* 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.
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 27, p. 7751 - 7755[2] Angew. Chem., 2016, vol. 128, p. 7882 - 7886,5
2
[ 64-17-5 ]
[ 501-97-3 ]
[ 23795-02-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 25℃; for 24 h;
General procedure: To a suspension of 3(4-hydroxyphenyl)propanoic acid 1 (0.05 mmol) in TMCS (0.1 mmol), the appropriate alcohol (1.0 mL) was added and the reaction mixture was stirred at 25°C. After 24 h, the reaction was stopped and evaporated under reduced pressure to afford 1a–d in quantitative yield without the need of purification: 3-(4-Hydroxyphenyl)propionic ethyl ester (1b) Oil; 1HNMR (400 MHz, CDCl3): δH (ppm) = 1.13 (3H, m, CH3), 2.82 (2H, m, CH2), 2.88 (2H, m, CH2), 4.00 (2H, m, OCH2), 6.75 (2H, m,Ph-H), 7.06 (2H, m, Ph-H); 13C NMR (50 MHz, CDCl3): δC (ppm) = 14.20 (CH3), 30.12 (CH2), 35.10 (CH2), 60.10 (CH2), 115.45 (2 CH), 129.48 (2 CH), 131.75 (C), 155.43 (C), 172.10 (CO); MS (EI): m/z 266; Elemental analysis: calcd C, 68.02;H, 7.27; O, 24.71, found C, 68.0; H, 7.26; O, 24.68.
94%
at 20℃; for 3 h;
To a stirred solution of acid 9 (3 g, 18 mmol) in 30 mL of ethanol, under ice-cooling, was addedthionyl chloride (1.1 eq, 1.44 mL, 19 mmol) dropwise over 20 min. After stirring the reaction mixturefor 3 h at room temperature, methanol is distilled out and 25 mL of water is added. The separatedester is extracted with ethyl acetate and washed with 10 mL of saturated sodium bicarbonate solution.Evaporation of the ethyl acetate gave the ester in pure form. Yield 94percent, yellow liquid; 1H-NMR (CDCl3) δ : 1.22 (d, 3H, CH3), 2.59 (t, 2H, CH2), 2.87 (t, 2H, CH2), 4.12, q, 2H, CH2), 6.74 (d, 2H, 2.09, 6.48,H-3A-H-5A), 7.03 (d, 2H, 6.54, H-2A, H-6A). 13C-NMR (CDCl3) : 14.2 (CH3), 30.2 (CH2), 36.3 (CH2),60.6 (CH2), 115.4 (C-3A, C-5A), 129.4 (C-2A, C-6A), 154.3 (C-4A), 173.6 (C=O). MS/EI: m/z (percent int. rel).194 (M+) 49percent, 142 (M - 74) 100percent.
