6, 400 MHz] δ: 13.79 (s, 1H, -OH), 6.09 (d, 1H, Ar-H), 6.07 (d, 1H, Ar-H), 3.85 (s, 3H, OCH3), 3.085 (s, 3H, OCH3), 2.537 (s, 3H, CH3). |
90% | With potassium carbonate In acetone for 12h; Reflux; | |
88% | With potassium carbonate In acetone | |
87% | With potassium carbonate In acetone Reflux; | 14 Preparation of derivatives of Hirtellanine B 5,6,7 (1 g, 5.95 mmol) was dissolved in 30 ml of acetone followed by the addition of potassium carbonate (4.11 g, 5 eq.), And dimethylsulfate (4 eq) was added dropwise. The suspension was refluxed for 5 to 8 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered and washed with acetone. The filtrate was evaporated under reduced pressure to give intermediate 5a (2-hydroxy-4,6-dimethoxyacetophenone) , 6a (2-hydroxy-4,6-diethoxyacetophenone) (5a, 1.01 g, yield 87%; 6a, 1.15 g, 79% yield); intermediate 5a, 6a, (4-hydroxy-5,7-dimethoxycoumarin), 6b (4-hydroxy-5,7-diethoxy coumarin) obtained by Method B of Method 9, (44 mg), 6b (50 mg) were each obtained by the method A of Example 9 to obtain the compound of the formula (5b, 1.00 g, yield 93%; 6b, 1.07 g, yield 91% 6,6 (Derivative 5, 60 mg, yield 74%; derivative 6,63 mg, 64%); nitration was carried out using Intermediate 6b (500 mg, 2 mmol) (see reaction of compound 2 (68 mg, yield 85%) was obtained from Intermediate 6c (59 mg, 0.2 mmol) followed by Method A of Example 9 to give the intermediate 6c (484 mg, yield 82% |
86% | With potassium carbonate In acetone at 25℃; for 15h; Inert atmosphere; | |
85.7% | With potassium carbonate In acetone for 1.5h; Reflux; | 2 Synthesis of 2,4-Dimethoxy-6-hydroxy-acetophenone (a kind of compound represented by structural formula 3, denoted as 3a) Compound 2 (10.0g, 0.059mol) was dissolved in 100ml of acetone, anhydrous potassium carbonate (24.58g, 0.178mol) was added, and while stirring, dimethyl sulfate (13ml, 0.137mol) was added dropwise and heated to reflux for 1.5h. Cooled to room temperature, filtered to remove solid potassium carbonate to obtain orange-yellow acetone solution. Rotary evaporation to obtain 11.24g yellow crude product. The crude product was recrystallized with 50ml ethanol-water to obtain white solid. Then vacuum dried at 45 for 12h to obtain orange-red solid 9.25g (85.7% yield). |
84.2% | With potassium carbonate In acetone for 5h; Reflux; | 5 4.1.5. 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethanone (16) 4.1.5 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethanone (16) To a mixture of 1-(2,4,6-trihydroxyphenyl)ethanone 15 (4.5 g, 24.2 mmol) and anhydrous K2CO3 (8.29 g, 55.6 mmol) in acetone (90 mL), Me2SO4 (6.84 mL, 72.5 mmol) was added dropwise with stirring. The resulting mixture was refluxed for 5 h and then filtered and concentrated under reduced pressure. The residue was purified on a silica gel chromatography using CH2Cl2 as eluent, obtaining compound 16; 84.2% yield; white solid; mp 78-79 °C (lit. 38 79-80 °C). |
84% | With potassium carbonate In acetone at 0 - 20℃; for 3h; Inert atmosphere; | Procedure for synthesis of compound 11 To a stirred solution of ketone 1 (1.18 g, 10 mmol) and K2CO3 (3.45 g 25 mmol) in acetone (20 mL), (CH3)2SO4 (2.37 mL, 25 mmol) was added dropwise at 0 °C. After stirring at room temperature for 3 h, the solvent was then removed under reduced pressure. The residue was dissolved in water (30 mL) and the solution was extracted three times with EtOAc. The combined organics were washed with water and brine, then dried over anhydrous MgSO4 and concentrated in vacuo to give compound 11 (1.65 g, 84%). 1H NMR (500 MHz, CDCl3) δ 14.03 (s, 1H), 6.08 (d, J = 2.4 Hz, 1H), 5.94 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.63 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 203.19, 167.58, 166.09, 162.91, 105.97, 93.45, 90.71, 55.55, 32.96; ESIMS: m/z = 197.2 [M+H]+. |
83% | With potassium carbonate In acetone at 20℃; for 18h; | |
83% | With potassium carbonate In acetone for 12h; | 1.1-3.1 1. Hydroxyl protection Trihydroxyacetophenone (16.8 g, 0.1 mol) was dissolved in 500 ml of acetone, anhydrous potassium carbonate (27.6 g, 0.2 mol) was added, and the mixture was heated to reflux at 56 ° C; Take dimethyl sulfate (25.2 g, 0.2 mol), add one-third to the reaction solution every 3 h, and reflux the reaction at 56 ° C for 9 h, then filter the reaction solution, and evaporate the filtrate to give a yellow solid. After washing three times with water, it was dried under low temperature to give a white solid product I (16.3 g). The yield was 83%. |
83% | With potassium carbonate In acetone at 45℃; for 4h; | 5.1.3. 4, 6-Dimethoxy-2-hydroxyacetophenone (12) Compound 11 (33.6 g, 0.2 mol) was dissolved in anhydrousacetone (350 mL) and K2CO3 (63.48 g, 0.46 mol) was added. Thendimethyl sulphate was added dropwise at room temperature andthe mixture was heated to 45 °C for 4 h. The reaction was monitoredby TLC. After the end of the reaction, the mixture was cooledto room temperature, filtered and the filtrate was poured into 5 volof water and adjusted to pH = 3-4 with 1M HCl to precipitate alarge amount of solid. The mixture was filtered and dried to give awhite solid (32.5 g, 83% yield). mp 80-82 °C. |
83% | With potassium carbonate In acetone at 20 - 45℃; for 5h; | 1.2 The second step: preparation of intermediate I-3 Add intermediate I-2 (33.6 g, 0.2 mol)To 350 mL of anhydrous acetone,Stir at room temperature,Add 63.48g K2CO3 (0.46mol),Dimethyl sulfate (39.78 mL, 0.42 mol) was added dropwise at room temperature.After 1 hour, the drop is completed.The reaction was continued at 45 ° C for 4 h.TLC detection (V petroleum ether: V ethyl acetate = 3:1) reaction is complete,Cool down to room temperature,Filter by suction and pour the filtrate into 5 volumes of water.Adjust pH to 3-4 with 1M HCl,A large amount of solid is precipitated.Filtered and dried to a white solid 32.5g.The yield was 83%. |
82% | With potassium carbonate In acetone at 20℃; | 2 1 -(2,4,6- trihydroxyphenyl)ethanone, 4, (16.8 g, 0.10 mol), anhydrous potassium carbonate (41.50 g, 0.30 mol) and anhydrous acetone (168 mL) were combined and stirred at room temperature after which dimethyl sulfate (26.9 g, 0.21 mol) was slowly added. Once the addition was complete, the reaction was stirred for 1 hour. The pH of the solution was adjusted to neutral using 2N HCl. The resulting yellow solid was collected by filtration and washed with water then dried to afford 16 g (82% yield) of the desired product as a white solid. M.p. 76-78 0C. |
82% | With potassium carbonate In acetone for 0.333333h; Reflux; Inert atmosphere; | Optimized Experimental Procedure for the Synthesis of 2′-Hydroxy-4′,6′-dimethoxyacetophenone K2CO3 (7.23 g, 52.32 mmol) and Me2SO4 (2.48 mL, 26.16 mmol) were added to a solution of 2′,4′,6′-trihydroxyacetophenone (1, 2.00 g, 11.89 mmol) in acetone (50 mL). The reaction mixture was refluxed for 20 min under nitrogen atmosphere. After that, K2CO3 was filtered off, the acetone evaporated, and the residue recrystallized in EtOH affording the 2′-hydroxy-4′,6′-dimethoxyacetophenonein good yield (82%, 1.91 g). |
82.5% | With potassium carbonate In acetone at 20℃; | Preparation of 2-hydroxy-4,6-dimethoxyacetophenone (2): white powder (EtOH) This compound was prepared from a mixture of 1 (17.85 mmol, 3 g), K2CO3 (43.47 mmol, 6 g), Me2SO4 (19.67 mmol, 3.85 g), and 50 ml acetone, which was stirred at RT for 5-6 h, and then, the mixture was poured into water (300 ml). The precipitated solid was filtered, washed with water, and crystallized from 95 % ethanol to give 2 as white powder, yield: 82.5 %; IR (KBr) νmax 2,960 (OH),1,620 (C=O) cm-1; 1H NMR (DMSO-d6, 400 MHz): δ = 14.15 (1H, s, OH), 6.36 (1H, d, J = 2.5 Hz, H-3), 5.97(1H, d, J = 2.7 Hz, H-5), 3.89 (3H, s, OCH3-4), 3.83 (3H,s, OCH3-6), 2.7 (3H, s, COCH3). 13C NMR (DMSO-d6,100 MHz): δ = 203.1 (C, C=O), 167.6 (C, C-4), 166.1(C,C-6), 162.9 (C, C-2), 106.0 (C, C-1), 92.9 (CH, C-3), 90.1(CH, C-5), 55.4 (2CH3, OCH3), 32.1(CH3, COCH3); ESI-MS: m/z 197.09 [M+H]+. Anal. Calcd. for C10H12O41 96.07: C, 61.22; H, 6.16. Found: C, 61.27; H, 6.19. |
81.36% | With potassium carbonate In acetone at 50℃; for 6h; | 20 Example 20 Preparation of 2-hydroxy-4,6-dimethoxyacetophenone (10) Anhydrous operation, 5 g of Intermediate 6 (26.85 mmol) was put in 80 ml of acetone, and 7.5 g of potassium carbonate was added(54.35 mmol) and 5.25 ml of dimethyl sulfate (20 mmol) were added, and the reaction solution was heated to 50 ° C, After the reaction was completed for 6 hours, the excess acetone was removed by distillation under reduced pressure, Purification by column chromatography gave a white solid in a yield of 81.36%. |
80% | With potassium carbonate In acetone at 25℃; for 4h; | 4.1.2.20 4,6-Dimethoxy-2-hydroxyacetophenone (13) To a solution of 12 (16.8g, 0.1mol) in dry acetone (180mL) was added K2CO3 (31.74g, 0.23mol) and dimethyl sulfate (20mL, 0.2mol). After stirring at 25°C for 4h the mixture was filtered. Then the filtrate was put into 100mL water and 0.5M HCl was conducted to adjust PH to 3-4. After filtration, the cake was washed with ice water for three times. The residue was dried to obtain 13 (16g, 80%). m.p. 81-83 ○C. |
78% | With potassium carbonate In acetone at 0℃; | |
78% | With potassium carbonate In acetone for 48h; Inert atmosphere; Reflux; | |
78% | With potassium carbonate In acetone for 20h; Reflux; | 1 preparation of Intermediate product (2) The 9g compound (1) is dissolved in 30 ml of acetone, is added under stirring 14g potassium carbonate, then using the constant voltage dropping funnel slowly add sulfuric acid dimethyl ester 15g, reflux stirring 20h, cooling to room temperature, adding ice water precipitating a large amount of white solid, filtered, methanol recrystallization to obtain 7.5g white solid (2), yield 78%. Compound mp: 74.4-75.1 °C. |
78% | With potassium carbonate In acetone for 20h; Reflux; | 1 Preparation of intermediate 2 The compound 1 (9g ) dissolved in 30ml of acetone, 14g of potassium carbonate was added under stirring, then added slowly with constant pressure dropping funnel dimethyl sulfate 15g, was stirred at reflux for 20h, cooled to at room temperature, ice water was added to precipitate large amount of white solid was suction filtered, and recrystallized from methanol to give a white solid 7. 5g (2), a yield of 78%. Compound mp 74. 4-75. 1 ° C. The product structure was confirmed by IR, NMR and MS analysis |
77% | With potassium carbonate In acetone at 20℃; for 3h; | |
76% | With potassium carbonate In acetone for 20h; Reflux; | 3.1 step one,Dissolve 9.300g of 2,4,6-trihydroxyacetophenone inIn 100 mL of anhydrous acetone,Slowly add with stirring14g anhydrous potassium carbonate,Then use a constant pressure dropping funnel15g of dimethyl sulfate was added dropwise within 10 minutes.Reflux 20h,Cool to room temperature,Add ethyl acetate,Pour in dilute hydrochloric acid,Water extraction,Dry with anhydrous sodium sulfate,Subsequent column chromatography V (petroleum ether):V (ethyl acetate) = 10:1,The first intermediate product in the form of white crystal(7.401g yield 76%),Structure by IR,NMR and MS analysis confirmed thatThe structure is as follows: |
76.6% | Stage #1: 2,4,6-trihydroxyacetophenone; dimethyl sulfate With potassium carbonate In acetone at 60℃; Stage #2: With sodium hydroxide In acetone at 60℃; for 1h; | 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone : compound 1-(2,4,6-trihydroxyphenyl)ethanone12.0 g (71.5 mmol, 1.0 eq) was dissolved into 50.0 ml acetone, then anhydrousK2CO3 29.6 g (214.5mmol, 3 eq) was added. The mixture was stirred for a whilefollowed by the addition of dimethylsulfate 22.5 g (178.8 mmol, 2.5 eq). Themixture was heated under 60 oC until the starting material wascompletely consumed. 10.0 % aq. NaOH solution was added carefully, and stirredunder 60 oC for about 1 hour, a large amount of the solvent wasremoved under reduced pressure, and 200.0 ml water was added, and extracted by ethylacetate for 3 times. The organic phase was combined and dried by anhydrousNa2SO4. The solvent was removed and the crude product was purified by si-gelchromatography (PE/EA=4/1) to afford 11.0 g 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanoneas white solid powder, yield 76.6%. 1H NMR (600 MHz, CDCl3):δ (ppm) = 2.60 (s, 3H), 3.81 (s, 3H), 3.84 (s, 3H), 5.92 (d, J = 2.2 Hz, 1H),6.05 (d, J = 2.2 Hz, 1H), 14.00 (s, 1H). |
75% | With potassium carbonate In acetone at 20℃; for 4h; | preparation of 2-hydroxy-4,6-dimethoxyacetophenone The 2,4,6-trihydroxyacetophenone monohydrate (3.72g, 20mmol) added to acetone (60 ml), then adding potassium carbonate (6.06g, 40mmol)with stirring, undissolved, then slowly dropping dimethyl sulfate (4 ml, 42mmol), after completion of dropwise addition the reaction was stirred at the room temperature 4 hours and degree of reaction was monitored by TLC monitoring. The end of the to be reacted, filtering off the solid insoluble materials, ten slowly adding water (100 ml), repeated oscillation, allowed to stand for half an for white solid precipitation. Filtering, drying to obtain the white solid (3.0g), yield 75%. |
74% | With potassium carbonate In acetone for 5h; Reflux; | Synthesis of 2’-hydroxy-4’,6’-dimethoxyacetophenone (4) To a solution of 2’,4’,6’-trihydroxyacetophenone (3) (10.0 g, 59.5 mmol) in acetone (350 mL)was added K2CO3 (16.45 g, 119 mmol, 2.0 equiv) while stirring with a KPG stirrer at room temperature. Dimethyl sulfate (14.15 g, 112.2 mmol, 10.6 mL) was added dropwise to the suspension under vigorous stirring and then the reaction mixture was refluxed for 5 h. Then the reaction mixture was allowed to cool down and was stirred overnight. Afterwards, the reaction mixture was filtered, the solvent was evaporated under vacuum and the residue was recrystallized from methanol (15 mL). The crystals were filtered, washed with water to yield 8.65 g (44.1 mmol, 74%) off-white solid; mp 74-75 °C [Lit. 73-76 °C]. Spectroscopic data is in accordance with the literature. |
72% | With potassium carbonate In acetone for 5h; Reflux; | |
70% | With potassium carbonate In acetone | |
54% | With potassium carbonate In acetone for 10h; Reflux; | 1 4.1 Synthesis of 1-(2-hydroxy-4,6-dimethoxyphenyl)ethan-1-one (1) A mixture of 1-(2,4,6-trihydroxyphenyl)ethan-1-one (2.50 g, 15 mmol), (CH3)2SO4 (2.85 mL, 30 mmol) and anhydrous K2CO3 (4.56 g, 33 mmol) in dry acetone (60 mL) was refluxed for 10 h. The reaction mixture was concentrated and poured on to ice-water (100 mL). The resulting precipitate was filtered off and washed with cold water. The obtained residue was purified by silica gel column chromatography with hexane: ethyl acetate (95: 5) as eluent. White solid, Yield: 54%, M.P: 78-80 °C; 1H NMR (CDCl3, 400 MHz, ppm) δ: 14.03 (s, 1H,-OH), 6.06-6.05 (d, J = 2.20 Hz, 1H, Ar-H), 5.93-5.92 (d, J = 2.20 Hz, 1H, Ar-H), 3.86, 3.82 (s, each 3H, 2 * -OCH3), 2.61 (s, 3H, -COCH3); 13C NMR (CDCl3, 100 MHz, ppm) δ: 203.17 (-C=O); 167.56; 166.06; 162.88; 105.97; 93.43; 90.72; 55.53 (-OCH3); 50.86 (-OCH3); 32.91 (-CH3). |
54.9% | With potassium carbonate In acetone for 2h; Reflux; | 14.A Step A: containing 2,4,6-trihydroxyacetophenone (25.0 g, 149 mmol), potassium carbonate (20.6 g, 149 mmol),A mixture of dimethyl sulfate (28.1 g, 223 mmol) and acetone (250 mL) was stirred under reflux for 2 hr.Cool to room temperature, remove insolubles by filtration, distill off the solvent under reduced pressure, and purify the product by column chromatography (200-300 mesh silica gel,Ethyl acetate:dichloromethane: petroleum ether = 1:1:40 to 1:1:6) eluted to give 1-(4-hydroxy-2,6-methoxy-phenyl)ethanone (86) (16.0 g), the yield was 54.9%. |
With potassium carbonate; acetone; benzene | ||
With potassium carbonate In acetone | ||
50 mg | With potassium carbonate In acetone for 0.5h; Heating; | |
With potassium carbonate In acetone at 50 - 60℃; for 0.5h; | ||
With sodium hydroxide In dichloromethane; water monomer at 20℃; for 24h; | ||
With potassium carbonate In acetone for 5h; Reflux; | ||
With potassium carbonate In acetone at 65℃; for 6h; | ||
With potassium carbonate In acetone Reflux; | ||
With potassium carbonate In acetone at 20℃; | ||
With potassium carbonate | ||
With potassium carbonate In acetone for 2h; Reflux; | ||
In acetone at 65℃; | ||
With potassium carbonate In acetone Reflux; | ||
With potassium carbonate In acetone at 20℃; for 3h; | ||
With potassium carbonate In acetone at 15 - 60℃; for 2h; | 1.1 To a mixture of 1- (2,· 4, 6-trihydro xyphenyl)ethanone (50 g, 297.36 mmol, 1 eq) and K2CO3 (102.74 g, 743.40 mmol, 2.5 eq) in acetone (500 mL) was added Me2S04 (78.76 g, 624.46 mmol, 59.22 mL, 2.1 eq) at 15 °C. The mixture was stirred at 60 °C for 2 h. The reaction mixture was filtered and the filter cake was washed with EtOAc (40 rnL*3). The filtrate was concentrated under reduced pressure to give l-(2-hydroxy-4,6-dimethoxy-phenyl)ethanone (53 g, crude) as gray solid. The product will be used directly in next step without further purification. H NMR: (CDCI3, 400 MHz) d - 14.01 (s, 1 H), 6.06 (d, I - 2.2 Hz, 1H), 5.92 (d, I = 2.4 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 2.61 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In sodium hydroxide; chloroform Ambient temperature; | |
89% | With potassium carbonate In acetone at 25℃; for 19h; Inert atmosphere; Reflux; | |
With potassium carbonate; acetone |
2,4,6-trihydroxyacetophenone Stage #2: dimethyl sulfate In sodium hydroxide | ||
In acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.2% | Stage #1: 3,5-dihydroxyphenol; acetonitrile With hydrogenchloride; zinc(II) chloride In di-isopropyl ether at 0℃; Stage #2: With water for 2h; Reflux; | Phloroacetophenone (1) A mixture of well-dried phloroglucinol(250 g, 1.98 mol), anhydrous acetonitrile (365 mL,6.95 mol), diisopropyl ether (838 mL, 5.95 mol) and finelypowdered fused zinc chloride (49.5 g, 0.036 mol) was cooledin an ice-salt mixture at 0 °C under stirring for 7 h, by passingdry HCl gas. The flask is allowed to cool in an ice-chest inrefrigerator for overnight. On decanting the diisopropyl ethera bulky orange-yellow precipitate was separated and washedthe precipitate with diisopropyl ether (100 mL). The solid wastransferred into a round bottom flask and added 2.5 L of distilledwater (2.5 L) and refluxed under stirring for 2 h at 120 °C. Themixture was cooled to room temperature and left overnight.Pale yellow needles were observed and the product was filteredand dried under vacuum oven at 120 °C. The yield was 96.2% with a purity of 99.9 % obtained. |
80% | Stage #1: 3,5-dihydroxyphenol; acetonitrile With hydrogenchloride; zinc(II) chloride In diethyl ether at -20℃; for 2h; Stage #2: With water for 2h; Reflux; | 2 To a 3-neck flask was added 1,3,5-trihydroxybenzene (10.1 g, 0.10 mol), anhydrous zinc chloride (2.5 g, 0.018 mol), and anhydrous ethyl ether (50 mL). After the solids had completely dissolved, anhydrous CH3CN (11 mL, 0.20 mol) was added. Dry HCl gas was introduced to the reaction solution for 2 hours at a temperature below -20 0C. The resulting white solid was collected by filtration and washed with ethyl ether. The crude product was dissolved in water (20 mL) and the solution was brought to reflux for 2 hours. The reaction was cooled and the resulting solid was collected by filtration to afford 13.5 g (80% yield) of the desired product as a light yellow solid. M.p. 218-219 0C. |
80.7% | With hydrogenchloride; zinc(II) chloride In diethyl ether for 6h; Cooling with ice; | 1 Synthesis of 2,4,6-trihydroxyacetophenone (compound shown in structural formula 2) Under ice-salt bath cooling, add Phloroglucinol 1 (10.0g, 0.080mol), anhydrous acetonitrile (9.7ml, 0.185 mol), anhydrous ZnCl2 (2.81g, 0.021mol) and anhydrous into a 250ml three-necked flask Ether 42ml, while stirring, dry HCl gas was introduced for 6h, a large amount of light yellow solid was formed. The reaction was stopped, and the reaction solution was placed in a refrigerator and allowed to stand for 3 days. Pass in N2 to remove residual HCl gas, filter, and wash the filter cake twice with 20 ml of anhydrous ether. The filter cake and 2.5g activated carbon were added to 500ml deionized water, refluxed for 2.5h, filtered while hot, and recrystallized to obtain pale yellow needle-like crystals. The solid was vacuum dried at 120°C for 4h to obtain orange-red crystals 10.76g (yield 80.7%) . |
75% | Stage #1: 3,5-dihydroxyphenol; acetonitrile With hydrogenchloride; zinc(II) chloride In diethyl ether; water at 0 - 70℃; for 12h; Stage #2: With water for 2h; | 1 Synthesis of intermediate e Weigh anhydrous zinc chloride powder (10.0g, 73.3mmol)Add anhydrous acetonitrile (30g, 0.73mol) and heat to60-70, stir vigorously until there are no zinc chloride particles,Phloroglucinol(20g, 0.15mol), after stirring and dissolving,The reaction liquid was cooled to 0-5°C.Add anhydrous ether (100mL),Pass in dry hydrogen chloride gas for 12 hours until no solids are formed.Place the reaction solution in a refrigerator at 4°C overnight.Suction filtration,The filter cake was washed with anhydrous ether. The filter cake is transferred to the in-situ flask,Add water (1L), boil for 2h, filter while hot, and let the filtrate cool overnight.Crystals are precipitated, filtered and dried to obtain the product with a yield of 75%. |
73% | With hydrogenchloride; zinc(II) chloride In diethyl ether for 0.95h; | 110 [00149] Procedure by Phloroglucinol (1.2 g, 9.5 mmol) was dissolved in anhydrous ether (60 mL) at room temperature (26° C.) forming a clear solution. ZnCl2 and acetonitrile (1.4 mL) were added to the clear solution. The addition of ZnCl2 resulted in the formation of some sediment. Through the solution was passed a dry stream of freshly generated hydrogen chloride gas (1 mole total amount), which apparently caused the solution to become cloudy. 5 minutes later, an orange oil formed and the solution brightened. After 2 additional minutes, the solution became orange and the oil darkened. About 50 minutes later, when gas passage was complete, the system was closed and the oil solidified. Cold water (60 mL) was added to the orange crystals and solubility was achieved by vigorous stirring. The solution was extracted with ether (2×120 mL) and evaporated (to 30 mL). Upon cooling, airy, woolly colorless crystals appeared (1.157 g, 73% yield). MS (EI+): 168.1 (M-, 46%), 153.1 (M+-CH3, 100%). |
