* 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
[ 5597-50-2 ]
[ 60-82-2 ]
Reference：
[1] Chemische Berichte, 1917, vol. 50, p. 618[2] Chem. Zentralbl., 1916, vol. 87, # II, p. 1025
3
[ 3943-97-3 ]
[ 5597-50-2 ]
Yield
Reaction Conditions
Operation in experiment
99%
With palladium on activated charcoal; hydrogen In ethanol at 20℃; for 21 h;
Methyl 3-(4-hydroxyphenyl)propanoate (0413) (0414) To a solution of (E)-methyl 3-(4-hydroxyphenyl)acrylate (1.0 g, 5.6 mmol) in EtOH (20 mL), Pd/C (0.1 g) was added. The reaction mixture was vigorously stirred under hydrogen atmosphere (1 bar) at room temperature for 21 h. The suspension was filtered through a Celite pad and evaporated to dryness under vacuum to afford 1.0 g (5.6 mmol, 99percent yield) of an oil identified as methyl 3-(4-hydroxyphenyl)propanoate. (0415) 1H NMR (400 MHz, CDCl3) δ 7.07 (ddd, J=8.8, 2.8, 2.0 Hz, 2H), 6.76 (ddd, J=8.8, 2.8, 2.0 Hz, 2H), 4.72 (br s, 1H), 3.67 (s, 3H), 2.88 (t, J=7.8 Hz, 2H), 2.60 (t, J=7.8 Hz, 2H).
Reference：
[1] Journal of Natural Products, 1999, vol. 62, # 1, p. 102 - 106
[2] Patent: EP2745876, 2014, A1, . Location in patent: Page/Page column
[3] Patent: US2015/344408, 2015, A1, . Location in patent: Paragraph 0413-0415
[4] Journal of Agricultural and Food Chemistry, 2007, vol. 55, # 26, p. 10635 - 10640
[5] Angewandte Chemie - International Edition, 2014, vol. 53, # 30, p. 7785 - 7788[6] Angew. Chem., 2014, vol. 53, # 30, p. 7919 - 7922,4
[7] Phytochemistry (Elsevier), 1992, vol. 31, # 4, p. 1179 - 1184
[8] Journal of the American Chemical Society, 2006, vol. 128, # 10, p. 3324 - 3334
[9] Synthetic Communications, 2011, vol. 41, # 11, p. 1603 - 1608
4
[ 67-56-1 ]
[ 501-97-3 ]
[ 5597-50-2 ]
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 acid methyl ester(1a) Oil; 1HNMR (400 MHz, CDCl3): δ H (ppm) = 2.66 (2H, m, CH2),3.05 (2H, m, CH2),3.65 (3H, m, OCH3), 6.73 (2H, m, Ph-H), 7.04(2H, m, Ph-H); 13C NMR (50 MHz, CDCl3): δ C (ppm) = 30.19 (CH2),35.23 (CH2), 50.99 (CH3),115.57 (2 CH), 129.54 (2 CH),131.59 (C), 155.71 (C), 172.74 (CO); MS (EI): m/z 252; Elemental analysis: calcd C, 66.65; H, 6.71; O, 26.64, found C, 66.64; H, 6.71;O, 26.63.
100%
With acetyl chloride In methanol at 0℃; for 1.5 h;
To a solution of3-(4-hydroxyphenyl)propanoic acid (2.50g, 15.04 mmol) in methanol(40 mL) were added dropwise 5.35 mL acetyl chloride (5.0eq,75.20 mmol) at 0 °C. The reaction mixture was stirred over 1.5 h at0 °C. After completion of the reaction, the mixture was concentratedin vacuo and ethyl acetate was added. The organic layer waswashed with NaHCO3 (3 x 50 mL) and concentrated in vacuo to givemethyl 3-(4-hydroxyphenyl)propanoate 38 (2.70 g, 100percent) as acolorless oil. UPLC-MS: 1.62 min, 100percent. 1H NMR (300 MHz, CD3OD) δ (ppm) 7.08-6.94 (m, 2H), 6.80-6.64 (m, 2H), 3.69-3.49 (m, 3H),2.87-2.70 (m, 2H), 2.60-2.45 (m, 2H). 13C NMR (75 MHz, CD3OD) δ (ppm) 174.4, 155.8, 131.8, 129.3, 115.3, 51.1, 36.1, 30.2. MS (ES) m/z181.7 (M + H)+. HRMS calculated for C10H12O3: 203.0679; found:203.0679 (M + Na)+.
