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CAS No. : | 118-71-8 | MDL No. : | MFCD00006578 |
Formula : | C6H6O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XPCTZQVDEJYUGT-UHFFFAOYSA-N |
M.W : | 126.11 | Pubchem ID : | 8369 |
Synonyms : |
Larixinic acid;Palatone;Veltol
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.17 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 31.97 |
TPSA : | 50.44 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.01 cm/s |
Log Po/w (iLOGP) : | 1.47 |
Log Po/w (XLOGP3) : | 0.09 |
Log Po/w (WLOGP) : | 0.65 |
Log Po/w (MLOGP) : | -0.84 |
Log Po/w (SILICOS-IT) : | 1.36 |
Consensus Log Po/w : | 0.55 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.17 |
Solubility : | 8.49 mg/ml ; 0.0673 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.7 |
Solubility : | 24.9 mg/ml ; 0.198 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.71 |
Solubility : | 2.48 mg/ml ; 0.0197 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.39 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P501-P270-P202-P201-P264-P280-P302+P352-P308+P313-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330-P405 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H341 | 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 |
---|---|---|
65.73% | (1) feedingIn a four-necked flask equipped with a stirrer, a thermometer and a ventilation tube were placed 350 g of an ethanol solution, 50 g of 1- (2-furyl) ethanol,1.1 g of chromium 7% molybdenum-silica molecular sieve doped with 0.5% silver and 1.15 g of 201x7 FC ion-exchange resin catalyst were added.(2) the first stage oxidation reactionWater bath heating control reaction temperature is 110 C, at the bottom of the reaction flask oxygen containing 30% oxygen and nitrogen gas mixture,The reaction was detected by gas chromatography for a period of time when the reaction material 1- (2-furyl) ethanol content of less than 0.5%, cooling.(3) the second stage oxidation reactionWhen the reaction temperature dropped to 30 when the oxygen content of 90% of the oxygen mixture of nitrogen and nitrogen, the reaction 2.5h, stop the reaction.(4) hydrolysisThe reaction mixture was filtered to remove the catalyst, 10% aqueous sulfuric acid was added to adjust the pH to between 2.5 and 3,Into the reactor heated to 95 heated 2.5h.(5) Post-processingDistillation after the removal of methanol off, vacuum distillation of the product Ethyl maltol, after recrystallization products, the yield was 65.73%;After repeated application of the catalyst in 10 batches, the yield was 64.32%. | |
53% | In tetrahydrofuran; water; bromine; | EXAMPLE 7 To a 4-neck round bottom flask equipped with a thermometer, a condensor and two addition funnels was charged 50 ml of tetrahydrofuran and 50 ml of water and the solution was cooled to 10 C. To this well stirred solution was added together in the two addition funnels bromine (0.20 mole) and 1(2-furyl)-1-ethanol (0.09 mole). The temperature of the reaction was maintained at 15 C. throughout the double addition. The reaction mixture was then heated to 75 C. for 10 hours. Maltol was isolated by the procedure of Example 1 (53% yield). |
With bromine; chlorine; In tetrahydrofuran; water; | EXAMPLE 6 In a 3-neck round bottom flask equipped with a magnetic stirring bar, a gas inlet tube, a thermometer and an addition funnel was added 50 ml of tetrahydrofuran and 50 ml of water. This solution was then cooled to 0 C. and chlorine (0.10 mole) was added slowly to the reaction flask while 1(2-furyl)-1-ethanol (0.09 mole) was added dropwise. The temperature of the reaction mixture was not allowed to exceed 10 C. Bromine (0.10 mole) was then added and the reaction mixture heated to reflux. Following the isolation procedure of Example 1, a yield of 5.7 g of maltol was obtained. |
With sodium hypochlorite; chlorine; In tetrahydrofuran; water; | EXAMPLE 10 To a solution of 1(2-furyl)-1-ethanol (0.05 mole) in 15 ml of tetrahydrofuran and 15 ml of water at 5 C. is added 21.7 ml of 2.8 M sodium hypochlorite solution. Chlorine (0.05 mole) is added to the reaction flask via a gas inlet tube maintaining the reaction temperature below 5 C. The reaction mixture is then heated to reflux and the tetrahydrofuran removed by distillation. Heating is continued for an additional hour. The reaction mixture is cooled and maltol is isolated by the procedure described in Example 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate In N,N-dimethyl-formamide | 5 Starting material, 4-chloro-2-methyl-3-trideuteriomethoxypyridine-Λ/-oxide was prepared according to method D for the non-deuterated analogue in J. Med. Chem. 1992, 35, 1049-1057: Starting from 3-hydroxy-2-methyl-4-pyrone, conversion with trideuterio-iodomethane in the presence of potassium carbonate in DMF yielded 2-methyl-3-trideuteriomethoxy-4-pyrone (yield: 83-96%), which upon heating with ammonia at 150 0C in ethanol gave, after crystallization from acetone/isopropanol 4:1 ; 4-hydroxy-2-methyl-trideuteriomethoxypyridine (yield: 52-60%). Treatment of this material with phosphorus oxychloride led to formation of 4-chloro-2-methyl-trideuteriomethoxypyridine (yield: 64- 81 %). Subsequent oxidation with hydrogen peroxide in acetic acid gave 4-chloro-2-methyl-3- trideuteriomethoxypyridine-Λ/-oxide as a slightly yellow solid (yield: 87-89%).The final transformations via 4-chloro-2-hydroxymethyl-3-trideuteriomethoxypyridine were carried out as described under Example 4 to give 4-chloro-2-chloromethyl-3-trideuteriomethoxypyridinium chloride as a colorless crystalline solid (m. p. 129-130 0C); yield 19.6 g (42%). |
83% | With potassium carbonate In N,N-dimethyl-formamide | 10 Starting material, 4-chloro-2-methyl-3-trideuteriomethoxypyridine-Λ/-oxide was prepared according to method D for the non-deuterated analogue in J. Med. Chem. 1992, 35, 1049-1057: Starting from 3-hydroxy-2-methyl-4-pyrone, conversion with trideuterio-iodomethane in the presence of potassium carbonate in DMF yielded 2-methyl-3-trideuteriomethoxy-4-pyrone (yield: 83-96%), which upon heating with ammonia at 150 0C in ethanol gave, after crystallization from acetone/isopropanol 4:1 ; 4-hydroxy-2-methyl-trideuteriomethoxypyridine (yield: 52-60%). Treatment of this material with phosphorus oxychloride led to formation of 4-chloro-2-methyl-trideuteriomethoxypyridine (yield: 64- 81%). Subsequent oxidation with hydrogen peroxide in acetic acid gave 4-chloro-2-methyl-3- trideuteriomethoxypyridine-Λ/-oxide as a slightly yellow solid (yield: 87-89%).The final transformations via 4-chloro-2-hydroxymethyl-3-trideuteriomethoxypyridine were carried out as described under Example 9 to give 4-chloro-2-chloromethyl-3-trideuteriomethoxypyridinium chloride as a colorless crystalline solid (m. p. 129-130 0C); yield 19.6 g (42%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 1.25h; Inert atmosphere; | |
100% | Stage #1: Maltol; benzyl bromide In N,N-dimethyl-formamide at 80℃; for 0.25h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide for 1h; | A-1.1; B-1.1 1) Mantol 1 (I 89g, 1,5mol) was dissolved in dimethylformamide (1890ml), and benzyl bromide (184ml, l,5mol) was added, Aftor the solution was stirred at 80°C for 15 minutes, potassium carbonate (228g, 1.65mol) was added, and the mixture was stirred for J hour, Aftor the reaction solution was cooled I o room temperature, an inorganic salt was filtered, and the filtrate was distilled off under reduced pressure. To the again precipitated inorganic salt was added tetrahydrofuran (1000ml), this was filtered, and the filtrate was distilled off tinder reduced pressure to obtain the crude product (329g, >100%) of 3-benzyloxy-2-methyl-pyran-4-one 2 as a brown oil.NMR (CDClβ)δ: 2.09(3H, s), 5.15(2H, s), 6.36(1PI, d, J=5.6Hz) , 7.29-7.4l(5H, m), 7,60(1H, d, J=5.61Iz) . |
100% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; | 1 Compounds of formula I are protected by benzyl to give compounds of formula II 189 g of a compound of formula I is dissolved in 1890 mL of N,N-dimethylformamide,Add 184 mL of benzyl bromide, 228 g of potassium carbonate, heat to 80 ° C, and keep for 2 hours.Thin layer chromatography was used to detect complete conversion of the starting material and to cool to room temperature.Add 1000 mL of tetrahydrofuran and filter to remove inorganic impurities.The filtrate was spun dry to give 329 gWhite solid, yield 100%. |
99% | With potassium hydroxide In methanol Ambient temperature; | |
99% | With potassium carbonate In acetone for 6h; Reflux; | 4.1.2 General procedures for the preparation of compounds 2a-c and 7a-b General procedure: A solution of maltol 1 or 6 (60 mmol), iodomethane or benzyl bromide or 4-methoxylbenzyl chloride (90 mmol), anhydrous K2CO3 (12.42 g, 90 mmol) and acetone (150 mL) was refluxed for 6 h. After the reaction was completed, the reaction mixture was evaporated under vacuum, and the residual was resolved in water (100 mL), extracted by DCM (4×100 mL) and washed by saturated brine (2×100 mL). The organic solution was evaporated to dryness to obtain 2a-c as yellow oil, 7a-b as white solid. |
99% | With potassium carbonate In acetone for 6h; Reflux; | 4; 7-11 preparation method N-(2-(2-Methyl-3-hydroxy-1(4H)-4-oxopyridyl)ethyl)-7-methoxy-2-oxo-2H-benzopyran-3 -Formamide (a2b1) Add maltol (7.56g, 60mmol), benzyl bromide (15.39g, 90mmol), anhydrous potassium carbonate (12.42g, 90mmol), acetone (100mL) into a 250mL single-necked flask, heat and reflux for 6 hours, TLC monitor the reaction, wait After the conversion of the raw materials is complete, stop the reaction, concentrate the reaction solution to obtain a solid, add 100 mL of water to dissolve, extract with 100 mL×4 dichloromethane, combine the organic layers, dry the organic layers with anhydrous sodium sulfate, and concentrate to obtain a yellow oily liquid 2-methyl -3-benzyloxypyran-4-one (12.83g), yield 99%. |
98% | In acetone for 6h; Reflux; | 3-8 Add maltol (7.56g, 60mmol) and acetone 100mL to a 250mL single-mouth bottle.Benzyl bromide (11.29g, 66mmol), heated under reflux for 6 hours, after the reaction was completed, cooled to room temperature, then the solvent was evaporated, dissolved in 100 mL of water, and extracted with dichloromethane (50 mL) 4 times.The organic layer was dried over anhydrous sodium sulfate.The organic layer was concentrated to give 2-methyl-3-benzyloxypyranone. The yield was 98%. |
95% | With potassium carbonate In acetonitrile for 16h; Reflux; | 36 4.2.36 3-(Benzyloxy)-2-methyl-4H-pyran-4-one (47) Potassium carbonate (4.8g, 35mmol) and benzyl bromide (1.3mL, 1.9g, 11mmol) were added to a solution of 3-hydroxy-2-methyl-4H-pyran-4-one (1.1g, 8.7mmol) in dry acetonitrile (50mL). After heating the mixture to reflux for 16h, water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was purified by flash column chromatography (=4cm, h=15cm, cyclohexane/ethyl acetate=8:2→2:1, V=30mL) to give 47 as yellowish oil (1.8g, 8.3mmol, 95% yield). Rf=0.49 (cyclohexane/ethyl acetate=1:1); 1H NMR (CDCl3): δ [ppm]=2.11 (s, 3H, CH3), 5.16 (s, 2H, OCH2Ph), 6.50 (d, J=5.6Hz, 1H, OCH=CHCO), 7.30-7.36 (m, 3H, 3′-Hphenyl, 4′-Hphenyl, 5′-Hphenyl), 7.37-7.40 (m, 2H, 2′-Hphenyl, 6′-Hphenyl), 7.64 (d, J=5.6Hz, 1H, OCH=CHCO); 13C NMR (CDCl3) δ [ppm]=15.0 (1C, CH3), 73.8 (1C, OCH2Ph), 117.0 (1C, OCH=CHCO), 128.5 (1C, C-4′phenyl), 128.6 (2C, C-3′phenyl, C-5′phenyl), 129.2 (2C, C-2′phenyl, C-6′phenyl), 136.9 (1C, C-1′phenyl), 143.8 (1C, OC=CCH3), 153.8 (1C, OCH=CHCO), 160.6 (1C, OC=CCH3) 175.3 (1C, OCH=CHCO); IR (neat): [cm-1]=3063, 3028, 2959, 2882, 1643, 1574, 1497, 1427, 1389, 1354, 1250, 1173, 1080, 1026, 972, 914, 829, 748, 702; LCMS (m/z): [M+H]+ calcd for C13H13O3: 217.0859, found: 217.0875; HPLC (method 1): tR=17.2min, purity 97.9%. |
93% | With sodium hydroxide In methanol for 16h; Heating; | |
93% | With sodium hydroxide In methanol for 16h; Heating; | |
93% | With sodium hydroxide In methanol at 75℃; for 6h; Reflux; | Synthesis of 3-benzyloxy-2-methyl-4-pyrone (1). To a solution of 10.00 g 3-hydroxy-2-methyl-4-pyrone(79 mmol) containing the equivalent amount of NaOH (3.16 g, 79 mmol) in 100 mL methanol, 13 mLbenzyl bromide (90 mmol) was dropwise added and then stirred for 6 h under reflux temperature.After cooling, the reaction mixture was evaporated under vacuum, and the residual oil was resolvedin 50 mL dichloromethane and washed with 5% NaOH aqueous solution (5 x 30 mL) and water(3 x 50 mL). The organic solution was evaporated to dryness to obtain the pure product as pale oil(15.7 g, 93%). UV-vis (CH3OH): λmax = 219, 260 nm. FT-IR (KBr): ν = 3065, 3031, 2958, 2877, 1644, 1575,1496, 1455, 1428, 1253, 1186, 1079, 973, 915, 832, 751, 703 cm-1. 1H NMR (300 MHz, CDCl3): δ=7.57 (d,J = 6.0 Hz, 1H), 7.25-7.40 (m, 5H), 6.33 (d, J = 6.0 Hz, 1H), 5.13 (s, 2H, CH2Ph), 2.06 (s, 3H, CH3) ppm.MS (APCI, CH3OH) m/z (%) = 217 (100) [M + H]+. C13H12O3 (216.3): calcd. C 72.22, H 5.56; found: C72.43, H 5.47. |
89% | With sodium hydroxide In methanol; water for 20h; Reflux; | |
87% | With sodium hydroxide In methanol; water for 24h; Reflux; | |
83% | With sodium hydroxide In methanol at 75℃; | |
83% | With sodium hydroxide In methanol at 75℃; | a a) BnBr, NaOH(aq), MeOH, 75 C, 83%; |
81% | With sodium hydroxide In methanol; water for 6h; Reflux; | 2-Methyl-3-benzyloxy-4-(4H)-pyranone (7) To a solution of maltol (50 g, 0.397 mol) in methanol (450 mL) was added aq sodium hydroxide (8.7 M, 50 mL of) and benzylbromide (74.66 g, 0.437 mol). The reaction mixture was heated to reflux for 6 h. After removal of solvent in vacuo, the oily residue was taken up in DCM (190 mL), washed with aq sodium hydroxide (5%, 2 × 190 mL) and water (2 × 190 mL). The organic fraction was dried over anhydrous sodium sulfate, filtered and concentrated to yield as an orange oil which solidified upon cooling. Recrystallization from Et2O gave 69.9 g of 7 as colorless needles (81% yield). Mp: 33-34 °C. 1H NMR (90 MHz, DMSO-d6, ppm) δ: 1.99 (s, 3H, CH3), 5.00 (s, 2H, CH2), 6.14-6.24 (m, 1H, ArCH), 7.20 (s, 5H, 5 × ArCH), 7.39-7.49 (m, 1H, ArCH). |
80% | With sodium hydroxide In methanol; water Heating; | |
80% | Stage #1: Maltol With sodium hydroxide In methanol; water Heating / reflux; Stage #2: benzyl bromide In methanol; water for 6h; Heating / reflux; | 1.a To a solution of maltol (1) (1Og, 0.079mol) in methanol (2OmL) was added sodium hydroxide (3.49g, 0.087mol, l.lequiv.) in water (1OmL). The reaction mixture was heated to reflux before benzyl bromide (10.4mL, 0.087mol, l.lequiv.) was slowly introduced dropwise and the mixture was left to reflux for 6 hours. After the solvent was removed, the residue was taken into water and dichloromethane. The aqueous fraction was discarded and the organic fraction washed with sodium hydroxide 5% (3?) followed by water (2?). The combined fractions were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Re-crystallisation from diethyl ether afforded off-white crystals, mp 54-56°C. Yield 80%. 1H NMR (CDCl3) ? 2.07 (3H, s, CH3), 5.15 (2H, s, CH2Ph), 6.36 (IH, d, J=5.7 Hz, 5-H), 7.31- 7.40 (5?, m, CR2Ph), 7.59 (IH5 d, J=5.7 Hz, 6-.H). C13H13O3. |
80% | Stage #1: Maltol With sodium hydroxide In methanol; water Reflux; Stage #2: benzyl bromide In methanol; water for 6h; Reflux; | 4.1.1. 2-Methyl-3-benzyloxypyran-4(1H)-one (2) To a solution of maltol (1) (10 g, 0.079 mol) in methanol (20 mL) was added sodium hydroxide (3.49 g, 0.087 mol, 1.1 equiv) in water (10 mL). The reaction mixture was heated to reflux before benzyl bromide (10.4 mL, 0.087 mol, 1.1 equiv) was slowly introduced dropwise and the mixture was left to reflux for 6 h. After the solvent was removed, the residue was taken into water and dichloromethane. The aqueous fraction was discarded and the organic fraction washed with sodium hydroxide 5% (3×) followed by water (2×). The combined fractions were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Re-crystallisation from diethyl ether afforded off-white crystals, mp 54-56 °C. Yield 80%. 1H NMR (CDCl3) δ 2.07 (3H, s, CH3), 5.15 (2H, s, CH2Ph), 6.36 (1H, d, J = 5.7 Hz, 5-H), 7.31-7.40 (5H, m, CH2Ph), 7.59 (1H, d, J = 5.7 Hz, 6-H); m/z (ESI): 202.0. |