71% | With hydrogenchloride; zinc(II) chloride In diethyl ether at 0℃; for 40h; | 5.1.2. 2, 4, 6-Trihydroxyacetophenone hydrate (11) Pyrogallol (10) (63 g, 0.5 mol) was dissolved in anhydrous ether(300 mL), then anhydrous ZnCl2 (13.4 g, 0.1 mol) and anhydrousacetonitrile (50 g, 1.25 mol) were added and then the reactionmixture was stirred in the presence of dried HCl gas at 0 °C for 40 h.The reaction was monitored by TLC. After the end of the reaction,the mixture was raised to room temperature and filtered. The filtercake was dried to constant weight and dissolved inwater (200 mL).Then the mixture was refluxed for 6 h and a large amount of solidwas formed. The mixture was cooled to room temperature, filtered,and the cake was dried to give a white solid (60 g, 71% yield). mp119-121 °C. |
71% | With hydrogenchloride; zinc(II) chloride In diethyl ether at 0℃; for 40h; | 1.1 First step: preparation of intermediate I-2 Addition of phloroglucinol I-1 (63 g, 0.5 mol)In 300 mL of anhydrous ether,Stir at room temperature,Then add anhydrous ZnCl2 (13.4 g, 0.1 mol)And anhydrous acetonitrile (50g, 1.25mol),The dried HCl gas was reacted at 0 ° C for 40 h.TLC detection (V petroleum ether: V ethyl acetate = 1: 2) reaction is complete,The temperature of the reaction solution is raised to room temperature.After suction filtration, the filter cake is dried to constant weight and dissolved in 200 mL of water.Heated back to reflux for 6 h,Precipitating a large amount of solids,Cool to room temperature,Filtered and dried to give a white solid 60g.The yield was 71%. |
71% | With hydrogenchloride; zinc(II) chloride In diethyl ether at 0℃; for 72h; | 4.1.2.19 2,4,6-Trihydroxyacetophenone hydrate (12) ZnCl2 (6.7g, 0.05mol) and dry acetonitrile (25g, 0.625mol) were added to a solution of 11 (31g, 0.25mol) in dry diethyl ether (150mL). The reaction mixture was then stirred at 0°C for three days. Meanwhile dry hydrogen chloride gas was led in. After reaction completion, the mixture was kept for a while till the temperature warmed up to rt. After filtration, the residue was dissolved in 100mL water. The reaction mixture was kept refluxing for further 6h. Followed by cooling to rt, the precipitate was filtered and dried to afford 12 (30g, 71%). m.p. 118-120°C. |
71% | Stage #1: 3,5-dihydroxyphenol; acetonitrile With hydrogenchloride; zinc(II) chloride In diethyl ether at 0℃; for 72h; Stage #2: In water for 8h; Reflux; | 4.1.2.1 2,4,6-Trihydroxyacetophenone hydrate (2) At room temperature, added ZnCl2 (6.7g, 0.05mol) and anhydrous acetonitrile (25g, 0.625mol) to the solution of 1 (32g, 0.25mol) in dry diethyl ether (150mL) solution. The reaction mixture was then stirred at 0°C for three days in the presence of hydrogen chloride gas. After reaction completion, the mixture was slowly raised to rt (room temperature) and the precipitate was isolated. Then the residue was dissolved in water (50mL). The resultant mixture was kept refluxing for further 8h and then cooled down to rt, the precipitate was separate out. The residue was dried to obtain 2 (30g, 71%). m.p. 120-122°C. HRMS (ESI+): m/z [M+ H]+ calcd for C8H9O4, 169.1456; found 169.1509. |
50% | Stage #1: 3,5-dihydroxyphenol; acetonitrile With hydrogenchloride; zinc(II) chloride In diethyl ether at 0 - 5℃; for 72h; Stage #2: With water In diethyl ether at 60℃; for 2h; | |
With hydrogenchloride; diethyl ether; zinc(II) chloride und Hydrolyse des entstandenen Imidhydrochlorids; | ||
With hydrogenchloride; diethyl ether; zinc(II) chloride und Erwaermen des Reaktionsprodukts mit Wasser; | ||
(i) HCl, ZnCl2, (ii) H2O; Multistep reaction; | ||
With trifluorormethanesulfonic acid 1.) room temperature, 1.5-3.5 h, 2.) 12 d; Yield given. Multistep reaction; | ||
Stage #1: 3,5-dihydroxyphenol; acetonitrile With zinc(II) chloride Stage #2: With hydrogenchloride | ||
Stage #1: 3,5-dihydroxyphenol; acetonitrile With hydrogenchloride; zinc(II) chloride In diethyl ether at 0 - 5℃; Stage #2: With water In diethyl ether Reflux; | ||
Stage #1: 3,5-dihydroxyphenol; acetonitrile With zinc(II) chloride Stage #2: With hydrogenchloride | ||
Stage #1: 3,5-dihydroxyphenol; acetonitrile With hydrogenchloride; zinc(II) chloride In diethyl ether at 0℃; Stage #2: With hydrogenchloride In water for 2h; Reflux; | ||
108 g | Stage #1: 3,5-dihydroxyphenol; acetonitrile at 20℃; for 1h; Stage #2: With trichlorophosphate | 5 Preparation of 1,2,4,6-trihydroxyacetophenone A 1000 ml three-necked flask equipped with a magnetic stirrer was charged with 100 g of anhydrous phloroglucinol and 110 mgAcetonitrile. Electromagnetic stirrer at room temperature to start fully stirred one hour after the start of phosphorus oxychloride 104 ml, 2 hours dropwisecomplete. Then continue stirring, the reaction 6h, overnight. The reaction solution was slowly poured into 400 ml of water, refluxed 2h, add 2 gActivated carbon continued to reflow 30min, hot filtered. The filtrate was allowed to cool and left to stand for 24 hours to precipitate crystals. Filter, filter cake drying. The yellow needles 108g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In acetone for 0.25h; Cooling with ice; Stage #2: methyl iodide In acetone for 10h; Cooling with ice; | 1.1 Step 1 Synthesis of compound 3 Compound 2 (5.0, 26.9 mmol) was dissolved in anhydrous acetone (80 mL), under ice bath conditions,Add anhydrous potassium carbonate (10.3, 74.6 mmol);After stirring for 15 minutes, iodomethane (7.5 mL, 107.6 mmol) was added to the reaction solution.After stirring and reacting in an ice bath for 10 hours, the potassium carbonate was removed by filtration, and the pH of the filtrate was adjusted to neutral with dilute hydrochloric acid.Add appropriate amount of water, extract 3 times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate,Filter out the desiccant, silica gel column chromatography, eluent: n-hexane/isopropanol=15:1,2.8 g of 3-methyl-2,4,6-trihydroxyacetophenone was obtained, and the yield was 52%; |
45% | With potassium carbonate In acetone at 0℃; for 9.08h; | |
With sodium methylate |
With potassium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide In ethanol for 48h; Ambient temperature; | ||
With potassium hydroxide In ethanol | ||
With potassium hydroxide In ethanol at 20℃; for 24h; Inert atmosphere; | General procedure for the preparation of 5,7-dihydroxy-2-phenyl-4H-chromen-4-one (2) General procedure: To prepare compound 2, initially, we have prepared3-phenyl-1-(2,4,6-trihydroxyphenyl)prop-2-en-1-one (1).Trihydroxy acetophenone (1 eq, 2 mmol) was condensedwith benzaldehyde (1 eq, 2 mmol) in presence of aq.KOH(60 %, 3 mL) in ethanol (10 mL). The reaction mixture wasstirred at room temperature for 24 h and poured into water(60 mL). After neutralization with 10 % HCl, ethanol wasevaporated and extracted thrice with ethyl acetate (50 mL).The combined organic phase was concentrated to yieldcrude chalcone (1) which subjected to column chromatographyto yield pure chalcone. To a solution of compound (1)(0.256 g, 1 mmol) in trigol was added iodine (0.38 g,1.5 mmol) and refluxed for 2 h at 120 C. After the completionof the reaction (TLC), the reaction mixture wastreated with hypo solution and extracted with ethyl acetate(3 9 20 mL), dried and concentrated. The product obtainedwas purified by column chromatography. The fraction elutedat 30 % ethyl acetate in petroleum ether contained pure 5,7-dihydroxy-2-phenyl-4H-chromen-4-one (2). |
With sodium hydroxide In methanol | ||
With sodium hydroxide In methanol; lithium hydroxide monohydrate at 80℃; for 5h; | a Specifically, 500 g (2.97 mol) of 1-(2,4,6-trihydroxyphenyl)ethanone and 315 g (2.97 mol) of benzaldehyde were dissolved in methanol (7 L), and 5.9 L of 4 N aqueous NaOH solution After adding the mixture, the mixture was heated and refluxed at 80 °C for 5 hours and stirred.After the reaction was completed, the reactor was cooled to room temperature, and then 6 L of 5 N HCl aqueous solution was added and stirred until the pH became 3 to 4.The reaction product was extracted with ethyl acetate, and the extracted organic layer was dried over anhydrous Na2SO4, filtered, and concentrated.The concentrated crude product was used as such in the reaction of step (b) without purification.600 g of the compound of Formula 3-1 as a yellow solid was obtained in a yield of 79%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 2′,4′,6′-trihydroxyacetophenone With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; Inert atmosphere; Stage #2: chloromethyl methyl ether In dichloromethane at 0 - 20℃; | |
94% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 0.25h; Inert atmosphere; | |
90% | With potassium carbonate In propan-2-one Reflux; |
90% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 5.33h; Inert atmosphere; regioselective reaction; | |
87% | In dichloromethane at 20℃; for 2h; | 4.1.1. 1-(2-Hydroxy-4,6-bis(methoxymethoxy)phenyl)ethan-1-one(3) To a stirred solution of 20,40,60-trihydroxyacetophenone (168 mg,1 mmol) and N,N-diisopropylethylamine (DIEA, 0.4 mL, 2.5 mmol)in dry dichloromethane (DCM, 5 mL) was slowly added chloromethylmethyl ether (MOMCl, 0.2 mL, 2.5 mmol) at 0 C andstirred for 2 h. The reaction mixture was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was diluted with DCM (20 mL). The organic layer was washed with H2O (3 10 mL),dried over anhydrous MgSO4 and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto afford compound 3 (176 mg, 87%) as a white solid. 1HNMR (400 MHz, CDCl3) d 2.67 (s, 3H), 3.47 (s, 3H), 3.52 (s, 3H), 5.17(s, 2H), 5.26 (s, 2H), 6.24e6.27 (m, 2H), 13.72 (s, 1H). |
86.62% | Stage #1: 2′,4′,6′-trihydroxyacetophenone With potassium carbonate In propan-2-one for 0.5h; Reflux; Stage #2: chloromethyl methyl ether In propan-2-one Reflux; | 1.1 (1) Preparation of 2,4-Dimethoxymethoxy-6-hydroxyacetophenone Dissolve 1g of 2,4,6-trihydroxyacetophenone in 30ml of acetone.Add 2.88g of anhydrous potassium carbonate,Stir at reflux for 30 minutes, cold1.31 ml of chloromethyl ether was added dropwise.Continue reflux,The TLC plate detects the completion of the reaction.Add water to quench the reaction,Ethyl acetate extraction,Dry with anhydrous magnesium sulfateFiltration, rotary steaming,2.32 g of 2,4-dimethoxymethoxy-6-hydroxyacetophenone was obtained.Yield 86.62%. |
86% | Stage #1: 2′,4′,6′-trihydroxyacetophenone With potassium carbonate In propan-2-one for 0.5h; Stage #2: chloromethyl methyl ether In propan-2-one at 0 - 20℃; | 1 (1) Hydroxyl protection: 2,4,6-trihydroxyacetophenone 0.1 molSoluble in 500ml of acetone,Add 0.7mol of potassium carbonate,Stir for 30minAfter cooling to 0 degrees,Slowly add 0.2mol to itChloromethyl methyl ether,The reaction was carried out at room temperature.After the reaction, 500 ml of ice water was added to the reaction solution.Ethyl acetate extraction *3,Combine the ethyl acetate layer,Wash it with saturated brine,Dry over anhydrous sodium sulfate,Evaporate under reduced pressure,The silica gel column was passed to give the objective product I (22 g, yield 86%). |
86% | Stage #1: 2′,4′,6′-trihydroxyacetophenone With potassium carbonate In propan-2-one for 0.5h; Stage #2: chloromethyl methyl ether In propan-2-one at 0 - 20℃; for 3h; | 1.1; 2.1; 2.1 Preparation Example 2:Synthesizing YS10 from scratch, as shown in Figure 2, includes the following steps: (1) hydroxyl protection:Dissolve 0.1 mol of 2,4,6-trihydroxyacetophenone in 500 ml of acetone,Add 0.7mol potassium carbonate,After stirring for 30min, the temperature is reduced to 0 ° C.0.2 mol of chloromethyl methyl ether was slowly added dropwise thereto, and allowed to react at room temperature.After the reaction was completed, 500 ml of ice water was added to the reaction solution, and extracted with ethyl acetate * 3.Combine the ethyl acetate layers,Wash it with saturated brine,Dried over anhydrous sodium sulfate,Evaporate to dryness under reduced pressure,Pass through a silica gel column (petroleum ether / ethyl acetate = 30/1) to obtain the target product I (22 g, yield 86%). |
85% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; Inert atmosphere; | |
85.9% | With N-ethyl-N,N-diisopropylamine In dichloromethane at -10 - 0℃; | 1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)ethanone, 9 The starting material 2’4’6’-trihydroxyacetophenone trihydrate (930 mg, 5 mmol) was dissolved in DCM (20 mL), and MOMCl (0.94 mL, 12.5 mmol) was added at -10°C. After 10 mins stirring, DIEA (2.2mL, 12.5mmol) was added slowly and the suspension heated to 0°C. Saturated sodium bicarbonate (20 mL) was added to quench reaction after 1h. The dichloromethane layer was separated, then the aqueous phase was extracted with dichloromethane (20 mL). The organic phase was merged, then washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/acetone = 20:1) to give 9 as white solids (1.1 g, 85.9%). |
84% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; | |
84% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h; | |
84% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 12h; Inert atmosphere; | 2’,4’-Bis(methoxymethoxy)-6’-hydroxyacetophenone Methoxymethyl (MOM) chloride (1.3 mL, 16.5 mmol, 2.2 equiv) was added dropwise under an atmosphere of argon to a cooled (0 °C) solution of 2’,4’,6’-trihydroxyacetophenone monohydrate (1.4 g, 7.5 mmol, 1.0 equiv) and N,N-diisopropylethylamine (13.1 mL, 75.0 mmol, 10.0 equiv) in 50 mL of dry DCM. The mixture was stirred for 12 h after which it was quenched with 20 mL of water and extracted with EtOAc (3 25 mL). The combined organic layers were washed dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (25% EtOAc/hexane) to yield the title compound as a white solid (1.6 g, 84%). The spectroscopic data (1H- and 13C-NMR) were consistent with that reported in the literature1. |
82% | With ammonia hydrochloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 6h; | 1 5.1.1 1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)ethan-1-one (4) 1-(2,4,6-trihydroxyphenyl)ethan-1-one (16.8 g, 100 mmol) in dry CH2Cl2 (500 mL) were added DMF (20 mL). The mixture was cooled to 0 °C and N,N-diethylpropan-2-amine (39.3 g, 250 mmol) was added slowly. After addtion chloro(methoxy)methane (17.7 g, 220 mmol) in dry CH2Cl2 (100 mL) was added dropwised. The reaction mixture was warmed to room temperature and stirred for 6 h. The reaction was quenched with NH4Cl (aq) and extracted with CH2Cl2 (3 * 500 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (petroleum ether/ethyl acetate 20:1) to afford a compound 4 (21.0 g, 82%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 13.66 (s, 1H), 6.17 (s, 2H), 5.19 (s, 2H), 5.10 (s, 2H), 3.46 (s, 3H), 3.41 (s, 3H), 2.58 (s, 3H). |
82% | In dichloromethane at 0 - 20℃; for 6h; | 3.1.1. 1-(2,6-Dihydroxy-4-(methoxymethoxy)phenyl)ethan-1-one (6) 1-(2,4,6-Trihydroxyphenyl)ethan-1-one (1.68 g, 10 mmol) in dry CH2Cl2 (100 mL)were added N,N-diethylpropan-2-amine (3.93 g, 25 mmol) and chloro(methoxy)methane(1.77 g, 22 mmol) at 0 C. The reaction mixture was warmed to room temperature andthen stirred for 6 h. The reaction was quenched with NH4Cl (aq) and extracted withCH2Cl2 (500 mL) three times. The combined organic layers were washed with brine,dried over Na2SO4, and concentrated under reduced pressure. The crude product waspuried by column chromatography on silica (petroleum ether/ethyl acetate 20:1) to afford1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)ethan-1-one (2.1 g, 82%) as a colorless oil. 1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)ethan-1-one (1.28 g, 5 mmol) in MeOH (50 mL)was added 2 N HCl (5 mL) at 0 C. After addition, the reaction mixture was warmed to40 C and then stirred for 3 h. The reaction was quenched with NaHCO3 (aq) and extractedwith EtOAc (100 mL) three times. The combined organic layers were washed with brine,dried over Na2SO4, and concentrated under reduced pressure. The crude product waspuried by column chromatography on silica (petroleum ether/ethyl acetate 10:1) to afforda compound 6 (0.65 g, 61%) as a white solid. 1H-NMR (400 MHz, d6-DMSO) 12.26 (s, 2H),6.02 (s, 2H), 5.17 (s, 2H), 3.36 (s, 3H), 2.58 (s, 3H). 13C-NMR (100 MHz, d6-DMSO) 203.8,164.4, 163.6, 105.8, 95.1, 93.9, 56.3, 33.0. |
80% | With dipropylethylamine In dichloromethane | 12 A second generation of analogs was developed pursuant to the identification of the importance of the double bond present in the benzopyran ring of Rottlerin (FIG. 15). These compounds were based on representing the left and right parts of Rottlerin, with the methylene linkage denoting the division.The left part (4) was represented by commercially available 2',4',6'-trihydroxyacetopheone, while the right part (5) was synthesized, also starting with the acetophenone (4). Bis-MOM (methoxymethyl) protection of (4) was accomplished using MOMCl and selective deprotection occurred using iodine as the Lewis acid to give (6). Cyclization using ethylenediamine diacetate and 3-methyl-2-butenal in refluxing xylenes gave protected intermediate (7), which could be elaborated to the right part molecule (5) through an aldol condensation with benzaldehyde and then deprotection. Evaluation of these analogs confirmed the activity of Rottlerin lies in the right portion of the molecule.Two new analogs (8, 9) were prepared, adjusting the electron density of the chalcone moiety by introducing a weak electron-donating group, bromine into the para position (8), and adding the catechol moiety (9) in the 3, 4-position to increase electron density. These analogs were synthesized in a similar manner as before, starting from intermediate (7), the aldol condensation was achieved using a substituted benzaldehyde to install the wanted group(s) on the chalcone system. In the case of analog (9), bis-protected aldehyde was used and all three protecting groups were removed at the same time in the final step. |
79% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 1h; Inert atmosphere; | |
79% | With N-ethyl-N,N-diisopropylamine at 0℃; for 1h; | |
79% | Stage #1: 2′,4′,6′-trihydroxyacetophenone With potassium carbonate In propan-2-one for 0.25h; Stage #2: chloromethyl methyl ether In propan-2-one for 5h; | 1.1; 2.1; 3.1; 4.1; 5.1; 6.1 (1) Synthesis of 2-hydroxy-4,6-dimethoxymethoxyacetophenone 1 g of 2,4,6-trihydroxyacetophenone was added to anhydrous acetone.Stir and dissolve,Take 6.1 g of potassium carbonate and add it to acetone;After 15 minutes,Then take 1.13ml of chloromethyl methyl ether,Add to acetone.After stirring the reaction for 5 hours,Filter and dry the filtrate.Finally, using petroleum ether / ethyl acetate mixed solvent volume ratio of 10:1, silica gel column chromatography:2.4g yellow oily solid2-hydroxy-4,6-dimethoxymethoxyacetophenone,The yield was 79%;This process takes place as follows: |
79% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
78% | With potassium carbonate In propan-2-one for 2h; Reflux; | |
78% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h; | 2 4.2 1-(2-Hydroxy-4,6-bis(methoxymethoxy)phenyl)ethanone (8) To a solution of 7 (1.0 g, 5.95 mmol) and DIPEA (4.4 mL, 23.8 mmol) in CH2Cl2 (20 mL), MOMCl (1.8 mL, 23.8 mmol) was added. The mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with CH2Cl2. The organic layers were combined, dried over Na2SO4, and evaporated. The residue was then subjected to column chromatography (silica gel, petroleum ether (PE)/ethyl acetate (EA) 9:1) to provide 8 (1.2 g, 78%) as a white solid: mp 49-51 °C (lit.4 49-50 °C). IR (neat): ν 2931, 2830, 1623, 1416, 1400, 1268, 1224, 1152, 1022, 927, 831 cm-1; 1H NMR (400 MHz, CDCl3): δ 13.73 (s, 1H, Ar-OH), 6.27 (d, J=2.2 Hz, 1H, Ar-H), 6.25 (d, J=2.2 Hz, 1H, Ar-H), 5.26, 5.18 (each s, 4H, 2× -OCH2O-), 3.52, 3.48 (each s, 6H, 2× -OCH3), 2.66 (s, 3H, -OCCH3). |
73% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 12h; | |
73% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 12h; | |
73% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 12h; | 1 2',4'-Bis(methoxymethoxy)-6'-hydroxyacetophenone.; To a cooled(0 0C) solution of 2',4',6'-trihydroxyacetophenone monohydrate 5 (1.4 g, 7.5 mmol, 1.0 equiv) and iV,N-diisopropylethylamine (13.1 mL, 75.0 mmol, 10.0 equiv) in 50 mL of dry THF was added dropwise chloromethylmethyl ether (1.3 mL, 16.5 mmol, 2.2 equiv) under an atmosphere of argon. The mixture was allowed to stir for 12 h after which it was quenched with 20 mL of water and extracted with EtOAc (3x25 mL). The combined organic layers were washed with 5% aqueous HCl, water, and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (0 to 15% EtOAc/hexanes) to yield the title compound as a white solid (1.4 g, 73%). The spectroscopic data (1H and 13C NMR) were consistent with that reported in the literature. Choi et al.,. Heterocycles 1996, 43, 1223-1228; incorporated herein by reference. |
73% | Stage #1: 2′,4′,6′-trihydroxyacetophenone With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.333333h; Stage #2: chloromethyl methyl ether In dichloromethane at 0 - 20℃; for 0.333333h; | |
73.4% | With 4-dimethylaminopyridine; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; | 3.4. 1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)ethan-1-one (12) 2,4,6-trihydroxyacetophone (500 mg, 2.97 mmol) was suspended in ice-old dichloromethane(10 mL) followed by the addition of N,N-diisopropylethylamine (6.0 mL) and DMAP (5 crystals).After around 10 min, MOMCl (515 mg, 6.40 mmol) was added drop-wise and the mixture was stirredovernight. After the disappearance of starting material shown on TLC, the mixture was poured intowater (10 mL), and extracted with dichloromethane (2 x 20 mL) two times. The organic phase waswashed with water (10 mL) and brine (10 mL), and dried using anhydrous sodium sulfate. The solventwas then removed under reduced pressure and the residue was purified on silica gel column usinghexane/ethyl acetate (9:1) to yield compound 12 (560 mg, 73.4%) as a colorless oil that was crystalizedas a white solid. 1H-NMR (400 MHz CDCl3) 2.66 (s, 3H, -COCH3), 3.47 (s, 3H, -OCH3), 3.51 (3H,s, -OCH3), 5.17 (2H, s, -OCH2O-), 5.25 (2H, s, -OCH2O-), 6.24 (1H, d, J = 2.3 Hz, Ar-H), 6.27 (1H, d,J = 2.3 Hz, Ar-H); 13C-NMR (100 MHz CDCl3) 33.1 (CH3, -COCH3), 56.6 (CH3, -OCH3), 56.9 (CH3,-OCH3), 94.2 (CH2, 2 -OCH2O-), 94.7 (CH, C-50), 97.4 (CH, C-30), 107.1 (C, C-10), 160.5 (C, C-60),163.6 (C, C-40), 167.0 (C, C-20), 203.4 (C=O, C-1). |