99%
With hydrogenchloride In 1,4-dioxane at 20℃; for 3 h;
[355] Preparation Example 4: 3-(4-hydroxy-phenyl)-propionic acid methyl ester[356] After 3-(4-hydroxy-phenyl)propionic acid (3 g, 18 mmol) was added with MeOH(6 mL), 4M HCl/dioxane solution (18 mL, 72 mmol) was added thereto, and themixture was stirred at room temperature for 3 hours. The reactant wasconcentrated, added with EtOAc, and then washed with NaCl aqueous solution. Theorganic layer was separated, dried with MgSO4, and filtered toobtain the title compound (3.26 g, 99percent). [357] 1H-NMR (CDCl3) δ 7.06(2H, m), 6.75(2H, m),4.79(1H, brs, OH), 3.66(3H, s), 2.88(2H, t), 2.59(2H, t)
98%
at 70℃; for 3 h;
4.61 g p-hydroxyphenpropionic acid, 50 ml methanol and 0.5 ml concentrated H2SO4 were refluxed at 70°C for 3 hours and cooled. Excessive acid was neutralized with saturated NaHCO3 solution. The neutralized solution was extracted with ethyl acetate for three times. The extract was dried, filtrated, evaporated and purified by column chromatograph (petroleum ether: ethyl acetate=2:1) to obtain 4.9 g white solid, yield 98percent. 1H-NMR (400MHz, DMSO-d6, δ ppm) δ 2.5(2H, m), 2.7(2H, t), 3.567(3H, s), 6.6(2H, d, J=6.4Hz), 7.0(2H, d, J=8.4Hz), 9.0(1H, s).
98%
at 70℃; for 3 h;
Intermediate 10: Methyl p-hydroxyphenpropionate 4.61 g p-hydroxyphenpropionic acid, 50 ml methanol and 0.5 ml concentrated H2SO4 were refluxed at 70° C. for 3 hours and cooled. Excessive acid was neutralized with saturated NaHCO3 solution. The neutralized solution was extracted with ethyl acetate for three times. The extract was dried, filtrated, evaporated and purified by column chromatograph (petroleum ether:ethyl acetate=2:1) to obtain 4.9 g white solid, yield 98percent. 1H-NMR (400 MHz, DMSO-d6, δ ppm) δ 2.5 (2H, m), 2.7 (2H, t), 3.567 (3H, s), 6.6 (2H, d, J=6.4 Hz), 7.0 (2H, d, J=8.4 Hz), 9.0 (1H, s).
98%
for 16 h; Reflux
General procedure: According to a literature protocol.[1] Propanoic acid derivative (10 g) was dissolved inmethanol (80 ml) and H2SO4 (700μl, 6 mmol) added. The resulting solution was refluxed for16 h and then allowed to cool to room temperature. The reaction mixture was reduced todryness and re-dissolved in ethyl acetate (20 ml). The organic phase was washed withsaturated aqueous sodium hydrogen carbonate (10 ml), brine (10 ml) and dried over MgSO4.Removal of the solvent gave the desired methyl ester. (Note: column chromatography is oftennot required for the methyl ester starting materials). Methyl 3-(4-hydroxyphenyl)propanoate (1a) Synthesized according to general procedure A (98percent); 1H NMR (500 MHz, d4-MeOH): δ 6.98(d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 3.60 (s, 3H), 2.78 (t, J = 7.6 Hz, 2H), 2.53 (t, J= 7.6 Hz, 2H); 13C NMR (125 MHz, d4-MeOH): 172.8, 155.6, 130.6, 129.1, 115.1, 51.2, 35.4,29.5; HRMS (EI) calculated for C10H12O3 [M]+: 180.078643; found: 180.078803.
98.2%
for 10 h; Reflux
20 g of p-hydroxyphenylpropionic acid was added to 300 ml of anhydrous methanol and2 ml of concentrated sulfuric acid, heated to reflux for 10 h, the solvent was evaporated under reduced pressure, then dissolved with ethyl acetate and washed sequentially with sodium hydrogen carbonate and water.Polyester, organic layer dried over anhydrous magnesium sulfate,The solvent was evaporated to give 21.2 g (yield: 98.2percent).
92%
at 20℃; for 16 h;
15 g (0.09 mol, 1 eq) of 3-(4-hydroxyphenyl)propanoic acid are dissolved in 50 ml of methanol and 4 drops of sulfuric acid are added. The reaction mixture is stirred for 16 hours at room temperature. The reaction is stopped by addition of 50 mL of saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 14.9 g of methyl 3-(4-hydroxyphenyl)propanoate are obtained. Yield = 92 percent
84%
at 20℃; for 8 h;
To a solution of 3-(4-hydroxyphenyl)propanoic acid (3 g, 18.1 mmol) in 50 mL MeOH was added ΒΡ3·Ε20 (0.3 mL). The mixture was stirred at rt for 8 h. The mixture was concentrated, and the residue was purified by flash chromatography (FC) (ethyl acetate (EtOAc) /hexane = 2/8) to give 2.72 g white solid A (yield: 84percent): 1HNMR(400 MHz, CDC13) δ: 7.07(d, 2H, J= 8.4 Hz), 6.76(d, 2H, J= 8.4 Hz), 4.72(s, 1H), 3.68(s, 3H), 2.89(t, 2H, J= 7.6 Hz), 2.60(t, 2H, J= 7.6 Hz). HRMS (ESI) calculated for C10H13O3 (M+H+), 181.0865; found, 181.0889
68%
for 12 h; Heating / reflux
0. 8g 4-hydroxy cinnamic acid in 40 ml methanol and 10 drops HCl were refluxed for 12 hours. Workup as above gave 0.6g oil, 68percent yield. NMR CDC13 7.02, 6.75 (4H, Abq, J=8.6 Hz), 3.66 (3H, s), 2.86 (2H, t, J=7.4 Hz), 2.60 (2H, t, J=7. 4 Hz).