80% | With potassium carbonate In acetone at 0 - 20℃; for 16h; | 8 Synthesis of compound 8b At 0°C, 8.22g of anhydrous K2CO3and 5.7 mL of benzyl bromide were sequentially added to a solution of 5 g of compound 8a in acetone (80 mL), and the reaction was moved to room temperature for 16 hours. After the reaction was completed, it was concentrated, and ethyl acetate and Water, separated the layers, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, concentrated, and separated by column chromatography to obtain 6.90 g of compound 8b, yield: 80%. |
75% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; | |
75% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; | 3 To a 500 mL flask with 10.0 g (0.08 mol) of maltol (3-hydroxy-2-methyl-4H-pyran-4-one) in 120 mL of anhydrous DMF was added 14.1 mL (0.12 mol) of benzyl bromide and potassium carbonate (16.4 g, 0.12 mol) and heated at 80° C. overnight. After cooling to room temperature, the reaction was filtered and the solvents evaporated. The residual oil was brought up in 100 mL CH2Cl2 and washed twice with a saturated NaHCO3 solution, water, and brine. The organic layer was dried over MgSO4, filtered and concentrated. Product was purified on a silica gel column eluting with 0.5% MeOH in CH2Cl2 to yield a pale yellow solid in 75% yield (12.8 g, 59 mmol). 1H NMR (400 MHz, CDCl3) δ=7.59 (d, J=5.6 Hz, 1H), 7.36 (m, 5H), 6.36 (d, J=5.6 Hz, 1H), 5.15 (s, 2H, OCH2), 2.08 (s, 3H, CH3). ESI-MS(+): m/z 217.03 [M+H]+, 239.07 [M+Na]+. |
With potassium carbonate In acetone for 72h; Ambient temperature; | ||
With sodium In methanol; water; ethyl acetate | 1 2-Methyl-3-(phenylmethoxy)-4H-pyran-4-one EXAMPLE 1 2-Methyl-3-(phenylmethoxy)-4H-pyran-4-one 11.5 g of sodium were dissolved in 300 ml CH3 OH and 63g of maltol were added and stirred at room temperature for one hour. 200 ml CH3 OH were added and then 102 g benzylbromide were dropped in (30 minutes). Refluxing for 3 hours and distilling off the CH3 OH then yielded a residue which was dissolved in 300 ml H2 O/300 ml ethyl acetate. The organic phase was washed with water and evaporated. The remaining oil was distilled in vacuo. B.P. (43 mm) =148°-150° C., 81.5 g colorless oil of the title compound was isolated. | |
With sodium In methanol; water; ethyl acetate | 1 2-Methyl-3-(phenylmethoxy)-4H-pyran-4-one Example 1 2-Methyl-3-(phenylmethoxy)-4H-pyran-4-one 11.5g of sodium were dissolved in 300ml CH3OH and 63g of maltol were added and stirred at room temperature for one hour. 200ml CH3OH were added and then 102g benzylbromide were dropped in (30 minutes). Refluxing for 3 hours and distilling off the CH3OH then yielded a residue which was dissolved in 300ml H2O/300ml ethyl acetate. The organic phase was washed with water and evaporated. The remaining oil was distilled in vacuo. B.P. (43mm) = 148-150°C, 81.5g colorless oil of the title compound was isolated. | |
With potassium carbonate In acetonitrile at 23 - 80℃; | A Example A; Maltol to Benzylmaltol 2a; Maltol: 200OgBnBr: [MW=171.04, d=1.444] 2848.2g (1..05eq) K2CO3 [MW=138.21] 2630.3g (1.2eq) MeCN 14L 7VTo the solution of 200Og of Maltol in MeCN (14L) was added BnBr (2848.2g) and K2CO3 (2630.3g) at room temperature, (around 23°C) After addition of reagent, the temperature of the reaction mixture was getting high.This reaction mixture was kept at 80°C for 5hr and then cooled down to room temperature.The reaction mixture was filtered and washed with MeCN (3L, 1L, 1L). Filtration was concentrated and added THF 2L and concentrated again, (check the KF 1.33%).THF 1.5L was added to the residue and concentrate again. (KF= 0.135%) The residue 2a : 3648g | |
With potassium carbonate In acetonitrile at 80℃; for 5h; | 1a To a slurry of 200O g of compound 1(1.0 eq.) in 14.0 L of MeCN were added 2848 g of benzyl bromide(1.05 eq.) and 2630 g of K2CO3(1.2 eq.). The mixture was stirred at 80 0C for 5 h and cooled to 13°C. Precipitate was filtered and washed with 5.0 L of MeCN. The filtrate was concentrated and 3.0 L of THF was added to the residue. The THF solution was concentrated to give 3585 g of crude compound 2 as oil. Without further purification, compound 2 was used in the next step.1H NMR(300 MHz, CDCI3) δ 7.60 (d, J = 5.7 Hz, 1H), 7.4-7.3 (m, 5H), 6.37 (d, J = 5.7 Hz, 1H), 5.17 (S, 2H), 2.09 (s, 3H). | |
With potassium carbonate In acetonitrile at 70℃; for 7h; Inert atmosphere; | ||
2.3 g | Stage #1: Maltol With potassium carbonate In N,N-dimethyl-formamide at 22 - 26℃; for 0.5h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 22 - 26℃; for 6h; | 1 Intermediate- 11 Methyl 2-((2-chloro-6-fluorophenyl)amino)-l-methyl-7,8-dihydro-lH- [l,4]dioxino[2,3-d]imidazo[ -b]pyridine-5-carboxylate Step-1 : -Preparation of 3-(benzylo -2-methyl-4H-pyran-4-one To a solution of 3-hydroxy-2-methyl-4H-pyran-4-one (2.0g, 0.0158 mol) in DMF (10 mL) was added potassium carbonate (2.6 g, 0.0189 mol). The reaction mass was stirred at RT for 30 minutes. The reaction mixture was added benzyl bromide (2.98 g, 0.017 mol) and continued stirring for 6 h at RT. After completion of reaction, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulphate and concentrated to afford 2.3 g of desired product. 1H NMR (DMSO- 6): δ 2.10 (s, 3Η), 5.0 (s, 2Η), ), 6.37 (d, J = 9.30 Hz, 1H), 7.60-7.30 (m, 5H), 8.07 (d, J= 6.0Hz, 1H), MS [M+H]+ : 258.08. |
155 g | With potassium carbonate In acetonitrile at 80℃; for 3h; | 1 Example 1: Preparation of 3-(benzyloxy)-2-methyl-4H-pyran-4-one Example 1: Preparation of 3-(benzyloxy)-2-methyl-4H-pyran-4-one Maltol (100 gm) was dissolved in acetonitrile (600 ml) and potassium carbonate (153 gm) and benzyl bromide (116 ml) was added to the solution. The contents were heated to 80°C and stirred for 3 hours. The reaction mass was cooled to room temperature and filtered. The solvent was distilled off from the filtrate thus obtained under reduced pressure to obtain 155 gm of 3-(benzyloxy)-2-methyl-4H-pyran-4-one. |
With potassium carbonate In acetonitrile Inert atmosphere; Reflux; Large scale; | 1.A Step A - Synthesis of Intermediate Compound lb Step A - Synthesis of Intermediate Compound lb To a 20L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-hydroxy-2-methyl-4H-pyran-4-one la (2 kg, 15.87 mol, 1.00 equiv), MeCN (10 L), potassium carbonate (2.63 kg, 19.01 mol, 1.20 equiv), BnBr (2.85 kg, 16.67 mol, 1.05 equiv). The resulting solution was heated to reflux overnight. The solid was filtered. The filtrate was concentrated in vacuo. This resulted in 3.5 kg (crude) of 3-(benzyloxy)- 2-methyl-4H-pyran-4-one lb as brown oil which was used directly. | |
With potassium carbonate In acetonitrile at 80℃; for 5h; | 1.a a) Synthesis of 2-methyl-3-[(phenylmethyl)oxy]-4H-py- ran-4-one (compound P-2). To a slurry of 2000 g ofcompound P-i (1.0 eq.) in 14.0 L of MeCN were added 2848 g of benzyl bromide (1.05 eq.) and 2630 g ofK2C03 (1.2 eq.). The mixture was stirred at 80° C. for 5h and cooled to 13° C. Precipitate was filtered and washed with 5.0 L of MeCN. The filtrate was concentrated and 3.0 L of THF was added to the residue. The THF solution was concentrated to give 3585 g of crudecompound P-2 as oil. Without further purification, com40 pound P-2 was used in the next step. ‘H NMR (300MHz, CDC13) ö 7.60 (d, J5.7 Hz, 1H), 7.4-7.3 (m, 5H), 6.37 (d, J5.7 Hz, 1H), 5.17 (s, 2H), 2.09 (s, 3H). | |
In methanol; water at 70℃; | ||
With potassium carbonate In acetonitrile at 13 - 80℃; for 5h; Large scale; | 1a; 3a To a slurry of 2000 g of compound 1(1.0 eq.) in 14.0 L of MeCN were added 2848 g of benzyl bromide (1.05 eq.) and 2630 g of K2CO3(1.2 eq.). The mixture was stirred at 80° C. for 5 h and cooled to 13° C. Precipitate was filtered and washed with 5.0 L of MeCN. The filtrate was concentrated and 3.0 L of THF was added to the residue. The THF solution was concentrated to give 3585 g of crude compound 2 as oil. Without further purification, compound 2 was used in the next step. | |
With potassium carbonate In acetonitrile at 80℃; for 5h; | 1.a ) Synthesis of 2-methyl-3-[(phenylmethyl)oxy]-4H-pyran-4-one (compound P-2). To a slurry of 200O g of compound P-1(1.0 eq.) in 14.0 L of MeCN were added 2848 g of benzyl bromide(1.05 eq.) and 2630 g of K2CO3(1.2 eq.). The mixture was stirred at 80 °C for 5 h and cooled to 13°C. Precipitate was filtered and washed with 5.0 L of MeCN. The filtrate was concentrated and 3.0 L of THF was added to the residue. The THF solution was concentrated to give 3585 g of crude compound P-2 as oil. Without further purification, compound P-2 was used in the next step. 1H NMR(300 MHz, CDCI3) δ 7.60 (d, J = 5.7 Hz, 1 H), 7.4-7.3 (m, 5H), 6.37 (d, J = 5.7Hz, 1 H), 5.17 (s, 2H), 2.09 (s, 3H). | |
With potassium carbonate In acetonitrile at 70℃; for 5h; Large scale; | ||
With potassium carbonate In acetone for 8h; Reflux; | General procedure for the preparation of compounds 3a-3c General procedure: A mixture of suitable Maltol (7.56g, 60mmol), anhydrous K2CO3 (9.12g, 66mmol), benzyl bromide (10.78g, 63mmol) and acetone (150mL) was refluxed for 8h. Once the reaction was completed, the mixture was cooled to room temperature. After the solvent was removed under reduced pressure, water (100mL) was added and the mixture was extracted four times with dichloromethane (50mL). The combined organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford intermediate 2a as yellow oil. Intermediates 2b, 2c wasprepared followed the similar procedure of 2a. 2a, 2b or 2c (4.33g, 40mmol) was then dissolved in ethanol 45mL and then 25% ammonia aqueous solution (60mL) was added, and the mixture was refluxed for 12h. Afterward, The solvent was evaporated off to obtain a pale brown solid residue, which was recrystallized from acetone/ethyl acetate, leaving the pure target compound as a pale colored solid. | |
With sodium hydroxide In methanol for 24h; Reflux; | ||
With sodium hydroxide In ethanol for 6h; Reflux; | 4.1.2. Synthesis of 3-(benzyloxy)-2-methyl-4H-pyran-4-one (1) Maltol (2-methyl-3-hydroxy-pyran-4-one, 1.261 g, 10 mmol)was dissolved in a solution of 12 mL of EtOH and 1.3 mL of 8.7 NNaOH and benzyl bromide (1.19 mL, d 1.44 g/mL, 10 mmol) wasadded. The solution was kept under stirring at reflux for 6 h. Afterremoval of solvent under reduce pressure, the residue was dissolvedin 20 mL of CH2Cl2 and washed with aqueous NaOH 5%(2 x 5 mL) and H2O (2 x 5 mL). The organic layer was then driedover anhydrous Na2SO4, filtered, and evaporated under vacuum togive the crude product, which was used for subsequent reactionswithout further purification. Yellow oil, 1.76 g, 82% yield. 1H NMR(400 MHz) (MeOD) δ (ppm): 7.94 (d, 1H, J 5.60 Hz, -O-CH]CHeC]O); 7.41e7.33 (m, 5H, aromatic); 6.42 (d, 1H, J 5.60 Hz, -OCH]CHeC]O); 5.08 (s, 2H, Ar-CH2-O-); 2.12 (s, 3H, -CH3). | |
With potassium carbonate In N,N-dimethyl-formamide at 80℃; | 1 Example 1 : 1-(9a,10-dihydroindeno[1 ,2-a]inden-4b(9H)-yl)-5-hydroxy-3-methyl-2,3- dihydro-1 H-pyrido[2, 1 -f][1 ,2,4]triazine-4,6-dione (A1 ) To a stirred solution of 3-hydroxy-2-methyl-4/-/-pyran-4-one 1 -1 (100 g, 793 mmol) in N,N-dimethylformamide (DMF; 1 L) were added potassium carbonate (219 g, 1.59 mol) and benzyl bromide (188 ml_, 1.59 mol) at room temperature (RT). The reaction mixture was stirred at 80 °C for 12 hours (hr). After consumption of starting material (as determined by TLC), the reaction mixture was quenched with ice-cold water (3 L), extracted with ethyl acetate (EtOAc) (5 x 1 L), dried over sodium sulfate (Na2S04), and concentrated under reduced pressure. The residue was dissolved in diethyl ether (3 L), washed with 1 N HCI (5 x1 L), ice-cold water (1 L), and saturated NaHCCh (2 x 1 L) solution, dried over Na2S04 and concentrated under reduced pressure to afford 3-(benzyloxy)-2-methyl-4/-/-pyran-4-one 1-2. TLC: 40% EtOAc/ petroleum ether; Rf: 0.4. LCMS (ESI): m/z 217.06 (M+H)+. | |
With potassium carbonate In acetone for 4h; Reflux; | 4.4. General procedure for the preparation of intermediate 8 A mixture of Maltol (1.260 g, 10 mmol), anhydrous K2CO3 (2.740 g,20 mmol), benzyl bromide (2.052 g, 12 mmol) and acetone (60 mL) was refluxed for 4 h. After the reaction was completed, the reaction mixture was evaporated under vacuum, and the residual was resolved in water(50 mL), extracted with DCM (20 mL) three times and washed by saturated brine (20 mL) three times. The organic solution was evaporated to dryness to obtain intermediate 8 as yellow oil. | |
With sodium hydroxide In ethanol for 6h; Reflux; | ||
With potassium hydroxide | ||
With potassium carbonate In acetone for 4h; Reflux; | ||
With potassium carbonate In N,N-dimethyl-formamide at 280℃; | 43.1 Step 1, the synthesis of compound 43-2 A DMF solution (200 mL) of 43-1 (20 g, 158.6 mmol), BnBr (32.6 g, 190.7 mmol, 22.8 mL) and potassium carbonate (43.8 g, 317.4 mmol) was added to a dry round bottom flask to dissolve,Stir at 80 °C for 2 hours, monitored by LC-MS.After the reaction, extract 3 times with water and ethyl acetate, collect the organic phase, wash twice with saturated brine, dry over anhydrous sodium sulfate and concentrate under reduced pressure without further purification, the crude product can be directly used in the next reaction to obtain the product 43-2 (34g, crude) is a yellow oil. | |
91.8 % | Stage #1: Maltol With potassium carbonate In N,N-dimethyl-formamide at 0℃; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 80℃; | 1 Synthesis of compound 2: At room temperature, compound 1 (100 g, 793 mmol, 1 eq) was dissolved in DMF (1.5 L),Potassium carbonate (219g, 1.59mol, 2eq) was added, cooled to 0°C in an ice-water bath,Benzyl bromide (203g, 1.19mol, 1.5eq) was added dropwise, and after the addition was complete, the reaction was maintained at 0°C for 30 minutes.Then move to an oil bath at 80°C for 5 hours.TLC (EA/PE=1/2, EA is ethyl acetate, and PE is petroleum ether) detects that only a small amount of raw materials remains, and after treatment, the system is lowered to room temperature and poured into water (3L).Ethyl acetate extraction (300mlx3), combined organic phase washing (100mlx3),Wash with saturated brine (200mlx1), dry over anhydrous sodium sulfate for 20 minutes,The organic phase was filtered, concentrated and purified by column chromatography (EA/PE=1/5-1/1) to obtain 157 g of the product.Yellow oil, yield 91.8%. |
91.8 % | Stage #1: Maltol With potassium carbonate In N,N-dimethyl-formamide at 0℃; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 80℃; | 1 Synthesis of compound 2: At room temperature, compound 1 (100 g, 793 mmol, 1 eq) was dissolved in DMF (1.5 L),Potassium carbonate (219g, 1.59mol, 2eq) was added, cooled to 0°C in an ice-water bath,Benzyl bromide (203g, 1.19mol, 1.5eq) was added dropwise, and after the addition was complete, the reaction was maintained at 0°C for 30 minutes.Then move to an oil bath at 80°C for 5 hours.TLC (EA/PE=1/2, EA is ethyl acetate, and PE is petroleum ether) detects that only a small amount of raw materials remains, and after treatment, the system is lowered to room temperature and poured into water (3L).Ethyl acetate extraction (300mlx3), combined organic phase washing (100mlx3),Wash with saturated brine (200mlx1), dry over anhydrous sodium sulfate for 20 minutes,The organic phase was filtered, concentrated and purified by column chromatography (EA/PE=1/5-1/1) to obtain 157 g of the product.Yellow oil, yield 91.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.4% | With potassium carbonate In acetonitrile for 5h; Reflux; | 4.1 Example 1 Preparation of 3-benzyloxy-2-methyl-4H-pyran-4-one 10.0 g of 3-hydroxy-2-methyl-4H-pyran-4-one and 16.4 g of potassium carbonate were added to 300 ml of acetonitrile.12.0 g of benzyl chloride was added, and the mixture was heated to reflux. After 5 hours, TLC ( petroleum ether: ethyl acetate = 1:1) was obtained.The reaction solution was cooled to room temperature, suction filtered, and the filter cake was washed with 100 ml of ethyl acetate, and the filtrate was directly dried.3-benzyloxy-2-methyl-4H-pyran-4-one 17.0 g was obtained in a yield: 99.4%. |
98% | With potassium carbonate In methanol for 1h; Reflux; | 1.1 Example 1: (1) 100 g of compound 1, 132 g of potassium carbonate and 105 g of benzyl chloride were added to 300 mL of methanol,The reaction was completed by heating under reflux for 1 hour.The system is cooled to room temperature,Filtration, concentration of the filtrate, and the residue was dissolved in dichloromethane (200 mL).Wash with 5% sodium hydroxide solution (50 mL×2) and saturated sodium chloride solution (50 mL).The organic phase is dry, Concentrated to obtain 168 g of yellow oil, intermediate 2 Yield: 98%. |