90%
at 145℃;
Alternative Synthesis Route for Compound 4'3-(4 Hydroxy-phenyl)-propionic acid ethyl ester (4'-1)4 drops of concentrated HCl are added, under stirring, to a solution of commercial 3-(4 Hydroxy-phenyl)-propionic acid (13.08 g; 78.79 mmol) in 100 mL of ethanol. The reaction medium is heated to reflux in a bath at 145° C. overnight. The ethanol is evaporated off and ethyl acetate is added. The organic phase is washed with a saturated NaHCO3 solution and with a NaCl solution. After drying over MgSO4 and evaporation, an oil is obtained. This latter is distilled by Kugelrohr (150-175° C.; 1.2 mmbar). A transparent oil which crystallizes is obtained in order to produce the expected compound 4'-1 (13.8 g; 71.1 mmol; 90percent) in the form of a white solid. C11H14O3 M=194 g.mol-1 Rf=0.31 (1:4 ethyl acetate/cyclohexane)UV: 278, 224, 199 nm.IR νmax (film, cm-1): 3391, 2983, 1709, 1615, 1517, 1447, 1374, 1225, 1036.1H NMR (400 MHz, CDCl3): δ=1.22 (t, J=7.2 Hz, 3H, -OCH2CH3), 2.59 (t, J=7.9 Hz, 2H, 2.x.H3), 2.86 (t, J=7.9 Hz, 2H, 2.x.H2), 4.12 (q, J=7.2 Hz, 2H, -OCH2CH3), 6.75 (d, J=8.5 Hz, 2H, 2.x.H2'), 7.01 (d, J=8.5 Hz, 2H, 2.x.H3').13C NMR (100 MHz, CDCl3): δ=14.2 (-OCH2CH3), 30.21 (C3), 36.5 (C2), 60.9 (-OCH2CH3), 115.5 (2.x.C2'), 129.4 (2.x.C3'), 132.1 (C1'), 154.5 (C4'), 174.2 (C1).LRMS (ESI+): m/z (percent) 217 (26) [M+Na]+, 107 (100).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5345 - 5351
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 7, p. 1495 - 1503
[3] Tetrahedron Letters, 2010, vol. 51, # 44, p. 5753 - 5756
[4] Molecules, 2018, vol. 23, # 2,
[5] Patent: US2010/298422, 2010, A1, . Location in patent: Page/Page column 18
[6] Journal of Organic Chemistry, 1995, vol. 60, # 21, p. 7072 - 7074
[7] Chemische Berichte, 1917, vol. 50, p. 618[8] Chem. Zentralbl., 1916, vol. 87, # II, p. 1025
[9] Bulletin of the Chemical Society of Japan, 1990, vol. 63, # 5, p. 1328 - 1334
[10] Journal of Medicinal Chemistry, 1982, vol. 25, # 12, p. 1408 - 1412
[11] Journal of Labelled Compounds and Radiopharmaceuticals, 2005, vol. 48, # 12, p. 855 - 871
[12] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 13, p. 4279 - 4290
[13] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 24, p. 7699 - 7708
[14] Patent: WO2015/66290, 2015, A1, . Location in patent: Page/Page column 113
[15] Patent: CN107721836, 2018, A, . Location in patent: Paragraph 0060-0062
[16] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 10, p. 1231
3
[ 7361-92-4 ]
[ 23795-02-0 ]
Yield
Reaction Conditions
Operation in experiment
98%
With palladium on activated carbon; hydrogen In ethyl acetate at 20℃;
General procedure: To asolution of α,β-unsaturatedester (1.0equiv) in EtOAc (0.2 M) was added Pd/C (5 wt.percent, 10 molpercent). The reaction mixturewas stirred at rt under H2 atmosphere. After completion of reaction,it was filtered through a pad of Celite, washed with EtOAc and concentrated in vacuo. Purification ofthe crude residue by column chromatography yielded the ester derivative.
Reference：
[1] Tetrahedron Letters, 2016, vol. 57, # 31, p. 3505 - 3509
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 5, p. 1278 - 1283
1) To an ice-cooled solution of 3-(p-hydroxyphenyl)-propionic acid (8.3 g, 50.0 mmol) in ethanol (100 mL) was dropwise added thionyl chloride (3.7 mL, 50.7 mmol). The mixture was stirred at room temperature over night, concentrated in vacuo and the residue purified by kugelrohr distillation, to give 9.6 g (99percent) of 3-(4-hydroxy-phenyl)-propionic acid ethyl ester as a colourless oil. 1H NMR (CDCL3): δ 1.21 (3H, t), 2.58 (2H, t), 2.86 (2H, t), 4.12 (2H, q), 6.75 (2H, d), 6.90 (1H, bs), 7.01 (2H, d).