68%
for 12 h; Heating / reflux
AV 32 [ CNHISNOG] Mol. Wt.: 209.24 A. 0.8 gr 4-hydroxy cinnamic acid in 40 [ML METHANOL] and 10 drops HCI were [REFLUXED] for 12 hours. Workup as above gave 0.6 gr oil, 68percent yield. NMR CDCl3 7.02, 6.75 (4H, Abq, J=8.6 Hz), 3.66 (3H, s), 2.86 (2H, t, J=7.4 [HZ),] 2.60 (2H, t, J=7. 4 Hz). B. 0.6 gr, 3.3 mM, ester from step A and 0.26 gr, 4.2 mM, ethanol amine were heated at 100 for 3 hours in an open vessel. Chromatography gave 0.3 gr recovered ester followed by amide. The viscous oil was triturated with acetone-methylene chloride and filtered to give 160 mg white solid, 23percent yield, mp-102. NMR acetone d6 8.10 (1H, s, OH), 7. [03,] 6.74 (4H, Abq, J=8. [8 HZ),] 3.90 (1H, t, J=5.2 Hz, NH), 3.54 (2H, q, J=7.1 Hz), 3.28 (2H, t, J=7.1 [HZ),] 2.80 (2H, t, J=8.2 Hz), 2.41 (2H, t, J=8.2 Hz).
68%
for 12 h; Heating / reflux
0. 8g 4-hydroxy cinnamic acid in 40 ml methanol and 10 drops HCl were refluxed for 12 hours. Workup as above gave 0.6g oil, 68percent yield. NMR CDC13 7.02, 6.75 (4H, Abq, J=8.6 Hz), 3.66 (3H, s), 2.86 (2H, t, J=7.4 Hz), 2.60 (2H, t, J=7. 4 Hz).
62%
for 24 h; Reflux
General procedure: After dissolving the carboxylic acid in the alcohol, three drops of H2SO4 95percent were added to the solution and the mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure and water was added to the crude mixture. The pH of the aqueous layer was adjusted to 7 adding drops of a saturated solution of NaHCO3 and brine was added in the mixture. The aqueous layer was extracted three times with ethyl acetate; the organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure yielding the final compound. Further purification step was made when it was necessary.
21.2 g
at 0℃; Inert atmosphere
To a solution of 3-(4-hydroxyphenyl)propionic acid (20 mg, 120 mmol) in MeOH (300 mL) was added SOCl2 (28.6 g, 240 mmol) at 0° C. under nitrogen. The resulting mixture was stirred overnight then concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (2*50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to yield Compound 1 as a red oil (21.2 g). A solution of Compound 1 (19 g, 106 mmol) in dry THF (200 mL) was slowly added to a suspension of LAH (6 g, 158 mmol) in dry THF (200 mL) at 0° C. under nitrogen. The mixture was allowed to reach room temperature and was then stirred for 2 hours. Then water (6 mL) and 15percent aqueous NaOH (24 mL) were added. Additional water (6 mL) was added to quench the reaction. The solids were filtered and the filter cake was washed with EtOAc several times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (hexanes:EtOAc 8:1˜5:1˜2:1) to yield Compound 2 as a yellow oil (10 g).
365.8 g
for 7 h; Reflux
2L three-mouth bottle, is provided with a stirring, thermometer and a condenser. Adding 340.0g the hydroxy phenylpropanoic acid, 3.4g concentrated sulfuric acid and 1500 ml methanol, heating reflux for 7 hours. Cooling to room temperature, using NaHCO 3 solution to neutral, rotary evaporimeter desolventizing, by adding 600 ml of water and 600 ml toluene, liquid separation, the organic phase washed to neutral, and to obtain the product solvent 365.8g, GC purity: 98.4percent.