98.2% | With triethylamine In ethyl acetate Reflux; | 1 Example 1: Synthesis of compound 2 At room temperature, 18.00 g of compound 1, 55 ml of ethyl acetate, 8.66 g of triethylamine, and 9.08 g of benzyl chloride were added to the reaction flask at room temperature, heated to reflux, and stirred until the reaction was completed. Add 30ml of water and extract twice and separate the liquids; combine the organic phases and concentrate to dryness to obtain compound 2: 15.12g of brown oil, yield 98.2%; |
95% | With sodium hydroxide In methanol Heating / reflux; | 32.A EXAMPLE 32; Preparation of 3-Hydroxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one; A. Preparation of 3-Benzyloxy-2-methyl-1H-pyridin-4-one; To a suspension of maltol (126 g, 1.0 mol) and methanol (450 mL) in a 2 L 3-necked round bottom flask equipped with a mechanical stirrer was added a 10.0 N sodium hydroxide solution (110 mL, 1.1 mol). A clear solution resulted upon stirring. Benzyl chloride (138 mL, 1.2 mol) was then added, and the resulting solution was heated to reflux for 1.5 h. To the reaction mixture was further added a 10.0 N sodium hydroxide (20 mL, 0.2 mol) and benzyl chloride (27 mL, 0.23 mol), and the reaction mixture was heated to reflux for another 2 h. The progress of the reaction was monitored by HPLC Method 4 (Example 24), and the amount of remaining unreacted maltol was about 2%. The reaction mixture was stirred overnight. The mixture was cooled to RT and filtered. The filtrate was concentrated in vacuo to a volume of about 300 mL, as two phases could be observed. The top layer was collected via separatory funnel, and was concentrated under reduced pressure to give 3-(benzyloxy)-2-methyl-4H-pyran-4-one as an oil (220 g, 95% yield, HPLC Method 4 (Example 24), RT=15.5 min, HPLC purity (peak percent area): 95% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 8.04 (d, J=5.5 Hz, 1H), 7.37, (m, 5H), 6.37 (d, J=5.5 Hz, 1H), 5.02 (s, 2H), 2.12 (s, 3H). |
95% | With sodium hydroxide In methanol; water at 74.84℃; | 3.2.1 2.3.2.1. 3-(benzyloxy)-2-methyl-4-pyrone. To a solution of 3-hydroxy-2-methyl-4H-pyran-4-one (20.07 g, 159.15 mmol) in 200 mL of MeOH, asolution of sodium hydroxide (6.98 g, 174.50 mmol) in 22 mL of waterwas added to this mixture, followed by dropwise addition of benzylchloride (22.0 mL, 191.00 mmol). The reaction mixture was heated toreflux at T=348 K for 12 h. The solvent was evaporated under reducedpressure and the remaining orange oil was dissolved in DCM (80 mL)and washed with 5% (w/v) of NaOH aqueous solution (3×30 mL) andwith water (2×30 mL). The organic phase was dried over anhydroussodium sulfate and filtered. The solvent was roto-evaporated and driedin vacuum to give a pale yellow oil product (32.93 g, η=95%). TLCswere performed in S1 mixture. 1H NMR (400 MHz, Methanol-d4), δ(ppm): 7.82 (1H, d, 6-HPy), 7.33 (5H, s, Ph), 6.35 (1H, d, 5-HPy), 5.03(2H, s, CH2Ph), 2.05 (3H, s, CH3). 13C NMR (100 MHz, Methanol-d4),δ(ppm): 175.81, 160.98, 155.05, 143.49, 136.81, 128.76, 128.19,128.18, 116.22, 73.37, 13.67; m/z (ESI-MS)=217 (M+1). |
94% | ||
94% | With sodium hydroxide In methanol; dichloromethane; water | 1 Synthesis of 2-methyl-3-benzyloxy-4-pyranone (1) EXAMPLE 1 Synthesis of 2-methyl-3-benzyloxy-4-pyranone (1) 20.0 g (159 mmol) of 2-methyl-3-hydroxy-4-pyranone and 22.1 g (175 mmol, 1.1 eq.) of benzyl chloride are introduced into 200 mL of methanol; then 6.98 g (175 mmol) of NaOH in 22 mL of water are added. The reaction medium is reflux agitated for 61/2 hours. The solvent is subsequently evaporated and the residue retaken up with 100 mL of dichloromethane. This solution is then washed with a 5% aqueous solution of soda (2*80 mL) and with water (2*80 mL). The organic phases are collected, dried on sodium sulphate, filtered and evaporated under reduced pressure; 32.3 g (149 mmol) of 2-methyl-3-benzyloxy-4-pyranone are isolated. Yield: 94%. NMR 1H: δ 8.00 (d, J5,6=5.7 Hz, H-6), 7.42-7.30 (m,5H Ph), 6.37 (d, J5,6=5.7 Hz, H-5), 5.04 (s, CH2-Ph), 2.10 (s, CH3); NMR 1H in CDCl3: δ 7.55 (d, H-6), 7.40 (s, 5H, aromatic H), 6.35 (d, H-5), 5.04 (s, CH2-Ph), 2.10 (s, CH3); NMR 13C: δ 173.9 (C-4), 159.1 (C-3), 154.8 (C-6), 143.1 (C-2), 136.6 (CIpso), 128.5 (2*Cortho), 128.2 (2*Cmeta), 128.0 (Cpara), 116.4 (C-5), 72.6 (CH2-Ph), 14.3 (CH3). |
94% | With sodium hydroxide In methanol; water for 6h; Heating / reflux; | X.a; XIV; XVI.a The iron chelators of the invention include, but are not limited to: 2-Alkyl-N-(2'-hydroxyethoxy)methyl-3-hydroxyl-4-pyridinone chelators, which were synthesized using established methods.82 Briefly, 3-benzyloxyl-2-alkyl-4-pyridinone was synthesized as described by Dobbin et al.83 with a minor modification. First, 2-alkyl-3-hydroxyl-4-pyranone and benzylchloride were refluxed in alkaline condition to protect the 3-hydroxyl group. Then, the substitution reaction of 3-benzyloxyl-2-alkyl-4-pyranone with aqueous ammonia reacted for 48 h. 3-benzyloxyl-2-alkyl-4-pyridinone were silylated in hexamethyldisilazane under refluxing for 2 h and then alkylated using trimethylsilyl trifluoromethanesulfonate as a catalyst with benzyloxyethoxymethylchloride which could be replaced by (2-acetoxyethoxy)methyl bromide. SnCl4 could also be used as catalyst in the alkylation reaction, but resulted in separation difficulties and low yields. Both of the protection groups were removed simultaneously by hydrogenation under H2/catalyst in aqueous ethanol or by BBr3 in CH2Cl2 at 4° C. The new chelators were obtained in pure form after crystallization from a 1:1 solution of CH3Cl/MeOH. Scheme 1. R=Me (1a), Et (1b). a: benzylchloride/NaOH, then NH4OH. b: hexamethyldisilazane, chlorotrimethylsilane. c: benzyloxyethoxymethylchloride, trimethylsilyl trifluoromethanesulfonate in 1,2-dichloroethane. d: H2, Pd/C, in aqueous EtOH (or with BBr3 in CH2Cl2 at 4° C.). Characterizations have been done using proton-NMR, MS, UV-visible spectroscopy and elemental analysis. The molecular structure of chelator 1b was also confirmed by X-ray crystallography and the molecular structure is shown; (2) The chelators of 2-alkyl-N-(2'-aminoethyl or 3'-amniopropyl)-3-hydroxyl-4-pyridinone were synthesized using the procedure as following (Scheme 2). Scheme 2. R=Me, Et. a: benzylchloride/NaOH. b: NH2(CH2)2NH2 and NH2(CH2)3NH2/NaOH. c: H2, Pd/C (or BBr3 in CH2Cl2 at 4° C.). In brief, 3-benzyloxy-2-methyl-4-pyrone was synthesized with benzylchloride in water and methanol (1:8 V/V) in the presence of NaOH and refluxed for 6 h. The product was then extracted 3 times with methylene chloride. It was reacted with 1,2-diaminoethane or 1,3-diamniopropane in 40% EtOH aqueous solution. After one week, the benzyl protective group was removed by BBr3 in CH2Cl2 at 4° C. The final products were purified by crystallization using methanol and ether. The 1H-NMR chemical shift assignments in DMSO-d6 are given as following. For n=2: 8.202 (1H, d, H-6), 7.153 (1H, d, H-5), 4.584 (2H, t, 1'-position ethylenic CH2), 3.295 (2H, m, 2'-position ethylenic CH2), 2.546 (3H, s, 2-position CH3). For n=3: 8.214 (1H, d, H-6), 7.104 (1H, d, H-5), 4.407 (2H, t, 1'-position propylenic CH2), 2.866 (2H, m, 3'-position propylenic CH2), 2.516 (3H, s, 2-position CH3), 2.021 (2H, m, 2'-position propylenic CH3).; The chelator 2-methyl-N-(3'-aminopropyl)-3-hydroxyl-4-pyridinone (MAHP) was synthesized using a modification of a procedure known in the art. In brief, 3-hydroxyl-2-methyl-4-pyranone (44.4 g, 0.352 mol) and benzyl chloride (51 g, 0.403 mol) were mixed in a solution of water (50 ml) and methanol (400 ml) in the presence of NaOH (15 g). The mixture was refluxed for 6 h with magnetic stirring. After removing methanol under vacuum, 70 ml of water were added and 3-benzyloxy-2-methyl-4-pyranone was extracted 3 times with 60 ml portions of methylene chloride. The combined methylene chloride was washed with 5% NaOH aqueous solution (50 ml), followed by water (50 ml) and dried over MgSO4. The product was obtained after evaporation of the solvent under vacuum (94% yield). The product (4.41 g, 0.019 mol) was then reacted with 1,3-diaminopropane (1.15 g, 0.019 mol) in aqueous ethanol solution (30 ml water and 20 ml ethanol) at room temperature. After one week, solvents and residual diamine were evaporated under vacuum and the residue was dissolved in chloroform, washed 3 times with water and dried using Na2SO4. After removing the chloroform, methanol was added and the pH adjusted to 1 with HCl. The 1-(3'-aminopropyl)-3-benzyloxy-2-methyl-4-pyridinone was precipitated as dihydrochloride salt and collected by filtration. The pure product was obtained by crystallization from methanol and ether (yield: 80%) and the product (2 g, 0.0058 mol) further reacted with BBr3 (30 ml, 1.0 M solution of CH2Cl2) in 120 ml of CH2Cl2. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. Then, 160 ml of water was added and stirring was continued for an additional 4 h. The aqueous phase containing the MAHP was separated and evaporated under vacuum. The crude MAHP was purified through crystallization twice using ethanol and ether (96% yield). Pure MAHP was identified by 1H-NMR and elemental analysis. 1H-NMR (DMSO-d6): 8.214 (1H, d, H-6), 7.104 (1H, d, H-5), 4.407 (2H, t, 1'-position propylenic CH2), 2.866 (2H, m, 3'-position propylenic CH2), 2.516 (3H, s, 2-position CH3), 2.021 (2H, m, 2'-position propylenic CH3). Elemental analysis: Calcd. For C9H14N2O2 2HBr C, 31.42; H, 4.69; N, 8.14. Found: 31.52; H, 4.79; N, 7.75, m.p.: 242° C.; Synthesis of iron chelator-nanoparticle systems: The general synthesis of the chelator 1 is described in scheme 3.86 Scheme 3. R=Me, Et. a: benzylchloride/NaOH/. b: NH4OH. C: hexamethyldisilazane/chlorotrimethylsilane/(2-acetoxyethoxy)methyl bromide, trimethylsilyl trifluoromethanesulfonate in 1,2-dichloroethane. c: basic hydrolysis with NH4OH. d: tosyl chloride in pyridine. e: nanoparticles with amino functional groups. f: BBr3/CH2Cl2 at 4° C. for 30 min. Instead of benzyloxyethoxymethylchloride, 2-acetoxyethoxy)methyl bromide is used and the synthetic method is the same as described herein. The acetyl protection group on the side chain is removed by basic hydrolysis in methanolic ammonia solution. The mixture is stirred at room temperature in a sealed flask for 24 h. After purification by silica gel chromatography using CHCl3-MeOH (8:1) as an eluent, the deprotected hydroxyl group is converted into P-toluene-sulphonyl (tosyl) ester by the reaction with tosyl chloride (1.1 moles per mole of chelator) in dry pyridine. After removal of the solvent, the crude ester is often used directly. Before conjugation, 1 mL (100 mg/mL) of amino-modified nanoparticles are washed in 10 mL of 0.1 M sodium phosphate buffer (pH 7.4). After second wash, resuspend pellet in 10 mL of tosyl activeted chelator solution, ensuring that the particles are completely suspended by vortexing. Allow to react at 37° C. for 24 hours with continuous mixing. Separate the particles conjugated with chelators by centrifugation and wash with phosphate buffered saline (pH 7.4) four times. Then, deprotect OH on pyridinone ring by BBr3 in CH2Cl2 at 4° C. with shaking for 30 min. The new chelator-particle system is obtained by centrifugation and wash four times with PBS buffer. Resuspend in 10 mL 25 mM Tris buffer (pH 7.4) and store at 4° C. until used. As mentioned above, if the nanoparticles could be damaged during the deprotective step, we will use an altered method to conjugate the chelator. The toluene sulfonic group (Tosyl-O-group) may be changed into an amino group by nucleophilic displacement reaction. To obtain primary amines in reasonable yield, sufficient excess ammonia is used. After that, first, deprotection of the OH group on the pyridinone ring by using the same deprotective method as above, then conjugate the chelator to Sulfo-NHS(N-hydroxysulfosuccinimide) preactivited carboxylic acid functinal nanoparticles just like chelators 2, 3, and DFO do. The chelator concentrations of the reaction solution before and after conjugation are determined by using UV-visible spectroscopy or HPLC, thereby the amount of the chelator conjugated to nanoparticles can be obtained by simply multiplying the difference of the concentrations with the reaction volume. |
92% | With sodium hydroxide In methanol; water for 6h; Heating; | |
92% | With sodium hydroxide In methanol; water | 10 3-Benzyloxy-2-methyl-4-pyrone 3-Benzyloxy-2-methyl-4-pyrone 3-Hydroxy-2-methyl-4-pyrone (22.2 g) in methanol (225 ml) is added to aqueous sodium hydroxide (25 ml H2 O containing 7.5 g NaOH). Benzyl chloride (25.5 g) is added and the mixture is refluxed for 6 hours and is then allowed to cool overnight. The bulk of the methanol is removed under vacuum and the residue is treated with water (50 ml). The mixture is extracted into dichloromethane (3*25 ml). The extracts are combined, washed with 5% w/v NaOH (2*25 ml), then water (2*25 ml) and dried over magnesium sulphate. Evaporation of the solvent gives crude 3-benzyloxy-2-methyl-4-pyrone (35 g, 92%) which is purified by distillation in nitrogen under reduced pressure to yield a colourless oil (28 g) of b.p. 148° C./0.2 mm. |
91% | With sodium hydroxide In methanol for 8h; Heating; | |
91% | With sodium hydroxide In methanol; water for 8h; Heating; | |
88% | With sodium hydroxide In methanol; water for 18h; Reflux; | |
88% | With sodium hydroxide In ethanol; water at 60℃; for 6h; | 1.2 Raw material 2: Preparation of 2-methyl-3-(benzyloxy)-4H-pyran-4-one: Dissolve 2-methyl-3-hydroxy-4H-pyran-4-one (1g, 8.0mmol) in 8ml of 95% ethanol, weigh out sodium hydroxide (352mg, 8.8mmol) and dissolve in 5ml of distilled water After the system was added, benzyl chloride (831ul, 7.2mmol) was added to the mixed system after the system was dissolved, and reacted at 60 degrees for about 6 hours. After the reaction was completed, the ethanol was spun off under reduced pressure, and the aqueous phase was extracted with dichloromethane (3 ×), the organic layers were combined, the organic layer was washed with water (3×), saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain compound 2 (1.52 g, yield 88%). |
87% | With sodium hydroxide In methanol; water for 12h; Reflux; | |
87% | With sodium hydroxide In methanol; water at 85℃; for 2h; | |
87% | With sodium hydroxide In methanol Reflux; | 6.1; 6.2; 6.3 (1) adding methyl maltol to methanol and stirring to dissolve;(2) adding a 7M sodium hydroxide solution to the mixture obtained in the step (1), followed by dropwise addition of a benzyl group, heating, refluxing overnight, molar ratio of methyl maltol to sodium hydroxide solution is 1:0.8, methyl maltol andThe molar mass ratio of the benzyl compound is 1:0.8;(3) The reaction liquid obtained in the step (2) is evaporated to remove the solvent, and the obtained oil is dissolved in dichloromethane.Wash with 5% solution of NaOH and distilled water, then dry the organic phase with anhydrous Na2SO4 overnight.Filtration, rotary evaporation, vacuum drying for 24 h to give compound B; yield 87%; |
86% | With sodium hydroxide In methanol Reflux; | |
85.6% | With sodium hydroxide In methanol; water for 6h; Heating; | |
85.6% | With sodium hydroxide In methanol; water for 6h; Heating; | |
85.8% | With sodium hydroxide In methanol for 8h; Reflux; | |
85% | With sodium hydroxide In ethanol at 60℃; for 6h; Reflux; | |
84% | With sodium hydroxide In methanol | |
84% | With sodium hydroxide In ethanol; water at 60℃; | 1.1 Step 1: Preparation of 2-methyl-3-benzyloxy-4H-pyran-4-one: Dissolve 100g commercially available benzyl maltol in 80mL 95% ethanol,Then add 83mL benzyl chloride and 115mL 30% sodium hydroxide aqueous solution,Let it react at 60 degrees Celsius for 6-18 hours,After the TLC tracking reaction is completed,45°C under reduced pressure distillation to remove ethanol,Add 300mL dichloromethane to extract,The dichloromethane layer obtained by liquid separation was washed with 30 mL of 4% sodium hydroxide solution,Add 30mL saturated brine to wash,The crude product obtained by evaporation under reduced pressure at 45°C is recrystallized by adding 60 mL ethyl acetate and 120 mL petroleum ether.Thus, 145.3 g of Compound 2 (yield 84%) can be obtained.Light yellow solid, |
83% | With sodium hydroxide In methanol; water for 6h; Heating; | |
83% | With sodium hydroxide In methanol for 12h; Heating; | |