General procedure: To a suspension of 3(4-hydroxyphenyl)propanoic acid 1 (0.05 mmol) in TMCS (0.1 mmol), the appropriate alcohol (1.0 mL) was added and the reaction mixture was stirred at 25C. After 24 h, the reaction was stopped and evaporated under reduced pressure to afford 1a-d in quantitative yield without the need of purification: 3-(4-Hydroxyphenyl)propionic ethyl ester (1b) Oil; 1HNMR (400 MHz, CDCl3): deltaH (ppm) = 1.13 (3H, m, CH3), 2.82 (2H, m, CH2), 2.88 (2H, m, CH2), 4.00 (2H, m, OCH2), 6.75 (2H, m,Ph-H), 7.06 (2H, m, Ph-H); 13C NMR (50 MHz, CDCl3): deltaC (ppm) = 14.20 (CH3), 30.12 (CH2), 35.10 (CH2), 60.10 (CH2), 115.45 (2 CH), 129.48 (2 CH), 131.75 (C), 155.43 (C), 172.10 (CO); MS (EI): m/z 266; Elemental analysis: calcd C, 68.02;H, 7.27; O, 24.71, found C, 68.0; H, 7.26; O, 24.68.
94%
With thionyl chloride; at 20℃; for 3h;
To a stirred solution of acid 9 (3 g, 18 mmol) in 30 mL of ethanol, under ice-cooling, was addedthionyl chloride (1.1 eq, 1.44 mL, 19 mmol) dropwise over 20 min. After stirring the reaction mixturefor 3 h at room temperature, methanol is distilled out and 25 mL of water is added. The separatedester is extracted with ethyl acetate and washed with 10 mL of saturated sodium bicarbonate solution.Evaporation of the ethyl acetate gave the ester in pure form. Yield 94%, yellow liquid; 1H-NMR (CDCl3) delta : 1.22 (d, 3H, CH3), 2.59 (t, 2H, CH2), 2.87 (t, 2H, CH2), 4.12, q, 2H, CH2), 6.74 (d, 2H, 2.09, 6.48,H-3A-H-5A), 7.03 (d, 2H, 6.54, H-2A, H-6A). 13C-NMR (CDCl3) : 14.2 (CH3), 30.2 (CH2), 36.3 (CH2),60.6 (CH2), 115.4 (C-3A, C-5A), 129.4 (C-2A, C-6A), 154.3 (C-4A), 173.6 (C=O). MS/EI: m/z (% int. rel).194 (M+) 49%, 142 (M - 74) 100%.
90%
hydrogenchloride; at 145℃;
Alternative Synthesis Route for Compound 4'3-(4 Hydroxy-phenyl)-propionic acid ethyl ester (4'-1)4 drops of concentrated HCl are added, under stirring, to a solution of commercial 3-(4 Hydroxy-phenyl)-propionic acid (13.08 g; 78.79 mmol) in 100 mL of ethanol. The reaction medium is heated to reflux in a bath at 145 C. overnight. The ethanol is evaporated off and ethyl acetate is added. The organic phase is washed with a saturated NaHCO3 solution and with a NaCl solution. After drying over MgSO4 and evaporation, an oil is obtained. This latter is distilled by Kugelrohr (150-175 C.; 1.2 mmbar). A transparent oil which crystallizes is obtained in order to produce the expected compound 4'-1 (13.8 g; 71.1 mmol; 90%) in the form of a white solid. C11H14O3 M=194 g.mol-1 Rf=0.31 (1:4 ethyl acetate/cyclohexane)UV: 278, 224, 199 nm.IR numax (film, cm-1): 3391, 2983, 1709, 1615, 1517, 1447, 1374, 1225, 1036.1H NMR (400 MHz, CDCl3): delta=1.22 (t, J=7.2 Hz, 3H, -OCH2CH3), 2.59 (t, J=7.9 Hz, 2H, 2×H3), 2.86 (t, J=7.9 Hz, 2H, 2×H2), 4.12 (q, J=7.2 Hz, 2H, -OCH2CH3), 6.75 (d, J=8.5 Hz, 2H, 2×H2'), 7.01 (d, J=8.5 Hz, 2H, 2×H3').13C NMR (100 MHz, CDCl3): delta=14.2 (-OCH2CH3), 30.21 (C3), 36.5 (C2), 60.9 (-OCH2CH3), 115.5 (2×C2'), 129.4 (2×C3'), 132.1 (C1'), 154.5 (C4'), 174.2 (C1).LRMS (ESI+): m/z (%) 217 (26) [M+Na]+, 107 (100).