72% | Stage #1: 2′,4′,6′-trihydroxyacetophenone With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.5h; Stage #2: chloromethyl methyl ether In dichloromethane for 4h; | |
71.4% | Stage #1: 2′,4′,6′-trihydroxyacetophenone With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: chloromethyl methyl ether In dichloromethane; N,N-dimethyl-formamide at 20℃; for 4h; Inert atmosphere; | 1-(2-Hydroxy-4,6-bis(methoxymethyl)phenyl)ethanone (11). To a stirred solution of1-(2,4,6-trihydroxyphenyl)ethanone (10, 1 g, 5.9 mmol) in CH2Cl2 (36 mL), was added DMF(1.2 mL). The reaction mixture was cooled to 0 C, DIPEA (3.1 mL, 17.7 mmol) was added and stirredfor 5 min. Chloro(methoxy)methane (1 g, 12.4 mmol) in CH2Cl2 (5.8 mL) was next added dropwise tothe reaction mixture under a N2 atmosphere. The mixture was warmed to room temperature andstirred for 4 h. The reaction mass was quenched with sat. aq. NH4Cl, and the organic layer wasseparated. The aqueous layer was further extracted with CH2Cl2 (2 50 mL), the combined organiclayer was washed with brine solution and dried over MgSO4, filtered, and evaporated under vacuum.The residue was purified by column chromatography (petroleum ether/ethyl acetate, 8:2, v/v) toafford compound 11 as a colorless oil (0.95 g, 71.4%). 1H-NMR (CDCl3)δ13.74 (s, 1H), 6.26 (s, 1H),6.24 (s, 1H), 5.26 (s, 2H), 5.17 (s, 2H), 3.52 (s, 3H), 3.47 (s, 3H), 2.66 (s, 3H). 13C-NMR (CDCl3) δ 203.2,166.8, 163.5, 160.4, 106.9, 97.1, 94.5, 94.0, 56.7, 56.5, 33.0. |
67% | With potassium carbonate In propan-2-one for 2h; Reflux; | 5.A Step A: 2,4,6-trihydroxyacetophenone (5.0 g, 29.7 mmol), chloromethyl methyl ether (9.7 g, 120.5 mmol), potassium carbonate (37.1 g, 269 mmol) and acetone (100 mL) The mixture was stirred at reflux for 2 hours.The solvent was evaporated under reduced pressure and water (50 mL) was added.Extracted with ethyl acetate (40 mL×3).The combined organic phases were washed with brine (30 mL).Dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure.The product is purified by column chromatography (200-300 mesh silica gel,Methyl tert-butyl ether: petroleum ether = 1:15 to 1:8),1-[2-Hydroxy-4,6-bis(methoxymethoxy)]acetophenone (8) (5.1 g) was obtained. The yield was 67.0%. |
67% | With potassium carbonate In propan-2-one for 2h; Reflux; | 1.B Step B: Will contain 2,4,6-trihydroxyacetophenone (5.0 g, 29.7 mmol),Chloromethyl methyl ether (9.7g, 120.5mmol),A mixture of potassium carbonate (37.1 g, 269 mmol) and acetone (100 mL) was stirred under reflux for 2 hr. Evaporate the solvent under reduced pressure.Add water (50mL),Extracted with ethyl acetate (40 mL×3).The combined organic phases were washed with brine (30 mL).Dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure.The product is purified by column chromatography (200-300 mesh silica gel, methyl tert-butyl ether: petroleum ether = 1:15 to 1:8).1-[2-Hydroxy-4,6-bis(methoxymethoxy)phenyl]ethanone (2) (5.1 g) was obtained. The yield was 67.0%. |
67% | With potassium carbonate In propan-2-one for 2h; Reflux; | 8.A Step A: Add 2,4,6-trihydroxyacetophenone (5.0g, 29.7mmol), chloromethyl methyl ether (9.7g, 120.5mmol), potassium carbonate (37.1g, 269mmol) and acetone (100mL) The mixture was stirred under reflux for 2 hours. The solvent was evaporated under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200300 mesh silica gel, methyl tert-butyl ether: petroleum ether = 1:151:8 elution) to obtain 1-[2-hydroxy-4, 6-Bis(methoxymethoxy)]acetophenone (26) (5.10 g). The yield was 67.0%. |
66% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 6h; Cooling with ice; | 1 Preparation example 1: Preparation of l-(2-hydroxy-4,6- dimethoxymethyloxy-phenyl)-ethanone [compound (2)] Diisopropylethylamine, DIPEA (8.4 mL, 48.327 mmols), followed by MOM chloride (3.7 mL, 48.327 mmols), was added drop by drop to a suspension, stirred and cooled in an ice bath, of 2',4'6'-trihydroxyacetophenone monohydrate, 1 , (3 g, 16.1 15 mmols), in anhydrous CH2C12 (36 mL). When the addition was complete, the temperature was gradually increased to RT, and the reaction was maintained under stirring, under these conditions, for 6 h. After that time the reaction mixture was returned to the ice bath and treated with a saturated aqueous solution of ammonium chloride (30 mL). The reaction was then heated to RT and left under stirring for 30 min. The resulting mixture was then extracted with CH2C12/water [3x100 mL (1 : 1)], and the resulting separated organic phase was dried on sodium sulphate, filtered and evaporated. The dark crude oil obtained (4.268 g) was then purified, after adsorption on 4.50 g of silica 230- 400 mesh, by flash chromatography on silica gel column (silica 230-400 mesh, diameter 4 cm, height 17 cm) using n-hexane/AcOEt (6: 1) as eluent, and collecting 12 mL fractions. 2.716 g of 2 in the form of a thick, transparent oil, tending to solidify at low temperature, was obtained from the fractions (test tubes 5-30, Vm: 500 mL). Yield: 66% TLC Rf: 0.16 in n-hexane/AcOEt (5: 1); 1H-NMR (200 MHz, CDC13): 6.27 (d, 1H, J = 2.2 Hz, Ar-H,), 6.24 (d, 1H, J = 2.2 Hz, Ar-H), 5.25 (s, 2H, 0-CH2-0), 5.17 (s, 2H, 0-CH2-0), 3.51 (s, 3H, OCH3), 3,47 (s, 3H, OCH3), 2.66 (s, 3H, COCH3). |
65% | With potassium carbonate In propan-2-one for 2h; Heating; | |
65% | With potassium carbonate In propan-2-one at 20℃; for 3h; Inert atmosphere; | |
65% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 19h; | |
64.1% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 2h; | |
64% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; | |
64% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 10h; | 2.2 4.2.2 2-Hydroxy-4,6-bis(methoxymethoxy)acetophenone (4) Compound 3 (110.1 g, 0.76 mol) was dissolved in dichloromethane. The mixture was cooled to 0 °C and N-ethyldiisopropylamine (293 g, 2.27 mol) was added slowly followed by the addition of chloromethyl methyl ether (137.1 g, 1.96 mol) dropwise. After being stirred at room temperature overnight, the reaction was quenched with ammonium chloride saturated aqueous solution (1300.0 ml) and washed with brine (1300.0 ml). The organic layer was concentrated and purified by column chromatography to give white solid 4 (111.6 g, 64%). 1H NMR (600 MHz, CDCl3) δ: 13.69 (s, 1H, OH), 6.22 (d, J = 2.3 Hz, 2H, ArH), 5.23 (s, 2H, O-CH2-O), 5.14 (s, 2H, O-CH2-O), 3.50 (s, 3H, OCH3), 3.44 (s, 3H, OCH3), 2.62 (s, 3H, COCH3); 13C NMR (100 MHz, CDCl3) δ: 203.18, 166.81, 163.46, 160.37, 106.91, 97.12, 94.50, 94.00, 56.68, 56.39, 32.94. HRMS calcd for C12H16O6 m/z [M+Na]+: 279.0839; found: 279.0843. |
64% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
63% | With potassium carbonate In propan-2-one for 0.5h; Heating; | |
63% | With potassium carbonate In propan-2-one for 4h; Reflux; | |
60% | With potassium carbonate In propan-2-one for 1h; Heating; | |
60% | With N-ethyl-N,N-diisopropylamine In dichloromethane; lithium hydroxide monohydrate at 20℃; for 6h; | |
60% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 6h; Inert atmosphere; | |
56% | Stage #1: 2′,4′,6′-trihydroxyacetophenone With 18-crown-6 ether; potassium-t-butoxide In acetonitrile at 20℃; Stage #2: chloromethyl methyl ether In acetonitrile at 20℃; for 3h; | |
56% | With potassium carbonate In propan-2-one at 20℃; for 1.5h; | |
53% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; Inert atmosphere; | |
53% | With N-ethyl-N,N-diisopropylamine | |
53% | With N-ethyl-N,N-diisopropylamine In dichloromethane at -5 - 20℃; for 2h; | 2.1 (1) Preparation of 2'-hydroxy-4',6'-bis(methoxymethoxy)acetophenone [2'-hydroxy-4',6'-bis(methoxymethoxy)acetophenone] (Step: a-2 ) 2',4',6'-trihydroxyacetophenone (504 mg, 3 mmol), diisopropylethylamine (852 mg, 6.6 mmol) in a 25 mL round bottom flask using dichloromethane (6 mL) as a solvent After mixing, chloromethyl methyl ether (507 mg, 6.3 mmol) was added dropwise at -5 °C, followed by stirring at room temperature for 2 hours. When the reaction was completed, the salt was removed with water and extracted with ethyl acetate. After removing the solvent, separation was performed by column chromatography to obtain the title compound, 2'-hydroxy-4',6'-bis(methoxymethoxy)acetophenone (408 mg, 53%). |
52% | With potassium carbonate In propan-2-one for 1h; Heating; | |
50% | With potassium carbonate In propan-2-one for 1.5h; Heating; | |
50.3% | Stage #1: 2′,4′,6′-trihydroxyacetophenone With potassium carbonate In propan-2-one Stage #2: chloromethyl methyl ether In propan-2-one for 1.5h; Heating / reflux; | I EXAMPLE I; The Total Synthetic Method for Preparing Protoapigenone Compound; Please refer to FIG. 1, which is a flowchart showing a total synthesis method for preparing the flavonoid compound in the present invention. Firstly, an exceed amount (for example, 7E (equivalent)) of potassium carbonate is added into an acetone solution containing 2',4',6'-Trihydroxy-acetophenone monohydrate to form a first mixture, and the first mixture is stirred. Then, 3E of chloromethyl methyl ether is added dropwise into the first mixture. For fully reacting, the first mixture is refluxed for 90 minutes. After cooling, the first mixture is filtrated to obtain a precipitation. The precipitation is rinsed with acetone and chloroform, and then evaporated and purified by column chromatography on a silica gel (isocratic elution, 90% n-hexane/10% ethyl acetate) to obtain a 2'-hydroxy-4'-6'-dimethoxymethyl-acetophenone with MOM protecting groups on the 4' and the 6' positions in 50.3% yield. |
50.3% | With potassium carbonate In propan-2-one for 1.5h; Heating / reflux; | 1 Please refer to Fig. 1, which is a flowchart showing a total synthesis method for preparing the flavonoid compound in the present invention. Firstly, an exceed amount (for example, 7E (equivalent)) of potassium carbonate is added into an acetone solution containing 2' ,4,6'-Trihydroxy-acetophenone monohydrate to form a first mixture, and the first mixture is stirred. Then, 3E of chloromethyl mcthyl ether is added dropwise into the first mixture. For fully reacting, the first mixture is refluxed for 90 minutes. After cooling, the first mixture is filtrated to obtain a precipitation. The precipitation is rinsed with acetone and chloroform, and then evaporated and purified by column chromatography on a silica gel (isocratic elution, 90% n-hexane / 10% ethyl acetate) to obtain a 2'-hydroxy-4'-6'-dimethoxymethyl-acetophenone with MOM protecting groups on the 4' and the 6' positions in 50.3% yield. |
48% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere; | |
47% | With potassium carbonate In propan-2-one for 2.5h; Ambient temperature; | |
46% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere; | |
36.5% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 17h; Inert atmosphere; | 1.1 1. Synthetic preparation of intermediate M1 In a 50mL reaction flask, add raw material 2′,4′,6′-trihydroxyacetophenone(S1, 3.97g, 23.60mmol) and anhydrous dichloromethane (20mL),Under argon protection, DIPEA (7.80 mL, 47.20 mmol) and MOMCl (3.58 mL, 47.20 mmol) were sequentially added at 0 °C, and the reaction was stirred at 0 °C for 17 h. After the reaction was completed, the reaction solution was quenched by adding water, dispersed and extracted with 100 mL of ethyl acetate and 100 mL of water each, and the obtained organic layer was washed with saturated NaCl and dried over anhydrous MgSO4.The solvent was recovered under reduced pressure to dryness, and the obtained residue was purified by 200-300 mesh silica gel column chromatography, using petroleum ether and ethyl acetate as mobile phases, and carrying out gradient elution from 10:1 to 1:1 by volume,2.21 g of white solid M1 was obtained, and the mass yield was 36.5%. |
30% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | Gereral procedure for MOM protected acetophenones General procedure: To a solution of 2’,4’-dihydroxyacetophenone (150 mg, 0.99 mmol) in dichloromethane (1.7 mL) were added N,N-diisopropylethylamine (0.5 mL, 3.0 mmol) and chloromethyl methyl ether (0.075 mL, 1.0 mmol), and the mixture was stirred at room temperature. After the reaction was complete, the mixture wasextracted with chloroform. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane-EtOAc (5:1) to give 2’-hydroxy-4’-(methoxymethoxy)acetophenone1 (178 mg, 0.91 mmol) in 92% yield as a colorless solid. |
20% | With potassium carbonate In propan-2-one for 4h; Reflux; | 1-(2-Hydroxy-4,6-bis(methoxymethoxy)phenyl)thenone (II): the title compound was synthesizedusing a modified procedure from the literature [19]. To a solution of 2,4,6-trihydroxyacetophenonemonohydrate (300 mg, 1.78 mmol, 1.0 equiv) and K2CO3 (615 mg, 4.45mmol, 2.5 equiv) in acetone (8 mL), MOM-Cl, (473 μL, 6.23 mmol, 3.5 equiv) was addeddropwise, and then the suspension was refluxed overnight at 50 °C. After cooling, the K2CO3 was filtered off, and the crude product was concentrated and purified by columnchromatography on silica gel (eluent: 2% EtOAc:hexanes to 5% EtOAc:hexanes) to affordthe title compound as a white solid (91 mg, 0.355 mmol, 20% yield). 1H-NMR (500 MHz,CDCl3): δ 6.25 (d, 1H, J = 2.3 Hz, ArH), 6.23 (d, 1H, J = 2.3 Hz, ArH), 5.24 (s, 2H, -OCH2O-), 5.15 (s, 2H, -OCH2O-), 3.50 (s, 3H, -OCH3), 3.48 (s, 3H, -OH3), 2.05 (s, 3H, CH3CO); 13CNMR(126 MHz, CDCl3): δ 203.31, 166.90, 163.54, 160.44, 107.00, 97.22, 94.54, 94.08, 56.77,56.51, 33.08. 1H and 13C data are consistent with the literature values [41]. |
6.5 g | With potassium carbonate In propan-2-one for 0.25h; Heating; | |
1.08 g | With potassium carbonate In propan-2-one for 0.25h; Heating; | |
4.09 g | With potassium carbonate In propan-2-one for 3h; Heating; | |
With potassium carbonate In propan-2-one at 20℃; for 2h; | ||
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 1h; | ||
With potassium carbonate In propan-2-one at 0 - 20℃; regioselective reaction; | ||
With potassium carbonate In propan-2-one at 0 - 20℃; | ||
With potassium carbonate In propan-2-one Reflux; | ||
With potassium carbonate In propan-2-one | ||
With potassium carbonate In propan-2-one at 0 - 20℃; | ||
With potassium carbonate In propan-2-one | ||
With N-ethyl-N,N-diisopropylamine In dichloromethane | ||
With potassium carbonate In propan-2-one at 20℃; | ||
Stage #1: 2′,4′,6′-trihydroxyacetophenone With N-ethyl-N,N-diisopropylamine In dichloromethane for 0.5h; Stage #2: chloromethyl methyl ether In dichloromethane at 0℃; for 3h; Inert atmosphere; | General procedure for preparation of Compounds 18 and 19 To a solution of trihydroxyacetophenone (14) in DCM (5 mL/1 mmol of substrate) was added DIPEA (2.9 eq.). After stirred for 0.5 h MOMCl (2.1 eq.) was added at 0°C, under N2 atm. Reaction mixture stirred for 3 h. Reaction stopped with saturated NH4Cl solution (2 mL/1 mmol of substrate). The combined extracts were dried over Na2SO4. The solvent was removed in vacuo and the remaining residue purified via coloumn chromatography over silica gel using gradient elution with EtOAc and hexanes to yield compound 15. | |
Stage #1: 2′,4′,6′-trihydroxyacetophenone With potassium carbonate In propan-2-one at 20℃; for 1h; Stage #2: chloromethyl methyl ether In propan-2-one for 4h; | 1.2 Step 2 Step 2 A 1000ml round bottom flask was added with 2,4,6-hydroxyacetophenone 18.2g, K2CO3 82.8g, acetone 100mL, and stirred at room temperature for 1h. Then added MOMCl 22.8ml, stirring was continued for 4h. 100 mL water was added, extracted with ethyl acetate 300ml, organic layers were combined, dried over anhydrous Na2SO4 30min, ethyl acetate was distilled off under reduced pressure to give a yellow solid of 2- hydroxy-4-methoxy-6-ethoxy-acetophenone crude yield of 71.5%. | |
With N-ethyl-N,N-diisopropylamine In dichloromethane | ||
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; | ||
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; | ||
With potassium carbonate | 1.1 (1) Using 2,4,6-trihydroxyacetophenone as a raw material, 2.1 times equivalent of K2CO3 was added to selectively release the hydroxyl groups at the 4th and 6th positions, and then 2.12 times equivalent of chloromethyl methyl ether was added.2-hydroxy-4,6-dimethyl methyl acetophenone was obtained, and then N,N-dimethyl dimethyl acetal was added to synthesize aminoketene at a temperature of 74 ° C in 88% yield.Finally, the synthesis of 5,7-dimethyl methyl ether-3-iodochromone was carried out in a simple step-by-loop reaction under the action of elemental iodine in a yield of 75%.3-Isochromanone 4 was dissolved in dichlorobenzene and placed on a stirrer for 4 h at medium speed. The methyl methyl ether at position 5 was removed to obtain 3-Isochromanone 5 | |
With potassium carbonate In propan-2-one at 20℃; for 5.33333h; Reflux; | 1 (1) Mix 2,4,6-trihydroxyacetophenone (1 mmol) with potassium carbonate (5 mmol),In a round bottom flask,Add 3 mL of acetone as the reaction solvent,Chloromethyl methyl ether (2.5 mmol) was added at room temperature.Maintain the temperature and stir for 20 min.The reaction was complete after transferring to an oil bath and refluxing at 60 ° C for 5 hours.Extraction and separation with water and ethyl acetate,Retain the organic layer,Anhydrous magnesium sulfate drying,After concentration under reduced pressure, column chromatography was performed to obtain product 2; | |
0.35 g | With N-ethyl-N,N-diisopropylamine In dichloromethane for 3h; Cooling with ice; Inert atmosphere; | |
Stage #1: 2′,4′,6′-trihydroxyacetophenone With N-ethyl-N,N-diisopropylamine In dichloromethane for 0.5h; Stage #2: chloromethyl methyl ether In dichloromethane at 0℃; for 3h; Inert atmosphere; | MOM protection part: General procedure: To a solution of trihydroxy acetophenone(34) or dihydroxy acetophenone (56) in DCM (5 mL/1 mmol of substrate) was added DIPEA (2.9 eq.). After stirredfor 0.5 h MOMCl (2.1 eq.) was added at 0 C, under N2 atm.Reaction mixture stirred for 3 h. Reaction stopped with saturatedNH4Cl solution (2 mL/1 mmol of substrate). The combinedextracts were dried over Na2SO4. The solvent wasremoved in vacuo and the remaining residue purified viacoloumn chromatography over silica gel using gradient elutionwith EtOAc and Hexanes to yield compounds 35and 57. | |
With oxygen; N-ethyl-N,N-diisopropylamine In dichloromethane | ||
Stage #1: 2′,4′,6′-trihydroxyacetophenone With potassium carbonate In propan-2-one for 0.25h; Reflux; Stage #2: chloromethyl methyl ether In propan-2-one for 6h; Reflux; | (1) Synthesis of Intermediate B: Dissolve 2,4,6-trihydroxyacetophenone A in acetone, add anhydrous potassium carbonate with stirring, heat to reflux for 15 minutes, and slowly drop chloromethyl methyl ether with a syringe , Continue to reflux for 6 hours, evaporate the solvent under reduced pressure, dissolve the residue in water, extract with ethyl acetate, combine the organic phases, wash with distilled water and saturated brine in turn, dry with anhydrous sodium sulfate, filter with suction, and purify with silica gel column chromatography; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.75h; | 2.6. Synthesis of 2,4,6-trimomoacetophenone 1 NaH (4.5 equiv) in dry DMF was slowly added while stirring at0-5 C (in an ice-water bath) to a solution of 2,4,6-trihydroxyacetophenone(1 equiv) in dry DMF. When the solution was cooledto 0-5 °C, chloromethyl methyl ether (4.5 equiv) was slowly addedover a period of 15 min so that the temperature was maintained atless than 5 °C. The reaction mixture was stirred at room temperaturefor another 30 min, quenched by the addition of cold distilledwater and extracted with EtOAc. The combined organic layer waswashed with distilled water and brine and then dried over Na2SO4.The filtered organic layer was concentrated under a vacuum andthe residue was purified by silica gel column chromatography elutingwith n-hexane and EtOAc to give compound 1: a colorless oil(80-95% yield). |
95% | With sodium hydride In N,N-dimethyl-formamide at 85℃; for 4h; | 1.A; 2.A; 3.A Wherein, the etherification step (A) is performed as follows: Under stirring, according to the molar ratio of 2,4,6-trihydroxyacetophenone, NaH and DMF of 1:4.5:30, dissolve 2,4,6-trihydroxyacetophenone and NaH in DMF. Wuxi Guanya Constant temperature Refrigeration Technology Co., Ltd. sold under the trade name Guanya Heating Circulation Device in the heating reflux device at a temperature of 85°C, followed by 2,4,6-trihydroxyacetophenone and chloromethyl The molar ratio of methyl ether is 1:5.0, then chloromethyl methyl ether is added, and heating is continued for 4.0 hours. When the reaction solution turns from clear to turbid, the reaction is finished. The TLC method described in the specification of this application is used to detect the content in the reaction solution. The compound of formula I and 2,4,6-trihydroxyacetophenone:When 2,4,6-trihydroxyacetophenone is not detected, it is quenched with ice water according to the volume ratio of ice water and DMF 1:2.0, and then continues to add ice water in the ice water under static conditions. The crystals of the compound of formula I are precipitated, filtered, and dried under heating conditions in an infrared drying oven drying device until the water content reaches below 1% by weight, and the compound of formula I is obtained.According to the same detection method as in Example 1, it was determined that the product was a compound of formula I, and the yield of this step was 95%. |
83% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: chloromethyl methyl ether In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.75h; Inert atmosphere; |
72% | With sodium hydride In N,N-dimethyl-formamide for 2h; Ambient temperature; | |
72% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium hydride In N,N-dimethyl-formamide; benzene at 20℃; Inert atmosphere; Cooling; Stage #2: chloromethyl methyl ether at 20℃; for 24.5h; Cooling with ice; | |
59.4% | With potassium carbonate In acetone for 3h; Heating; | |