83% | With sodium hydroxide In ethanol; water at 60℃; | 4 3-Hydroxy-2-methyl-4H-pyran-4-one (accession 4-b) 3-Hydroxy-2-methyl-4H-pyrone 100g (800mmol) was added to the reaction flask, 80mL of 95% ethanol was added to form a white cloudy liquid, 35.2g (880mmol) of sodium hydroxide was dissolved in 80mL of water and slowly added dropwise The system was heated to 60 degrees after the addition, and 82.5 mL (720 mmol) of benzyl chloride was added dropwise, the reaction was stirred at 60 degrees, and the reaction was detected by TLC (volume ratio of petroleum ether/ethyl acetate=1:1). After the reaction, the reaction solution was rotated by a rotary evaporator until there was no distillate, dissolved in 120 mL of water, extracted three times with 3×150 mL of dichloromethane, and the organic layers were combined, and the organic layer was washed three times with 3×100 mL of 5% sodium hydroxide solution. Methyl maltol raw material remained, the organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation until there was no distillate, cooled and solidified, crushed and air-dried to obtain the product 3-(benzyloxy)-2-methyl 143.3 g of base-4H-pyrone, yield 83% |
83% | Stage #1: Maltol With sodium hydroxide In ethanol; water at 60℃; Stage #2: benzyl chloride In ethanol; water at 60℃; | 4 3-Hydroxy-2-methyl-4H-pyran-4-one (accession 4-b) 3-Hydroxy-2-methyl-4H-pyrone 100g (800mmol) was added to the reaction flask, 80mL of 95% ethanol was added to form a white cloudy liquid, 35.2g (880mmol) of sodium hydroxide was dissolved in 80mL of water and slowly added dropwise The system was heated to 60 degrees after the addition, and 82.5 mL (720 mmol) of benzyl chloride was added dropwise, the reaction was stirred at 60 degrees, and the reaction was detected by TLC (volume ratio of petroleum ether/ethyl acetate=1:1). After the reaction, the reaction solution was rotated by a rotary evaporator until there was no distillate, dissolved in 120 mL of water, extracted three times with 3×150 mL of dichloromethane, and the organic layers were combined, and the organic layer was washed three times with 3×100 mL of 5% sodium hydroxide solution. Methyl maltol raw material remained, the organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation until there was no distillate, cooled and solidified, crushed and air-dried to obtain the product 3-(benzyloxy)-2-methyl 143.3 g of base-4H-pyrone, yield 83% |
82% | Stage #1: Maltol With sodium hydroxide In methanol; water Reflux; Stage #2: benzyl chloride In methanol; water for 18h; Reflux; | |
82% | With sodium hydroxide In methanol; water for 8.5h; Reflux; | |
82% | Stage #1: Maltol With sodium hydroxide In methanol; water Stage #2: benzyl chloride In methanol; water for 12.5h; Heating; | |
81% | With sodium hydroxide In methanol Heating; | |
81% | Stage #1: Maltol With sodium hydroxide In methanol Reflux; Stage #2: benzyl chloride for 0.5h; Reflux; | |
81% | With sodium hydroxide In methanol; water Reflux; | 1 2-Methyl-3-benzyloxypyran-4(1H)-one (2) 2-Methyl-3-benzyloxypyran-4(1H)-one (2) To a solution of methyl maltol 1 (63 g, 0.5 mol) in methanol (500 mL) was added sodium hydroxide (22 g, 0.55 mol) dissolved in water (50 mL), and the mixture was heated to reflux. Benzyl chloride (70 g, 0.55 mol) was added dropwise over 30 mins, and the resulting mixture was refluxed overnight. After removal of solvent by rotary evaporation, the residue was mixed with water (200 mL) and extracted with dichloromethane (3*150 mL). The combined extracts were washed with 5% aqueous sodium hydroxide (2*200 mL) followed by water (200 mL). The organic fraction was then dried over anhydrous sodium sulphate, filtered and rotary evaporated to yield an orange oil which solidified on cooling. Recrystallization from diethyl ether gave the pure product 2 as colourless needles (87.5 g, 81%); mp 51-52° C. 1H-NMR (CDCl3) δ: 2.12 (s, 3H), 5.11 (s, 2H), 6.25 (d, J=6 Hz, 1H), 7.28 (s, 5H), 7.47 (d, J=6 Hz, 1H). |
79% | With sodium hydroxide In methanol; water Heating; | |
79% | With sodium hydroxide In water for 40h; Reflux; | |
78% | With sodium hydroxide In ethanol; water at 60℃; for 3.5h; | 1 Example 1. 3-benzyloxy-2-methyl-4H-pyran-4-one Example 1. 3-benzyloxy-2-methyl-4H-pyran-4-one [0037] [0038] 122.3 g NaOH was dissolved into 278 mL water, then mixed into solution of 390 g maltol and 1160 mL ethanol, and 422 g benzyl chloride was then added under stirring. Keep stirring at 60 °C for 3.5 h after fully mixing. After cooling the reaction system, filter it to remove solid impurities, wash the residues with ethanol, which was then mixed with filtrate and spin-dried. The remaining substances were dissolved by methylene chloride (DCM), then washed with 5% NaOH, finally washed with suitable amount of water. The organic layer was dried by anhydrous Na2SO4, then spin-dried the solvent the yellow oily liquid was obtained. After cooling and recrystallization in ether to get crystals, the yield is 78%, melting point is 56∼57°C. |
76.8% | With sodium hydroxide In methanol; water | 1.1 (1) (1) 3-Benzyloxy-2-methyl-4-pyrone A solution of sodium hydroxide (126 g, 1.1 mol) in 1000 ml of methanol in water (9:1 v/v) was added to 3-hydroxy-2-methyl-4-pyrone (126.12 g, 1 mol). Benzyl chloride (126.59 ml, 1.1 mol) was then added slowly and the mixture was refluxed for 10 hours with rapid stirring. The resultant solution was cooled, the methanol removed by rotary evaporation and the aqueous solution was extracted with dichloromethane (3*250 ml). The combined dichloromethane extracts were washed with 5% sodium hydroxide and then with water, dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The resultant solid was recrystallized from diethylether to yield the title compound in 76.8% yield as colourless needles, m.p. 53°-55° C. |
69% | With sodium hydroxide In methanol at 92℃; for 22h; | |
With sodium hydroxide In methanol; water | 1 Preparation of 1,8-di-(3-hydroxy-2-methyl-4-oxopyrid-1-yl)octane and other related compounds EXAMPLE 1 Preparation of 1,8-di-(3-hydroxy-2-methyl-4-oxopyrid-1-yl)octane and other related compounds 3-Hydroxy-2-methyl-4-pyrone (22.2 g) in methanol (225 ml) is added to aqueous sodium hydroxide (25 ml H2 O containing 7.5 g NaOH). Benzyl chloride (25.5 g) is added and the mixture is refluxed for 6 hours and is then allowed to cool overnight. The bulk of the methanol is removed under vacuum and the residue is treated with water (50 ml). The mixture is extracted into dichloromethane (3*25 ml). The extracts are combined, washed with 5% w/v NaOH (2*25 ml), then water (2*25 ml) and dried over magnesium sulphate. Evaporation of the solvent gives crude 3-benzyloxy-2-methyl-4-pyrone or "benzyl maltol" (35 g, 92%) which is purified by distillation in nitrogen under reduced pressure to yield a colourless oil (28 g) of b.p. 148° C./0.2 mm. | |
In ethanol; water | ||
With sodium hydroxide In methanol at 65℃; for 16h; | ||
With potassium hydroxide | ||
With sodium hydroxide In methanol Reflux; | ||
With sodium hydroxide In methanol; water for 6h; Reflux; | 1 To a one liter flask were added: 0.35 mole 3-hydroxy-2-methyl-4-pyrone, 450 ml methanol, 0.4 mole benzyl chloride and a solution of 0.37 mole sodium hydroxide in 50 ml water. The mixture was refluxed for six hours and then stirred at room temperature overnight. The methanol was then evaporated using vacuum and the residue was mixed with 200 ml water and then extracted using three separate 100 ml aliquots of methylene chloride. The three methylene chloride extracts were pooled and washed with three changes of 50 ml 5% NaOH and then three changes of 50 ml water. The extract was then dried over solid MgSO4. Following filtration to remove the MgSO4 and evaporation of the solvent, 76.6 gram of crude 3-benzyloxy-2-methyl-4-pyrone was recovered. This material was then mixed in a one-liter flask with 500 ml ethanol, 1.65 mole ethylenediamine and 2 ml water and stirred overnight at room temperature. The solvent and excess ethylenediamine were removed under reduced pressure to yield a yellow-brown oily liquid that was triturated with 400 ml water to yield 65.5 g yellow 1-(2-aminoethyl)-3-benzyloxy-2-methyl-4-(1H)-pyridinone. This product was dissolved in 500 ml 6 M HCl and the solution was stirred at room temperature overnight. A pale yellow product solid was recovered after evaporation to dryness in vacuum. This was re-dissolved in 500 ml 6 M HCl and stirred at room temperature for four days and evaporated to dryness again. The solid residue was washed with approximately 50 ml acetone to obtain the crude product. Because this was difficult to filter, 150 ml 4 M HCl and 70 ml ethanol were added and the mixture was refluxed until the solids had dissolved. The product was then re-crystallized by storage in a refrigerator, washed with acetone dried and weighed. The final AHMP product was yellow. | |
In methanol; water Reflux; Alkaline conditions; | ||
With sodium hydroxide In methanol; water for 20h; Reflux; | ||
With potassium carbonate In acetonitrile at 70℃; for 15h; Large scale; | 1.1; 2.1; 3.1; 4.1; 5.1 (1) Synthesis of 3-o-benzyl maltol: 100kg of maltol and 105.4kg of benzyl chloride were dissolved in 600kg of acetonitrile, To the reaction system, 165kg of solid potassium carbonate was added, and the system was heated to 70°C for 15h. After the reaction of the raw materials is completed, the temperature is lowered and suction filtered, After concentrating to dryness under reduced pressure, 3-o-benzyl maltol was obtained, which was directly used in the next step without purification; | |
79 % | With sodium hydroxide In ethanol; water at 60℃; | 1.1; 2.1; 3.1 Step 1: Preparation of Benzyl Maltol (III) Maltol (II, 50.4g, 0.40mol) was dissolved in a mixed solvent of 80mL ethanol and 80mL water, and sodium hydroxide (17.6g, 0.44mol) and benzyl chloride (46.8g, 0.37mol) were added successively under stirring, React at 60°C overnight (ie, about 12 hours). After TLC detected that the benzyl chloride reaction was complete, the ethanol was removed by rotary evaporation, and the remaining mixed solution was extracted twice with 80 mL of dichloromethane. It was dried over sodium sulfate and concentrated by rotary evaporation to obtain the crude product, which was recrystallized from PE and EA (1:1, v/v) to obtain brown solid III (62 g, 79%). |
81 % | Stage #1: Maltol With sodium hydroxide In methanol; water Reflux; Stage #2: benzyl chloride In methanol; water Reflux; | 4.1.2. Synthesis of 3-(Benzyloxy)-2-methyl-4H-pyran-4-one (2) Maltol 1 (25.22 g, 0.2 mol) was dissolved in methanol (250 mL) and sodium hydroxide (8.8 g, 0.22 mol) dissolved in water (50 mL) was added to it. The solution was heated to reflux, and benzyl chloride (25.3 g, 0.22 mol) was then added dropwise over 15 min. The reaction mixture was refluxed overnight. The orange oil obtained after the evaporation of the solvent was mixed with 100 mL CH2Cl2 and washed with 5% aqueous sodium hydroxide (3×70 mL) followed by water (3×70 mL). The organic fraction was then dried over magnesium sulfate, filtered, and concentrated. The residue was solidified by diethyl ether and crushing with a glass rod. The obtained precipitate was washed with Et2O to give 2 as pure white solid. Yield: 81%; mp: 50.5-52.0 °C (lit. mp 51.0-52.0 °C); IR (KBr, cm-1): 1643 (C=O) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dmap; triethylamine In dichloromethane at 0℃; Inert atmosphere; | |
99% | With 1H-imidazole In dichloromethane at 23℃; for 2h; Inert atmosphere; | |
98% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 1 A solution of imidazole (Im, 5.45 g, 0.08 mol) in N,N-dimethylformamide (20 ml) is added in an inert atmosphere and dropwise to a solution containing 3- hydroxy-2-methyl-4-pyrone (5.00 g, 0.04 mol) and tert- butyl-dimethylchlorosilane (TBDMSCl, 7.00 g, 0.044 mol) in N,N-dimethylformamide (100 ml) . The mixture obtained thereby is maintained stirring at a room temperature for 6 h and then diluted by adding a 5% hydrogen carbonate aqueous solution (150 ml) . The mixture obtained thereby is extracted with hexane (6 x 50 ml); the extracted organic phases are combined, anhydrified on sodium sulphate, and evaporated under vacuum obtaining the desired 3- (tert-butyl-dimethylsilyl) oxy-2-methyl-4- pyrone compound as a colourless crystalline solid (9.61 g) -Yield: 98 %IH-NMR (200 MHz, 25 0C, CDC13 , ppm) : 7.58 (d, IH, J=5.56 Hz), 6.29 (d, IH, J=5.56 Hz), 2.31 (s, 3H), 0.96 (s, 9H), 0.26 (s, 6H)13C-NMR (200 MHz, 25 0C, CDC13, ppm): 3.8, 14.8, 18.7, 25.9, 115.5, 142.8, 152.8, 154.6, 174.0. |
98% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 6h; Inert atmosphere; | |
95% | With 1H-imidazole In N,N-dimethyl-formamide for 5h; Inert atmosphere; | |
95% | With 1H-imidazole In dichloromethane at 20℃; for 6h; Cooling with ice; | 2-Methyl-3-(tert-butyldimethylsiloxyl)-4H-pyran-4-one (18) To the solution of maltol (1.0 g, 7.9 mmol) in CH2Cl2 (25 mL) was added imidazole (806 mg, 11.9 mmol). The mixture was stirred in an ice bath, and TBDMSCl (1.43 g, 9.5 mmol) in CH2Cl2 (20 mL) was added dropwise. After addition, the reaction mixture was warmed to room temperature and stirred for 6 h before it was washed with brine and water. The organic phase was separated, dried over Na2SO4, concentrated and purified by silica gel to give a colorless solid (1.8 g, 95% yield). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, 1H, J = 5.6 Hz), 6.28 (d, 1H, J = 5.6 Hz), 2.30 (3H, s), 0.95 (9H, s), 0.24 (6H, s). MS (EI) m/z: 240 (M)+. |
92% | With 1H-imidazole In dichloromethane at 28℃; for 12h; Schlenk technique; Inert atmosphere; | |
92% | With 1H-imidazole In dichloromethane at 20℃; | 54.1 Take maltol (0.1mol, 1.0eq.) and imidazole (0.25mol, 2.5eq.),Dichloromethane (200ml) was added, and TBSCl (0.11mol, 1.1eq.) was added.Stir at room temperature until the reaction is complete as monitored by TLC. The reaction solution was filtered through a short silica gel and then the solvent was removed by spinning.The compound M1 (22.1 g, 92%) was isolated by column chromatography. |
With 1H-imidazole In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium hydroxide cooling; | |
With potassium hydroxide | ||
With potassium hydroxide In lithium hydroxide monohydrate at 0℃; for 4h; |
With potassium hydroxide | ||
With sodium hydroxide In lithium hydroxide monohydrate at 20℃; for 4h; | ||
Alkaline conditions; | ||
With sodium hydroxide In dichloromethane at 14 - 45℃; for 7h; | 1; 2; 3 Example 1: Add 50 g of methyl maltol to 250 g of pre-configured 10% sodium hydroxide solution and stir to dissolve. 14 °C dropwise add 65g dimethyl sulfate, control temperature about 40 °C, control the pH of the reaction liquid at about 9, dropwise added, heated to 45 °C insulation reaction for 7 hours, the reaction is cooled to 20 °C or less, add 300ml of dichloromethane in three extractions, combined with the dichloromethane phase and concentrated to dry. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; at 75 - 90℃; for 5.5h; | 10mmol(1. 26g) Compound A was added to 20ml of distilled water and heated to 75 C for 30min, After confirming that the raw material was completely dissolved, An aqueous 10 ml (25%) solution of methylamine was added, The reaction temperature was 90 C, 5 hours after the reaction with the amount of activated carbon decolorization, Recrystallization gave B |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.4% | With potassium carbonate In acetone for 3h; Reflux; | 1 Example 1: Synthesis of Compound 5,6 Add 500 mg of a single-mouth flask to maltol 1 (15.10 g, 120 mmol) or ethyl maltol 2 (16.80 g, 120 mmol), methyl iodide (51.10 g, 360 mmol), anhydrous K2CO3 (49.70 g, 360 mmol), Acetone (100 mL) was heated to reflux for 3 h. TLC monitors the reaction, after the conversion of the raw materials is completed, The reaction was stopped, the reaction solution was concentrated to give a solid, and 180 mL of water was added. The organic layer was extracted with 180 mL of 3 dichloromethane, and the organic layer was washed with 100 mL×2 saturated brine. Drying with anhydrous sodium sulfate gave a yellow liquid 3 16.70 g (99.4%) or a yellow liquid 4 18.40 g (99.5%). |