With chloro-trimethyl-silane; at 25℃; for 24h;
General procedure: To a suspension of acidic phenols 1a-d (0.05mmol) in TMCS (0.1mmol), the alcohol (1.0mL) was added and the reaction mixture was stirred at 25C. After 24h, the reaction was stopped and evaporated under reduced pressure to afford 2a-l in quantitative yield without the need of purification:
With sulfuric acid;Reflux;
As outlined in Scheme 7d, a novel methodology was applied to synthesis TG42 in fair yield ~ 40% by reacting the phenolic compound 1 with 2-bromoacetic acid under basic conditions for 6 h to yield compound 2. Vilsmeier formylation using phosphorous oxychloride and DMF was conducted on 2 for 5h followed by basic workup to form the decarboxylated bis- aldehyde 3. Compound 3 was allowed to react with the quaternary salt using sodium acetate in boiling ethanol for around 3-5 h to afford the desired compound.As such, in another aspect, the invention provides a method of preparing a compound, the method comprising reacting a decarboxylated bis-aldehyde with a quarternary salt to produce the compound.
With sulfuric acid; at 35℃; for 4h;
3-(4-Hydroxyphenyl)propionic acid (8 g, 48.14 mmol) was dissolved in ethanol (40 mL),catalyzed by thedropwise addition of concentrated sulfuric acid (0.4 mL), reacted at 35 C. for 4 h, and concentrated under reduced pressure to remove some of the methanol. was added 10mL of water, adjusted to pH 6 with saturated sodium bicarbonate,with 20mL ethyl acetate three times, washed three times with 20mL saturated brine, dried over anhydrous sodium sulfate under reduced pressure to remove acetic acidethyl ester to give 3- (4- Ethyl hydroxyphenyl) propionate.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 1h;Inert atmosphere;
General procedure: To astirred suspension of LiAlH4 (1.5 equiv) in THF (0.4 M) was addeddropwise a solution of ester derivative (1.0 equiv) in THF (0.3 M) at 0 C. Thereaction mixture was stirred under argon from 0 C to rt for 1 h. The reaction mixture was then added H2O,conc. HCl and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried with anhydrous Na2SO4and concentrated in vacuo. Purification of the crude residue by columnchromatography gave the corresponding alcohol derivative.
68%
A suspension of LAH (10.5 g, w/w) in dry THF (500 mL) was refluxed for 3 hr. A solution of ethyl 3- (4-hydroxyphenyl) propionate (10 g, 1 eq, 55. 55 mmol) in dry THF (50 mL) was added drop wise at reflux temperature. After the addition, reaction mixture was refluxed for 6 hr. Reaction mixture was quenched with ethyl acetate (40mL, 4 eq with respect to LAH), followed by the addition of saturated Na2SO4 solution. To the workup mixture conc. HCI was added to adjust the pH at 7.0. Then reaction mixture was filtered through celite and washed with ethyl acetate. Combined filtrate was dried (Na2SO4), condensed, and the residue was chromatographed using ethyl acetate and hexane to obtain the title compound as white solid (5.7 g, 68 % yield). Mp: 52-54C. 'H NMR (CDC, 200 MHz) 8 : 1. 78-1.86 (m, 2H); 2.63 (t, J=7.9 Hz, 2H); 3.67 (t, J= 6. 3 Hz, 2H); 6.74 (d, J= 8.8 Hz, 2H); 7.05 (d, J= 8.8 Hz, 2H). IR (neat) cm-1 : 3485,3029, 2940, and 1505. Mass m/z (CI) : 152 [M+1].