54.4% | With potassium carbonate In acetone at 20℃; for 2h; | 1.2 2) take the first step 5.0g,Dissolved in 50 ml of acetone,Anhydrous potassium carbonate (15 g)1.58 ml of chloromethyl methyl ether was slowly added dropwise at room temperature,20min drops finished,After stirring at room temperature for 2 hours, the reaction was completed.The anhydrous potassium carbonate solid was filtered off, the acetone solution was evaporated under reduced pressure,The residue was washed with 20 ml of water and extracted three times with ethyl acetate (30 ml x 3). The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate,Vacuum drying organic solvent, silica gel mixing, silica gel column separation. Petroleum ether: ethyl acetate (15: 1)A pale yellow oil of about 4.3 g, yield 56.4%. |
51.2% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium hydride In N,N-dimethyl-formamide; benzene at 4 - 20℃; Inert atmosphere; Stage #2: chloromethyl methyl ether In N,N-dimethyl-formamide; benzene at 4 - 20℃; for 24h; Inert atmosphere; | |
48% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; Stage #2: chloromethyl methyl ether In N,N-dimethyl-formamide; mineral oil at 20℃; for 4h; | |
43% | With sodium hydride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; | |
39% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; Inert atmosphere; | |
35% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 25℃; for 0.5h; Stage #2: chloromethyl methyl ether In N,N-dimethyl-formamide; mineral oil for 16h; | 1 To a solution of 1-(2,4,6-trihydroxyphenyl)ethanone (50.00 g, 297.35 mmol, Sigma- Aldrich) in DMF (1.00 L) was added NaH (41.60 g, 1.04 mol, 60% dispersion in mineral oil, Sigma-Aldrich) portionwise at 0-10 °C. The mixture was stirred at 25°C for 30 mm, chloro(methoxy)methane (83.79 g, 1.04 mol, 79.05 mL, Sigma-Aldrich) was added dropwise and stirred for another 16 hours. The mixture was poured into water (3 L) and extracted with ethyl acetate (2x 1 L), the combined organic layers were washed with brine (1 L) and dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give a black oil. 1-(2,4,6- tris(methoxymethoxy)phenyl) ethanone (55.0 g, 61% yield) was isolated by silica gel chromatography (eluent, 30% ethyl acetate in hexane). Yield: 35%. MS (ES): calculated, m/z 279.3 (MH); found, 300.0. ‘H NMR (400MHz, CDC13) 6 = 6.51 (s, 2H), 5.19 - 5.11 (m, 6H),3.51 - 3.42 (m, 9H), 2.54 - 2.42 (m, 3H). |
1.08 g | With potassium carbonate In acetone for 0.25h; Heating; | |
With sodium hydride In tetrahydrofuran | ||
With potassium carbonate In acetone for 8h; Reflux; | ||
With potassium carbonate In acetone for 12h; | ||
With potassium carbonate In acetone Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1H-imidazole In N,N-dimethyl-formamide for 0.5h; | |
92% | With 1H-imidazole In N,N-dimethyl-formamide for 2h; | |
83% | With triethylamine In dichloromethane at 20℃; for 1.5h; Inert atmosphere; |
40% | Stage #1: 2,4,6-trihydroxyacetophenone With 1H-imidazole In acetone for 0.0833333h; Stage #2: tert-butyldimethylsilyl chloride In acetone at 20℃; for 2h; regioselective reaction; | 2.3 4.2.3 Synthesis of (S)-1-(2,4-bis((tert-butyldimethylsilyl)oxy)-6-hydroxyphenyl)-2-methylbutan-1-one (5) General procedure: Acylphloroglucinol 4 (9.71 g, 46.19 mmol) was dissolved in part in dry acetone (150 mL) and transferred into a 250 mL round bottom flask. Imidazole (3.43 g, 138.6 mmol, 3 equiv) was added to the solution and the reaction mixture stirred for 5 min followed by the addition of TBDMS-Cl (14.61 g, 97.0 mmol, 2.1 equiv). The reaction mixture was stirred for 2 h at room temperature. Acetone was removed from the reaction mixture under reduced pressure and the residue taken up in chloroform and washed with 1 m HCl (150 mL). The organic layer was dried using anhydrous magnesium sulphate, filtered and the solvent was removed under reduced pressure. The crude product purified by VLC over silica gel using hexane and EtOAc of increasing polarity. VLC fractions eluted with 2.5-7.5% EtOAc in hexane afforded (S)-1-(2,4-bis((tert-butyldimethylsilyl)oxy)-6-hydroxyphenyl)-2-methylbutan-1-one as a pale yellow oil (16.4 g, 37.26 mmol, 81%). |
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran | ||
With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate In acetone for 2h; Heating; | |
48% | With tetra-(n-butyl)ammonium iodide; sodium hydroxide In dichloromethane; water | 12 Another analog was made of our basic right part molecule 5 protected with methyl ethers (11). Both analogs were made using a slight modification to the synthesis, namely using a methyl ether (OMe) instead of a methoxymethyl (OMOM) ether. The key intermediate (12) could be methylated using methyl iodide to give analog (11), or cyclized using sodium acetate as base to give analog (10). |
31.4% | With potassium carbonate In acetone for 2h; Reflux; | 10.D Step D: containing 2,4,6-trihydroxyacetophenone (25.6 g, 149 mmol), potassium carbonate (20.6 g, 149 mmol),A mixture of dimethyl sulfate (28.1 g, 223 mmol) and acetone (250 mL) was stirred under reflux for 2 hr.The reaction solution was cooled to room temperature, and the insoluble matter was removed by filtration.The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: methylene chloride: petroleum ether = 1:1:40 to 1:1:6) to give 1-(2) , 6-Dihydroxy-4-methoxy-phenyl)ethanone (59) (8.51 g), yield 31.4%. |
25% | With potassium carbonate In acetone | |
24% | With potassium carbonate In acetone at 10℃; | 1.1 (1) Preparation of 2'6'-dihydroxy-4'-methoxyacetophenone [2',6'-dihydroxy-4'-methoxyacetophenone] (Step: a-1-1) After mixing 2',4',6'-trihydroxyacetophenone (840 mg, 5 mmol) and potassium carbonate (691 mg, 5 mmol) in a 50 mL round bottom flask using acetone (20 mL) as a solvent At 10° C., dimethyl sulfate (630 mg, 5 mmol) was added dropwise. When the reaction was completed after 1.5 hours, the salt was removed with water and extracted with ethyl acetate. After removing the solvent, separation by column chromatography to obtain the title compound, 2'6'-dihydroxy-4'-methoxyacetophenone (219 mg, 24%). |
With sodium hydroxide In dichloromethane; water at 20℃; for 24h; | ||
With potassium carbonate In acetone at 20 - 65℃; for 24.3333h; | 1 (1) Mix 2,4,6-trihydroxyacetophenone (1 mmol) with potassium carbonate (3 mmol),Place it in a round bottom flask and add 3 mL of acetone as the reaction solvent.Add dimethyl sulfate (0.6 mmol) at room temperature and stir at a constant temperature for 20 min.The reaction was complete after transferring to an oil bath at 65 ° C under reflux for 24 hours.Extraction and separation with water and ethyl acetate, retaining the organic layer, drying over anhydrous magnesium sulfate,After concentration under reduced pressure, column chromatography was performed to obtain product 10; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium carbonate In acetone for 5h; Heating; | |
50% | With potassium carbonate In acetone for 5h; Reflux; | |
45% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 25℃; |
36% | With potassium carbonate In acetone for 24h; Reflux; Darkness; | 1 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethan-1-one 21 4.1.1 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethan-1-one 21 2,4,6-Trihydroxyacetophenone (2 g, 10.7 mmol), methyl iodide (2.70 mL, 42.9 mmol) and K2CO3 (2.96 g, 21.4 mmol) were dissolved in 50 mL of acetone. The mixture was heated to reflux for 24 h in the dark. The reaction mixture was filtered under vacuum, and the filtrate was evaporated under reduced pressure. The crude product was purified by flash chromatography using cyclohexane/ethyl acetate 95:5 as eluting system; 1.13 g of title compound 21 were obtained. Yield: 36%. 1H NMR (CDCl3) δ: 6.05 (d, J = 2.4 Hz, 1H, CH arom.); 5.92 (d, J = 2.4 Hz, 1H, CH arom.); 3.85 (s, 3H, OCH3); 3.81 (s, 3H, OCH3); 2.60 (s, 3H, CH3) ppm. |
1.2 g | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 48h; | 9 Heating 2, 4, 6-tri-hydroxy acetophenone 2g (12mmol), added to the 15mlDMF in, then adding CH 3 I1.72g (12.1mmol), K 2 CO 3 5 g. Stir at room temperature reaction 48h, is poured into the reaction liquid to the ice water, stirring 1h, then filter. Drying the obtained solid, recrystallized with ethanol, to obtain 2-hydroxy -4,6-di-methoxy acetophenone 1.2 g. |
With potassium carbonate | 1 General procedure: First, with 2,4-dihydroxyacetophenone (a) or 2,4,6-trihydroxyacetophenone as raw material, The intermediate 2,4-dimethoxyacetophenone is obtained by methylation (b) or 2-hydroxy-4,6-dimethoxyacetophenone, Secondly, Use 2,4-dimethoxyacetophenone or 2-Hydroxy-4,6-dimethoxyacetophenone and different substituted benzaldehydes undergo condensation reactions to obtain target molecules and their analogs. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 35% 2: 40% | With boron trifluoride diethyl etherate In benzene for 0.5h; microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 6h; | Preparation of 2,4-dibenzyloxy-6-acetophenone, intermediate 5 2,4,6-trihydroxyacetophenone (4.2 g, 25 mmol), bromobenzyl (9 mL,75 mmol), K2C03 (10.35 g, 75 mmol), DMF 50 ml, stirred at room temperature for 6 h, and monitored by TLC. After the reaction was completed, the reaction solution was poured into 200 mL of water, extracted three times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: (Eluent: DCM / MeOH (v / v) = 40: 1) to give 8.26 g of a white solid, intermediate 5 in 95% yield. |
94% | With potassium carbonate In N,N-dimethyl-formamide | |
91% | With potassium carbonate In acetonitrile for 3h; Reflux; |
85% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | |
85% | Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In acetone at 65℃; for 1h; Stage #2: benzyl bromide In acetone for 16h; | Synthesis of 2-hydroxy-4,6-bis(benzyloxy) Acetophenone(2) The solution of 2,4,6-trihydroxyacetophenone (5 g,29.76 mmol) and anhydrous K2CO3 (15 g, 108.6 mmol) in120 mL dry acetone was refluxed at 65 °C for 1 h. Then BnBr (7.5 mL, 63.05 mmol) was added dropwise. After stirring for 16 h, the organic phase was separated. The solvent was removed, and the residue was purified by column chromatography on silica gel (petroleum ether-EtOAc, v/v, 30:1) to give 2 (8.8 g, 85%) as white solids, mp 95-96 °C; |
70% | Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 0.25h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 23℃; | 18.1 10219] Step 1: Synthesis of 1-(2,4-bis(benzyloxy)-6-hy-droxyphenyl)-ethanone: Step 1: Synthesis of 1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)-ethanone: To a stirred solution of [50] (3.0 g, 16.19 mmol) in DMF, anhydrous K2CO3 (5.56 g, 40.32 mmol) was added at 0° C. under nitrogen atmosphere. After an additional stirring at this for 15 minutes at same temperature, benzyl bromide (4.92 ml, 40.32 mmol) was added drop-wise. The reaction temperature was allowed to increase up to 23° C. and stirring was continued for overnight. Consumption of [50] was monitored by TLC. After complete consumption of [50], water (50 ml) was added and organic layer was extracted with ethyl acetate (2*100 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light brown sticky material which was further purified using silica gel column chromatography using 5% ethyl acetate/hexane as eluent to afford [51] as white powder (3.2 g, 70%). ESIMS: 349[M+1] |
69% | Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: benzyl bromide In N,N-dimethyl-formamide for 1h; | |
69% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 1h; | 1 Synthesis of 2,4-dibenzyloxy-6-hydroxyacetophenone (6) To a solution of 5 (59.6 mmol) in DMF was added K2CO3 (2.2. equiv.). After stirring for 10 min at 0° C., BnBr (2.2. equiv.) was added and the mixture stirred for 1 h at room temperature. [0081] HCl 2M was added and the mixture was poured into water and extracted with EtOAc. Organic layers were combined, washed with brine, dried over MgSO4 and concentrated. Compound 6 was purified by CC (10:1 hexane/EtOAc) in 69% yield. Rf=0.73 (4:1 P. Ether/EtOAc); pf. 103.5-104.0° C. (Lit. [66] p.f.=108-109° C.); 1H RMN (CDCl3) δ 14.17 (s, 1H, OH-8); 7.47-7.40 (m, 20H, CH, Ph); 6.22 (d, 1H, J5,7=2.32 Hz, H-7); 6.15 (d, 1H. J5,7=2.32 Hz, H-5); 5.09 (s, CH2Ph-4); 5.08 (s, CH2Ph-6); 2.61 (s, 3H, H-1); 13C RMN (CDCl3) δ 203.2 (C-2); 167.6 (C-6 e C-8); 162.1 (C-4); 135.9 (Cq-4); 135.7 (Cq-6); 128.8; 128.7; 128.5; 128.4; 128.1; 127.7 (CH, Ph); 106.3 (C-3); 94.8 (C-7); 92.4 (C-5); 71.2 (CH2Ph-6); 70.3 (CH2Ph-4); 33.4 (C-1). |
38.5% | Stage #1: 2,4,6-trihydroxyacetophenone; benzyl bromide With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 21 - 24h; Stage #2: With hydrogenchloride; water In N,N-dimethyl-formamide | 1 Examples; Example 1 - Preparation of 2-Hydroxy-4,6-bis(benzyloxy)- acetophenone.; [0042] This example describes the preparation and purification of the title compound from commercially available 2,4,6-trihydroxy acetophenone. A stirred suspension of 2,4,6-trihydroxyacetophenone (10 g, 0.054 mol, 1 eq) and potassium carbonate (16.3 g, 0.118 mol, 2.2 eq) in N1N- dimethylformamide (100 mL, 10 vol, 1 g/10 ml_) was heated at 8O0C. To this suspension was added benzyl chloride (13.6 mL, 0.118 mol, 2.2 eq) in one portion. The suspension was kept at 809C for about 1 h. The reaction mixture was cooled to RT and carefully acidified with 1 M hydrochloric acid (200 mL). The aqueous layer was extracted twice with ethyl acetate (100 mL) The combined organic layers were washed twice with water (100 mL) and twice with brine (100 mL), dried over sodium sulfate, and filtered. The solvent was removed under vacuum to afford a red viscous oil. The oil was dissolved in dichloromethane and passed through a 200 g plug of silica gel. The silica gel was eluted with 1 L of dichloromethane. The combined solvent was evaporated under reduced pressure to produce an oil which solidified upon standing at RT. The yield was 18.7 g. HPLC purity was 69% purity. The product contained 19.7% of a tribenzyl impurity. EPO [0043] The crude solid was dissolved in hot dichloromethane (15 mL) and methanol (20 ml_) was added slowly. The solids started to appear immediately. The suspension was allowed to cool to RT with agitation. The solids were suction filtered, washed with methanol (75 mL), and dried under high vacuum to produce 9.1 g of an off-white solid. The yield was 49%. HPLC purity was 96.9%. The product contained about 2.54% of the tribenzyl impurity.; A number of reaction conditions and various benzylating reagents (benzyl bromide (BnBr) and benzyl chloride (BnCI) were screened to optimize the selective benzylation. The results are set out in Table 1. |
35% | With potassium carbonate In N,N-dimethyl-formamide for 73h; | |
33% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | |
30% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | |
With potassium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide | ||
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 0 - 20℃; | 14 To a mixture of 2',4',6'-trihydroxyacetophenone monohydrate (5 g) and potassium carbonate (7.42 g) inN,N-dimethylformamide (100 mL) was added benzyl bromide (6.39 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 10/1 - 5/1) to give 2',4'-dibenzyloxy-6'-hydroxyacetophenone (5.71 g). This material was suspended in ethanol (45 mL) - water (15 mL). To the suspension was added potassium hydroxide (11.0 g), and the mixture was stirred at room temperature for 10 minutes. Benzaldehyde (2.51 mL) was added to the mixture, and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was acidified by addition of concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give 2',4'-dibenzyloxy-6'-hydroxychalcone (4.85 g). This material was dissolved inN,N-dimethylformamide (40 mL) - acetone (12 mL). To the solution were added potassium carbonate (2.3 g) and methyl bromoacetate (1.1 mL), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (30 mL). To the solution was added 10% palladium-carbon powder (0.5 g), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate = 3/1 - 2/1) to give the title compound (2.26 g).1H-NMR (CDCl3) δ ppm: 3. 0-3 . 05 (2H, m), 3. 45-3 . 5 (2H, m), 3. 66 (3H, s), 4 . 63 (2H, s), 5.58 (1H, brs), 5.75 (1H, d, J=2.3Hz), 6.03 (1H, d, J=2.3Hz), 7.15-7.35 (5H, m), 13.89 (1H, s) | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 7.a (a) 1-(2,4-Bis-benzyloxy-6-hydroxyphenyl)-ethanone (13) (a) 1-(2,4-Bis-benzyloxy-6-hydroxyphenyl)-ethanone (13) To a solution of the compound 12 (8.00 g, 43.0 mmol) and K2CO3 (13.7 g, 99.1 mmol) in DMF (100 mL) was added benzyl bromide (15.1 g, 88.3 mmol), and the mixture was stirred at room temperature overnight. DMF was removed under vacuum. Ethyl acetate and water was added. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give a residue. The residue was purified by silica gel chromatography (ethyl acetate:petroleum ether=40:1) to give a crude product of the compound 13 (7.55 g) as a yellow solid. | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With boron trifluoride diethyl etherate In ethyl acetate at 40℃; for 10h; | 3.1; 8.3 (1) Preparation of 2,4,6-trihydroxyacetophenone (intermediate S5) Weigh 10g (0.08mol) of phloroglucinol into the reaction vessel,Add 40 mL of ethyl acetate to dissolve,Add 10mL of acetic anhydride,Slowly add 8 mL of BF3·Et2O solution under stirring at room temperature.Then slowly heat to 40 ° C reaction,2 mL of acetic anhydride was added every two hours for the first 6 hours during the reaction.1mL of BF3·Et2O solution,The reaction was checked for 10 h and the starting material was completely reacted.150 mL of water was added to the reaction solution, stirred, and the solvent was distilled off under reduced pressure.A large amount of yellow solid precipitated in the distillation flask.The yellow solid was recrystallized with water, placed in a crystal, and suction filtered.Drying was weighed to give intermediate S5 in a yield of 90%. |
90% | With boron trifluoride diethyl etherate In ethyl acetate at 40℃; for 10h; | 2.2.2. General Preparation for Chalcones A1-A7 Phloroglucinol 1 (18.9 g, 0.15 mol) and Ac2O (19 mL) were dissolved in ethyl acetate (100 mL), and BF3*Et2O (15 mL) was added dropwise. The reaction mixture was heated at 40 °C for 10 h. Then, H2O (150 mL) was added and the mixture was extracted with EtOAc. After evaporation of the solvent, the solid was recrystallized from H2O to give 2 (Yellow solid, yield 90%). To a mixture of 2 (16.8 g, 0.1 mol) and K2CO3 (28 g, 0.2 mol) in ethanol (250 mL) was added TsOCH3 (38 mL, 0.25 mol) dropwise at room temperature, then refluxed at 80°C for 3 h. After 500 mL of water was added, standing overnight. The crude product was obtained by suction filtration and purified by column chromatography to obtain white crystals 3 of 13.3 g, yield 68%. To a stirred solution of 3 (1.96 g, 10 mmol) in chlorobenzene (50 mL) was added anhydrous AlCl3 (2 equ.). The reaction mixture was heated at 130 °C for 1 h. Then, the reaction was added 40 mL 10% hydrochloric acid solution, a large amount of white solid was produced at room temperature. After filtration, the solid was dissolved in EtOAc, and then extracted three times with 10% NaOH solution. The aqueous phase was combined and modulated PH = 6 with glacial acetic acid, which extracted with EtOAc (3 * 30 mL) and purified through a silica gel column to give intermediate 4. |
88% | With boron trifluoride diethyl etherate at 20℃; for 15h; Inert atmosphere; |
86% | With boron trifluoride diethyl etherate In ethyl acetate at 50℃; for 10h; | |
86% | With boron trifluoride diethyl etherate In ethyl acetate at 50℃; for 10h; | 1.1; 1.2; 1.3 Preparation of 2,4,6-trihydroxyacetophenone Step 1-1, 79.7 mmol (10 g) of phloroglucinol, 190 mmol (19.4 g) of acetic anhydride and 40 ml of ethyl acetate were weighed out,Added to the first three-necked flask, and then 97.2mmol (13.8g) of boron trifluoride diethyl ether was added dropwise to the first three-necked flask to obtainTo the mixture .Step 1-2, the mixture I was stirred at 50 ° for 10 hours, the reaction solution .Step 1-3: The reaction mixture I was removed by rotary evaporation of ethyl acetate and recrystallized from water to give 14.5 g of yellow crystals. |
78% | With boron trifluoride diethyl etherate at 0 - 20℃; for 49h; | |
72% | With boron trifluoride diethyl etherate for 36h; Inert atmosphere; Heating; | |
67% | With boron trifluoride diethyl etherate In ethyl acetate at 75℃; for 15h; | 2,4,6-Trihydroxyacetophenone (4) m-Trihydroxybenzene (2.5 g, 0.02 mol) and acetic anhydride 4.5 mL (0.045 mol) were dissolved in ethyl acetate (10 mL), and BF3-Et2O 4 mL (0.032 mol) was added dropwise. The reaction mixture was heated at 75 °C for 15 h. Then, H2O (20 mL) was added and the reaction mixture was extracted with ethyl acetate. After evaporation of the solvent, the crude products were purified by a silica-gel column chromatography with petroleum ether and CH2Cl2 (3 : 1) as eluent to give the desired compound 4 (2.25 g); yield 67%, yellow crystals, m.p. 222-223 °C (lit. 23 221 °C) 1H NMR (500 MHz, DMSO-d6): 12.23 (s, 2H, OH), 10.38 (s, 1H, OH), 5.79 (s,2H, ArH), 2.50 (s, 3H, COCH3). IR νmax (KBr/cm-1): 3201 (OH), 1616(C=O). |
67% | With boron trifluoride diethyl etherate at 20℃; for 16h; Inert atmosphere; | |
65% | With boron trifluoride diethyl etherate; acetic acid for 6h; Reflux; | |
64.9% | With boron trifluoride diethyl etherate In ethyl acetate at 50℃; for 10h; | 4 4.1.4. 1-(2,4,6-Trihydroxyphenyl)ethanone (15) 4.1.4 1-(2,4,6-Trihydroxyphenyl)ethanone (15) Phloroglucinol 14 (10 g, 79.4 mmol) and acetic anhydride (18 mL, 190.0 mmol) were dissolved in ethyl acetate (40 mL), and BF3·Et2O (12 mL, 97.2 mmol) was added dropwise. The reaction mixture was heated at 50 °C for 10 h. Then, H2O (150 mL) was added and the reaction mixture was extracted with ethyl acetate. After evaporation of the solvent the raw material was recrystallised from H2O to give compound 15; 64.9% yield; yellow crystal; mp 220-221 °C (lit. 37 221 °C). |
64% | With boron trifluoride diethyl etherate; sodium acetate at 20℃; for 34h; | |