99% | With potassium carbonate In acetone for 6h; Reflux; | 4.1.2 General procedures for the preparation of compounds 2a-c and 7a-b General procedure: A solution of maltol 1 or 6 (60 mmol), iodomethane or benzyl bromide or 4-methoxylbenzyl chloride (90 mmol), anhydrous K2CO3 (12.42 g, 90 mmol) and acetone (150 mL) was refluxed for 6 h. After the reaction was completed, the reaction mixture was evaporated under vacuum, and the residual was resolved in water (100 mL), extracted by DCM (4×100 mL) and washed by saturated brine (2×100 mL). The organic solution was evaporated to dryness to obtain 2a-c as yellow oil, 7a-b as white solid. |
99.4% | With potassium carbonate In acetone for 3h; Reflux; | 1 Preparation method of N-(2-(2-Methyl-3-hydroxy-1(4H)-4-oxopyridinyl)ethyl)-2-oxo-2H-benzopyran-3-carboxamide (a1b1) Add maltol (7.56g, 60mmol), methyl iodide (25.56g, 180mmol), anhydrous potassium carbonate (24.84g, 180mmol), acetone (100mL) into a 250mL single-necked flask, heat to reflux for 3h, TLC monitor the reaction, wait for the raw materials After the conversion is complete, stop the reaction, concentrate the reaction solution to obtain a solid, add 100 mL of water to dissolve, extract with 100 mL×4 dichloromethane, combine the organic layers, dry the organic layers with anhydrous sodium sulfate, and concentrate to obtain a yellow oily liquid 2-methyl- 3-Methoxypyran-4-one (8.35g), yield 99.4%. |
98% | In acetone for 6h; Reflux; | 1; 2 2-methyl-3-hydroxy-1-((coumarin-3-yl)methyl)pyridine-4(1H)-one (1a) Add maltol (7.56g, 60mmol) and acetone 100mL to a 250mL single-mouth bottle.Methyl iodide (9.37 g, 66 mmol), heated to reflux for 6 hours.After the reaction was completed, it was cooled to room temperature, and the solvent was dissolved by stirring, and dissolved in 100 mL of water.It was extracted 4 times with dichloromethane (50 mL) and dried over anhydrous sodium sulfate.Concentrated organic layer2-methyl-3-methoxypyranone. The yield was 98%. |
95% | With potassium carbonate In acetone for 3h; Inert atmosphere; Reflux; | |
68% | With potassium carbonate In acetone for 19h; Heating; | |
With silver(l) oxide for 20h; Heating; | ||
With potassium carbonate In acetone for 8h; Reflux; | General procedure for the preparation of compounds 3a-3c General procedure: A mixture of suitable Maltol (7.56g, 60mmol), anhydrous K2CO3 (9.12g, 66mmol), benzyl bromide (10.78g, 63mmol) and acetone (150mL) was refluxed for 8h. Once the reaction was completed, the mixture was cooled to room temperature. After the solvent was removed under reduced pressure, water (100mL) was added and the mixture was extracted four times with dichloromethane (50mL). The combined organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford intermediate 2a as yellow oil. Intermediates 2b, 2c wasprepared followed the similar procedure of 2a. 2a, 2b or 2c (4.33g, 40mmol) was then dissolved in ethanol 45mL and then 25% ammonia aqueous solution (60mL) was added, and the mixture was refluxed for 12h. Afterward, The solvent was evaporated off to obtain a pale brown solid residue, which was recrystallized from acetone/ethyl acetate, leaving the pure target compound as a pale colored solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | at 90℃; for 6h; | 2.2. Synthesis of DDMP from maltol Maltol (10 g, 80 mmol) was dissolved in acetic anhydride (15 mL), the mixture was heated at 90 C for 6 h, then cooled and ethyl acetate (200 mL) was added. The ethyl acetate solution was washed with saturated aqueous NaHCO3 (1 × 100 mL), then aqueous NaCl (2 × 200 mL), dried over anhydrous Na2SO4 then evaporated under reduced pressure to give 2 as a yellow oil 13.2 g, yield 98%. 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 5.7 Hz, 1H, H-2), 6.40 (d, J = 5.7 Hz, 1H, H-3), 2.34 (s, 3H, -OCH3), 2.27 (s, 3H, H-7). 13C NMR (150 MHz, CDCl3) δ 172.0 (C- 4), 167.6 (-O-C- - O), 159.1 (C-2), 154.3 (C-6), 138.7(C-5), 116.8 (C-3), 20.3 (-OCH3), 15.0 (C-7). HR-ESI-MS m/z calculated for C8H8O4 [M + H]+ 169.0495, found 169.0494. |
84% | With acetic acid at 80℃; for 18h; Inert atmosphere; | |
75% | With sodium acetate In chloroform at 125℃; for 0.25h; Irradiation; |
at 80℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.7% | Stage #1: Maltol With ammonium hydroxide at 40℃; for 2h; Stage #2: With ammonium carbonate at 40℃; for 10h; Reflux; | 1-4 Example 1: Preparation of 3-hydroxy-2-methyl-4-pyridone. 40 g of 3-hydroxy-2-methyl-4-pyrone and 200 g of aqueous ammonia (20%) were added to the reaction flask, and the temperature was slowly raised to dissolve.Incubate at 40 ° C for 2 h, slowly add 30 g of ammonium carbonate, and keep at 40 ° C for 2 h.Slowly add 62g ammonium carbonate, heat at 40 ° C for 3h, slowly warmed to reflux and kept at reflux for 5h, then cooled to 0 ° C,It was suction filtered and rinsed with a small amount of water, and dried to give 38 g of 3-hydroxy-2-methyl-4-pyridone (yield 95.7%) |
85% | With ammonia In water for 10h; Reflux; | |
79% | With ammonia In water for 10h; Reflux; | 1 Example 1 Preparation of the target compounds 5, 6 Maltol (10 mmol) was dissolved in 15 mL of water and excess ammonia (6 mL) was added. The reaction mixture was refluxed for 10 hours, and ammonia water and the solvent were removed under reduced pressure. The mixture was cooled to room temperature overnight. The resulting solid product was recrystallized from a 50% water/methanol mixture in the presence of activated carbon. The activated carbon was filtered off, and the product was concentrated under reduced pressure. The final product was dried in a desiccator with phosphorus pentoxide. The title compound 5 (1.01 g, 7.93 mmol) was obtained. Gray solid, mp 285-287 ° C, yield 79%. |
69% | With ammonium hydroxide at 130℃; for 0.5h; Irradiation; | |
24% | With ammonia In ethanol; water at 66 - 75℃; | 32.D D. Preparation of 3-hydroxy-2-methyl-1H-pyridin-4-one; A 500-mL high-pressure reaction vessel equipped with a magnetic stir bar and a thermometer was charged with maltol (20 g, 0.16 mol), ethanol (40 mL) and ammonium hydroxide solution (28.0-30.0%, 35 mL, 0.52 mol). The reaction vessel was sealed and heated at 66° C. for 2.5 h. HPLC analysis (HPLC Method 1, Example 24) indicated that only 26% of product (peak percent area) was formed. Another 30 mL of conc. ammonium hydroxide (28.0-30.0%, 0.45 mol) was added, and the resulting mixture was sealed and heated to 75° C. for overnight. Upon cooling, a solid separated, and it was collected by suction filtration (8.7 g). HPLC analysis of the solid indicated presence of the desired product and maltol in about 4/1 ratio. The solid was slurried in methanol (30 mL), and the resulting mixture was stirred. The solid 3-hydroxy-2-methyl-1H-pyridin-4-one was collected by suction filtration (4.8 g, 24% yield, HPLC purity (peak percent area): 99.7% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 11.6 (br s, 1H), 7.40 (d, J=6.8 Hz, 1H), 6.09 (d, J=6.8 Hz, 1H), 2.17 (s, 3H). |
Multi-step reaction with 3 steps 1: 73 percent 2: 80.5 percent / NH4OH / 1.) refluxm 12 h, 2.) room temperature, 4 h 3: 77 percent / 48percent HBr / 4 h / 140 - 150 °C | ||
Multi-step reaction with 3 steps 1: 95 percent / by a literature procedure 2: 60 percent / NH3 / ethanol 3: 82 percent / HBr / acetic acid | ||
Stage #1: Maltol With ammonium hydroxide In water at 45℃; for 2h; Stage #2: With ammonium carbonate In water for 10h; Reflux; | ||
78 % | With ammonia at 80℃; Microwave irradiation; Enzymatic reaction; | 2.2.1.1. 3-Hydroxy-2-methyl-4(1H)-pyridinone (Hmpp) ligand In a 30ml microwave vessel with a magnetic bar, 1 g of Maltol was dispersed in10 ml of ammonia solution at 32%. The reaction vessel was placed in themicrowave's cavity, where it was irradiated for 1 h at 80 °C. After that,the reaction vessel was placed in an ice bath, allowing Hmpp to precipitate.The resulting powder was filtered under reduced pressure usinga Buchner funnel and washed with cold acetone. Hmpp was obtainedwith a 78% yield.1H NMR (400 MHz, CDCl3) δ (ppm): 7,71 (1H, d, J = 5,6 Hz, H-6),6.41 (d, J = 5,6 Hz, H-5), 2,36 (3H, s, CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With hydrogenchloride In ethanol; water at 160℃; for 12h; Autoclave; | |
83% | With hydrogenchloride In ethanol; water at 160℃; for 12h; Autoclave; | 2 Example 2: Preparation of the target compound 7-37. Maltol (10 mmol) and excess aniline (15 mmol) were added to an acidic solution of 18.0 mL of water, 0.4 mL of HCl, and 2.0 mL of ethanol (pH = 5). And the resulting mixture was heated in an autoclave at 160 ° C for 12 hours. After the reaction was completed, the reaction mixture was adjusted to pH = 7 using sodium hydroxide solution (2N), and the product was collected by filtration. Finally, the residue was purified by silica gel column chromatography (CH2Cl2: CH3OH = 50: 1), the title compound 7 (1.67 g, 8.3 mmol) was obtained. White solid, mp 206-207 ° C, yield 83%. |
56% | With hydrogenchloride In water at 165℃; for 0.5h; Microwave irradiation; |
35% | Stage #1: Maltol; aniline With hydrogenchloride In ethanol; water Reflux; Stage #2: With sodium hydroxide In ethanol; water | |
6.56% | With hydrogenchloride In ethanol; water at 110℃; for 72h; Reflux; | |
With hydrogenchloride for 72h; Heating; | ||
With hydrogenchloride for 5h; Heating; | ||
With hydrogenchloride In methanol; water Reflux; Inert atmosphere; | ||
In ethanol; water at 170℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With hydrogenchloride In water at 165℃; for 0.5h; Microwave irradiation; | |
36% | In ethanol; water at 20 - 50℃; | |
21% | In methanol for 18h; Heating; |
With hydrogenchloride In water at 165℃; for 0.5h; Microbiological reaction; | ||
93 % | With toluene-4-sulfonic acid In methanol at 20℃; | 2.1.1. Synthesis of 1-benzyl-3-hydroxy-2-methylpyridin-4(1H)-one(BHM) Maltol (1.0060 g, 7.9771 mmol) and benzylamine (0.8548 g,7.9771 mmol) were dissolved in 50 mL methanol. p-tolunesulfoni cacid monohydrate (0.8548 g, 7.9771 mmol) was added and the reaction mixture was stirred at room temperature for 72 h. p-tolunesulfonic acid monohydrate was filtered and the filtrate was left for evaporation, which resulted in yellow crystals.The schematic representation of the synthesized ligand is illustrated in Scheme 1 below. Yield = 1.6001 g, 93 %; 1H NMR (400 MHz, DMSO d6) d (ppm):7.78-7.73 (m, 1H), 7.41-7.26 (m, 3H), 7.10-7.04 (m, 2H),6.23 - 6.18 (m, 1H), 5.25 (d, J = 5.0 Hz, 2H), 2.18-2.05 (m, 3H).13C NMR (400 MHz, DMSO d6) d (ppm): 169, 145, 139, 138, 137,129, 128, 127, 126, 111, 110, 56, 55, 40, 39, 38, 12, 11. IR (cm1):OH = 3178, CH = 3056, C=O = 628, C=C = 1577 and C-N = 1233. |
In ethanol; water at 170℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With air at 400 - 450℃; Formation of xenobiotics; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | In water for 67h; Heating; | |
41% | In water for 70h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 68 percent / K2CO3 / acetone / 19 h / Heating 2: 77 percent / conc. ammonia / 3 h / 110 °C 3: 85 percent / POCl3 / 10 h / Heating 4: NaOMe / 10 h / Heating 5: 98 percent / 84percent m-CPBA / CH2Cl2 / 4 h / Ambient temperature | ||
Multi-step reaction with 3 steps 1.1: ammonium hydroxide / 2 h / 40 °C 1.2: 10 h / 40 °C / Reflux 2.1: potassium hydroxide / water / 20 h / 10 - 20 °C 3.1: acetic acid; sodium tungstate; dihydrogen peroxide / 4 h / 40 - 95 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With pyridine In tert-butyl methyl ether at 3 - 20℃; for 3.33333h; | 2.b Maltol (9.35 g, 74 mmol, 1.05 equiv.), pyridine (9.8 ml, 120 mmol, 1.7 equiv.) and 4-dimethylaminopyridine (112 mg) are suspended in methyl f-butylether (MTBE, 100 ml) and the suspension is cooled with an icebath. A solution of 3-chlorocarbonyl-acrylic acid ethyl ester (11.29 g, 70 mmol) in MTBE (30 ml) is added dropwise during 20 min. The resulting suspension is stirred for 30 min. at 3°C, than for 2.5 h at room temperature. The mixture is hydrolyzed with ice/ 2N aq. HCI and extracted with EtOAc. The organic layer is washed with 0.5 N aq. HCI-solution, then twice with brine and dried over MgSO4. The crude obtained after removal of the solvents is purified via FC on SiO2 (hexane/EtOAc 1 :4) to isolate ethyl 2-methyl-4-oxo-4H-pyran-3-yl fumarate as a viscous, red-brown oil (8.95 g, 51%).IR: 1753 m, 1721 s, 1659 vs, 1643 vs, 1421 m, 1292 s, 1240 s, 1161 vs, 1133 vs, 1029 m, 976 m,831m. 1H-NMR: 7.94 (d, J=5.8, 1 H), 6.63 (d, J=5.8, 1 H), 4.50 (q, /=7.1, 2 H), 2.49 (s, 3 H),1.54 (t, ./=7.1, 3 H).13C-NMR: 171.23 (s), 164.26 (s), 161.36 (s), 159.05 (s), 154.27 (d), 138.22 (s), 136.08 (d),131.12 (d), 116.66 (d), 61.42 (t), 14.84 (q), 13.94 (q).MS: 253(1, [MHhH]+) , 224 (4), 207 (16), 179 (5), 154 (8), 137 (8), 127 (100), 126 (18), 99 (23), 55 (22). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.4% | With sodium In 1,4-dioxane at 20℃; | |
64% | With pyridine at 20℃; Inert atmosphere; | |
31% | With triethylamine In dichloromethane at 20℃; for 0.166667h; | 3.2. General procedure for the synthesis of sulfonate derivatives ofmaltol (3a-p) General procedure: To a solution of maltol (1, 1.0 mmol) and ethanesulfonyl chloride/arylsulfonyl chloride(2, 1.2 mmol) in dry dichloromethane (DCM, 10 ml) at room temperature, a solution of triethylamine (Et3N) (1.5 mmol) in dry DCM (5 ml) was added dropwise for 10 min. When the reaction was completed by TLC analysis, the reaction mixture was diluted with water (15 ml), and extracted with DCM (30 ml 3). Subsequently, the combined organic phase was washed by saturated aq. brine (30 ml), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography to obtain in 28-97% yields. The data for 3a-p are shown as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water aq. solns. of Fe salt and ligand (molar ratio 1:5) mixed at pH 5-6; not isolated; detd. by method of isomolar series; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water anhydrous FeCl3, pH 7.5 (addn. of NH3), stirring for 1 h; EtOH removed, extrd. with CHCl3, CHCl3 removed, crystd. by slow evapn. of soln. of chlorobenzene, elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In toluene byproducts: NH3, C6H6; soln. of B compd. and ligand refluxed for 12 h; hot filtered, cooled on ice, filtered, air-dried; elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: Maltol With potassium carbonate In N,N-dimethyl-formamide for 0.0833333h; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In N,N-dimethyl-formamide at 20℃; | 1.1 (1) Add potassium carbonate (60 mmol, 3.0 eq.) To a solution of methyl maltol (S1, 20 mmol, 1.0 eq.) In N, N-dimethylformamide (40 ml). After stirring for 5 minutes, N-phenylbis (trifluoromethanesulfonyl) imide (22 mmol, 1.1 eq.) Was added. Stir at room temperature until the raw material is completely consumed (monitored by TLC). The reaction solution was filtered, diluted with water, and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over sodium sulfate, filtered, and concentrated. Column chromatography was eluted with petroleum ether and ethyl acetate (PE / EA = 2: 1) to obtain the product 2-methyl-3- (trifluoromethanesulfonate) -4H-pyran-4-one(M1, 3.35g, 65%). |
With potassium carbonate In N,N-dimethyl-formamide for 0.5h; | ||
Stage #1: Maltol With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Schlenk technique; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In N,N-dimethyl-formamide at 20℃; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With woollins’ reagent In 1,4-dioxane at 125℃; for 0.5h; Microwave irradiation; | |
57% | With woollins’ reagent In toluene at 80℃; for 12h; Inert atmosphere; | 3 Synthesis of 3-hydroxy-2-methyl-4H-pyran-4-selenone (hmps) was carried out by dissolving 3-hydroxy-2-methyl-4H-pyran-4-one (2 mmol) in toluene at 80 ° C. , Woolins' reagent (1 mmol) which is a selenocarbonyl reagent, and the mixture was stirred at 80 ° C. for 12 hours under a nitrogen atmosphere.The solution was concentrated and separated and purified by column chromatography using dichloromethane to obtain the desired product.Yield: 57%. |
57% | With woollins’ reagent In toluene at 80℃; for 12h; Inert atmosphere; |
57% | With woollins’ reagent In toluene at 80℃; for 12h; Inert atmosphere; | 3.3 2.3.3. 3-Hydroxy-2-methyl-4(H)-pyran-4-selenone (hmps) Woollins' reagent was added to a hot solution of maltol ( hmpo ) in dry toluene at 80 °C under nitrogen gas. The resulting solution was heated with stirring for 12 h, cooled to room temperature, and clarified by filtration. The filtrate was evaporated to yield a dark red oil. The dark red oil was purified by silica gel column (0.0040-0.0063 mm mesh, dichloromethane solvent). The oil cooled in freezer was turned into a dark red solid substance (yield: 57%). Anal. found (Calcd.) for C6H6O2Se: C, 38.11 (38.11); H, 2.98 (3.20). EI(+)-MS: m/z 190 (M+). |