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 21, p. 3351 - 3354
[2] Journal of Organic Chemistry, 2009, vol. 74, # 11, p. 4236 - 4241
[3] Organic Letters, 2013, vol. 15, # 23, p. 6058 - 6061
[4] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5345 - 5351
[5] Organic Letters, 2016, vol. 18, # 11, p. 2600 - 2603
[6] European Journal of Medicinal Chemistry, 2017, vol. 129, p. 110 - 123
[7] Synlett, 2018, vol. 29, # 9, p. 1239 - 1243
[8] Tetrahedron Asymmetry, 1993, vol. 4, # 2, p. 261 - 272
[9] Patent: WO2014/69963, 2014, A1, . Location in patent: Paragraph 355-357
[10] Patent: EP2952517, 2015, A1, . Location in patent: Paragraph 0217
[11] Patent: EP2184277, 2010, A1, . Location in patent: Page/Page column 13
[12] Patent: US2011/9427, 2011, A1, . Location in patent: Page/Page column 8
[13] Tetrahedron Letters, 2013, vol. 54, # 25, p. 3294 - 3297
[14] Patent: CN108640834, 2018, A, . Location in patent: Paragraph 0020; 0028; 0029; 0034
[15] Organic Letters, 2003, vol. 5, # 13, p. 2215 - 2217
[16] Tetrahedron, 2005, vol. 61, # 30, p. 7144 - 7152
[17] Chemistry - An Asian Journal, 2011, vol. 6, # 8, p. 2034 - 2039
[18] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 4, p. 428 - 432
[19] Organic and Biomolecular Chemistry, 2003, vol. 1, # 9, p. 1486 - 1497
[20] Nucleosides, Nucleotides and Nucleic Acids, 2004, vol. 23, # 1-2, p. 89 - 115
[21] Tetrahedron, 1990, vol. 46, # 20, p. 7105 - 7118
[22] Analytical Chemistry, 2002, vol. 74, # 2, p. 468 - 478
[23] Patent: WO2006/18326, 2006, A1, . Location in patent: Page/Page column 22
[24] Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 17, p. 9476 - 9482
[25] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1993, # 11, p. 1225 - 1234
[26] Organic and Biomolecular Chemistry, 2015, vol. 13, # 22, p. 6225 - 6241
[27] European Journal of Medicinal Chemistry, 2009, vol. 44, # 1, p. 332 - 344
[28] Patent: WO2017/116994, 2017, A1, . Location in patent: Paragraph 0072
[29] Bioconjugate Chemistry, 2016, vol. 27, # 5, p. 1314 - 1323
[30] Synthetic Communications, 2012, vol. 42, # 5, p. 722 - 726
[31] Patent: WO2005/92305, 2005, A2, . Location in patent: Page/Page column 25
[32] Patent: WO2004/31129, 2004, A2, . Location in patent: Example 1
[33] Patent: WO2005/92305, 2005, A2, . Location in patent: Page/Page column 25
[34] Bulletin of the Polish Academy of Sciences, Chemistry, 1986, vol. 34, # 3-4, p. 115 - 122
[35] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 351 - 359
[36] Chemische Berichte, 1917, vol. 50, p. 618[37] Chem. Zentralbl., 1916, vol. 87, # II, p. 1025
[38] Tetrahedron, 1966, vol. 22, p. 861 - 866
[39] Collection of Czechoslovak Chemical Communications, 1981, vol. 46, # 5, p. 1173 - 1187
[40] Journal of Medicinal Chemistry, 1982, vol. 25, # 12, p. 1408 - 1412
[41] Gazzetta Chimica Italiana, 1996, vol. 126, # 2, p. 121 - 125
[42] Tetrahedron, 1997, vol. 53, # 12, p. 4387 - 4410
[43] Synthetic Communications, 1998, vol. 28, # 4, p. 747 - 751
[44] Journal of Agricultural and Food Chemistry, 1998, vol. 46, # 4, p. 1670 - 1676
[45] Patent: WO2005/16862, 2005, A1, . Location in patent: Page/Page column 411
[46] Patent: WO2004/74270, 2004, A2, . Location in patent: Page 316
[47] Patent: US2005/176701, 2005, A1, . Location in patent: Page/Page column 152
[48] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 1939 - 1944
[49] Patent: US2004/44258, 2004, A1, . Location in patent: Page 57
[50] Patent: WO2003/95441, 2003, A1, . Location in patent: Page/Page column 15
[51] ACS Medicinal Chemistry Letters, 2010, vol. 1, # 7, p. 345 - 349
[52] Journal of Materials Chemistry A, 2013, vol. 1, # 6, p. 2256 - 2266
[53] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 24, p. 7699 - 7708
[54] Patent: US2013/323271, 2013, A1, . Location in patent: Paragraph 0387; 0388
[55] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6874 - 6878
[56] Patent: CN103539640, 2016, B, . Location in patent: Paragraph 0070; 0082; 0083
[57] Patent: CN107721836, 2018, A, . Location in patent: Paragraph 0043; 0044-0046
5
[ 501-97-3 ]
[ 74-88-4 ]
[ 5597-50-2 ]
Yield
Reaction Conditions
Operation in experiment
95.9%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: at 0 - 20℃; for 3 h;
Intermediate 2: Methyl 3-(4-hydroxyphenyl) propanoateTo a 1000 mL RB flask fitted with magnetic stirrer was charged 250 mL of DMF, 3-(4- Hydroxy-phenyl)-propanoic acid (25.0 g, 150.43 mmol) and K2C03 (41.58 g, 300.87 mmol). The resulting mixture was stirred at RT for 30 minutes. Methyl Iodide (25.627 g, 180.51 mmol) was added to the resulting mixture which was precooled to 0 3/4. The resulting mixture was stirred at RT for 3 h. After completion of the reaction (reaction monitored by TLC), the solvent was removed under reduced pressure and the crude mass was dissolved in ethyl acetate (250 mL). The organic layer was washed with water (250 mL), saturated sodium bicarbonate solution (250 mL X 2), and saturated brine solution (250 mL). The organic layer was dried over anhydrous Na2S04 and the solvent was removed under reduced pressure. The product was obtained as yellow color oil (26 g, Yield: 95.9 percent): MS (ESI, 120 eV) : m/z = 178.9 (M- H)+; 1H NMR (300MHz, CDCI3): δ 6.97-7.00(d, 2H), 6.66-6.69(d, 2H), 4.94(s, 1 H), 3.59(s, 3H), 2.78-2.83(t, 2H), 2.50-2.55(t, 2H).