[4-(3-ethyloxetan-3-ylmethoxy)phenyl]propionic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; sodium hydroxide; In ethanol; water; toluene;
17.4 g of ethyl 3-(4-hydroxyphenyl)propionate and 6.1 g of potassium hydroxide were added to 150 ml of ethanol, and stirred at 60 C. for 1 hour. This was cooled to 40 C., and 30 g of 3-[(tosyloxy)methyl]-3-ethyloxetane was dropwise added to it. Then, this was refluxed for 3 hours. Ethanol was evaporated away, and water and toluene were added to it for liquid-liquid separation. The toluene layer was washed with 3% hydrochloric acid, saturated sodium hydrogencarbonate and water, and then toluene was evaporated away. To the resulting residue, added were 20 g of sodium hydroxide, 100 ml of ethanol and 50 ml of water, and this was refluxed for 2 hours. Ethanol was evaporated away, and the resulting residue was poured into 500 ml of 5% hydrochloric acid, and a crystal was thus formed. The crystal taken out through filtration was recrystallized from a mixed solvent of ethanol and water, and 5 g of [4-(3-ethyloxetan-3-ylmethoxy)phenyl]propionic acid (OX7) was obtained. Its melting point was 85 C.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at -20 - 21℃; for 18.1667h;
Intermediate 28Ethyl 3-(4-[3-(hexahydro-1H-azepin-1-yl)propyl]oxy}phenyl)propanoate,3-(Hexahydro-1H-azepin-1-yl)-1-propanol (for example, as disclosed in E. L. Strogryn, J. Med. Chem., 13:864-6, (1970)) (412 mg, 3 mmol) and ethyl (4-hydroxyphenyl)propionate (commercially available, for example, from Maybridge) (641 mg, 3.3 mmol) were added to a stirred mixture of triphenylphosphine (1.02 g, 3.9 mmol) and diisopropyl azodicarboxylate (0.66 ml, 3.9 mmol) in THF (15 ml) at -20 0C. After 10 min, the solution was allowed to warm to 21 0C. After 18 h, no input material was apparent by LCMS. MeOH was added to quench any excess reagent and the mixture was evaporated to <n="74"/>dryness. The residue was loaded onto two 100 g Flashmaster Il silica cartridges which were run with 0 - 50% EtOAc in cyclohexane over 40 min. The cartridges were re-run using 0 - 25% MeCH in EtOAc over 40 min. The UV-detector did not detect the product so the waste eluate was evaporated to give the crude product (782 mg). This was further purified on a 50 g silica cartridge run in 0 - 50% MeOH in DCM over 40 min to give the title compound (306 mg). LCMS RT = 2.39 min, ES+ve m/z 334 [M+H]+
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 14h;
Ethyl 3-(4-t-butyldimethylsilyloxyphenyl)propionate To a solution of ethyl 3-(4-hydroxyphenyl)propionate (940 mg, 4.84 mmol) in anhydrous dimethylformamide (9.4 mL) were added t-butyldimethylsilyl chloride (1.0 g, 6.6 mmol) and imidazole (490 mg, 1.5 mmol) at room temperature, and the mixture was left standing at the same temperature for 14 h. The reaction mixture was directly concentrated, and subjected to silica gel column chromatography (hexane-ethyl acetate 25:1?20:1) to give 1.49 g (quantitative) of the title compound as a solid. 1H NMR (CDCl3) delta 0.18 (s, 6H), 0.97 (s, 9H), 1.23 (t, J=7.0 Hz, 3H), 2.57 (t, J=7.3 Hz, 2H), 2.88 (t, J=7.3 Hz, 2H), 4.12 (q, J=7.0 Hz, 2H), 6.57 (m, 2H), 6.87 (m, 2H).
3-(4-{2-[2-(2-{2-[2-(4-{2-[2-(2-methyl-[1,3]dioxolan-2-ylmethyl)-[1,3]dioxolan-2-yl]-ethyl}-phenylcarbamoyl)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-phenyl)-propionic acid ethyl ester[ No CAS ]
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