27% | With phosphorus; selenium In m-xylene for 12h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; | 175 mg of <strong>[71125-38-7]meloxicam</strong> was ground with 62.8 mg of maltol and 400 muL of ethyl acetate was added to the solid mixture. The solids gathered after grinding were stored in screw cap vials for subsequent analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: Maltol With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 0.166667h; Stage #2: 4-nitrophenyl 4-(4’,4’,5’,5’-tetramethyl-1’,3’-dioxa-2’-borolan-2’-yl)benzyl carbonate In N,N-dimethyl-formamide at 80℃; for 1.5h; | |
80% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 1.5h; | 3 Maltol (0.032 g, 0.25 mmol) was dissolved in 5 mL of dry DMF and K2CO3 (0.10 g, 0.75 mmol) was added. The reaction was heated to 80° C. for 10 minutes before adding B21a (0.10 g, 0.25 mmol). The reaction was allowed to go for 1.5 h. After cooling to room temperature, DMF was removed by rotary evaporation. The residue was brought up in EtOAc, washed with water (3×) and with brine. The organics were dried over MgSO4, filtered and concentrated for column purification. B21 was eluted with 1% MeOH in DCM giving a pale orange compound in 80% yield (0.078 g, 0.2 mmol). 1H NMR (400 MHz, CDCl3) δ=7.82 (d, J=8.0 Hz, 2H), 7.68 (d, J=6.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 6.43 (d, J=5.6 Hz, 1H), 5.30 (s, 2H), 2.30 (s, 3H), 1.34 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=172.1, 159.6, 154.6, 152.2, 139.3, 137.6, 135.3, 127.6, 117.3, 115.9, 84.2, 71.1, 25.1, 15.2. ESI-MS(+): m/z 387.07 [M+H]+, 409.13 [M+Na]+. Anal. calcd. for C20H23BO7: C, 62.20; H, 6.00. Found: C, 61.85; H, 6.40. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In methanol for 1h; Reflux; | 1. General procedure for preparation of pyrylium sulfanates General procedure: 0.03 mole of sulfonic acid was dissolved in 50 mL methanol and equimolar amount of 4-pyrone soluble in methanol was added. The mixture was stirring and heating at boiling point of methanol using reflexive condenser for 1h. Methanol was removed under reduced pressure (60 °C, 30×102 Pa). The obtained liquid product was shaken with 20 mL diethyl ether and dried out under vacuum for 3 hours or obtained solid product was crystallized from the mixture of methanol/toluene, 1:5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With pyridine at 20℃; Inert atmosphere; | |
49% | With triethylamine In dichloromethane at 20℃; for 0.166667h; | 3.2. General procedure for the synthesis of sulfonate derivatives ofmaltol (3a-p) General procedure: To a solution of maltol (1, 1.0 mmol) and ethanesulfonyl chloride/arylsulfonyl chloride(2, 1.2 mmol) in dry dichloromethane (DCM, 10 ml) at room temperature, a solution of triethylamine (Et3N) (1.5 mmol) in dry DCM (5 ml) was added dropwise for 10 min. When the reaction was completed by TLC analysis, the reaction mixture was diluted with water (15 ml), and extracted with DCM (30 ml 3). Subsequently, the combined organic phase was washed by saturated aq. brine (30 ml), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography to obtain in 28-97% yields. The data for 3a-p are shown as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine In dichloromethane at 20℃; | 2.1-2.2 1) In a 50 ml flask add maltol (3-hydroxy-2-methyl-4-pyrone, compound 1, 1mmol), substituted sulfonyl chloride (compound 2 b, 1.6 mmol), and add 10 ml dichloromethane to dissolve completely, then dropwise triethylamine dichloromethane solution (by the triethylamine and dichloromethane is mixed, wherein the solvent dichloromethane for 5 ml, triethylamine is 1.8 mmol), then completing the reaction under room temperature, TLC tracking and monitoring until a reaction is finished. 2) After the reaction, by adding 30 ml of water, then dichloromethane is used for extraction, the combined organic phase, saturated salt water after washing, final drying with anhydrous sodium sulfate, concentrated to evaporate the solvent after the silica gel column chromatography separation to obtain the target product 3 b, its appearance is a white solid, having a melting point of 106 - 107 °C, the yield is 88%. |
78% | With triethylamine In dichloromethane at 20℃; for 0.166667h; | 3.2. General procedure for the synthesis of sulfonate derivatives ofmaltol (3a-p) General procedure: To a solution of maltol (1, 1.0 mmol) and ethanesulfonyl chloride/arylsulfonyl chloride(2, 1.2 mmol) in dry dichloromethane (DCM, 10 ml) at room temperature, a solution of triethylamine (Et3N) (1.5 mmol) in dry DCM (5 ml) was added dropwise for 10 min. When the reaction was completed by TLC analysis, the reaction mixture was diluted with water (15 ml), and extracted with DCM (30 ml 3). Subsequently, the combined organic phase was washed by saturated aq. brine (30 ml), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography to obtain in 28-97% yields. The data for 3a-p are shown as follows. |
71% | With pyridine at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In acetonitrile at -20 - 20℃; | Synthesis of (malt)2VV(O)(OiPr) (7)Complex 7 has been reported previously (Caravan, P.; Gelmini, L.; Glover, N.; Herring, F. G.; Li, H.; McNeill, J. H.; Rettig, S. J.; Setyawati, I. A.; Shuter, E.; Sun, Y.; Tracey, A. S.; Yuen, V. G.; Orvig, C. J. Am. Chem. Soc. 1995, 117, 12759-12770). Maltol (1.199 g, 9.516 mmol) was suspended in CH3CN (10 mL). VV(O)(OiPr)3 (1.161 g, 4.758 mmol) was added, yielding a dark red reaction mixture, which was stirred at room temperature 5 minutes. Upon cooling the mixture to -20° C. overnight, dark red needles formed. The supernatant was decanted, and the crystals washed with diethyl ether (2×3 mL) and dried under vacuum. Yield: 1.766 g (98%). 1H NMR (400 MHz, CD2Cl2): δ 7.85 (br s, 2H, malt), 6.45 (br s, 2H, malt), 6.30 (h, 1H, J=6.0 Hz, V-OCH), 2.47 (s, 6H, malt), 1.42 (br s, 6H, V-isopropoxide). 13C{1H} NMR (100 MHz, CD2Cl2): 174.8 (br), 155.5, 150.6 (br), 110.9 (br), 92.2, 24.8, 14.9. 51V NMR (105 MHz, CD2Cl2): -433 (s). IR (thin film): νV=O=967 cm-1. 1H NMR data in CDCl3 matched those reported for 7 (Caravan, P.; Gelmini, L.; Glover, N.; Herring, F. G.; Li, H.; McNeill, J. H.; Rettig, S. J.; Setyawati, I. A.; Shuter, E.; Sun, Y.; Tracey, A. S.; Yuen, V. G.; Orvig, C. J. Am. Chem. Soc. 1995, 117, 12759-12770). Anal. Calcd for C15H17O8V: C, 47.89; H, 4.55. Found: C, 48.06; H, 4.48. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.6% | In octane for 72h; Inert atmosphere; Reflux; | A Synthesis of [Ru3(CO)8(C12H10O6)], 1 Ru3(CO)i2 (639.34 mg, 1.0 mmol) and maltol (2-methyl-3-hydroxy-4-pyrone) (252.22 mg, 2.0 mmol) were added to a two-necked 100-mL round bottom flask under inert atmosphere. 25 mL of degassed anhydrous octane was added under argon atmosphere and the solution was refluxed gently for 3 days. The insoluble light yellow solid from the reaction mixture was filtered using a frit. The solid in the frit was washed with hexanes (3 x 10 mL) to remove traces of Ru3(CO)i2. Alternatively, the product was also purified by silica gel column chromatography by eluting with dichloromethane. The solid thus obtained weighed to give 720 mg, (92.6%) based on Ru3(CO)i2; m.p. 185-195° C (dec). Single crystals were grown from solutions of diethyl ether containing few drops of methylene chloride at - 10° C. Spectroscopic data for 1: IR (CH2C12): D(C-H) 3052 (m), 2958 (w), 2858 (w); v(terminal CO): 2091 (s), 2020 (s, sh), 1926 (s), 2030 (s); v(C-O) due coordinated maltol ligands: 1615 (s), 1574 (s), 1510 (s). 1H NMR: (CD2C12): δ 7.61 (d, 2H, 3JC_H = 5Hz), 6.26 (d, 2H, 3Jc-H= 5Hz), 2.53 (s, 6H). ESI-APCI mass spectrum calculated for C2oH10O14Ru3, 777.4950[M+]; Found : 779.7302 [M+2H]+, 694.7239 [M+- 3CO). Analytical calculated for C20HioOi4Ru3, C, 30.90%, H, 1.30%. Found: C, 31.02%, H, 1.13% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: Diphenylphosphine oxide With triethylamine In tetrachloromethane at 20 - 22℃; for 0.166667h; Inert atmosphere; Stage #2: Maltol In tetrachloromethane at 50 - 52℃; for 10h; Inert atmosphere; | General procedure for the synthesis of diorganylphosphino-chalcogenoates 10a-e General procedure: A mixture of secondary phosphine chalcogenide 2-5 or 9 (1.0 mmol) and Et3N(1.0 mmol) in 4 mL of CCl4 was stirred at 20-22 C for 10 min. 4-Pyrone 8(1.0 mmol) was added, and the mixture was stirred at 50-52 C for 5-10 h (seealso Table 2). The solvent was removed under reduced pressure, and 1,4-dioxane (3 mL) was added. The precipitated white solid (triethylammoniumchloride) was filtered, and the 1,4-dioxane was evaporated under vacuum.CHCl3 (3 mL) was added to the residue and the mixture was stirred. Unreactedmaltol was filtered off. The filtrate was precipitated in hexane and allowed tostand for 2-3 h at 2-5 C. The solution was separated by decanting, and theresidue (crystalline product) was dried under vacuum to givephosphinochalcogenic esters 10b,d,e. In the case of esters 10a,c the residue(after 1,4-dioxane had been evaporated under vacuum) was dissolved intoluene and passed through Al2O3; any anhydride (side product) was elutedfrom the adsorbent and esters 10a,c remained on the alumina. The latter wasrinsed with CHCl3 and the solvent evaporated under reduced pressure to affordphosphinochalcogenoic O-esters 10a,c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: diphenylphosphane sulfide With triethylamine In tetrachloromethane at 20 - 22℃; for 0.166667h; Inert atmosphere; Stage #2: Maltol In tetrachloromethane at 50 - 52℃; for 6h; Inert atmosphere; | General procedure for the synthesis of diorganylphosphino-chalcogenoates 10a-e General procedure: A mixture of secondary phosphine chalcogenide 2-5 or 9 (1.0 mmol) and Et3N(1.0 mmol) in 4 mL of CCl4 was stirred at 20-22 C for 10 min. 4-Pyrone 8(1.0 mmol) was added, and the mixture was stirred at 50-52 C for 5-10 h (seealso Table 2). The solvent was removed under reduced pressure, and 1,4-dioxane (3 mL) was added. The precipitated white solid (triethylammoniumchloride) was filtered, and the 1,4-dioxane was evaporated under vacuum.CHCl3 (3 mL) was added to the residue and the mixture was stirred. Unreactedmaltol was filtered off. The filtrate was precipitated in hexane and allowed tostand for 2-3 h at 2-5 C. The solution was separated by decanting, and theresidue (crystalline product) was dried under vacuum to givephosphinochalcogenic esters 10b,d,e. In the case of esters 10a,c the residue(after 1,4-dioxane had been evaporated under vacuum) was dissolved intoluene and passed through Al2O3; any anhydride (side product) was elutedfrom the adsorbent and esters 10a,c remained on the alumina. The latter wasrinsed with CHCl3 and the solvent evaporated under reduced pressure to affordphosphinochalcogenoic O-esters 10a,c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: bis(2-phenylethyl)phosphane sulfide With triethylamine In tetrachloromethane at 20 - 22℃; for 0.166667h; Inert atmosphere; Stage #2: Maltol In tetrachloromethane at 50 - 52℃; for 8h; Inert atmosphere; | General procedure for the synthesis of diorganylphosphino-chalcogenoates 10a-e General procedure: A mixture of secondary phosphine chalcogenide 2-5 or 9 (1.0 mmol) and Et3N(1.0 mmol) in 4 mL of CCl4 was stirred at 20-22 C for 10 min. 4-Pyrone 8(1.0 mmol) was added, and the mixture was stirred at 50-52 C for 5-10 h (seealso Table 2). The solvent was removed under reduced pressure, and 1,4-dioxane (3 mL) was added. The precipitated white solid (triethylammoniumchloride) was filtered, and the 1,4-dioxane was evaporated under vacuum.CHCl3 (3 mL) was added to the residue and the mixture was stirred. Unreactedmaltol was filtered off. The filtrate was precipitated in hexane and allowed tostand for 2-3 h at 2-5 C. The solution was separated by decanting, and theresidue (crystalline product) was dried under vacuum to givephosphinochalcogenic esters 10b,d,e. In the case of esters 10a,c the residue(after 1,4-dioxane had been evaporated under vacuum) was dissolved intoluene and passed through Al2O3; any anhydride (side product) was elutedfrom the adsorbent and esters 10a,c remained on the alumina. The latter wasrinsed with CHCl3 and the solvent evaporated under reduced pressure to affordphosphinochalcogenoic O-esters 10a,c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: diphenylphosphine selenide With triethylamine In tetrachloromethane at 20 - 22℃; for 0.166667h; Inert atmosphere; Stage #2: Maltol In tetrachloromethane at 50 - 52℃; for 5h; Inert atmosphere; | General procedure for the synthesis of diorganylphosphino-chalcogenoates 10a-e General procedure: A mixture of secondary phosphine chalcogenide 2-5 or 9 (1.0 mmol) and Et3N(1.0 mmol) in 4 mL of CCl4 was stirred at 20-22 C for 10 min. 4-Pyrone 8(1.0 mmol) was added, and the mixture was stirred at 50-52 C for 5-10 h (seealso Table 2). The solvent was removed under reduced pressure, and 1,4-dioxane (3 mL) was added. The precipitated white solid (triethylammoniumchloride) was filtered, and the 1,4-dioxane was evaporated under vacuum.CHCl3 (3 mL) was added to the residue and the mixture was stirred. Unreactedmaltol was filtered off. The filtrate was precipitated in hexane and allowed tostand for 2-3 h at 2-5 C. The solution was separated by decanting, and theresidue (crystalline product) was dried under vacuum to givephosphinochalcogenic esters 10b,d,e. In the case of esters 10a,c the residue(after 1,4-dioxane had been evaporated under vacuum) was dissolved intoluene and passed through Al2O3; any anhydride (side product) was elutedfrom the adsorbent and esters 10a,c remained on the alumina. The latter wasrinsed with CHCl3 and the solvent evaporated under reduced pressure to affordphosphinochalcogenoic O-esters 10a,c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: bis(2-phenylethyl)phosphine selenide With triethylamine In tetrachloromethane at 20 - 22℃; for 0.166667h; Inert atmosphere; Stage #2: Maltol In tetrachloromethane at 50 - 52℃; for 7h; Inert atmosphere; | General procedure for the synthesis of diorganylphosphino-chalcogenoates 10a-e General procedure: A mixture of secondary phosphine chalcogenide 2-5 or 9 (1.0 mmol) and Et3N(1.0 mmol) in 4 mL of CCl4 was stirred at 20-22 C for 10 min. 4-Pyrone 8(1.0 mmol) was added, and the mixture was stirred at 50-52 C for 5-10 h (seealso Table 2). The solvent was removed under reduced pressure, and 1,4-dioxane (3 mL) was added. The precipitated white solid (triethylammoniumchloride) was filtered, and the 1,4-dioxane was evaporated under vacuum.CHCl3 (3 mL) was added to the residue and the mixture was stirred. Unreactedmaltol was filtered off. The filtrate was precipitated in hexane and allowed tostand for 2-3 h at 2-5 C. The solution was separated by decanting, and theresidue (crystalline product) was dried under vacuum to givephosphinochalcogenic esters 10b,d,e. In the case of esters 10a,c the residue(after 1,4-dioxane had been evaporated under vacuum) was dissolved intoluene and passed through Al2O3; any anhydride (side product) was elutedfrom the adsorbent and esters 10a,c remained on the alumina. The latter wasrinsed with CHCl3 and the solvent evaporated under reduced pressure to affordphosphinochalcogenoic O-esters 10a,c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: Maltol; bis(acetylacetonate)oxovanadium; 2-chloro-N′-(3-ethoxy-2-hydroxybenzylidene)benzohydrazide In methanol at 20℃; for 0.5h; Stage #2: With air In methanol | 2.2. Synthesis of the complexes General procedure: Complexes 1, 2, and 3 were prepared by the method described here. A methanolic solution (30 mL) of VO(acac)2 (0.27 g, 1.0 mmol) was added to a methanolic solution (20 mL) of H2L (0.32 g, 1.0 mmol) and the bidentate ligands (1.0 mmol each), with stirring. The mixtures were stirred at room temperature for30 min to give deep brown solution. The resulting solution was allowed to stand in air for a few days until three-quarters of the solvent evaporated. Brown block-shaped single crystals of the complexes,suitable for X-ray single-crystal diffraction, were formed at the bottom of the vessel. The crystals were isolated by filtration, washed three times with cold methanol, and dried in air. Yields: 2.56 g, 56% (1);3.71 g, 73% (2); 3.56 g, 68% (3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 88.5% 2: 99.8% | With sodium sulfate In water at 26℃; for 3h; | 7 Embodiment 7 To the four 250 ml flask are added respectively in three 90 ml water, by adding sodium sulfate under stirring 7.3g (equimolar amount), 7.7g (excessive 5%), 8.1g (surfeits 10%), 8.8g (excess 20%) is dissolved, are respectively joined according to example 5 preparation of methyl malt phenol barium 20g, at room temperature 26 °C stirring for 3 hours, filtered, using 10 ml water to wash the filter cake, combined filtrate and cleaning solution, sodium solution to obtain methyl maltol, acidified with sulfuric acid to PH2-3, crystallization at room temperature 4 hours, after filtering, washing, drying, to obtain white powdery methyl maltol 11.0g, 11 . 2g, 11.4g, 11.5g, yield of 84.6%, 86.2%, 87.7%, 88.5%. The filter cake 105 °C drying, to obtain white powdery barium sulfate 11.7g, 11 . 9g, 12.0g, 12.0g, to yield 97.3%, 98.9%, 99.8%, 99.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide | Synthesis of AB09 [00358] AB09 was synthesized from commercially available maltol and chlorobutenolide prepared by methods described above. The alkylation of maltol with chlorobutenolide was achieved under various conditions. The use of dichloromethane solvate with pyridine as base or the use of Ν,Ν'-dimethylformamide (DMF) with potassium carbonate as base was preferred. Purification was achieved by column chromatography and re-crystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With hydrogenchloride In ethanol; water at 160℃; for 12h; Autoclave; | |