Reference：
[1] Synthetic Communications, 2005, vol. 35, # 1, p. 145 - 152
[2] Patent: WO2012/11125, 2012, A1, . Location in patent: Page/Page column 59; 60
[3] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 6, p. 1462 - 1469
6
[ 7400-08-0 ]
[ 5597-50-2 ]
Reference：
[1] Journal of the American Chemical Society, 2006, vol. 128, # 10, p. 3324 - 3334
[2] Analytical Chemistry, 2002, vol. 74, # 2, p. 468 - 478
[3] Journal of Natural Products, 1999, vol. 62, # 1, p. 102 - 106
[4] Bulletin of the Polish Academy of Sciences, Chemistry, 1986, vol. 34, # 3-4, p. 115 - 122
[5] Phytochemistry (Elsevier), 1992, vol. 31, # 4, p. 1179 - 1184
[6] Patent: US5571506, 1996, A,
[7] Patent: EP2745876, 2014, A1,
[8] Angewandte Chemie - International Edition, 2014, vol. 53, # 30, p. 7785 - 7788[9] Angew. Chem., 2014, vol. 53, # 30, p. 7919 - 7922,4
[10] Patent: US2015/344408, 2015, A1,
7
[ 3943-97-3 ]
[ 5597-50-2 ]
Reference：
[1] Canadian Journal of Chemistry, 2012, vol. 90, # 9, p. 758 - 761
[2] Pharmazie, 2010, vol. 65, # 12, p. 913 - 918
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 14, p. 4608 - 4617
With sulfuric acid In methanol; silica gel; toluene
(a) Methyl 3-(4-Hydroxyphenyl)propionate A solution of 17 gm (0.1 mole) of 3-(4-hydroxyphenyl)propionic acid in 500 ml methanol and 2 ml concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3 A molecular sieves. The solution was heated to reflux for 72 hours and the sieves were exchanged at 24 hours intervals. The reaction medium was then evaporated to an oil which was dissolved in 100 ml toluene and extracted with 3*100 ml water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to provide 15 gm (80percent) of a clear oil. The NMR spectrum was consistent with the assigned structure and this material was utilized directly in the next reaction step.
80%
With sulfuric acid In methanol; silica gel; toluene
Methyl 3-(4-Hydroxyphenyl)propionate A solution of 17 gm (0.1 mole) of 3-(4-hydroxyphenyl)propionic acid in 500 mL methanol and 2 mL concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3 A molecular sieves. The solution was refluxed for 72 hours and the sieves were exchanged at 24 hour intervals. The reaction medium was then evaporated to an oil which was dissolved in 100 mL toluene and extracted with 3*100 mL water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to provide 15 gm (80percent) of a clear oil. The NMR spectrum was consistent with the assigned structure and this material was utilized directly in the next reaction step.