55% | With boron trifluoride diethyl etherate In ethyl acetate at 50℃; for 10h; | 3. Applied synthesis of natural phytohormone G3 factor To a mixture of phloroglucinol (2.58 g) and Ac2O (4.5 mL) in EtOAc (14 mL) was added BF3•Et2O (3 mL), then stirred at 50 °C for 10 h. Water (38 mL) was added and the aqueous solution was extracted with EtOAc. The solvent was removed in vacuo and the residue was separated by column chromatography on silica gel eluting with EtOAc/hexane (50:50 v/v) to form the acetylphloroglucinol (1.88 g, 55% yield). The obtained acetylphloroglucinol (0.44 g) and NaOMe (1.03 g) were dissolved in dry MeOH (40 mL) and methyl iodide (1 mL) was added. The mixture was stirred at room temperature for 24 h, then acidified with 2 M HCl. The resulting mixture was extracted with EtOAc, the combined extracts were dried over anhydrous MgSO4, then concentrated to dryness. To the obtained residue was added 6 M HCl (40 mL) and heated under reflux for 24 h and extracted with EtOAc. Separation using EtOAc/hexane (50:50 v/v) was performed affording syncarpic acid (0.27 g, 56% yield in two steps). Syncarpic acid (53.6 mg, 0.29 mmol) and piperidine (0.2 mL) were dissolved in dry CH2Cl2 (10 mL), then isobutyraldehyde (0.2 mL) was added. The mixture was stirred for 10 min at room temperature under an argon atmosphere. The solvent was removed in vacuo, and the residue was dissolved in CH2Cl2 (10 mL). The solution was treated with a saturated aqueous solution of NH4Cl in 1 M HCl (6 mL) at room temperature for 30 min. The resulting mixture was extracted with CHCl3, and the combined extracts were washed with water, dried over anhydrous MgSO4, and concentrated to dryness. The obtained isopropenylcyclohexanetrione intermediate G without purification was dissolved in AcOH (10 mL), then Mn(OAc)3•2H2O (0.4 mg, 0.0016 mmol) was added. The mixture was stirred at room temperature in a dry air stream for 24 h. Water (10 mL) was added, the aqueous solution was extracted with CHCl3, the combined extracts were washed with a saturated aqueous solution of NaHCO3, water, dried over anhydrous MgSO4, and concentrated to dryness. The crude product was purified by column chromatography on silica gel eluting with EtOAc/hexane (2:8 v/v), giving G3 factor (48.4 mg, 61% yield in three steps). |
16.5% | With boron trifluoride diethyl etherate In ethyl acetate at 50℃; for 12h; | 4.2. General Procedure for Preparation of 2-Hydroxyacetophenone Derivatives (I) General procedure: The synthesis of 5-9 was conducted according to literature [9]. Thus, phenol derivatives(1-4) (13.2 mmol) dissolved in acetic anhydride (Ac2O) (3 mL, 30 mmol) were addedin ethyl acetate (AcOEt) (5 mL). Then, boron trifluoride-diethyl ether (BF3-Et2O, 800 L,6.4 mmol) was slowly added to the reaction mixtures, a reflux setup allowed the mixturesto be heated in a controlled manner at 50 °C for 12 h without the loss of solvent. Thework-up process was performed using 100 mL of water, neutralization with NaHCO3, andextraction with CH2Cl2 (3 x 100 mL). The organic phase was brought to dryness and theresulting solid was eluted on a silica gel 60 columns using hexane:ethyl acetate (Hex:AcOEt)(2:1) (v:v). The synthesis of 5-9 was achieved in an overall yield of 16.5-56%. |
With boron trifluoride diethyl etherate | ||
With boron trifluoride diethyl etherate at 20℃; for 34h; | ||
With boron trifluoride diethyl etherate | ||
With boron trifluoride diethyl etherate | ||
With boron trifluoride diethyl etherate In ethyl acetate at 50℃; for 10h; | ||
With boron trifluoride diethyl etherate at 50℃; Inert atmosphere; | ||
With silica sulphuric acid In neat (no solvent) at 60℃; Green chemistry; | ||
With methanesulfonic acid; acetic acid In neat (no solvent) at 80℃; for 0.25h; Inert atmosphere; | 1.2 .General synthesis of diacyl phloroglucinol General procedure: The commercial phloroglucinol (1 mmol), acetic anhydride (2 mmol) or acyl chlorides (2 mmol of isobutyryl chloride or isovaleryl chloride), acetic acid and MSA were placed in a 25 mL flame-dried flask. Then, the resulted mixture was then stirred for 15 min at ambient temperature under an inert atmosphere. For conventionally heating method, the resulting mixture was heated at 25; 60; 80 °C until the phloroglucinol was totally converted into the expected product (controlled by TLC). For the ultrasonic-assisted method, the resulting mixture was further sonicated for 15-20 min at 25; 60; 80 °C. After cooled at room temperature, 30 mL of water was poured into the mixture to be followed by 20 mL of ethyl acetate (EtOAc). Afterwards, the organic phase was formed and separated, followed by gently extraction with EtOAc (3 × 20 mL). The combined organic layer phase was neutralised with brine solution, dried over Na2SO4 and concentrated in vacuum to obtain the crude solid product. In the final step, a short flash column chromatography was performed to afford the desired product using hexane/EtOAc = 4:1 eluent system. Finally, the isolated product was then purified and subjected to further characterise in detail using 1H NMR and 13C NMR and all of the results were compared to the previous | |
2.9 g | With boron trifluoride diethyl etherate at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium hydroxide In methanol for 0.166667h; Cooling with ice; Stage #2: iodomethane In methanol at 20℃; for 12.5h; Cooling with ice; | 1 4-(1-(3,5-diacetyl-2,4,6-trihydroxyphenyl)-3-methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione, i.e, the preparation of I1: Under ice bath conditions, compound II (100 mmol) was dissolved in 300 mL of anhydrous methanol solution, and then sodium hydroxide (600 mmol) was added slowly.After stirring uniformly in an ice bath for 10 minutes, iodomethane (600 mmol) was slowly added dropwise to the reaction system.After continuing stirring under ice bath conditions for 30 minutes, the reaction mixture was stirred at room temperature for 12 hours.After the reaction, 300 mL of 2N aqueous hydrochloric acid was added to terminate the reaction, the mixture was extracted with ethyl acetate (500 mL) four times, and the organic phases were combined.The obtained organic phase was washed twice with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound III with a yield of 90% |
86% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium methoxide In methanol for 0.166667h; Stage #2: iodomethane In methanol at 0 - 20℃; for 24.5h; | |
86% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium methoxide In methanol at 0℃; for 0.166667h; Inert atmosphere; Stage #2: iodomethane In methanol at 0 - 20℃; for 24h; Inert atmosphere; | 4.2.3 The synthesis of 4-acyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione 7 Sodium methoxide (7.18 g, 133 mmol) was slowly dissolved in anhydrous methanol (60 mL) at 0 °C. To this clear solution, acylphloroglucinol 6b (2.75 g, 16.5 mmol) was added carefully and the mixture was stirred for 10 min under nitrogen atmosphere. After that, methyl iodide (14.2 mL, 228 mmol) was slowly added. The ice bath was then removed, and the mixture was stirred at room temperature for 24 h. The crude mixture was quenched with 2 N HCl (60 mL) and extracted with CHCl3 (5 × 60 mL), washed with brine, and concentrated in vacuum. The crude product was purified by flash chromatography (silica gel, hexane:EtOAc = 5:l) to provide 7 (3.17 g, 14.2 mmol, 86% yield) as a yellow rod-like crystal. 1H NMR (500 MHz, CDCl3): δ 1.33 (s, 6H), 1.42 (s, 6H), 2.57 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 23.8, 24.3, 27.4, 52.0, 56.7, 109.4, 196.7, 199.1, 201.7, 210.0. |
86% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium methoxide In methanol for 0.166667h; Cooling with ice; Stage #2: iodomethane at 20℃; for 24.5h; Cooling with ice; | Synthesis of compound 7 Under an ice bath condition, acetyl phloroglucinol (2.75 g, 16.5 mmol)Was dissolved in 60 mL of anhydrous methanol solution and then slowly added sodium methoxide (7.2 g, 133 mmol).After stirring for 10 minutes, methyl iodide (14.2 mL, 228 mmol) was slowly added dropwise to the reaction system.The mixture was stirred for an additional 30 minutes under ice-cooling, followed by stirring the reaction mixture at room temperature for 24 hours.The reaction was then quenched by the addition of 100 mL of 2N aqueous hydrochloric acid. The mixture was extracted four times with ethyl acetate (100 mL)Combine the organic phase. The resulting organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate and filtered.The residue was subjected to flash column chromatography (n-hexane: ethyl acetate = 5: 1)Further purification gave 3.17 g of the compound (compound 7) as a colorless oil,Yield 86% light brown flaky solid. |
86% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium methoxide In methanol for 0.166667h; Stage #2: iodomethane In methanol at 0 - 20℃; for 24.5h; | The synthesis of 4-acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione. A flame-dried 250 mL flask was charged with acetylphloroglucinol (5.50 g, 33.0 mmol) and anhydrous MeOH (120 mL). Sodium methoxide (14.4 g, 266 mmol) was added slowly. After stirring for 10 min, methyl iodide (14.2 mL,228 mmol) was added dropwise at 0 C and kept it stirring at this temperature for 30 min. Then the ice bath was removed, the reactionmixture was stirred for another 24 h at room temperatureuntil all the starting material was consumed. The mixture was thenquenched with 2 N HCl (150 mL). The resulting mixture wasextracted with EtOAc (4 150 mL), and the combined organicphases were dried with Na2SO4 and then concentrated in vacuo.The residue was purified by flash chromatography (silica gel; hexane/EtOAc, 5:l) to afford 4-acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (6.36 g, 86% yield) as a colorless needlecrystal. 1H NMR (500 MHz, CDCl3): d 1.33 (s, 6H), 1.42 (s, 6H),2.57 (s, 3H); 13C NMR (125 MHz, CDCl3): d 23.8, 24.3, 27.4, 52.0,56.7, 109.4, 196.7, 199.1, 201.7, 210.0. |
86% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium methoxide In methanol for 0.166667h; Cooling with ice; Stage #2: iodomethane In methanol at 20℃; for 24.5h; Cooling with ice; | 6 Synthesis of acetyl β-trione compound 36: Acetyl phloroglucinol compound 35 (5.5 g, 30 mmol) was dissolved in 120 mL of anhydrous methanol under ice-cooling, and sodium methoxide (14.4 g, 266 mmol) was slowly added. After uniformly stirring for 10 minutes, methyl iodide (14.2 mL, 228 mmol) was slowly added dropwise to the reaction system. The stirring was continued for 30 minutes under an ice bath, and then the reaction mixture was stirred at room temperature for 24 hours. Then 50 mL of 2N aqueous hydrochloric acid was added to terminate the reaction. The mixture was extracted 4 times with ethyl acetate (150 mL) and the organic phases were combined. The resulting organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate and filtered. The residue was further purified by flash column chromatography (n-hexane:ethyl acetate=5:1) to obtain 3.17 g of Compound 36 as a colorless oil in a 86% yield of light brown plate-like solid. |
86% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium methoxide In methanol at 0℃; for 0.166667h; Inert atmosphere; Stage #2: iodomethane In methanol at 20℃; for 24h; | 1.3 3, Synthesis of 4-acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione 6 : Sodium methoxide (7.18 g, 133 mmol) was slowly dissolved in anhydrous methanol (60 mL) at 0 °C. To the clear solution was carefully added acyl phenol (Compound 5c) (2.75 g, 16.5 mmol), and the mixture was stirred under nitrogen for 10 min. Thereafter, methyl iodide (14.2 mL, 228 mmol) was slowly added. Then remove the ice bath, The mixture was stirred at room temperature for 24 hours. Crude mixture with 2N HCl (60 mL) Quenched and extracted with CHCl3 (5×60 mL) Wash with brine and concentrate in vacuo. The crude product was purified by flash chromatography (silica gel, hexane:EtOAc = 5:1) Obtaining a yellow rod-like crystal compound 6 (3.17 g, 14.2 mmol, 86% yield). |
85% | With sodium methoxide In methanol for 12h; Reflux; | |
84% | With sodium methoxide In methanol for 6h; Inert atmosphere; Reflux; | 3 4.3. 4-Acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (acylsyncarpic acid)13 (9) A solution of NaOMe was prepared by adding sodium (30.6 g, 1.33 mol, 8.16 equiv) in several portions to absolute methanol (1 L) followed by stirring the mixture at room temperature until the solution became clear. Then acylphloroglucinol (7) (27.46 g, 0.163 mol) was added followed by addition of iodomethane (142 mL, 2.28 mol, 14 equiv). The resulting mixture was refluxed for 6 h (reaction progress was checked using TLC, where the product appears as a tail using petroleum ether/ethyl acetate system, 2:1 as eluent) and then cooled down to room temperature. The mixture was concentrated under reduced pressure and the residue redissolved in water, acidified with 1 M HCl, before it was extracted with diethyl ether (4300 mL). The combined organic layers were washed with saturated sodium sulfite solution (400 mL). These washings were acidified with 3MHCl (until a white solid appeared) and extracted with diethyl ether (3100 mL). All organic layers were combined and after drying them over MgSO4, filtration and concentration in vacuo, a yellow solid was obtained, which could be recrystallized from petroleum ether to provide the title compound (30.6 g, 84%) as orange crystals. |
84% | With sodium methoxide In methanol for 6h; Reflux; | |
84% | With sodium methoxide for 6h; Reflux; | 2.2.3 2.3 Synthesis of 4-Acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(acylsyncarpic acid) (7) Preparation of sodium methoxide:30.6g of sodium (1.33mol, 8.16equiv) was added several times to 1L of anhydrous methanol solution.Stir at room temperature until completely dissolved.After adding 142mL methyl iodide (2.28mol, 14equiv),Add 27.46g compound 6 (0.163mol),The mixed solution was refluxed for 6 hours (tested with a thin-layer plate during the period, developed with petroleum/ether ethyl acetate 2:1 v/v), and cooled to room temperature.Concentrate under reduced pressure, and dissolve the remaining part in water,It was extracted four times with 300Ml ether, and then acidified by adding 1M hydrochloric acid.Acidify the organic phase with 400mL saturated sodium sulfite solution,Then add 3M hydrochloric acid until white appears.Extract three times with 100 mL ether.Combine all the compounds, add magnesium sulfate, filter, concentrate, and vacuum dry.A yellow solid was obtained, which could be recrystallized from petroleum ether to obtain compound 7 (30.6 g, 84%). |
84% | With methanol; natrium for 6h; Inert atmosphere; Reflux; | 2.2.3 2.3 Synthesis of 4-Acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (acylsyncarpic acid) (7) Preparation of sodium methoxide: 30.6 g of sodium (1.33 mol, 8.16 equiv) were added to 1 L of anhydrous methanol solution in several portions. Stir at room temperature until completely dissolved. After adding 142mL methyl iodide (2.28mol, 14equiv), 27.46g compound 6 (0.163mol) was added, and the mixture was refluxed for 6h, (detection by thin-layer plate during the period, developed with petroleum/ether ethyl acetate 2:1 v/v), cooled to room temperature. Concentrated under reduced pressure, the remaining part was dissolved in water, extracted four times with 300 mL ether, and then acidified by adding 1M hydrochloric acid. The organic phase was acidified with 400 mL of saturated sodium sulfite solution, followed by the addition of 3M hydrochloric acid until a white color appeared. Extract three times with 100 mL of ether. All compounds were combined, magnesium sulfate was added, filtered, concentrated, and dried in vacuo. A yellow solid was obtained, which could be recrystallized from petroleum ether to obtain compound 7 (30.6 g, 84%). |
82% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium hydroxide In methanol at 0℃; for 0.166667h; Inert atmosphere; Stage #2: iodomethane In methanol at 0 - 20℃; for 24h; Inert atmosphere; | |
82% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium hydroxide In methanol at 0℃; for 0.166667h; Stage #2: iodomethane In methanol at 20℃; for 24h; | 1.1.1 1. Synthesis of 4-Acyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione 6 Sodium hydroxide (5.3 g, 133 mmol) was slowly dissolved in anhydrous methanol (60 mL) at 0 °C. To this clear solution was carefully added acetylresorcinol 5 (2.8 g, 16.5 mmol) and after stirring the mixture under nitrogen for 10 minutes, methyl iodide (14.2 mL, 228 mmol) was slowly added. The ice bath was then removed, and the mixture was stirred at room temperature for 24 hours. The resulting crude mixture was quenched with 2N aqueous hydrochloric acid (60 mL) and extracted three times with CHCl3 (5 × 60 mL). After the organic phases were combined and washed with brine, they were dried over anhydrous Na2SO4 and filtered, and concentrated in vacuo. The obtained crude product was quickly purified by silica gel column chromatography (n-hexane: ethyl acetate = 5:1) to obtain the target product 6 (3.0g, 13.5mmol, yield 82%). |
82% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium hydroxide In methanol at 0℃; for 0.166667h; Inert atmosphere; Stage #2: iodomethane In methanol at 20℃; for 24h; Inert atmosphere; | |
77% | Stage #1: 2,4,6-trihydroxyacetophenone With methanol; natrium at 0℃; for 0.5h; Stage #2: iodomethane at 20℃; for 40h; | |
71% | With sodium methoxide In methanol for 6h; Reflux; | 4-Acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (Acylsyncarpicacid) (5) To a solution of NaOMe (35.9 g, 0.665 mol) and acylphloroglucinol (4) (13.7 g, 0.081mol) in MeOH (500 ml), iodomethane (71 mL, 1.14 mol, 14 equiv) was added and the resulting mixture was refluxed for 6 h (reaction progress was checked using TLC). Then the mixture was cooled down to room temperature and concentrated under reduced pressure. The residue redissolved in water, acidified with 1M HCl, before it was extracted with diethyl ether (4 × 500 mL). The combined organic layers were washed with saturated sodium sulfite solution. These washings were acidified with 3M HCl and extracted with diethyl ether (3 × 100 mL). All organic layers were combined and after drying them over MgSO4,filtration and concentration in vacuo to afforded acylsyncarpic acid (5)(13.0 g, 71%). 1H NMR (500 MHz, CDCl3): δ 1.36 (s, 6H, 2CH3), 1.45 (s,6H, 2CH3), 2.60 (s, 3H, COCH3); 13C NMR (125MHz, CDCl3):δ 24.0(2CH3), 24.4 (2CH3), 27.4 (COCH3), 52.2 (C-6),56.8 (C-2), 109.5 (C-4), 196.9 (C-5), 199.3 (C-3), 201.7 (CH3C=O), 210.1(C-1); HRESIMS: m/z 223.0977[M-H]- (calcd for C12H15O4,223.0976) |
71% | With sodium methoxide In methanol for 6h; Inert atmosphere; Reflux; | |
43% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium methoxide In methanol at 20℃; for 0.166667h; Stage #2: iodomethane at 0 - 20℃; for 24.5h; | |
With sodium methoxide | ||
3.17 g | Stage #1: 2,4,6-trihydroxyacetophenone With sodium methoxide In methanol at 0℃; for 0.166667h; Inert atmosphere; Stage #2: iodomethane In methanol at 20℃; for 24h; Inert atmosphere; | |
Stage #1: 2,4,6-trihydroxyacetophenone With sodium methoxide In methanol at 0℃; for 0.166667h; Inert atmosphere; Stage #2: iodomethane In methanol at 20℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate In acetone at 65℃; for 24h; Inert atmosphere; | 1.4. Synthesis of 2-p-methoxybenzyl-5,7-dihydroxychromone (2) To a solution of 2,4,6-trihydroxyacetophenone (1.68 g, 10 mmol) in acetone under argon/open atmosphere, was added K2CO3 (13.82 g, 100 mmol, 10 equiv). The mixture was stirred at room temperature for 10 min and then 4-methoxybenzoyl chloride (2.56 g, 15 mmol, 1.5 equiv) was added. The mixture was stirred under reflux for 24 h. After cooling to room temperature the undissolved K2CO3 was filtered off, washed with acetone and evaporated under reduced pressure to a residue. The crude mixture was extracted with ethyl acetate (30 mL × 3), washed with water, brine, dried with anhydrous Na2SO4 and concentrated under reduced pressure to a residue. The residue was purified by silica gel column chromatography using hexane/ethyl acetate (4:1) as eluent. Yield: 2.05 g (72%). Rf 0.17. Mp 138-142 °C. 1H NMR (400 MHz, DMSO) δ 2.07 (s, 1H), 2.63 (s, 1H), 3.56 (s, 3H), 6.29 (s, 1H), 6.96-7.11 (m, 2 H), 7.88-7.92 (m, 2H), 8.02-8.09 (m, 2H). 13C NMR (100.6 MHz, DMSO) δ 14.34, 30.79, 33.12, 40.13, 55.68, 60.51, 101.03, 108.68, 114.29, 130.25, 132.29, 156.56, 163.52, 204.59. MS (m/z): 285.27 (M + 1)+. Anal. Calcd for C16H12O5: C, 67.60; H, 4.25. Found: C, 67.49; H, 4.36. |
71% | Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In acetone at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 4-methoxy-benzoyl chloride In acetone at 60℃; for 24h; Inert atmosphere; | 2.1; 2.2; 2.3; 2.4; 2.5 Preparation of 5,7-dihydroxy-4'-methoxyflavone III Step 2-1, under nitrogen protection, weighed 59.5mmo (l10g) 2,4,6-trihydroxyacetophenone II, 594.7mmol (82.2g) of potassium carbonate and 100ml of acetone was added to a second three-necked flask, After stirring at room temperature for 10 minutes, 89.2 mmol (15.2 g) of p-methoxybenzoyl chloride was weighed into a second three-necked flask to obtain a mixture II.Step 2-2, the mixture was stirred at 60°C for 24 hours, cooled to room temperature to obtain the reaction solutionII.Step 2-3, the reaction solution II was filtered and washed with acetone to obtain a filtrate I. Step 2-4, the filtrate I was extracted three times with 200ml of ethyl acetate, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to remove ethyl acetate to obtain a solid powder I.Step 2-5, the solid powder I was subjected to column chromatography using a solution of hexane: ethyl acetate = 4: 1 in a volume ratio to obtain 12 g of a solid powder. |
45% | Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In acetone at 20℃; for 0.166667h; Stage #2: 4-methoxy-benzoyl chloride In acetone for 24h; Heating; |
Stage #1: 2,4,6-trihydroxyacetophenone; 4-methoxy-benzoyl chloride With potassium carbonate In pyridine at 120℃; for 3h; Heating / reflux; Stage #2: With potassium hydroxide; water In methanol for 20h; Heating / reflux; Stage #3: With acetic acid In water | 9 To a solution of 80 ml dry pyridine was added 9.62 g 2',4',6'-trihydroxyacetophenone and 30 g anhydrous K2CO3 and 31 g 4-methoxybenzoyl chloride successively, then extracted reaction solution with chloroform when it was refluxed 3 hours at 120° C. by oil bath, and washed the chloroform extraction by water (100 ml), the chloroform was dried by anhydrous K2CO3 and decoloured by active carbon, then concentrated it in vacuo. The residue was dissolved with 60 ml anhydrous ethanol, and have deposition in solution, filtered it, afforded 13.53 g intermediate.To a solution of 50 ml methanol was added 6.3 g above intermediate and 6% KOH solution, stirred and refluxed it 20 hours, then recovered most of methanol in vacuo, and extracted it with chloroform to remove some extraneous component, the deposit was obtained after the water phase was acidified pH 9 by 10% acetic acid, and filtered it, washed by water, dried it, 1.83 g acacetin was obtained at last. | |