60% | With toluene-4-sulfonic acid In water at 150℃; for 48h; Autoclave; Sealed tube; | General Procedure for Synthesis of Pyridinones 1a-1c General procedure: A mixture of 3-hydroxy-2-methyl-4-pyrone (maltol, 1 g,7.93 mmol), appropriate aromatic amine (7.93 mmol) and p-toluenesulfonic acid (0.1500 g, 0.79 mmol) in water (20 mL) was heated in a sealed thick-walled glass tube for 48 h at 150 °C. The crude product, obtained by cooling the reaction mixture to room temperature, was filtered off and recrystallized (from methanol). The purity of the products was monitored by TLC (ethyl acetate : methanol = 5 : 1, v / v). 3-HYDROXY-2-METHYL-1-(m-METHYLPHENYL)PYRIDIN-4-ONE (1a) Yellow solid, 1.0201 g (60 %), mp 168.8-170.6 °C. 1H NMRδ / ppm: 1.97 (s, 3H, CH3), 2.38 (s, 3H, CH3-Ar), 6.20 (d, 1H,J = 7.31 Hz, H-5), 7.24 (d, 1H, J = 7.80 Hz, H-Ar), 7.27 (s, 1H,H-Ar), 7.35 (d, 1H, J = 7.61 Hz, H-Ar), 7.44 (t, 1H, J = 7.65 Hz,H-Ar), 7.53 (d, 1 H, J = 7.31 Hz, H-6). 13C NMR δ / ppm: 13.25,20.64, 110.71, 123.88, 127.30, 129.30, 129.61, 128.50,137.75, 139.41, 141.48, 144.94, 169.88. ESI-MS: m / z 216.2[M+H]+ |
In ethanol; water at 170℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: Maltol; 1,2-bis(dichlorophosphino)ethane In dichloromethane for 0.0833333h; Inert atmosphere; Stage #2: With triethylamine In dichloromethane for 0.0833333h; Inert atmosphere; | In situ generation of (CH2P(Ma)2)2 (1) 1,2-Bis(dichlorophosphino)ethane ((CH2PCl2)2) (0.1628g, 0.7023 mmol) and maltol (Hma) (0.3542 g, 2.809 mmol) were added to a round bottom flask. Dry methylene chloride (~20 mL) was cannula transferred to the round bottom flask and left to stir for 5 minutes. An excess of Et3N (1 mL) was then cannula transferred to reaction mixture, producing an opaque cloud above the solution and colloidal solution, which turned completely clear in 5 minutes. 1H NMR (500 MHz, CDCl3): 7.58 (d, J = 5 Hz, 4 H), 6.26 (d, J = 5 Hz, 4 H), 2.37 (vt, J ~ 7 Hz, 4 H), 2.31 (s, 12 H, -CH3). 31P{1H} NMR: 195.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With air In methanol at 20℃; | 2.2 Synthesis of the complexes Complexes 1 and 2 were prepared by the same method as described here. A methanolic solution (30mL) of VO(acac)2 (0.27g, 1.0mmol) was added to a methanolic solution (20mL) of the aroylhydrazones (1.0mmol each) and maltol (1.0mmol), with stirring. The mixtures were stirred at room temperature for 30min to give deep brown solution. The resulting solution was allowed to stand in air for a few days until two quarters of the solvent was evaporated. Brown block-shaped single crystals of the complexes, suitable for X-ray single crystal diffraction were formed at the bottom of the vessel. The crystals were isolated by filtration, washed three times with cold methanol and dried in air. Yields: 61% (1) and 62% (2). 1 IR data (cm-1): 3436(m), 2968(w), 1607(s), 1549(m), 1445(s), 1331(m), 1260(s), 1200(m), 1088(m), 981(s), 942(w), 863(w), 749(w), 615(w), 545(w) 476(w). UV (λ, ): 215 2.69×104L·mol-1·cm-1; 276nm, 2.07×104L·mol-1·cm-1; 350 5.81×103L·mol-1·cm-1469nm, 5.16×103L·mol-1·cm-1. 1H NMR (300MHz, d6-DMSO): δ 9.02 (s,1H, maltol-CH), 8.46 (d, 1H, CH=N), 7.34 (d, 1H, ArH), 7.23 (d,1H, ArH), 6.97 (t, 1H, ArH), 6.69 (d, 1H, maltol-CH), 1.29 (t, 3H, CH3), 1.10(m, 9H, C(CH3)3), 3.78(t, 3H, OCH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: iron(III) chloride hexahydrate With sodium hydroxide In water Stage #2: Maltol With L-lysine In water | 1 Example 1: Ferric trimaltol from L-lyslne coated ferric hydroxide Synthesis of lysine-coated ferric hydroxide colloid (0127) 14.87g FeCl3. 6H20 was added to 25 mL UHP water and stirred until dissolved. 14.9g NaOH 5M was then added drop-wise to this solution with constant stirring, during which a ferric hydroxide colloid was gradually produced. This colloidal suspension was then added to a L-Lysine suspension (5.02g in 25mL ddH2 | |
1.7g | With sodium hydroxide In water at 55℃; for 0.5h; | 1 Preparation of Ferric Maltol Technical 1 gm of maltol was dissolved into 30 ml water at RT. Solution containing 0.69 gm ferric chloride hexahydrate in 10 ml of water was slowly added in above solution at RT. pH of the solution was adjusted to around 7 by using sodium hydroxide solution (0.16 gm in 3 ml of water). Reaction mixture was stirred for 30 minutes. Reaction mixture was distilled under vacuum below 55° C. Dichloromethane 10 ml was charged in above residue. The solution is filtered to remove undissolved particulate matters. The filtered solution then completely evaporated under vacuum below 50° C. to get Ferric maltol technical.Yield: 1.3-1.7 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: Maltol With sodium hydroxide In water Stage #2: iron With oxygen In water for 120h; | 1 Example 1 : FTM from iron filings Example 1 : FTM from iron filings 7 g of NaOH pellets were added to 50 mL UHP water and stirred until dissolved. Next, 24.5g maltol were added and stirred until dissolved. Then, 3.07 g iron fillings were added and the resulting suspension was stirred whilst bubbling with oxygen. A considerable amount of dark red precipitate (i.e. FTM) was observable 48 hours later but the synthesis was allowed to continue for a further 3 days. Undissolved iron filings were then removed with a magnetic bar and FTM recovered by centrifugation (4500 rpmxlO min) . The FTM material was then dried at 50 ±5°C and its structure confirmed by analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: Maltol With potassium carbonate In acetonitrile at 20℃; for 0.0833333h; Schlenk technique; Stage #2: propargyl bromide In acetonitrile at 80℃; for 12h; Schlenk technique; | |
88% | With potassium carbonate In acetonitrile at 80℃; for 12h; | 2.1 15g of compound I-2 methyl maltol, 3 equivalents of potassium carbonate and 1.2 equivalents of propargyl bromide were added to 300 ml of acetonitrile, heated at 80 ° C for 12 hours, then cooled to room temperature, and a short silica gel column was used. After filtration, the solvent was distilled off under reduced pressure, and then passed through a column by column chromatography to obtain 17.2 g of compound II-2 in a yield of 88%. |
88% | With potassium carbonate In acetonitrile at 80℃; for 12h; | 1 Specifically, 1.5 g of 3-hydroxy-2-methyl-4-pyrone (compound WI-1), 3 equivalents of potassium carbonate and 1.2 equivalents of propargyl bromide were added to 300 mL of acetonitrile. The mixture was heated to 80° C. and held for 12 hours. Thereafter, the mixture was filtered using a silica gel column; the solvent was evaporated under reduced pressure. The remaining solution was separated through column chromatography, thereby obtaining 17.2 g of the compound V-1, with a yield of 88%. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=5.6 Hz, 1H), 6.39-6.30 (m, 1H), 4.88 (d, J=2.4 Hz, 2H), 2.44 (t, J=2.4 Hz, 1H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 174.84, 160.82, 153.77, 143.02, 117.29, 79.19, 75.75, 58.85, 15.42 |
2.9 g | Stage #1: Maltol With potassium carbonate In acetonitrile at 20℃; for 0.0833333h; Stage #2: propargyl bromide In acetonitrile at 80℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.2% | 0.5 g of <strong>[10543-12-1]4-acetoxy-3-methoxybenzoic acid</strong> obtained in Preparation Example 2 was added to DCM 10 mL, andthe mixture was stirred at 10C. 0.74 g of PCl5 was added at 10C or lower, the mixture was stirred for 2 hours whilemaintaining the temperature at 0 to 10C, and 10 ml of purified water was added thereto, followed by layer separation.The aqueous layer was discarded and the organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated,10 mL of DCM was added, cooled to 0C, and 0.27 g of maltol was added. 0.5 mL of TEA was added dropwise whilemaintaining the temperature at 0C, the temperature was gradually raised to room temperature, and the mixture wasstirred for 2 hours. DCM was concentrated and 10 mL of EtOAC and 10 mL of purified water were added, followed bylayer separation. The aqueous layer was extracted with 10 mL of EtOAc, the aqueous layer was discarded, and theorganic layer was concentrated. 5 mL of MeOH, 5 mL of purified water and 3.3 mL of TEA were added to the concentrate,and the mixture was refluxed for 4 hours. The MeOH was concentrated, and the resulting solid was filtered and washedwith purified water to obtain 0.35 g of the title compound as a white solid.Yield: 53.2%1H NMR (400MHz, DMSO-d6) delta 10.24 (s, 1H), 8.21 (d, J = 5.6 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.53(s, 1H), 6.95 (d, J= 8.0 Hz, 1H), 6.48 (d, J = 5.6 Hz, 1H), 3.85(s, 3H), 2.83(s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: N,N-dimethyl-formamide / 0.25 h / 80 °C 1.2: 1 h 2.1: sodium hydroxide; ammonia / ethanol; water / 1 h / 90 °C 3.1: N-Bromosuccinimide / acetonitrile / 1.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.5% | With sodium hydroxide In water at -5 - 30℃; | 1-4 Example 2 350.0g of methanol was added in a clean reaction vessel.200.0g of water,Cool down to -20 ° C ~ -15 ° C with stirring,A mixture of filtrate and methanol 220.0 g was prepared by adding dropwise.At the same time, chlorine gas is introduced for chlorine oxidation reaction.The reaction is exothermic,Control the drop rate and the rate of chlorine passing,Keep the reaction temperature at -20 ° C ~ -15 ° C,After about 5 to 6 hours, the addition is completed.Continue to pass chlorine for 30min,The reaction was terminated when the total chlorine content was 160 g.Recover residual chlorine gas under reduced pressure,Then atmospheric distillation to recover methanol,Until the internal temperature reaches 100 ° C,Change to reflux hydrolysis reaction for 2-3h,Cool to 20 ° C ~ 30 ° C,30% aqueous sodium hydroxide solution with stirring,Adjust the pH to 2~3,Then freeze to -5 ° C,The crude maltol crystals were precipitated to 149.2 g (moisture 26%).The crude product is dissolved by edible alcohol,Decolorization,crystallization,Filter and wash,After drying and other processes,Obtaining 101.5g of maltol finished product,Yield 80.5%,The content is 99.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine In dichloromethane at 20℃; | 1.1-1.2 1) In a 50 ml flask add maltol (3-hydroxy-2-methyl-4-pyrone, compound 1, 1mmol), substituted sulfonyl chloride (compound 2 a, 1.3 mmol), and add 10 ml dichloromethane to dissolve completely, then dropwise triethylamine dichloromethane solution (by the triethylamine and dichloromethane is mixed, wherein the solvent dichloromethane for 5 ml, triethylamine is 1.6 mmol), then completing the reaction under room temperature, TLC tracking and monitoring until a reaction is finished. 2) After the reaction, by adding 30 ml of water, then dichloromethane is used for extraction, the combined organic phase, saturated salt water after washing, final drying with anhydrous sodium sulfate, concentrated to evaporate the solvent after the silica gel column chromatography separation to obtain the target product 3 a, its appearance is the yellow oily liquid, yield is 86%. |
66% | With triethylamine In dichloromethane at 20℃; for 0.166667h; | 3.2. General procedure for the synthesis of sulfonate derivatives ofmaltol (3a-p) General procedure: To a solution of maltol (1, 1.0 mmol) and ethanesulfonyl chloride/arylsulfonyl chloride(2, 1.2 mmol) in dry dichloromethane (DCM, 10 ml) at room temperature, a solution of triethylamine (Et3N) (1.5 mmol) in dry DCM (5 ml) was added dropwise for 10 min. When the reaction was completed by TLC analysis, the reaction mixture was diluted with water (15 ml), and extracted with DCM (30 ml 3). Subsequently, the combined organic phase was washed by saturated aq. brine (30 ml), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography to obtain in 28-97% yields. The data for 3a-p are shown as follows. 3.2.1. Data for 3a Yield 66%, Yellow oily liquid. 1H NMR (400 MHz, CDCl3) d: 7.70 (d, J5.6 Hz,1H), 6.42 (d, J5.6 Hz, 1H), 3.72 (q, J7.6 Hz, 2H), 2.46 (s, 3H), 1.60 (t, J7.6 Hz,3H). HRESIMS: m/z 219.0325 [M+H]+ (calcd for C8H11O5S, 219.0322). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 100mL single-neck flask was added (3.303g, 30mmol), 30mL of concentrated sulfuric acid, stirred at -5 placed to the whole solution was slowly added dropwise (6.600g, 40mmol) controlling the reaction temperature for 24h.The reaction was poured into 300mL ice water, stirred for 2h, filtered dried to give a white solid.Yield 83%.100mL was added to the first step to give a white solid (1.050g, 5mmol), 2,5- difluorobenzyl bromide (1.38g, 6mmol), potassium carbonate (0.959g, 7mmol), 40mL acetone was refluxed 4h, spin dry, was added 40mL of water and extracted three times with 40mL dichloromethane and the combined rotary evaporation to give a white yellow solid.Yield 88%.In 250mL single-neck flask was added maltol (1.260g, 10mmol), potassium carbonate (2.010g, 20mmol), benzyl bromide (2.052g, 12mmol), 130mL acetone, 56 reaction 2h, spin dry, 100mL of water was added to dissolve, with 80mL extracted four times with dichloromethane The combined organic phases were spin-dried, to give a yellow oily liquid.Yield 97%.The third step is to take the product obtained (1.080g, 5mmol) in 100mL single-neck flask, was added 30mL of ethanol and 30mL of water was added sodium hydroxide (0.240g, 6mmol), ethylenediamine (0.900g, 15mmol), in 78 reaction 50min, cooled to room temperature, concentrated hydrochloric acid was added to pH 1-2, rotary evaporation, the solid was washed with 30mL acetone, the filter cake was dissolved in water, adjusted to pH 13, extracted with dichloromethane four times with 5M aqueous sodium hydroxide solution The organic layers were combined, rotary evaporation to give a dark brown oily liquid, yield 69%.In 100mL mono vial was added solid (0.672g, 2mmol) obtained in the second step, the fourth step obtained oily liquid (0.556g, 2mmol), 40mL tetrahydrofuran, potassium iodide (0.017g, 0.1mmol), at 66 C the reaction 12h, column chromatography, to give a yellow oily liquid.In 30% yield.The last step to give a yellow oily liquid (0.558g, 1mmol), single-neck flask was placed 50mL of dry dichloromethane was added 15mL, stirred at -48?, was added 10mL of anhydrous methylene chloride at a constant pressure dropping funnel, 1.5mL of 1M boron trichloride in dichloromethane was slowly added dropwise, the reaction incubated 2h, moves at room temperature 12h, 5mL of methanol was added dropwise to quench the reaction, spin-dried to give a yellow solid from methanol / ether and recrystallized system to give a white solid, (Ij).Yield of 84%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine In dichloromethane at 20℃; for 0.166667h; | 3.2. General procedure for the synthesis of sulfonate derivatives ofmaltol (3a-p) General procedure: To a