Reference：
[1] Patent: US4623652, 1986, A,
[2] Patent: US4387103, 1983, A,
10
[ 23795-02-0 ]
[ 5597-50-2 ]
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 27, p. 7751 - 7755[2] Angew. Chem., 2016, vol. 128, p. 7882 - 7886,5
11
[ 501-97-3 ]
[ 616-38-6 ]
[ 5597-50-2 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 22, p. 11606 - 11611
12
[ 501-97-3 ]
[ 77-78-1 ]
[ 5597-50-2 ]
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 10, p. 3606 - 3609
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 27, p. 7751 - 7755[2] Angew. Chem., 2016, vol. 128, p. 7882 - 7886,5
33
[ 106-44-5 ]
[ 5597-50-2 ]
Reference：
[1] Patent: CN108640834, 2018, A,
34
[ 140-39-6 ]
[ 5597-50-2 ]
Reference：
[1] Patent: CN108640834, 2018, A,
35
[ 52727-95-4 ]
[ 5597-50-2 ]
Reference：
[1] Patent: CN108640834, 2018, A,
36
[ 830-09-1 ]
[ 5597-50-2 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1981, vol. 46, # 5, p. 1173 - 1187
37
[ 6386-38-5 ]
[ 5597-50-2 ]
[ 36837-50-0 ]
[ 115-11-7 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1987, vol. 36, # 4, p. 681 - 684[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1987, # 4, p. 752 - 756
38
[ 186581-53-3 ]
[ 501-97-3 ]
[ 5597-50-2 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1963, vol. 663, p. 74 - 82
39
[ 5597-50-2 ]
[ 100-39-0 ]
[ 24807-40-7 ]
Yield
Reaction Conditions
Operation in experiment
88%
With potassium carbonate In acetonitrile for 1 h; Reflux
Methyl 3-[4-(benzyloxy)phenyl]propanoate; BnBr (4.39 g, 25.64 mmol) was added to a suspension of K2CO3 (3.55 g, 25.64 mmol) and methyl 3-(4-hydroxyphenyl)propanoate (1.54 g, 8.55 mmol) in CH3CN (40 ml_). The reaction mixture was warmed up to reflux, and allowed to react for 1 h. It was poured into H2O (120 ml_), taken up to pH = 2 with HCI (10percent aqueous solution) and extracted with EtOAc (2x100 ml_). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (0-->5percent EtOAc/hexanes) to give 2.01 g of methyl 3-[4- (benzyloxy)phenyl]propanoate (white solid, yield: 88percent).1 H NMR (CDCI3, 250 MHz) δ ppm: 7.51 -7.29 (m, 5H), 7.14 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.05 (s, 2H), 3.69 (s, 3H), 2.92 (t, J = 7.6 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H).
Reference：
[1] Patent: US2002/65246, 2002, A1,
[2] Patent: US6414179, 2002, B1,
[3] Patent: WO2010/70076, 2010, A1, . Location in patent: Page/Page column 104
[4] Patent: EP2952517, 2015, A1, . Location in patent: Paragraph 0217
[5] Bulletin of the Polish Academy of Sciences, Chemistry, 1986, vol. 34, # 3-4, p. 115 - 122
[6] Journal of Medicinal Chemistry, 2001, vol. 44, # 21, p. 3351 - 3354
[7] Tetrahedron, 1973, vol. 29, p. 1405 - 1411
[8] Patent: WO2004/74270, 2004, A2, . Location in patent: Page 316-317
[9] Patent: US2005/176701, 2005, A1, . Location in patent: Page/Page column 153
[10] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 1939 - 1944
[11] Patent: WO2003/95441, 2003, A1, . Location in patent: Page/Page column 15-16
[12] Patent: EP1849465, 2007, A1, . Location in patent: Page/Page column 81
[13] ACS Medicinal Chemistry Letters, 2010, vol. 1, # 7, p. 345 - 349
[14] RSC Advances, 2016, vol. 6, # 46, p. 40238 - 40249
[15] Patent: WO2008/130514, 2008, A1, . Location in patent: Page/Page column 104
40
[ 5597-50-2 ]
[ 100-51-6 ]
[ 24807-40-7 ]
Yield
Reaction Conditions
Operation in experiment
59%
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0℃; for 2 h;
Reference Example 1 Methyl 4-(phenylmethoxy)benzenepropanoate To a solution of ice-cooled methyl 4-hydroxybenzenepropanoate (0.70 g, 3.9 mmol), benzyl alcohol (0.48 mL, 4.7 mmol) and triphenylphosphine (1.2 g, 4.7 mmol) in tetrahydrofuran (5 mL) was added dropwise diethyl azodicarboxylate (0.73 mL, 4.7 mmol), and the mixture was stirred for 2 hours with ice cooling. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate = 17: 3) to give the title compound (0.62 g, yield 59percent) as powders. 1H NMR (CDC13) δ 2.59 (2H, t, J=7.5 Hz), 2.89 (2H, t, J=7.5 Hz), 3.66 (3H, s), 5.04 (2H, s), 6.90 (2H, d, J=8.6 Hz), 7.11 (2H, d, J=8.6 Hz), 7.29-7.44 (5H, m).
59%
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0℃; for 2 h;
Reference Example 1 methyl 4-(phenylmethoxy)benzenepropanoate To an ice-cooled solution of methyl 4-hydroxybenzenepropanoate (0.70 g, 3.9 mmol), benzyl alcohol (0.48 mL, 4.7 mmol) and triphenylphosphine (1.2 g, 4.7 mmol) in tetrahydrofuran (5 mL) was added dropwise diethyl azodicarboxylate (0.73 mL, 4.7 mmol), and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=17:3) to give the title compound (0.62 g, yield 59percent) as a powder. 1H NMR (CDCl3) δ 2.59 (2H, t, J=7.5 Hz), 2.89 (2H, t, J=7.5 Hz), 3.66 (3H, s), 5.04 (2H, s), 6.90 (2H, d, J=8.6 Hz), 7.11 (2H, d, J=8.6 Hz), 7.29-7.44 (5H, m).