Stage #1: 2,4,6-trihydroxyacetophenone; 4-methoxy-benzoyl chloride With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene for 8h; Reflux; Stage #2: With sodium hydroxide In 1,4-dioxane; methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 2,4,6-trihydroxyacetophenone; N,N-dimethyl-formamide With trichlorophosphate In ethyl acetate at 20℃; for 1h; Stage #2: In water; ethyl acetate | |
70% | With trichlorophosphate at 20℃; | |
64.7% | With trichlorophosphate In ethyl acetate at 20℃; for 1h; Cooling with ice; | 3-Acetyl-2,4,6-trihydroxybenzaldehyde (7) DMF (0.4 ml, 5 mmol) and phosphoryl chloride (0.5 mL, 5.5 mmol) to the solution of 2,4,6-trihydroxyacetophenone (841 mg, 5 mmol) and EtOAc (10 mL) in an ice bath. Then the reaction mixture was further stirred for 60 min at room temperature. Ice water was added to the reaction mixture and extracted with EtOAc. The EtOAc layer was washed with brine solution, dried over Na2SO4, and concentrated to afford the crude product. The residue was purified by column chromatography on silica gel with petroleum ether-EtOAc (5:1 to 7:3 v=v) as an eluent to obtain 7 (635 mg, 64.7%) as colorless solid, which was used directly in the next reaction without recrystallization. |
With trichlorophosphate In ethyl acetate at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene for 24h; | 3.2 (2) 3-Prenyl-2,4,6-trihydroxyacetophenone (intermediate S6) At room temperature,Intermediate S5 (1.68 g, 0.01 mol),Prenyl bromide(1.17 mL, 0.01 mol) was added to toluene (150 mL).Additional DBU (1,8-diazabicycloundec-7-ene) (1.49 mL, 0.1 mol) was added.Then, the reaction was cooled to room temperature at 35 ° C for 24 hours.30 ml of water was added to the system and then extracted 3 times with ethyl acetate.80mL each time,The combined organic layers were dried over anhydrous sodiumThe residue was purified by silica gel columnYellow oily intermediate S6,1.72 g, yield 73%. |
65% | With potassium hydroxide In methanol at 20℃; for 24h; | |
65% | With magnesium succinate In N,N-dimethyl-formamide at 60℃; for 16h; Inert atmosphere; |
57% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 18h; Inert atmosphere; | |
40% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 12h; | |
37% | With potassium carbonate In acetone at 20℃; for 24h; Reflux; Inert atmosphere; | |
35% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 12h; | |
27% | With lithium hydroxide In ethanol; water at 20℃; for 16h; | |
With potassium hydroxide | ||
With potassium hydroxide | ||
With potassium carbonate In methanol for 8h; Reflux; | 3.1.2. Two-Step Reaction: Friedel-Crafts Acylation and Direct C-Alkylation (3d, 4a-g) General procedure: Friedel-Crafts acylation: Small amounts of phloroglucinol (0.05 mol) and anhydrous aluminumchloride (0.1 mol) were first dissolved in dichloromethane (50 mL) and kept heated for 1 h at 40 °C.Acyl chloride (0.05 mole) was added dropwise into the reaction mixture, reuxed for 8 h, and quenchedwith 0.05 mole of HCl upon completion of the reaction. After the reaction was completed, the reactionmixture was extracted with ethyl acetate and concentrated under reduced pressure. The residueswere subjected to column chromatography using silica gel eluted with hexane/ethyl acetate (10:1) [25].Direct C-alkylation: A well-mixed mixture of acylphloroglucinol (1 mmol), geranyl bromide or prenylbromide (1 mmol), and anhydrous potassium carbonate (0.5 mmol) in dry methanol (3 mL) wasrefluxed for 8 h. After completion of the reaction, excess methanol was removed through high vacuumand the residues were extracted with ethyl acetate. The organic layers were combined, dried, andconcentrated. Column chromatography over silica gel eluted with petroleum ether/ethyl acetate (10:1)gave geranylated/prenylated compounds [11]. | |
With 1,8-diazabicyclo[5.4.0]undec-7-ene at 30℃; Inert atmosphere; | 4.3.1. 2,4,6-Trihydroxy-3-(3-methylbut-2-en-1-yl) acetophenone(2) To a stirred solution of 2,4,6-trihydroxyacetophenone 1 (1.68 g,0.01 mol) in dry methylbenzene (150 mL) was added prenyl bromide(1.17 mL, 0.01 mol) in the presence of DBU (1.49 mL, 0.1 mol)as base, at room temperature under nitrogen atmosphere, for 48 h. After completion of the reaction as indicated by TLC, the mixturewas diluted with water and extracted with ethyl acetate(3 x 150 mL). The combined organic layer was washed with brine,dried over Na2SO4, and concentrated under vacuum, the residue was chromatographed on silica gel to afford 2 [30]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Eicosapentaenoic acid (EPA, 10.4 mg, Aldrich, Mlw, USA) was taken in methanol (5 ml), and the mixture was kept at ordinary temperature (25+/-2 C.) for 7 days. EPA did not exhibit the presence of any detectable amount of DBPs (1 and 2, Scheme-II) at the onset of the reaction (beginning of day-1). After autooxidation for 7 days, the products were subjected to GC-MS analysis, as the trimethylsilyl (TMS) derivatives. A small portion of the transformed product of EPA (ca. 3 mg) was dissolved in chloroform-methanol (2:1, 5 ml). An aliquot (10 mul) of this solution was treated with N,O-bis (trimethylsilyl)-trifluoroacetamide (Wako) at 60 C. for 1 hour. A portion of the silyl derivatives was injected into the GC-MS assembly. The presence of 3,8-dihydroxy-dibenzo-alpha-pyrone and benzoic acid as TMS derivatives, in the mixture was detected (FIG. 1). Analysis of the product on day-2 showed the presence of 3-hydroxy-dibenzo-alpha-pyrone (C-13) and benzoic acid (C-7) in the mixture. Among the 20-C units of EPA, DBPs comprise 13-carbons and the remaining 7-carbons constitute benzoic acid. The yield of DBPs was appreciably increased (FIG. 1) when catalytic amount of ferrous sulphate (0.1 mg) was added to the autooxidation mixture. The autooxidation of DHA was also studied similarly, when both 3-hydroxy- and 3,8-dihydroxy-dibenzo-alpha-pyrones (1 and 2, Scheme-II) were detected in the transformed products (monitored on day-2 to day-7). The remaining 9-carbons (C-22-C-13) of DHA, constituted hydroxyacetophenones (strs. 7-9, Scheme-II), which were also detected in the autooxidation mixture as their trimethylsilyl derivatives by GC-MS analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With magnesium succinate; potassium iodide In N,N-dimethyl-formamide at 40℃; for 16h; Inert atmosphere; | 2 Dissolve compound 2,4,6-trihydroxyacetophenone monohydrate (1.0 g, 5.37 mmol) in 5 mL of dry DMF at room temperature.Subsequently, magnesium succinate (0.75 g, 5.37 mmol), prenyl chloride (0.56 g, 5.37 mmol), Potassium iodide (90 mg, 0.54 mmol).After the addition, under the protection of argon, the temperature was raised to 40 ° C and the reaction was stirred for 16h.Reaction until TLC monitors the disappearance of raw materials, and the reaction liquid is cooled to room temperature.It was poured into ice water to quench the reaction, extracted with 3 × 10 mL of ethyl acetate, the organic phases were combined and washed sequentially with saturated sodium chloride solution,After drying over anhydrous sodium sulfate, the organic phase was concentrated to dryness under reduced pressure,Then purified by silica gel column chromatography [V (petroleum ether): V (ethyl acetate) = 6: 1] to obtain compound ii as a white solid with a mass of 0.82 g and a yield of 65%. |
55% | With sodium chloride; potassium carbonate In tetrahydrofuran | P.12 Production Example 12 Production Example 12 In 250 ml of anhydrous tetrahydrofuran was dissolved 50.0 g of 2',4',6'-trihydroxyacetophenone, and 123.15 g of anhydrous potassium carbonate was added to the solution and the mixture was stirred at room temperature for 30 minutes. Then, 37.23 g of 1-chloro-3-methyl-2-butene was dropped into the solution over a period of 20 minutes and a reaction was carried out at room temperature for 24 hours. After the reaction, the reaction mixture was extracted with 2 l of ethyl acetate, and the ethyl acetate layer was washed with water (500 ml*4 times), shaken with a saturated aqueous solution of sodium chloride (300 ml*2 times), dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation and the obtained residue was recrystallized from a mixed solvent of benzene and petroleum ether to obtain 38.6 g (yield=55.0%) of 2',4',6'-trihydroxy-3'-(3-methyl-2-butenyl)acetophenone in the form of a yellow prism. Infrared absorption spectrum νmaxKBr cm-1: 3420, 3328, 2976, 2924, 1640, 1600, 1562, 1524, 1512, 1452, 1434, 1402, 1368, 1282, 1234, 1172, 1150, 1070, 816, 588. Proton nuclear magnetic resonance spectrum (δ ppm in acetone-d6): 1.62 (3H, d, J=1.2 Hz), 1.73 (3H, s), 2.60 (3H, s), 3.23 (2H, d, J=7.3 Hz), 5.22 (1H, dd, J=7.3 Hz, 1.2 Hz), 6.05 (1H, s). Mass spectrum: M/Z (%) 236 (M+, 64), 221 (33), 203 (14), 193 (30), 181 (100), 165 (37), 163 (28), 153 (24), 43 (57). |
55% | With potassium carbonate In tetrahydrofuran | P.3 Production Example 3 Production Example 3 In 250 ml of anhydrous tetrahydrofuran was dissolved 50.0 g of 2',4',6'-trihydroxyacetophenone, and 123.1 g of anhydrous potassium carbonate was added to the solution and the mixture was stirred at room temperature for 30 minutes. Then, 37.2 g of 1-chloro3-methyl-2-butene was added dropwise to the mixture over a period of 20 minutes and reaction was carried out at room temperature for 24 hours. After the reaction, the reaction mixture was extracted with 2 l of ethyl acetate and the solvent was removed from the ethyl acetate layer by distillation, and the residue was recrystallized from a benzene/petroleum ether mixed solvent to obtain 38.6 g (yield=55.0%) of 2',4',6'-trihydroxy-3'-(3-methyl-2-butenyl)acetophenone in the form of a yellow prism. |
34% | With sodium chloride; potassium carbonate In tetrahydrofuran; water | P.1 Production Example 1 Production Example 1 In tetrahydrofuran were dissolved and suspended 66.5 g of 2',4',6'-trihydroxyacetophenone and 173.0 g of potassium carbonate, and 56.0 ml of 1-chloro-3-methyl-2-butene was dropped into the solution. The mixture was stirred at room temperature for 2 hours and extracted with dimethyl ether, and the organic layer was washed with a 5% solution of potassium carbonate and then with water. The organic layer was shaken with a saturated solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under a reduced pressure. Recrystallization from benzene gave 31.8 g (yield=34.0%) of 2',4',6'-trihydroxy-3'-(3-methyl-2-butenyl)acetophenone. |
54 %Chromat. | With magnesium succinate In N,N-dimethyl-formamide at 60℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.4% | With potassium carbonate; dimethyl sulfate In acetone | P.7 Production Example 7 Production Example 7 To 50.1 g of 2',4',6'-trihydroxyacetophenone and 123.5 g of anhydrous potassium carbonate was added 500 ml of anhydrous acetone, and the mixture was stirred at room temperature for 30 minutes. Then, 78.9 g of dimethyl sulfate was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours to effect a reaction. After the reaction, the reaction mixture was neutralized with dilute hydrochloric acid, extracted with diethyl ether and filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was recrystallized from n-hexane to obtain 55.2 g (yield=94.4%) of 2'-hydroxy-4',6'-dimethoxyacetophenone in the form of a colorless prism. Melting point: 77° to 78° C. Infrared absorption spectrum νmaxKBr cm-1: 1622, 1596, 1574, 1460, 1440, 1424, 1368, 1272, 1222, 1206, 1156, 1110, 1080, 894, 834, 596. Proton nuclear magnetic resonance (δ ppm in CDCl3): 2.61 (3H, s), 3.82 (3H, s), 3.85 (3H, s), 5.92 (1H, d, J=2.4 Hz), 6.05 (1H, d, J=2.4 Hz), 14.03 (1H, s, disappeared by addition of D2 O). |
With dimethylsulfide; potassium carbonate In acetone at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.5% | With potassium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide; water | 1.a Synthesis of Trans-5,7-Dihydroxy-2-(3,4,5-Trimethoxy-Phenyl)-3,4-Dihydro-2H-Chroman-3-YL, 3,4,5-Trihydroxy-Benzoic Acid Ester (SR 13194) (a) Preparation of 4',6'-bisbenzyloxy-2'-hydroxyacetophenone (2) from 2',4',6'-trihydroxyacetophenone (1): A mixture of 2',4',6'-trihydroxyacetophenone (20 g, 0.12 mol, dried in the oven at 140° C.) and anhydrous potassium carbonate (50 g, 0.36 mol) in hexamethylphosphoramide (160 mL) was treated with benzyl chloride (30 mL, 0.26 mol), and the suspension heated at 90-93° C., under an argon atmosphere, for 1.5 h. The mixture was then cooled and filtered. The filtrate was added to 300 mL ice-cold water and acidified to pH 4 with 6N HCl. The resulting suspension was heated to 70 ° C. for 1 h, and then cooled at 4° C. for 16 h. The deposited sticky solid was filtered off and washed with water. This solid was air dried, and recrystallized from boiling methanol/acetone (2:1). Cooling the solution afforded the product 8 as off-white crystals (27.55 g, 66.5% yield). 1H NMR (300 MHz, CDCl3): δ 2.56 (s, 3H, CH3), 5.06 (s, 4H, CH2), 6.10 and 6.16 (2s, 2H, 3',5'-Ar-H), 7.40 (m, 10H, Ar-H), 14.01 (s, 1H, OH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate In acetone Reflux; regioselective reaction; | |
78% | With potassium carbonate In acetone for 6h; Reflux; regioselective reaction; | |
74% | With potassium carbonate In acetone for 24h; Heating; |
74% | With potassium carbonate In acetone for 24h; Reflux; Inert atmosphere; | |
72% | With potassium carbonate In acetone Reflux; | |
68% | With potassium carbonate In acetone at 20℃; for 18h; | |
58% | With potassium carbonate In acetone for 24h; Reflux; | 4.3 General procedure for synthesising 4a-e General procedure: A mixture of 3a-e (1equiv), geranyl bromide (1equiv), and K2CO3 (2equiv) in acetone was refluxed for 24h. Evaporating the acetone, adding a 2N HCl solution, extracting with EtOAc, and removing the solvent were followed by a flash column chromatography on silica gel with PE (bp. 50-70°C)/EtOAc (5:1) to yield the corresponding products [26]. |
35% | With sodium hydroxide In ethanol; water at 20℃; for 16h; | |
With potassium carbonate In acetone for 6h; Reflux; | 2.1. tHGA synthesis A well-stirred mixture of phloracetophenone (1.000 g, 6 mmol), geranyl bromide (0.876 g, 4.80 mmol), and anhydrous potassium carbonate (0.415 g, 3.00 mmol) in dry acetone (3.5 ml) was refluxed for 6 h. The reaction mixture was filtered and evaporated under reduced pressure to give an oily orange residue that was purified by flash column chromatography on Si gel (petroleum ether-EtOAc, 10:1) to afford 2,4,6-trihydroxy-3-geranylacetophenone (tHGA) as a light yellow powder; mp 128-130 °C. 1H NMR (CD3OD) δH 1.58 (3H, s,Me), 1.63 (3H, s, Me), 1.76 (3H, s, Me), 2.64, (3H, s, COMe), 1.96 (2H,q, J =7.5 Hz), 2.06 (2H, m), 3.21 (2H, d, J =6.5 Hz), 5.08 (1H, t, J=7 Hz), 5.20 (1H, t, J =6.5 Hz), 5.92 (1H, s, ArH); IR (KBr) νmax 3405,1627 cm-1; EIMS m/z (%) [M] +304 (38), 289 (3), 261 (9), 235 (25),181 (100) (Fig. 1A). tHGA purity was more than 99%. | |
With potassium carbonate In methanol for 8h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 5h; Inert atmosphere; | 1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)ethanone (10) To a solution of 2 (5.0 g, 26.8 mmol) in dichloromethane (120.0 mL) at 0 °C in an ice bath was added DIPEA (13.4 ml, 80.5 mmol) and MOMBr (4.8 ml, 59.1 mmol). The solution was stirred for 5 h. Methanol was added to quench the reaction, and the reaction mixture was diluted with dichloromethane. The solution was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether-acetone, 6:1) to obtain 10 (6.2 g, 91%) as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 13.67 (s, 1H), 6.25 - 6.13 (m, 2H), 5.20 (s, 2H), 5.11 (s, 2H), 3.47 (s, 3H), 3.41 (s, 3H), 2.58 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 203.1, 166.7, 163.4, 160.3, 106.8, 97.0, 94.4, 94.0, 93.9, 56.6, 56.3, 32.9. |
76% | With potassium carbonate In acetone at 60℃; for 3.33h; | |
75.5% | Stage #1: bromethyl methyl ether; 2,4,6-trihydroxyacetophenone With N-ethyl-N,N-diisopropylamine In dichloromethane for 0.333333h; Cooling with ice; Stage #2: bromethyl methyl ether In dichloromethane for 12.3h; | 3 Synthesis of 2,4-Dimethoxymethyl-6-hydroxy-acetophenone (a kind of compound represented by structural formula 3, denoted as 3b) In a 250ml dry three-necked flask, add 2,4,6-trihydroxyacetophenone 2 (8.23g, 0.044mol) and 200ml of anhydrous dichloromethane, stir to dissolve. Under ice water bath, slowly add N,N-diisopropylethylamine (15.99g, 0.123mol), after stirring for 20min, add bromomethyl methyl ether (MOMBr) (12.16g, 0.097mol) dropwise. After the addition, the stirring was continued at low temperature for 20 minutes, the ice-water bath was removed, and the mixture was stirred at room temperature for 12 hours. The reaction was detected by TLC. Add 30ml of deionized water and stir for 30min to quench the reaction. After standing to separate the layers, the organic layer was taken, the aqueous layer was extracted with dichloromethane (3×30 mL), the organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Separation and purification by column chromatography (petroleum ether: ethyl acetate (V: V) = 10:1) yielded 8.55 g of white needle-like crystals with a yield of 75.5%. |
74.5% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 3℃; for 3h; Inert atmosphere; | 4.3 Preparation of 2,4-di(methoxymethoxy)-6-hydroxyacetophenone 9 To a stirred suspension of phloroglycinol hydrate (13.97 g, 75 mmol) in dichloromethane (300 mL) under nitrogen was added N,N-diisopropylethylamine (65.3 mL, 375 mmol), while cooling in an ice bath (3 °C). Bromomethyl methyl ether (14.3 mL, 158 mmol corrected for 90% purity) was added dropwise at a rate to keep the reaction temperature below 8 °C. The mixture was stirred at 3 °C for 3 h, then quenched with saturated aqueous sodium bicarbonate (250 mL). The mixture was stirred at room temperature for a few minutes, after which the phases were separated, and the aqueous solution extracted with dichloromethane (2 × 75 mL). The combined organic solution was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in the minimal amount of dichloromethane and then added to a silica gel column. Elution with dichloromethane and then with 1.5% ethyl acetate/dichloromethane afforded 2,4-di(methoxymethoxy)-6-hydroxyacetophenone 9 (14.32 g, 74.5%) as a white solid after evaporation: mp 49-50 °C (lit.34 49-52 °C); LC/MS m/z 257 [M+H]; 1H NMR (CDCl3, 400 MHz) δ 2.65 (s, 3H), 3.47 (s, 3H), 3.51 (s, 3H), 5.16 (s, 2H), 5.25 (s, 2H), 6.25 (ABq, JAB = 2.3, ΔνAB = 8.3, 2H), 13.70 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 33.1, 56.6, 56.8, 94.2, 94.7, 97.4, 107.2, 160.5, 163.6, 167.0, 203.3. Anal. Calcd for C12H16O6: C, 56.25; H, 6.29. Found: C, 56.38; H, 6.23. |
68% | With potassium carbonate In acetone for 3h; Heating; | |
68% | With potassium carbonate In acetone for 3h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 2,4,6-trihydroxyacetophenone; methyl iodide With potassium <i>tert</i>-butylate In methanol for 7h; Reflux; Stage #2: With hydrogenchloride In methanol; water at 0℃; | |
57% | With potassium <i>tert</i>-butylate In methanol for 7h; Reflux; | |
56% | Stage #1: 2,4,6-trihydroxyacetophenone; methyl iodide With sodium methylate In methanol Stage #2: With hydrogenchloride In methanol; water | 1.a. Dissolving 2,4,6,-trihydroxyacctophenone (1,487 mg, 2.9 mmol) with methyl iodide (1.95 ml, 3.7 mmol) in the presence of MeOH (3 ml) and sodium methoxide (0.6 ml, 3.3 mmol) to obtain a mixture. The mixture was cooled and acidified with HCL, then extracted with EtOAc for three times to obtain organic layers; the organic layers were combined, dried and concentrated to obtain a residue. The residue was chromatographed on silica gel with EtOAC-hexane (1:9 to 1:4, v/v) as an eluent to produce 2-Acetyl-4,6,6-trimethylcyclonhexa-1,3,5-trione in 56% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: 2,4,6-trihydroxyacetophenone; sodium acetate With acetic anhydride at 180℃; for 0.666667h; Microwave irradiation; Stage #2: With potassium carbonate In water for 2h; Reflux; | |
47% | With acetic anhydride at 180℃; for 0.666667h; Microwave irradiation; | 1.1 Step 1. 5,7-dihydro-2-methyl-4H-chromen-4-one: A mixture of 1 -(2,4,6-trihydroxyphenyl)ethan-1-one (2.02 g, 12.0 mmcl), AcONa (0.984 g, 12.0 mmol) in Ac20 (6.0 mL) was heated at 180 °C for 40 mm in a microwave reactor. The reaction mixture was poured into water, extracted with ethyl acetate (EA) , washed with sat’d NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was treated with a solution of K2003 (4.98 g, 36 mmol) in H20 (90 mL) and refluxed for 3 h. Acidified with 3 N HCI. The precipitate was collected by vacuum filtration to afford 1 .09 g (47%) of 5,7-dihydro-2-methyl-4H-chromen-4-one as a yellow solid. Rff 0.45 (hexanes: EA = 1: 1); LC-MS (ESI): mlz 193 [M+1]’H NMR (400 MHz, DMSO-d6) ö (ppm) 2.35 (s, 3H), 6.17 (d, J=2.0 Hz, 2H), 6.33 (d, J=2.0 Hz, 1H), 10.78 (s, IH), 12.82 (s, IH) |
31% | Stage #1: 2,4,6-trihydroxyacetophenone; sodium acetate With acetic acid at 180℃; for 0.666667h; Microwave irradiation; Stage #2: With potassium carbonate In water at 100℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: Dimethoxymethane With acetyl chloride; zinc dibromide In dichloromethane at 20 - 30℃; for 3.5h; Stage #2: 2,4,6-trihydroxyacetophenone With N-ethyl-N,N-diisopropylamine In dichloromethane at 5 - 10℃; | 35 5.1.35. 1-[2-Hydroxy-4,6-bis(methoxymethoxy)phenyl]ethanone (49) To a stirred solution of dimethoxymethane (66 mL, 745 mmol)and zinc bromide (447 mg, 1.12 mmol) in DCM (580 mL) wasadded dropwise acetyl chloride (53 mL, 745 mmol) during 30 minmaintaining the temperature below 30 C. After stirring 3 h atroom temperature, the solution was diluted with DCM (1.2 L), thencooled at 5 C before the portion wise addition of 1-(2,4,6-trihydroxyphenyl)ethanone (48, 50.0 g, 298 mmol) followed by the dropwiseaddition of N,N-diisopropylethylamine (208 mL, 1.19 mol).After 1 h the ice bath was removed and the temperature was allowedto rise to room temperature. The resulting cloudy solutionwas stirred overnight, and then was washed with NH4Cl saturatedsolution, followed by washing with 10% citric acid solution. Afterdrying over Na2SO4, the solvent was removed to give 49 (78.0 g,100%). 1H NMR (400 MHz, DMSO-d6) d 13.31 (s, 1H), 6.24 (d,J = 2.3 Hz, 1H), 6.19 (d, J = 2.3 Hz, 1H), 6.19 (d, J = 2.3 Hz, 1H),5.30 (s, 2H), 5.22 (s, 2H), 3.44 (s, 3H), 3.38 (s, 3H), 2.60 (s, 3H);LC-MS (ESI): m/z 257 [M+H]+; HRMS (ESI): m/z calcd forC12H16O6+H+ 257.1020, found 257.1019. |