solution of maltol (1, 1.0 mmol) and ethanesulfonyl chloride/arylsulfonyl chloride(2, 1.2 mmol) in dry dichloromethane (DCM, 10 ml) at room temperature, a solution of triethylamine (Et3N) (1.5 mmol) in dry DCM (5 ml) was added dropwise for 10 min. When the reaction was completed by TLC analysis, the reaction mixture was diluted with water (15 ml), and extracted with DCM (30 ml 3). Subsequently, the combined organic phase was washed by saturated aq. brine (30 ml), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography to obtain in 28-97% yields. The data for 3a-p are shown as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In dichloromethane at 20℃; for 0.166667h; | 3.2. General procedure for the synthesis of sulfonate derivatives ofmaltol (3a-p) General procedure: To a solution of maltol (1, 1.0 mmol) and ethanesulfonyl chloride/arylsulfonyl chloride(2, 1.2 mmol) in dry dichloromethane (DCM, 10 ml) at room temperature, a solution of triethylamine (Et3N) (1.5 mmol) in dry DCM (5 ml) was added dropwise for 10 min. When the reaction was completed by TLC analysis, the reaction mixture was diluted with water (15 ml), and extracted with DCM (30 ml 3). Subsequently, the combined organic phase was washed by saturated aq. brine (30 ml), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography to obtain in 28-97% yields. The data for 3a-p are shown as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine In dichloromethane at 20℃; for 0.166667h; | 3.2. General procedure for the synthesis of sulfonate derivatives ofmaltol (3a-p) General procedure: To a solution of maltol (1, 1.0 mmol) and ethanesulfonyl chloride/arylsulfonyl chloride(2, 1.2 mmol) in dry dichloromethane (DCM, 10 ml) at room temperature, a solution of triethylamine (Et3N) (1.5 mmol) in dry DCM (5 ml) was added dropwise for 10 min. When the reaction was completed by TLC analysis, the reaction mixture was diluted with water (15 ml), and extracted with DCM (30 ml 3). Subsequently, the combined organic phase was washed by saturated aq. brine (30 ml), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography to obtain in 28-97% yields. The data for 3a-p are shown as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine In dichloromethane at 20℃; for 0.166667h; | 3.2. General procedure for the synthesis of sulfonate derivatives ofmaltol (3a-p) General procedure: To a solution of maltol (1, 1.0 mmol) and ethanesulfonyl chloride/arylsulfonyl chloride(2, 1.2 mmol) in dry dichloromethane (DCM, 10 ml) at room temperature, a solution of triethylamine (Et3N) (1.5 mmol) in dry DCM (5 ml) was added dropwise for 10 min. When the reaction was completed by TLC analysis, the reaction mixture was diluted with water (15 ml), and extracted with DCM (30 ml 3). Subsequently, the combined organic phase was washed by saturated aq. brine (30 ml), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography to obtain in 28-97% yields. The data for 3a-p are shown as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With triethylamine; In dichloromethane; at 20℃; for 0.166667h; | General procedure: To a solution of maltol (1, 1.0 mmol) and ethanesulfonyl chloride/arylsulfonyl chloride(2, 1.2 mmol) in dry dichloromethane (DCM, 10 ml) at room temperature, a solution of triethylamine (Et3N) (1.5 mmol) in dry DCM (5 ml) was added dropwise for 10 min. When the reaction was completed by TLC analysis, the reaction mixture was diluted with water (15 ml), and extracted with DCM (30 ml 3). Subsequently, the combined organic phase was washed by saturated aq. brine (30 ml), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography to obtain in 28-97% yields. The data for 3a-p are shown as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: [(4,7-diphenyl-1,10-phenanthroline)2RuCl2] With sodium hydroxide In ethanol for 0.5h; Stage #2: Maltol In ethanol for 3h; Reflux; Inert atmosphere; Darkness; Stage #3: ammonium hexafluorophosphate In ethanol; water at 4℃; Inert atmosphere; | |
90% | Stage #1: [(4,7-diphenyl-1,10-phenanthroline)2RuCl2] With sodium hydroxide In ethanol; water for 0.5h; Inert atmosphere; Stage #2: Maltol In ethanol; water for 3h; Inert atmosphere; Reflux; Darkness; Stage #3: ammonium hexafluorophosphate In ethanol; water at 4 - 20℃; | Compound 2 ([Ru(DIP)2(mal)](PF6)) Ru(DIP)2Cl2 (0.150 g, 0.18 mmol) and aq. NaOH (0.28 mL, 1 M) were dissolved in ethanol (18 mL). The solutionwas degassed for 30 min and maltol (3-Hydroxy-2-methyl-4H-pyran-4-one) (0.036 g, 0.29 mmol) was added. The mixturewas heated to reflux for 3 h under N2 atmosphere and protected from light. After cooling to r.t., H2O (200 mL) and NH4PF6(1 g, 6 mmol) were added. The mixture was stored in the fridge (4 °C) overnight. The precipitate was filtered with aBuchner funnel and washed with H2O (3 x 50 mL), Pentane (3 x 50 mL) and Et2O (3 x 50 mL). Further wash with Et2Oand Heptane were necessary in order to obtain clean product. The solid with the washing solvent (10 mL) was sonicatedfor 10 min and then centrifuged. This procedure was repeated three times for each solvent. The solid was collected withDCM and dried under vacuum to deliver a clean product as the PF6 salt (0.17 g, 0.16 mmol, 90%). IR (Golden Gate,cm-1): 1590w, 1545w, 1490w, 1465w, 1445w, 1415w, 1400w, 1275w, 1205w, 1085w, 1025w, 915w, 830s, 765s, 735m,700s. 1H NMR (400 MHz, CD2Cl2): δ/ppm = 9.49 (d, J = 5.4 Hz, 1H), 9.33 (d, J = 5.5 Hz, 1H), 8.23 (dd, J = 9.4, 4.6 Hz,2H), 8.13 (dd, J = 9.4, 1.1 Hz, 2H), 8.04 (d, J = 5.6 Hz, 2H), 7.98 (dd, J = 13.5, 5.4 Hz, 2H), 7.78 - 7.60 (m, 11H), 7.59- 7.47 (m, 10H), 7.33 (dd, J = 5.6, 3.0 Hz, 2H), 6.54 (d, J = 5.1 Hz, 1H), 2.37 (s, 3H). 13C NMR (125 MHz, CD2Cl2):δ/ppm = 185.00, 159.02, 155.49, 154.10, 154.01, 151.75, 151.47, 151.06, 150.64, 150.17, 149.98, 149.92, 147.66,147.13, 146.01, 145.71, 136.50, 136.47, 136.23, 136.20, 130.15, 129.86, 129.81, 129.47, 129.44, 129.28, 129.21,129.10, 128.78, 128.61, 128.55, 128.46, 125.96, 125.82, 125.77, 125.77, 125.69, 125.51, 125.25, 125.05, 112.40, 29.84.HRMS (ESI+): m/z 891.19042 [M - PF6]+. Elemental Analysis: calcd. for C54H39F6N4O4PRu = C, 61.54; H, 3.73; N, 5.32.Found = C, 61.53; H, 3.38; N, 5.17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate In acetone for 12h; Reflux; | 1-28 Preparation method of N-(2-(2-methyl-3-hydroxy-1(4H)-4-oxopyridyl)ethyl)-benzamide (11a) Add maltol (7.56g, 60mmol) into a 250mL single-mouth bottle, P-methoxybenzyl chloride (28.19g, 180mmol), Anhydrous potassium carbonate (24.84g, 180mmol), Acetone (100mL), heated to reflux for 12 hours, TLC monitors the reaction. After the raw material is completely converted, Stop the reaction, concentrate the reaction liquid to obtain a solid, Add water (100mL) to dissolve, Extract with dichloromethane (100mL×4), The organic layers were combined, and the organic layer was dried with anhydrous sodium sulfate, Concentrate to obtain a yellow oily liquid 2-methyl-3-p-methoxybenzyloxypyran-4-one (14.61g), The yield was 99%. |
97% | With potassium carbonate In acetone for 6h; Reflux; | 4.1.2 General procedures for the preparation of compounds 2a-c and 7a-b General procedure: A solution of maltol 1 or 6 (60 mmol), iodomethane or benzyl bromide or 4-methoxylbenzyl chloride (90 mmol), anhydrous K2CO3 (12.42 g, 90 mmol) and acetone (150 mL) was refluxed for 6 h. After the reaction was completed, the reaction mixture was evaporated under vacuum, and the residual was resolved in water (100 mL), extracted by DCM (4×100 mL) and washed by saturated brine (2×100 mL). The organic solution was evaporated to dryness to obtain 2a-c as yellow oil, 7a-b as white solid. |
65% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 5h; |
With potassium carbonate at 80℃; for 2h; | ||
With potassium carbonate In acetone Reflux; | ||
96 % | With potassium carbonate In N,N-dimethyl-formamide at 80℃; | 1 Embodiment 1: the preparation method of a1 Add maltol (63.000g, 500mmol), DMF (750mL), p-methoxybenzyl chloride (102.050g, 650mmol) and potassium carbonate (103.500g, 750mmol) in a single-necked bottle,React at 80° C. for 4 h, check the progress of the reaction by spotting the TLC plate, add water (750 mL) after the reaction,Extracted with 100 mL×10 DCM, combined the organic phases, dried over anhydrous sodium sulfate, and then distilled off the solvent under reduced pressure to obtain 2-methyl-3-p-methoxybenzylpyran-4-one (118.080 g), yield 96%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sodium hydroxide / ethanol / 6 h / 60 °C / Reflux 2: potassium carbonate / ethanol; water / 18 h / Reflux 3: 5%-palladium/activated carbon; hydrogen / ethanol; water / 4 h / 20 °C / 760.05 Torr | ||
Multi-step reaction with 3 steps 1: potassium hydroxide 2: sodium hydroxide 3: palladium on activated charcoal; hydrogen |
Yield | Reaction Conditions | Operation in experiment |
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92% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 4.2.18. Synthesis of tert-butyl 4-(2-((2-methyl-4-oxo-4H-pyran-3-yl)oxy)ethyl)piperazine-1-carboxylate (18) A mixture of tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate(17, 233 mg, 0.79 mmol), K2CO3 (219 mg, 1.59 mmol)and 3-hydroxy-2-methyl-4H-pyran-4-one (100 mg, 0.79 mmol) inDMF (5 mL) was stirred at room temperature until the reactioncomplete. The product was collected by filtration. The solvent wasremoved under reduced pressure. The crude product was purified by flash chromatography (DCM: MeOH 20: 1) to give a white solid(247 mg, yield 92%). 1H NMR (400 MHz, CDCl3) d 7.60 (d, J 5.5 Hz,1H), 6.31 (d, J 5.5 Hz, 1H), 4.17 (t, J 4.9 Hz, 2H), 3.50e3.34 (m,4H), 2.69 (t, J 4.9 Hz, 2H), 2.56e2.40 (m, 4H), 2.33 (s, 3H), 2.03 (s,1H), 1.43 (s, 9H). 13C NMR (101 MHz, CDCl3) d 174.92, 159.17, 154.73,153.39, 144.65, 117.11, 79.59, 77.35, 77.03, 76.71, 68.58, 58.03, 53.08,28.39, 28.22, 14.80. |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 16.3 3). Synthesis of compound 9: Compound 8 (233mg, 0.79mmoL), compound 1 (100mg, 0.79mmoL),Potassium carbonate (219mg, 1.59mmoL) was added to a 50mL round bottom flask,Add 20mL of N,N-dimethylformamide, stir and react overnight at room temperature,After TLC detects the completion of the reaction, use a rotary evaporator to remove the solvent,The compound 9 was isolated by silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: Maltol; D-(R)-phenylalanine With boric acid In water at 100℃; for 2h; Stage #2: With hydrogenchloride In water for 1h; Reflux; | 1; 1-1; 1-2; 1-3; 1-4; 1-5; 1-6 Example 1 Preparation of (R)-3,4-dihydroxy-N-(1'-benzyl-2'-hydroxyethyl)-2-picoline chloride (Compound A) General procedure: Add methyl maltol (16mmol, 2.02g), D-phenylalanine (17.6mmol, 2.66g), boric acid (16mmol, 1.95g), and 10ml of water into a 50ml three-necked flask in turn, and react at 1002 Hours, the reaction is over.The reaction solution was adjusted to pH 8.5 with sodium hydroxide solution (0.01mol/mL), extracted with dichloromethane (10mL×3), and the organic phases were combined and added with 20ml hydrochloric acid solution (6mol/L), stirred and refluxed for 1h, and then Stir and crystallize for 12 h at 5 to 5°C, and wash with dichloromethane (10 mL×2) to obtain 3.42 g of white solid with a yield of 72%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium phosphate In acetonitrile at 20℃; | α-Fluoro-β-ketone Ethers 5a-x; General Procedure General procedure: A reaction tube containing a magnetic stir bar was charged with α-bromo-α-fluoroketone 1 (0.2 mmol, 1.0 equiv), phenol 4 (0.22 mmol,1.1 equiv) and K3PO4 (0.4 mmol, 2.0 equiv). After CH3CN (2.0 mL) had been added, the reaction tube was capped with a rubber stopper and the contents were stirred for 1-2 h at room temperature. The reaction mixture was then quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash column chromatography on silica gel (PE/EtOAc = 10:1 to 100:1) to give the α-fluoro-β-ketone ether 5a-x. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: Maltol With triethylamine In dichloromethane at 25℃; for 0.166667h; Cooling with ice; Stage #2: (Z)-9-octadecenoyl chloride In dichloromethane at 25℃; Cooling with ice; | 3 Example 3 15ml of dichloromethane and 0.8ml of triethylamine were added to 5mmol of maltol, and stirred in an ice bath for 10 minutes; 5mmol of oleoyl chloride was dissolved in 5ml of dichloromethane, slowly added dropwise to the vanillin solution, and stirred at 25°C for 8h. The reaction product was added with 200ml of dichloromethane, washed three times with 50ml of 1M dilute hydrochloric acid each time, and then washed once with 50ml of saturated brine, concentrated in vacuo to remove the solvent, and chromatographed with petroleum ether:ethyl acetate=20:1-15:1 The product LSD18 was isolated in a yield of 82%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: Maltol; β-phenethylamine With phenylboronic acid In lithium hydroxide monohydrate at 80℃; Stage #2: With hydrogenchloride at 20℃; for 6h; | 1 Example 1. Synthesis of 3-hydroxy-2-methyl-1-phenethylpyridine-4(1H)-one hydrochloride (number CJ-B-01) 126 mg (1 mmol) of 3-hydroxy-2-methyl-4H-pyrone and 122 mg (1 mmol) of phenylboronic acid were added to the reaction flask, 5 mL of water was added, the mixture was heated to 80 degrees, and 132 μL (1.05 mmol) of phenethylamine was added. , continue to stir the reaction at 80 degrees, and TLC detects the reaction (dichloromethane/methanol=20:3 volume ratio). After the reaction, the reaction solution was spin-dried by a rotary evaporator, 5 mL of concentrated hydrochloric acid was added and stirred at room temperature for 6 h to form a salt, concentrated by rotary evaporation, and 3 mL of acetonitrile was added to obtain the precipitate and suction filtration. Salt product 252 mg, yield 95%. |
95% | Stage #1: Maltol; β-phenethylamine With phenylboronic acid In lithium hydroxide monohydrate at 80℃; Stage #2: With hydrogenchloride In lithium hydroxide monohydrate at 20℃; for 6h; | 1 Example 1. Synthesis of 3-hydroxy-2-methyl-1-phenethylpyridine-4(1H)-one hydrochloride (number CJ-B-01) 126 mg (1 mmol) of 3-hydroxy-2-methyl-4H-pyrone and 122 mg (1 mmol) of phenylboronic acid were added to the reaction flask, 5 mL of water was added, the mixture was heated to 80 degrees, and 132 μL (1.05 mmol) of phenethylamine was added. , continue to stir the reaction at 80 degrees, and TLC detects the reaction (dichloromethane/methanol=20:3 volume ratio). After the reaction, the reaction solution was spin-dried by a rotary evaporator, 5 mL of concentrated hydrochloric acid was added and stirred at room temperature for 6 h to form a salt, concentrated by rotary evaporation, and 3 mL of acetonitrile was added to obtain the precipitate and suction filtration. Salt product 252 mg, yield 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With dmap; triethylamine In dichloromethane at 0 - 25℃; | 4.3. Synthesis of title compounds 3a-3n General procedure: To a solution of substituted phenol, 4-hydroxyquinolone, 7-hydroxylcoumarin, hydroxyl pyrone or anthraquinone (1.0 mmol) in dichloromethane (CH 2 Cl 2 , 10 mL) was added 4-dimethylaminopyridine (DMAP, 0.2 mmol) and triethylamine (Et 3 N, 1.10 mmol). Subsequently, L-10-camphorsulfonyl chloride (1.20 mmol) was added into the solution separately at 0 °C. The mixture was then stirred for 1~ 5 h at room temperature. When the reaction was completed, the organic phase was filtered and concentrated. The crude product was purified with column chromatography to afford the title compounds 3a-3n. |
51 % | With dmap; triethylamine In dichloromethane at 0 - 25℃; | 9 Example 9 The intermediate methyl maltol (1.0 mmol), 4-dimethylaminopyridine (0.1 mmol), and triethylamine (1.1 mmol) were dissolved in anhydrous dichloromethane, cooled to 0 °C, and L-10 was added in batches. -Camphorsulfonyl chloride (1.2 mmol) was raised to 25°C for 2 h. The reaction of the raw materials was monitored by TLC. The organic layer was washed with water 3 times (8 ml*3), washed with saturated brine 3 times (8 mL*3), dried, suction filtered, concentrated to remove dichloromethane, and the crude product was subjected to column chromatography (CH2Cl2: MeOH=20:1) to obtain the target compound IV-1, white solid, m.p.108-109, yield 51% |
Tags: 118-71-8 synthesis path| 118-71-8 SDS| 118-71-8 COA| 118-71-8 purity| 118-71-8 application| 118-71-8 NMR| 118-71-8 COA| 118-71-8 structure
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