Reference：
[1] Patent: CN107011149, 2017, A, . Location in patent: Paragraph 0064-0067
44
[ 6386-38-5 ]
[ 5597-50-2 ]
[ 36837-50-0 ]
[ 115-11-7 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1987, vol. 36, # 4, p. 681 - 684[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1987, # 4, p. 752 - 756
45
[ 5597-50-2 ]
[ 1374516-07-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4511 - 4515
With hydrogenchloride In 1,4-dioxane at 20℃; for 2h;
100%
With sulfuric acid for 2h; Inert atmosphere; Reflux;
100%
With thionyl chloride at 0 - 20℃;
100%
With chloro-trimethyl-silane at 25℃; for 24h;
SI 4. General procedure for the preparation of esters 1a-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 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 acid methyl ester(1a) Oil; 1HNMR (400 MHz, CDCl3): δ H (ppm) = 2.66 (2H, m, CH2),3.05 (2H, m, CH2),3.65 (3H, m, OCH3), 6.73 (2H, m, Ph-H), 7.04(2H, m, Ph-H); 13C NMR (50 MHz, CDCl3): δ C (ppm) = 30.19 (CH2),35.23 (CH2), 50.99 (CH3),115.57 (2 CH), 129.54 (2 CH),131.59 (C), 155.71 (C), 172.74 (CO); MS (EI): m/z 252; Elemental analysis: calcd C, 66.65; H, 6.71; O, 26.64, found C, 66.64; H, 6.71;O, 26.63.
100%
With sulfuric acid for 2h; Reflux;
100%
With acetyl chloride In methanol at 0℃; for 1.5h;
Methyl 3-(4-hydroxyphenyl)propanoate (38)
To a solution of3-(4-hydroxyphenyl)propanoic acid (2.50g, 15.04 mmol) in methanol(40 mL) were added dropwise 5.35 mL acetyl chloride (5.0eq,75.20 mmol) at 0 °C. The reaction mixture was stirred over 1.5 h at0 °C. After completion of the reaction, the mixture was concentratedin vacuo and ethyl acetate was added. The organic layer waswashed with NaHCO3 (3 x 50 mL) and concentrated in vacuo to givemethyl 3-(4-hydroxyphenyl)propanoate 38 (2.70 g, 100%) as acolorless oil. UPLC-MS: 1.62 min, 100%. 1H NMR (300 MHz, CD3OD) δ (ppm) 7.08-6.94 (m, 2H), 6.80-6.64 (m, 2H), 3.69-3.49 (m, 3H),2.87-2.70 (m, 2H), 2.60-2.45 (m, 2H). 13C NMR (75 MHz, CD3OD) δ (ppm) 174.4, 155.8, 131.8, 129.3, 115.3, 51.1, 36.1, 30.2. MS (ES) m/z181.7 (M + H)+. HRMS calculated for C10H12O3: 203.0679; found:203.0679 (M + Na)+.
100%
With sulfuric acid for 2h; Reflux;
100%
With sulfuric acid for 6h; Reflux;
99%
With hydrogen cation esterification;
99%
With hydrogenchloride In 1,4-dioxane at 20℃; for 3h;
4 [355] Preparation Example 4: 3-(4-hydroxy-phenyl)-propionic acid methyl ester
[355] Preparation Example 4: 3-(4-hydroxy-phenyl)-propionic acid methyl ester[356] After 3-(4-hydroxy-phenyl)propionic acid (3 g, 18 mmol) was added with MeOH(6 mL), 4M HCl/dioxane solution (18 mL, 72 mmol) was added thereto, and themixture was stirred at room temperature for 3 hours. The reactant wasconcentrated, added with EtOAc, and then washed with NaCl aqueous solution. Theorganic layer was separated, dried with MgSO4, and filtered toobtain the title compound (3.26 g, 99%). [357] 1H-NMR (CDCl3) δ 7.06(2H, m), 6.75(2H, m),4.79(1H, brs, OH), 3.66(3H, s), 2.88(2H, t), 2.59(2H, t)
99%
With sulfuric acid In dichloromethane for 41h; Reflux;
99.6%
Stage #1: methanol With thionyl chloride at 5℃; for 0.5h;
Stage #2: 4-hydroxyphenylpropionic acid at 35℃;
1.1
Add 70.00g methanol into the reaction flask, stir and cool to 5°C, add 15.00g (0.126mol) thionyl chloride dropwise at 5°C, and finish the dropwise addition at 0.5h, and react at 5°C for 0.5h.Add 20.00g (0.120mol) p-hydroxyphenylpropionic acid (II), raise the temperature to 35, control the temperature at 35 to react for 0.5-1.0h, TLC will detect the reaction is complete, control the temperature at 30-40 and distill under reduced pressure to obtain a light yellow oil 21.62g, purity 99.9%, 21.60g converted to methyl p-hydroxyphenylpropionate (III), molar yield 99.6%
98%
With sulfuric acid at 70℃; for 3h;
4.61 g p-hydroxyphenpropionic acid, 50 ml methanol and 0.5 ml concentrated H2SO4 were refluxed at 70°C for 3 hours and cooled. Excessive acid was neutralized with saturated NaHCO3 solution. The neutralized solution was extracted with ethyl acetate for three times. The extract was dried, filtrated, evaporated and purified by column chromatograph (petroleum ether: ethyl acetate=2:1) to obtain 4.9 g white solid, yield 98%. 1H-NMR (400MHz, DMSO-d6, δ ppm) δ 2.5(2H, m), 2.7(2H, t), 3.567(3H, s), 6.6(2H, d, J=6.4Hz), 7.0(2H, d, J=8.4Hz), 9.0(1H, s).