50% | Stage #1: Dimethoxymethane With acetyl chloride; zinc dibromide at 20℃; for 2h; Inert atmosphere; Stage #2: 2,4,6-trihydroxyacetophenone With diisopropylamine In dichloromethane for 3h; Inert atmosphere; Cooling with ice; regioselective reaction; | |
Stage #1: Dimethoxymethane With acetyl chloride; zinc dibromide In dichloromethane at 20℃; for 3.5h; Stage #2: 2,4,6-trihydroxyacetophenone With N-ethyl-N,N-diisopropylamine In dichloromethane at 5℃; | 3.1 Preparation of Ethyl 5-[2,4-dihydroxy-6-(4-nitrophenoxy)phenyl]isoxazole-3-carboxylate, via PG = methoxymethyl[(XXXI), (Z)-R=4-Nitrophenoxy, X=O, Y=N, W=CH, FT1=CO2C2H5]; Step 1; 1-[2-Hydroxy-4,6-bis(methoxymethoxy)phenyl]ethanone; To a stirred solution of dimethoxymethane (66 mL, 745 mmol) and zinc bromide (0.5 g) in DCM (580 mL) was added drop wise acetyl chloride (53 mL, 745 mmol) during half an hour maintaining the temperature under 200C.After stirring 3 hours at room temperature, the solution was diluted with DCM (1200 mL), then cooled at 5 0C before the portion wise addition of 1-(2,4,6-trihydroxyphenyl)ethanone (phloroacetophenone) (50 g, 208 mmol) followed by the drop wise addition of DIPEA (208 mL, 1.19 mol). The resulting cloudy solution was stirred overnight, and then was washed with a NH4CI saturated solution followed by washing with 10% citric acid solution. After drying overNa2SU4, the solvent was removed and the residue (78 g) nearly pure was used for the next step.1H NMR (400 MHz, DMSO-d6) δ ppm 2.60 (s, 3 H) 3.38 (s, 3 H) 3.44 (s, 3 H) 5.22 (s, 2 H) 5.30 (s, 2 H) 6.19 (d, 1 H)6.24 (d, 1 H) 13.31 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; | 3.1 Preparation of Ethyl 5-[2,4-dihydroxy-6-(4-nitrophenoxy)phenyl]isoxazole-3-carboxylate, via PG = 2- methoxyethoxy) methyl (MEM);[(XXXI), (Z)-R=4-Nitrophenoxy, X=O, Y=N, W=CH, R^=CO2C2H5]; Step 1; 1-{2-Hydroxy-4,6-bis[(2-methoxyethoxy)methoxy]phenyl}ethanone; To a stirred solution of 2,4,6-trihydroxyacetophenone (1.7 g, 10 mmol) in THF (50 mL) was added DIPEA (17 mL,100 mmol, 10 eq) followed by the addition of 2-methoxyethoxymethylchloride (2.75 g, 22 mmol, 2.2 eq) at 00C.After stirring overnight at 00C, the solvent was removed, and the residue taken up in ethyl acetate was washed with1 M HCI solution then with 1 M NaHCO3 solution and dried. The crude was carefully chromatographed on silica gel eluting with hexane /ethyl acetate 6/4 to provide the title compound (2.2 g, 64 % yield).1H NMR (400 MHz, DMSOd6) δ ppm 2.59 (s, 3 H) 3.23 (s, 3 H) 3.23 (s, 3 H) 3.42-3.51 (m, 4 H) 3.69-3.74 (m, 1 H)3.75-3.80 (m, 2 H) 5.29 (s, 2 H) 5.35 (s, 2 H) 6.19 (d, 1 H) 6.26 (d, 1 H) 13.32 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Stage #1: 1-iodo-butane; 2,4,6-trihydroxyacetophenone With methanol; sodium methylate Reflux; Stage #2: With hydrogenchloride In methanol; water at 0℃; | 4.1. 2-Acetyl-4,4,6-tributyl-3,5-dihydroxycyclohexa-2,5-dienone (6) A solution of 2,4,6-trihydroxyacetophenone (4, 595 mg, 3.5 mmol), sodium methoxide (2.5 mL, 11.6 mmol, 25% MeOH solution) and butyl iodide (1.2 mL, 10.6 mmol) in anhydrous MeOH (3 mL) was refluxed overnight. The reaction mixture was cooled to 0 °C and acidified with 1 N aqueous HCl solution, then extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was chromatographed on silica gel with EtOAc-hexane (1:9 to 1:4, v/v) as an eluent to obtain 6 (516 mg, 44%) as colorless solid, which was used directly in the next reaction without recrystallization. 1H NMR (300 MHz, CDCl3): δ 19.03 and 18.40 (2:1, each s, 1H, chelated-OH), 5.95 and 5.38 (2:1, each s, 1H, OH), 2.72 and 2.62 (1:2, each s, 3H, COCH3), 2.48-2.38 (m, 2H), 2.04-1.87 (m, 2H), 1.80-1.67 (m, 2H), 1.52-1.32 (m, 4H), 1.29-1.13 (m, 4H), 1.06-0.90 (m, 8H), 0.86-0.78 (m, 6H). MS (ESI, m/z) 337 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | Stage #1: Isobutyl iodide; 2,4,6-trihydroxyacetophenone With methanol; sodium methylate Reflux; Stage #2: With hydrogenchloride In methanol; water at 0℃; | 4.1. 2-Acetyl-4,4,6-tributyl-3,5-dihydroxycyclohexa-2,5-dienone (6) General procedure: A solution of 2,4,6-trihydroxyacetophenone (4, 595 mg, 3.5 mmol), sodium methoxide (2.5 mL, 11.6 mmol, 25% MeOH solution) and butyl iodide (1.2 mL, 10.6 mmol) in anhydrous MeOH (3 mL) was refluxed overnight. The reaction mixture was cooled to 0 °C and acidified with 1 N aqueous HCl solution, then extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was chromatographed on silica gel with EtOAc-hexane (1:9 to 1:4, v/v) as an eluent to obtain 6 (516 mg, 44%) as colorless solid, which was used directly in the next reaction without recrystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | Stage #1: isopentyl iodide; 2,4,6-trihydroxyacetophenone With methanol; sodium methylate Reflux; Stage #2: With hydrogenchloride In methanol; water at 0℃; | 4.1. 2-Acetyl-4,4,6-tributyl-3,5-dihydroxycyclohexa-2,5-dienone (6) General procedure: A solution of 2,4,6-trihydroxyacetophenone (4, 595 mg, 3.5 mmol), sodium methoxide (2.5 mL, 11.6 mmol, 25% MeOH solution) and butyl iodide (1.2 mL, 10.6 mmol) in anhydrous MeOH (3 mL) was refluxed overnight. The reaction mixture was cooled to 0 °C and acidified with 1 N aqueous HCl solution, then extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was chromatographed on silica gel with EtOAc-hexane (1:9 to 1:4, v/v) as an eluent to obtain 6 (516 mg, 44%) as colorless solid, which was used directly in the next reaction without recrystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | Stage #1: 2,4,6-trihydroxyacetophenone; prenyl bromide With potassium hydroxide In water at 0 - 20℃; for 2.33333h; Inert atmosphere; Stage #2: With hydrogenchloride In water Inert atmosphere; | 4.1. 2-Acetyl-4,4,6-tributyl-3,5-dihydroxycyclohexa-2,5-dienone (6) General procedure: A solution of 2,4,6-trihydroxyacetophenone (4, 595 mg, 3.5 mmol), sodium methoxide (2.5 mL, 11.6 mmol, 25% MeOH solution) and butyl iodide (1.2 mL, 10.6 mmol) in anhydrous MeOH (3 mL) was refluxed overnight. The reaction mixture was cooled to 0 °C and acidified with 1 N aqueous HCl solution, then extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was chromatographed on silica gel with EtOAc-hexane (1:9 to 1:4, v/v) as an eluent to obtain 6 (516 mg, 44%) as colorless solid, which was used directly in the next reaction without recrystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: 2,4,6-trihydroxyacetophenone; 2,3,4,6-tetra-O-benzyl-D-glucopyranose trichloroacetimidate With boron trifluoride diethyl etherate In tetrahydrofuran; dichloromethane at -78 - 55℃; for 9h; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; dichloromethane; water for 0.0833333h; | 3 Example 3; An intermediate III for use in the production of aspalathin was produced as follows.4 -Bis-hydroxy-3-C-(2,3,4,Q-tetra-0-benzyl-^-D-glucopyranosyl)-2- hydroxyacetophenone 111IIITo a solution of 2,3,4,6-tetra-O-benzyl-glycosyl imidate [Formula 6] (2.32 g, 3.4 mmol) in DCM (25 mL) and 2,4,6-trihydroxy-acetophenone (1.6 g, 10 mmol) in THF (3 mL), was added 0.1 mL (1.2 mmol) of BF3OEt2, followed by stirring at -78°C for 2 h. The reaction mixture was warmed up to ambient temperature for 2h, and then refluxed at 55 °C for 5h, after which aqueous NaHC03 (5 mL) was added the reaction mixture was stirred vigorously for 5 min. The resulting mixture was filtered through a short flash celite column, dried over MgS0 and then evaporated in vacuo. The residue was purified by flash-column chromatography on silica gel (4:1 :1 hexane-EtOAc) to give compound III (1.49 g, 48%) as a colourless syrup. Although NMR data was has yet to be obtained for this intermediate, its production is evidenced by the NMR data for compound IV. The product III was acetylated to yield IV to facilitate structure elucidation:IV NMR table for compound IV |
48% | With boron trifluoride diethyl etherate In tetrahydrofuran; dichloromethane at -78 - 55℃; for 9h; Reflux; | 3 Example 3 [0083] An intermediate III for use in the production of aspalathin was produced as follows. Example 3 [0083] An intermediate III for use in the production of aspalathin was produced as follows. RRN 114,6-Bis-hydroxy-3-C-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-2-hydroxyacetophenone III [0084] 2,3,4,6-tetra-O-benzyl-glycosyl imidate [Formula 6] (2.32 g, 3.4 mmol) in DCM (25 mL) and 2,4,6-trihydroxy-acetophenone (1.6 g, 10 mmol) in THF (3 mL), was added 0.1 mL (1.2 mmol) of BF3OEt2, followed by stirring at -78° C. for 2 h. The reaction mixture was warmed up to ambient temperature for 2 h, and then refluxed at 55° C. for 5 h, after which aqueous NaHCO3 (5 mL) was added the reaction mixture was stirred vigorously for 5 min. The resulting mixture was filtered through a short flash celite column, dried over MgSO4 and then evaporated in vacuo. The residue was purified by flash-column chromatography on silica gel (4:1:1 hexane-EtOAc) to give compound III (1.49 g, 48%) as a colourless syrup. [0086] Although NMR data was has yet to be obtained for this intermediate, its production is evidenced by the NMR data for compound IV. The product III was acetylated to yield IV to facilitate structure elucidation: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium carbonate; In ethanol; at 80℃; | 16.8 g (0.1 mol) in a dry 150 mL three-necked flask2,4,6-trihydroxyacetophenone (intermediate S5),Add 250mL of ethanol solution,Further, 28 g (0.2 mol) of potassium carbonate and 38 mL (0.25 mol) of methyl p-toluenesulfonate were added.Heat to 80 C,Reflux for 3h,Stop the reaction,The reaction solution was diluted with 500 mL of water and allowed to stand overnight.Pumping to get a crude product,Recrystallization from methanol gave the compound recrystallized to give white crystals, 13.3 g.The yield was 68%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 2,4,6-trihydroxyacetophenone; tert-butyldimethylsilyl chloride With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Stage #2: With pyridinium p-toluenesulfonate In methanol for 4h; Inert atmosphere; Reflux; | 4.6 Preparation of 2,6-dihydroxy-4-(t-butyldimethylsilyloxy)acetophenone 11 A stirred solution of phloroglucinol hydrate (13.96 g, 75 mmol) and imidazole (15.32 g, 225 mmol) in anhydrous DMF (175 mL) was treated in portions with t-butyldimethylsilyl chloride (24.87 g, 165 mmol), then stirred at room temperature for 1 h and diluted with water (700 mL). The mixture was extracted with ethyl acetate (500 mL, then 2 × 100 mL), and the combined organic extracts were washed with water (2 × 200 mL), dried (MgSO4), and concentrated in vacuo. The residue was dissolved in a minimal volume of dichloromethane and loaded onto a silica gel column and eluted with dichloromethane to afford a mixture of mono-11 and disilylated 12 products after evaporation. This mixture was dissolved in methanol (250 mL) under nitrogen, treated with pyridinium p-toluene sulfonate (3.77 g, 15 mmol), and refluxed for 4 h, then concentrated in vacuo. The residue was dissolved in a minimal volume of dichloromethane and loaded onto a silica gel column and eluted with dichloromethane to afford 2,6-dihydroxy-4-(t-butyldimethylsilyloxy)-acetophenone 11 (21.01 g, 99%) as a pale yellow solid: mp 97-98.5 °C; LC/MS m/z 283 [M+1]; 1H NMR (CDCl3, 400 MHz) δ 0.22 (s, 6H), 0.95 (s, 9H), 2.69 (s, 3H), 5.89 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ -5.2, 17.3, 24.7, 31.9, 99.4, 104.9, 162.0, 162.4, 202.9. Anal. Calcd for C14H22O4Si: C, 59.54; H, 7.85. Found: C, 59.70; H, 7.99. |
Stage #1: 2,4,6-trihydroxyacetophenone; tert-butyldimethylsilyl chloride With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: With pyridinium p-toluenesulfonate In methanol for 2h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.3% | With boron trifluoride diethyl etherate In N,N-dimethyl-formamide at 20 - 90℃; for 3.83h; | 1 Preparation of Compound a (5,7-dihydroxychromone) 5.58 g of 2,4,6-trihydroxyacetophenone was dissolved in 50 ml DMF (N, N'- dimethylformamide), and then at room temperature was added slowly with stirring 15.2 ml of boron trifluoride in 50 minutes diethyl ether complex (purchased from Sinopharm, before re-use steamed), followed by 15 ml of DMF solution containing 6.95 ml of methanesulfonyl chloride. The reaction mixture was stirred for 3 hours at 90 ° C, then cooled to room temperature, poured slowly under vigorous stirring 120 ml of ice water, filtered, washed with water to give 6.8 g of crude product was a dark yellow solid. The filtrate was extracted three times by ethyl acetate, 100 ml each, the combined extracts were purified by column chromatography to give 4.82 g (90 • 3%) of yellow solid Compound a. Melting point: 255 ° C (degradation); |
57% | With boron trifluoride diethyl etherate In N,N-dimethyl-formamide at 90℃; for 3h; | Step A: 5,7-Dihydroxy-4H-chromen-4-one. BF3•Et2O (11.3 mL, 89.6 mmol) was added dropwise to a solution of 1-(2,4,6-trihydroxyphenyl)ethanone (5.0 g, 30 mmol) and DMF (40 mL). The mixture was treated with a solution of methanesulfonyl chloride (14.2 g, 124 mmol) in DMF (10 mL) and then heated at 90 °C for 3 hours before cooling to room temperature and pouring it into ice/water (300 mL) slowly. The solid was isolated via filtration and discarded The filtrate was extracted with ethyl acetate (200 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate, 10:1 to 2:3, gradient elution) to afford the title compound (3.0 g, 57%) as a yellow solid. MS (ESI): mass calcd. for C9H6O4178.03 m/z found 179.0 [M+H]+.1H NMR (400 MHz, acetone-d6) δ 12.77 (s, 1H), 9.72 (s, 1H), 8.06 (d, J=5.9 Hz, 1H), 6.39 (d, J=2.0 Hz, 1H), 6.26 (d, J=2.2 Hz, 1H), 6.22 (d, J=5.9 Hz, 1H). |
53% | Stage #1: 2,4,6-trihydroxyacetophenone With boron trifluoride diethyl etherate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: methanesulfonyl chloride In N,N-dimethyl-formamide at 90℃; for 5h; |
47% | With boron trifluoride diethyl etherate In N,N-dimethyl-formamide at 90℃; for 3h; Inert atmosphere; | |
5% | Stage #1: 2,4,6-trihydroxyacetophenone With boron trifluoride diethyl etherate In N,N-dimethyl-formamide for 0.25h; Stage #2: methanesulfonyl chloride In N,N-dimethyl-formamide at 90℃; for 3h; | 4.1.2 5,7-Dihydroxy-chromen-4-one (5) BF3·Et2O (7.6mL, 60mmol) was added drop wise to a solution of acetylphloroglucinol 1b (2.8g, 15mmol) in anhydrous DMF (25mL) for 15min. A solution of methanesulfonyl chloride (3.5mL, 45mmol) in anhydrous DMF (10mL) was added to the mixture, which was heated at 90°C for 3h, cooled, and slowly poured into ice-water (50mL) under strong stirring. The crude product was filtered off and washed with water to afford the dark yellow solid. The crude product was purified by silica gel chromatography with ethyl acetate and petroleum ether (1:3) to afford 5 as yellow solid. Yield 91.0%, ESI-MS m/z: 179.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With potassium hydroxide In water at 0 - 20℃; for 2.5h; | 85.3 Step 3: preparing 1-[2,4,6-trihydroxy-3,5-di(3-methyl-2-buten-1-yl)phenyl]ethanone Step 3: preparing 1-[2,4,6-trihydroxy-3,5-di(3-methyl-2-buten-1-yl)phenyl]ethanone [0277] 1-(2,4,6-trihydroxyphenyl]ethanone (2.0 mg, 11.9 mmol) was dissolved in a 5% potassium hydroxide aqueous solution (20 mL). After the mixture was cooled below 0° C., isopentenyl bromide (3.6 g, 24 mmol) was slowly added dropwise within 30 min. The reaction mixture was stirred at room temperature for 2 hours, then poured into an ice water and acidified to pH 2. The reaction mixture was extracted with ethyl acetate. The extract was collected and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography (dichloromethane as eluent) to give the desired compound (0.7 g, yield 20%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With zinc(II) chloride In ethyl acetate at 40℃; for 5h; Reflux; | ArCH-4’); 159.3 (ArC-2’); 159.7 (ArC-6’); 205.5 (CH3C=O).1-(2’,4’,6’-Trihydroxy-3’-(3’’-methyl-2’’-buten-1’’-yl)phenyl)ethanone(12) General procedure: The appropriate acetophenone or benzaldehyde (1 mol equiv.) andanhydrous ZnCl2 (2 mol equiv.) were placed in a round-bottom flask anddissolved in ethyl acetate (100 mL). Under vigorous stirring, a solution of3-methyl-2-buten-1-ol (10, 2 mol equiv.) in ethyl acetate (10 mL) was addeddropwise during 1 h at 40 °C. The reaction mixture was then heated to refluxtemperature while the stirring continued. After 2 - 4 h, a pH 1 aqueous HClsolution was added to the reaction mixture to decompose the Zn complex. Then,the organic layer was separated, and a new extraction with ethyl acetate wasperformed. The pooled organic solutions were dried over anhydrous sodiumsulphate and filtered; the solvent was evaporated under reduced pressure.The mixture was subjected to silica gel flash column chromatography (ethylacetate/hexanes as the mobile phase) to yield the products. |
10.1% | Stage #1: 2,4,6-trihydroxyacetophenone; 3-methyl-2-buten-1-ol at 50℃; for 0.25h; Stage #2: With boron trifluoride diethyl etherate In water at 20℃; for 24h; | 4.3. General Procedure for Prenylation of 2-Hydroxyacetophenone Derivatives (III) General procedure: Into round-bottom flasks (10 mL) the 2-Hydroxyacetophenone derivatives 5-9 (4 mmol)were dissolved individually in 3-Methyl-2-buten-1-ol (2 mL, 20 mmol). The resultingmixtures were stirred at 50 C for 15 min to obtain a full homogenization. Then, thereaction mixtures were poured into ice-water, and BF3-Et2O (150 L, 1.20 mmol) was addeddropwise [10]. After the addition of BF3.Et2O, the mixtures were then stirred at roomtemperature for 24 h. The work-up process consisted of an addition of 50 mL water, andsuccessive extractions with dichloromethane. The organic layer was dried over sodiumsulfate and concentrated to dryness. The compounds 14-18 were purified using columnchromatography with silica gel 60, eluting with Hex:AcOEt (2:1) (v/v). The synthesis of14-18 has been achieved in an overall yield of 5.1-12.3%.4.3.1. |
9% | With potassium carbonate In tetrahydrofuran for 48h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With acetic acid; In methanol; for 3.0h;Reflux; | General procedure: To a mixture of 2-(4-chloro-2-methylphenoxyacetic acid) hydrazide (1 mmol) in methanol (25 mL) was added a substituted aldehyde (1 mmol) and 3 drops of glacial acetic acid and the mixture was refluxed for 3 h. After completion of the reaction (TLC analysis), it was cooled and evaporated on a rotary evaporator. The resultant crude product was crystallized from methanol to afford 80%-90% yields of pure product. The structures of synthetic compounds 1-28 were determined by different spectroscopic techniques, including 1H-NMR, and EI MS spectroscopy. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With calcium sulfate; trimethylsilyl trifluoromethanesulfonate In dichloromethane; acetonitrile | |
56% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane; acetonitrile at -40 - 20℃; for 3.5h; Inert atmosphere; | |
56% | With calcium sulfate; trimethylsilyl trifluoromethanesulfonate In dichloromethane; acetonitrile at 0 - 20℃; for 5h; Inert atmosphere; |
41% | Stage #1: 2,3,4,6-Tetra-O-benzyl-D-glucopyranose; 2,4,6-trihydroxyacetophenone In dichloromethane; acetonitrile Inert atmosphere; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane; acetonitrile at -40 - 20℃; for 13h; | Preparation of 3-C-(2',3',4',6'-tetra-O-benzyl-β-D-glucopyranosyl)-2,4,6-trihydroxyacetophenone: A third compound (8.05 g, 14.89 mmol) was added to a 500 mL vial, dissolved in dry dichloromethane (120 mL) and then 2,4,6-trihydroxyacetophenone (4.51 g, 26.80 mmol) Acetonitrile (120mL) solution, argon replacement system,Stir well and mix the system evenly, and cool down to -40 °C.Injection of trimethylsilyl triflate (1.15 mL, 7.44 mmol), low temperature reaction for 1 h,It was then allowed to react to room temperature for 12 h and was quenched with saturated aqueous sodium bicarbonate (30 mL).Distilled water (100 mL) was added and extracted with dichloromethane (100 mL).Separation by column chromatography (200-300 mesh silica gel, mobile phase V (petroleum ether): V (dichloromethane): V (ethyl acetate) = 5:5:1),Dry to obtain a yellow oily liquid fourth compound3-C-(2',3',4',6'-tetra-O-benzyl-β-D-glucopyranosyl)-2,4,6-trihydroxyacetophenone (4.24 g,Yield 41%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With hydrogenchloride In ethanol; water at 20℃; for 72h; | 4′,5,7-Trihydroxyflavanone (1): Method (b3) A mixture of compound 4 (3.36 g, 0.02 mol) and 4-hydroxybenzaldehyde (2.7 g, 0.022 mol) was dissolved in ethanol (20 mL), and 15% aqueous HCl 15 mL was added dropwise. The solution was vigorously stirred for 72 h at room temperature. The precipitate was washed with water and the crude product was purified by a silica-gel column chromatography with petroleum ether and EtOAc (8 : 1) as eluent to give the desired title compound (2.45 g); yield 45%, yellow crystals, m.p. 253-254 °C (lit.26 247-250 °C) 1H NMR (500 MHz, DMSO-d6) (δ, ppm): 12.15 (s, 1H, CH), 10.80 (s, 1H, ArH), 9.60 (s, 1H, ArH), 7.73-7.64 (m, 4H, ArH), 5.87 (s, 2H, OH), 5.48-5.37 (m, 1H, OH), 3.27 (dd, J = 17.2, 12.9 Hz, 1H, CH2), 2.66 (dd, J = 17.0,3.0 Hz, 1H, CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium carbonate In dimethyl sulfoxide at 120℃; | 2-Hydroxy-4,6-dimethoxyacetophenone (3): Method (b2) Compound 4 (2.5 g, 0.015 mol), K2CO3 (1.7 g, 0.01 mol), and DMC (7.5 mL, 0.09 mol) in DMSO (20 mL) were heated at 120 °C until TLC showed that compound 4 had disappeared. Then the mixture was cooled to room temperature and H2O (30 mL) was added. The reaction mixture was neutralised to pH 3-4 with 10% aqueous HCl and the precipitate was filtered and recrystallised from methanol to give compound 3 (2.0 g), yield 69%, white crystals, m.p. 81-82 °C (lit.22 80-81 °C) 1H NMR (500 MHz, DMSO-d6) (δ, ppm): 2.60 (s, 3H,COCH3), 3.81 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.92 (s, 1H, ArH), 6.05 (s, 1H, ArH), 14.02 (s, 1H, OH). IR νmax (KBr/cm-1): 3461 (OH), 1619 (C=O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.83% | With sodium hydrogencarbonate In water at 70℃; for 10h; Inert atmosphere; | 6 4.1.6. 1-(4-(Dimethylamino)-2,6-dihydroxyphenyl)ethanone (17) 4.1.6 1-(4-(Dimethylamino)-2,6-dihydroxyphenyl)ethanone (17) To a mixture of dimethylamine hydrochloride (1.8 g, mmol) and NaHCO3 (1.6 g, 19.05 mmol) in H2O (4 mL), 1-(2,4,6-trihydroxyphenyl)ethanone (15) (200 mg, 1.07 mmol) was added. The reaction mixture was warmed to 70 °C and stirred for 10 h under an argon atmosphere. H2O (10 mL) was added and the reaction mixture was extracted with ethyl acetate (5 mL * 3), the combined organic phases were washed successively with saturated aqueous Na2CO3 (5 mL * 3) and saturated aqueous NaCl (10 mL), dried over sodium sulfate, and filtered. The solvent was evaporated to dryness under reduced pressure. The residue was purified on a silica gel chromatography using CH2Cl2 as eluent, obtaining compound 17; 67.83% yield; white solid; mp 192-193 °C. 1H NMR (400 MHz, CDCl3) δ 5.65 (s, 2H), 3.06 (s, 6H), 2.63 (s, 3H). |
With sodium hydrogencarbonate In water at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With copper(II) oxide In toluene at 110℃; for 2.5h; | 4.2. Representative experimental procedure for preparationof diethyl 6-methyl-2-oxo-2H-pyran-4,5-dicarboxylate (3bb) General procedure: To a magnetically stirred mixture of ethyl acetoacetate (130 mg,1.0mmol) and diethyl acetylenedicarboxylate (204 mg, 1.2mmol) in1.3 mL dry toluene in a 10 mL round bottom flask, CuO (4 mg,0.05 mmol) as a catalyst was added and stirred for 3 h at 110 Ctemperature. The progress of the reaction was monitored by TLC.After completion of the reaction, the solvent was evaporated underreduced pressure, and crude product was purified by column chromatography(using 60e120 mesh silica gel) eluting with 10% ethylacetate in petroleumether to afford 3bb (249 mg, 0.83mmol, 83%) asa colourless liquid; Rf (20% EtOAc/petroleum ether) 0.25; 1H NMR(300MHz,CDCl3) d 6.46(s,1H),4.32(q, J7.2Hz,2H), 4.28(q, J7.2Hz,2H), 2.47 (s, 3H),1.36 (t, J7.2 Hz, 3H),1.29 (t, J7.2 Hz, 3H); 13CNMR(75 MHz, CDCl3) d 166.7, 164.3, 164.2, 159.8, 146.2, 113.6, 109.5, 62.6,62.0, 19.3, 13.9 (2); HRMS calcd for C12H14O6 254.0790, found254.0798; IR (KBr): n1755, 1732, 1632, 1556, 1470, 1446, 1408, 1385,1263, 1180, 1082, 1036, 1016, 951, 876, 862, 777, 629 cm1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With copper(II) oxide In toluene at 110℃; for 2.5h; | 4.2. Representative experimental procedure for preparationof diethyl 6-methyl-2-oxo-2H-pyran-4,5-dicarboxylate (3bb) General procedure: To a magnetically stirred mixture of ethyl acetoacetate (130 mg,1.0mmol) and diethyl acetylenedicarboxylate (204 mg, 1.2mmol) in1.3 mL dry toluene in a 10 mL round bottom flask, CuO (4 mg,0.05 mmol) as a catalyst was added and stirred for 3 h at 110 Ctemperature. The progress of the reaction was monitored by TLC.After completion of the reaction, the solvent was evaporated underreduced pressure, and crude product was purified by column chromatography(using 60e120 mesh silica gel) eluting with 10% ethylacetate in petroleumether to afford 3bb (249 mg, 0.83mmol, 83%) asa colourless liquid; Rf (20% EtOAc/petroleum ether) 0.25; 1H NMR(300MHz,CDCl3) d 6.46(s,1H),4.32(q, J7.2Hz,2H), 4.28(q, J7.2Hz,2H), 2.47 (s, 3H),1.36 (t, J7.2 Hz, 3H),1.29 (t, J7.2 Hz, 3H); 13CNMR(75 MHz, CDCl3) d 166.7, 164.3, 164.2, 159.8, 146.2, 113.6, 109.5, 62.6,62.0, 19.3, 13.9 (2); HRMS calcd for C12H14O6 254.0790, found254.0798; IR (KBr): n1755, 1732, 1632, 1556, 1470, 1446, 1408, 1385,1263, 1180, 1082, 1036, 1016, 951, 876, 862, 777, 629 cm1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With acetic acid In butan-1-ol for 3h; Reflux; | 4-((6-chloro-2-oxoindolin-3-ylidene)methyl)benzohydrazide Schiff bases (5-24) General procedure: Equimolarquantities (1 mmol) of (E)-4-((6-chloro-2-oxoindolin-3-ylidene)methyl)benzohydrazide(5) and appropriate (6-35) substituted benzaldehydes and acetophenone (1 mmol) in of n-butanol (25 mL) were refluxed for 3 h in the presence of catalytic amount of glacial acetic acid. The resulting solid was filtered and crystallized in n-butanol in good yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: 2,4,6-trihydroxyacetophenone; methyl iodide With sodium methylate Stage #2: With hydrogenchloride In water Reflux; | |
67% | With hydrogenchloride; sodium methylate In water Reflux; | |
53% | Stage #1: 2,4,6-trihydroxyacetophenone; methyl iodide With sodium methylate Stage #2: With hydrogenchloride In water Reflux; | 4 The preparation of precursor compound 7 was carried out using phloroglucinol compound 19 and acetyl chloride as starting materials. First, acetyl phloroglucinol was obtained through Friedel's acylation reaction using phloroglucinol compound 19 and acetyl chloride under the catalysis of aluminum trichloride; Acetyl-phloroglucinol is C-methylated under basic conditions, and then protonic acid-catalyzed inverse Claisen condensation can be used to obtain precursor compound syncarpic acid compound 20, With allyl bromide catalyzed by diisopropylethylamine, an allylated intermediate compound 21 is obtained via a C-alkylation reaction. The intermediate compound 21 undergoes intramolecular cation ring closure under PTSA catalysis to generate the tetrahydrofuran intermediate compound 7 (shown by Formula IV). Compound 7 can be converted into secondary alcohol compound 22 by further acid hydrolysis under the lithium aluminum hydrogen reduction condition; compound 22 can be used to obtain target compound 6 through further AZADO oxidation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 10h; Inert atmosphere; | 4 5.1.4 1-(2-hydroxy-4,6-diisopropoxyphenyl)ethanone (7) K2CO3 (9.86 g, 71.37 mmol) and (CH3)2CHI (12.13 g, 71.37 mmol) were added to a stirred solution of 5 (5.00 g, 29.74 mmol) in dry DMF (10 mL). After the addition, the mixture was heated to 60 °C and stirred for 10 h. The reaction was cooled to room temperature, filtered and diluted with ethyl acetate (100 mL) and the resulting solution was poured into aqueous HCl (1 M, 100 mL). The organic layer was separated, washed with brine (3 * 100 mL) and dried over anhydrous Na2SO4. After concentrated to dryness under reduced pressure, the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 100:1) to afford the known compound 7 (6.90 g, 92%) as a yellow oil. |
76% | With potassium carbonate In acetone; acetonitrile at 60℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 14h; | |
49.61% | Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; for 16h; | Preparation of second compound: The first compound (2,4,6-trihydroxyacetophenone) (5.000 g, 26.858 mmol), anhydrous potassium carbonate (12.992 g, 94.003 mmol) was dissolved in 70 mL of dry N,N- Dimethylformamide DMF was stirred at room temperature for 0.5 hour, and then benzyl bromide (11.160 mL, 94.003 mmol) was added dropwise, and the mixture was reacted at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, 70 mL of distilled water was added, and then extracted three times with ethyl acetate 70 mL, and ethyl acetate layer was combined. The ethyl acetate layer was washed three times with water, once with saturated sodium hydrogencarbonate, and once with saturated brine, and then dried. The second compound, 5.843 g (13.325 mmol, 49.61%) was obtained as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 4-chlorophenylethylamine; copper(I) bromide at 5℃; for 35h; Reflux; | 3 In a reaction vessel equipped with a stirrer, a thermometer, and a reflux condenser, both were addedBenzenephenol0.21 mol, 4-chlorophenethylamine0.41 mol, mass55% butyl acetate 200ml, copper bromide 0.025mol, reduce the solution temperature to 5 , control the stirring speed 120rpm, put it aside 35h, filterThe solid was placed in a 3 L reaction vessel and 1.7 L of water was added. The reaction mixture was cooled to & lt; RTI ID = 0.0 & gt;The temperature of the solution was raised to 85 and refluxed for 3.5h. The molecular sieve was decolorized and filtered, and the filter cake was washed with 90% para-xylene solution.Solution and washing solution, reduce the solution temperature to 9 , place 35h, filter out the colorless solid 2.3kPa low pressure drying, 2,4,6-trihydroxyacetophenone 32.46g, yield 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium carbonate / acetone / 0.17 h / 20 °C / Inert atmosphere 1.2: 24 h / 60 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluoroacetic acid / 5 h / 20 °C 3.1: sodium; copper(ll) bromide / N,N-dimethyl-formamide / 1 h / 20 - 120 °C / Inert atmosphere; Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.62% | Stage #1: 2,4,6-trihydroxyacetophenone With potassium carbonate In acetone for 0.5h; Reflux; Stage #2: bis(2-chloromethyl)ether In acetone Reflux; | 1.1 (1) Preparation of 2,4-Dimethoxymethoxy-6-hydroxyacetophenone Dissolve 1 g of 2,4,6-trihydroxyacetophenone in 30 ml of acetone and add 2.88 g of anhydrous potassium carbonate.After stirring at reflux for 30 min, it was cooled slightly, and 1.13 ml of chloromethyl ether was added dropwise. The reflux was continued and the reaction was completed on the TLC plate.The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to give 1.32 g of 2,4-dimethoxymethoxy-6-hydroxyacetophenone in a yield of 86.62%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium methylate In methanol for 0.5h; Cooling with ice; Stage #2: 1-iodo-propane In methanol at 0 - 40℃; for 9h; | 4.2.2. 2-Acetyl-3,5-dihydroxy-4,6,6-triethylcyclohexa-2,4-dienone (2a) and 2-acetyl-3,5-dihydroxy-4,6,6-tripropylcyclohexa-2,4-dienone (2b) General procedure: To the solution of 2, 4, 6-trihydroxyacetophenone (10 g, 59.4 mmol) in anhydrousMeOH (100 ml), was added 30% sodium methoxide (42 ml, 220 mmol) solution underice bath. After stirring for 30 minutes, ethyl bromide (21.2 g, 196.4 mmol) or n-propyliodide (33.4 g, 196.4 mmol) was slowly added to the reaction mixture at 0 C. Thereaction mixture was stirred for 1 h at 0 and at 40 C for 8 h. After the reaction mixturewas cooled to room temperature and poured into ice-cold 1 N HCl, lots of precipitatesappeared at the bottom. Then the precipitate was extracted with EtOAc,washed with brine, dried over Na2SO4 and concentrated under vacuum. The residuewas chromatographed on silica gel with petroleum ether-EtOAc to provide (2a or 2b) (8.9 g, 59.4% or 9.1 g, 52%) as yellow prism. Compounds were characterized by comparingits 1H-NMR and 13C-NMR data with literature values [9]. 2a: ESI-MS m/z:275.12 [MNa]; 2b: ESI-MS m/z: 293.17 [M-H]-. |
52% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium methylate In methanol at 0℃; for 0.5h; Stage #2: 1-iodo-propane In methanol at 0 - 40℃; for 9h; Darkness; | 1.2 Step 1: Preparation of 2-acetyl-3,5-dihydroxy-4,6,6-trialkyl-2,4-cyclohexadienone General procedure: 10.0 g (59.4 mmol) of 2,4.6-trihydroxyacetophenone was placed in a 250 ml single-mouth bottle.Dissolved in 100 ml of methanol,Stir at 0 ° C in a low temperature reactor.42 ml (220 mmol) of a 30% MeONa/MeOH solution was added dropwise to the system using a constant pressure dropping funnel.After stirring for 30 minutes,196.4 mmol of a halogenated C2-6 alkane was added to the reaction liquid (note that the reaction was protected from light), and the reaction was carried out at 0 ° C for 1 hour, and then the temperature was raised to 40 ° C for 8 hours.After TLC monitors the reaction,In the ice bath, 2N hydrochloric acid was added dropwise to the system to acidify to about pH 4.Along with a large amount of precipitation,Extract three times with EtOAc.Combine the organic phase with water,Washed with saturated saline,Dry over anhydrous MgSO4.R/E is dried to give a crude product.Recrystallized from petroleum ether-ethyl acetate system,The target compound was obtained. Wherein R = R1 = R2 = R3 = C2-6 alkyl. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.4% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium methylate In methanol for 0.5h; Cooling with ice; Stage #2: ethyl bromide In methanol at 0 - 40℃; for 9h; | 4.2.2. 2-Acetyl-3,5-dihydroxy-4,6,6-triethylcyclohexa-2,4-dienone (2a) and 2-acetyl-3,5-dihydroxy-4,6,6-tripropylcyclohexa-2,4-dienone (2b) General procedure: To the solution of 2, 4, 6-trihydroxyacetophenone (10 g, 59.4 mmol) in anhydrousMeOH (100 ml), was added 30% sodium methoxide (42 ml, 220 mmol) solution underice bath. After stirring for 30 minutes, ethyl bromide (21.2 g, 196.4 mmol) or n-propyliodide (33.4 g, 196.4 mmol) was slowly added to the reaction mixture at 0 C. Thereaction mixture was stirred for 1 h at 0 and at 40 C for 8 h. After the reaction mixturewas cooled to room temperature and poured into ice-cold 1 N HCl, lots of precipitatesappeared at the bottom. Then the precipitate was extracted with EtOAc,washed with brine, dried over Na2SO4 and concentrated under vacuum. The residuewas chromatographed on silica gel with petroleum ether-EtOAc to provide (2a or 2b) (8.9 g, 59.4% or 9.1 g, 52%) as yellow prism. Compounds were characterized by comparingits 1H-NMR and 13C-NMR data with literature values [9]. 2a: ESI-MS m/z:275.12 [MNa]; 2b: ESI-MS m/z: 293.17 [M-H]-. |
59.4% | Stage #1: 2,4,6-trihydroxyacetophenone With sodium methylate In methanol at 0℃; for 0.5h; Stage #2: ethyl bromide In methanol at 0 - 40℃; for 9h; Darkness; | 1.1 Step 1: Preparation of 2-acetyl-3,5-dihydroxy-4,6,6-trialkyl-2,4-cyclohexadienone General procedure: 10.0 g (59.4 mmol) of 2,4.6-trihydroxyacetophenone was placed in a 250 ml single-mouth bottle.Dissolved in 100 ml of methanol,Stir at 0 ° C in a low temperature reactor.42 ml (220 mmol) of a 30% MeONa/MeOH solution was added dropwise to the system using a constant pressure dropping funnel.After stirring for 30 minutes,196.4 mmol of a halogenated C2-6 alkane was added to the reaction liquid (note that the reaction was protected from light), and the reaction was carried out at 0 ° C for 1 hour, and then the temperature was raised to 40 ° C for 8 hours.After TLC monitors the reaction,In the ice bath, 2N hydrochloric acid was added dropwise to the system to acidify to about pH 4.Along with a large amount of precipitation,Extract three times with EtOAc.Combine the organic phase with water,Washed with saturated saline,Dry over anhydrous MgSO4.R/E is dried to give a crude product.Recrystallized from petroleum ether-ethyl acetate system,The target compound was obtained. Wherein R = R1 = R2 = R3 = C2-6 alkyl. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With potassium hydroxide In methanol at 20℃; for 25h; Cooling with ice; | S1 Synthesis of S1,6-acetyl-5,7-dihydroxy-2-methyl-(4'-methyl-3'-pentenyl)-dihydro-1-benzopyran (2) 2,4,6-Trihydroxyacetophenone monohydrate 1 (3.7232 g, 20 mmol) was added to a 250 mL single-mouth flask, and added with CH3OH (80 mL) until the solute was completely dissolved. 97% citral (3.7665 g, 24 mmol) was added, and KOH (3.3600 g, 60 mmol) was dissolved in CH3OH (10 mL) and added dropwise in an ice-water bath. After 1h, it was warmed to room temperature and stirred for 24 h.The reaction was monitored by a thin layer chromatography plate, and the reaction was quenched by dropwise addition of a 3 mol/L hydrochloric acid solution.Adjust to solution Ph=3~4, extract with ethyl acetate (3×40 mL), the combined organic phases were washed with water (2×20 mL) and brine (1×20 mL).The organic phase was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. column chromatography gave compound 2 (1.9932 g, 6.6 mmol) as pale yellow oil. the yield was 33%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With sodium hydroxide In water; isopropyl alcohol at 75℃; for 10h; Inert atmosphere; | 1.1 Example 1: Preparation of Compound Y-1: Step (1): Take (1.379 g, 8.2 mmol) of substituted acetophenone F-1 and (0.536 g, 4 mmol) of m-xylylene formaldehyde in 10 mL of propanol, and add sodium hydroxide dropwise under nitrogen protection and ice-water bath The solution (7.2 g in 8 mL of water) was heated to 75 ° C, and the reaction was maintained at this temperature for 10 hours. 10% hydrochloric acid was added to neutralize it to about pH 7, and extraction was performed with dichloromethane, followed by silica gel column chromatography (eluent: ethyl acetate: petroleum ether (60-90 ° C) = 20: 1) to obtain 1.01 g Chalcone M-1 with a yield of 58% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | Stage #1: 4-amino-benzoic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Stage #2: 2,4,6-trihydroxyacetophenone In dichloromethane for 16h; | 1 Preparation of compound 1-1: 1.2 equivalents of p-aminobenzoic acid (4.28 mmol, 587.22 mg), 1.5 equivalents of EDAC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) (5.35 mmol, 830.94 mg), 0.15 equivalent of DMAP (4-dimethylaminopyridine) (535.24mol, 65.39mg) was dissolved in dichloromethane and stirred at room temperature for 30min, then 1 equivalent of 2,4,6-trihydroxyacetophenone was added to dissolve (3.57 mmol, 600 mg), react for 16 hours. No substrate was found by TLC detection. Triethylamine was added and stirred overnight. After the reaction was completed, the solvent was spin-dried. The crude sample was purified by silica gel column (n-hexane:ethyl acetate=3:1, volume ratio). Then a white solid 1-1 was obtained with a reaction yield of about 15%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: 2,4,6-trihydroxyacetophenone; 4-nitro-benzoyl chloride With potassium carbonate In dichloromethane; water at 50℃; for 0.5h; Stage #2: With tetrabutylammomium bromide In dichloromethane; water for 3h; Reflux; | 4.1.2.2 1-(4-Nitrophenyl)-3-(2, 4, 6-trihydroxyphenyl)propane-1, 3-dione (3a) 2 was dissolved (2.92g, 17mmol) in 50mL anhydrous CH2Cl2 and then p-nitrobenzol chloride (13.20g, 70mmol) and saturated potassium carbonate aqueous (50mL) were added to the mixture. The reaction mixture was heated to 50°C and kept stirring for 0.5h. After adding TBAB (3.38g, 26mmol), the reaction mixture was kept refluxing for another 3h and then cooled down to rt, the precipitate was separate out. Then the filtrate was extracted with 40mL DCM for twice. The organic layer was combined and rinsed by water together with brine, dried over anhydrous Na2SO4 and rotary evaporation was performed to concentrate the solvent, The crude product was purified by silica gel column chromatography to obtain a yellow solid (5g, 46%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: 2,4,6-trihydroxyacetophenone; 4-hydroxy-benzaldehyde With potassium hydroxide In ethanol at 20℃; for 4h; Stage #2: With iodine In dimethyl sulfoxide at 110℃; for 8h; | 40 Example 40 1-((5,7-Dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromium-8-yl)methyl)piperidine-4-carboxylic acid methyl ester (Compound 40) VI-1 (1.6g, 0.01mol) was dissolved in absolute ethanol, and potassium hydroxide solid (2.8g, 0.05mol) was added under vigorous stirring at room temperature, and the color of the reaction system gradually turned red. After 4h, adjust the PH=5 with 2M hydrochloric acid. During the process, a yellow solid was gradually precipitated. After dilution with water (200mL), the solid was filtered out and used directly after drying. The intermediate obtained in the previous reaction was dissolved in anhydrous dimethyl sulfoxide (30mL), and iodine (0.13g, 0.5mmol) was added as a catalyst, and then reacted at 110°C for 8h. After the reaction, the reaction was cooled to At room temperature, 10% sodium thiosulfate solution (50mL) was added. After 10 minutes, the mixture was extracted with ethyl acetate/water system. The organic phase was taken, dried and spin-dried. The residue was purified by silica gel chromatography to obtain VII-1 ( 1.3g, the two-step yield is 48%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: 2,4,6-trihydroxyacetophenone; sodium methylate; methyl iodide With boron trifluoride diethyl etherate In methanol at 20℃; for 24h; Stage #2: With hydrogenchloride for 24h; Reflux; | 3. Applied synthesis of natural phytohormone G3 factor To a mixture of phloroglucinol (2.58 g) and Ac2O (4.5 mL) in EtOAc (14 mL) was added BF3•Et2O (3 mL), then stirred at 50 °C for 10 h. Water (38 mL) was added and the aqueous solution was extracted with EtOAc. The solvent was removed in vacuo and the residue was separated by column chromatography on silica gel eluting with EtOAc/hexane (50:50 v/v) to form the acetylphloroglucinol (1.88 g, 55% yield). The obtained acetylphloroglucinol (0.44 g) and NaOMe (1.03 g) were dissolved in dry MeOH (40 mL) and methyl iodide (1 mL) was added. The mixture was stirred at room temperature for 24 h, then acidified with 2 M HCl. The resulting mixture was extracted with EtOAc, the combined extracts were dried over anhydrous MgSO4, then concentrated to dryness. To the obtained residue was added 6 M HCl (40 mL) and heated under reflux for 24 h and extracted with EtOAc. Separation using EtOAc/hexane (50:50 v/v) was performed affording syncarpic acid (0.27 g, 56% yield in two steps). Syncarpic acid (53.6 mg, 0.29 mmol) and piperidine (0.2 mL) were dissolved in dry CH2Cl2 (10 mL), then isobutyraldehyde (0.2 mL) was added. The mixture was stirred for 10 min at room temperature under an argon atmosphere. The solvent was removed in vacuo, and the residue was dissolved in CH2Cl2 (10 mL). The solution was treated with a saturated aqueous solution of NH4Cl in 1 M HCl (6 mL) at room temperature for 30 min. The resulting mixture was extracted with CHCl3, and the combined extracts were washed with water, dried over anhydrous MgSO4, and concentrated to dryness. The obtained isopropenylcyclohexanetrione intermediate G without purification was dissolved in AcOH (10 mL), then Mn(OAc)3•2H2O (0.4 mg, 0.0016 mmol) was added. The mixture was stirred at room temperature in a dry air stream for 24 h. Water (10 mL) was added, the aqueous solution was extracted with CHCl3, the combined extracts were washed with a saturated aqueous solution of NaHCO3, water, dried over anhydrous MgSO4, and concentrated to dryness. The crude product was purified by column chromatography on silica gel eluting with EtOAc/hexane (2:8 v/v), giving G3 factor (48.4 mg, 61% yield in three steps). |
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H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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