98%
With sulfuric acid at 70℃; for 3h;
Intermediate 10: Methyl p-hydroxyphenpropionate 4.61 g p-hydroxyphenpropionic acid, 50 ml methanol and 0.5 ml concentrated H2SO4 were refluxed at 70° C. for 3 hours and cooled. Excessive acid was neutralized with saturated NaHCO3 solution. The neutralized solution was extracted with ethyl acetate for three times. The extract was dried, filtrated, evaporated and purified by column chromatograph (petroleum ether:ethyl acetate=2:1) to obtain 4.9 g white solid, yield 98%. 1H-NMR (400 MHz, DMSO-d6, δ ppm) δ 2.5 (2H, m), 2.7 (2H, t), 3.567 (3H, s), 6.6 (2H, d, J=6.4 Hz), 7.0 (2H, d, J=8.4 Hz), 9.0 (1H, s).
98%
With sulfuric acid for 16h; Reflux;
Typical procedure for synthesis of methyl esters
General procedure: According to a literature protocol.[1] Propanoic acid derivative (10 g) was dissolved inmethanol (80 ml) and H2SO4 (700μl, 6 mmol) added. The resulting solution was refluxed for16 h and then allowed to cool to room temperature. The reaction mixture was reduced todryness and re-dissolved in ethyl acetate (20 ml). The organic phase was washed withsaturated aqueous sodium hydrogen carbonate (10 ml), brine (10 ml) and dried over MgSO4.Removal of the solvent gave the desired methyl ester. (Note: column chromatography is oftennot required for the methyl ester starting materials). Methyl 3-(4-hydroxyphenyl)propanoate (1a) Synthesized according to general procedure A (98%); 1H NMR (500 MHz, d4-MeOH): δ 6.98(d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 3.60 (s, 3H), 2.78 (t, J = 7.6 Hz, 2H), 2.53 (t, J= 7.6 Hz, 2H); 13C NMR (125 MHz, d4-MeOH): 172.8, 155.6, 130.6, 129.1, 115.1, 51.2, 35.4,29.5; HRMS (EI) calculated for C10H12O3 [M]+: 180.078643; found: 180.078803.
98.2%
With sulfuric acid for 10h; Reflux;
2.5 5) Preparation of methyl 3-(4-hydroxyphenyl)propanoate:
20 g of p-hydroxyphenylpropionic acid was added to 300 ml of anhydrous methanol and2 ml of concentrated sulfuric acid, heated to reflux for 10 h, the solvent was evaporated under reduced pressure, then dissolved with ethyl acetate and washed sequentially with sodium hydrogen carbonate and water.Polyester, organic layer dried over anhydrous magnesium sulfate,The solvent was evaporated to give 21.2 g (yield: 98.2%).
97%
With sulfuric acid Reflux;
97%
With sulfuric acid
96%
With thionyl chloride at 20℃; for 24h;
95%
With hydrogenchloride at 20℃; for 3h;
95%
With thionyl chloride at -40 - 20℃; for 12h; Cooling with acetonitrile-dry ice;
95%
With sulfuric acid at 60℃; for 6h;
95%
With sulfuric acid at 35℃; for 4h;
95.3%
With sulfuric acid for 6h; Reflux;
1.1 1. Preparation of methylparaben:
150g of p-hydroxyphenylacetic acid, 400g of anhydrous methanol, 0.2ml of concentrated sulfuric acid, heated to reflux for 6 hours, after the reaction was completed, 3.0g of sodium carbonate was added to neutralize the sulfuric acid, then the methanol was evaporated under reduced pressure, 400g of toluene was added, and 500g of purified water was extracted and layered Then, an organic phase was obtained, and the organic phase was concentrated under reduced pressure to obtain 154.4 g of methylparaben, the purity detected by HPLC was 99.0%, and the yield was 95.3%.
94%
With sulfuric acid for 3h; Heating;
93%
With sulfuric acid In dichloromethane for 5h; Heating;
92.7%
With hydrogenchloride Heating;
92%
at 20℃; for 12h;
92%
With sulfuric acid at 20℃; for 16h;
4.b
15 g (0.09 mol, 1 eq) of 3-(4-hydroxyphenyl)propanoic acid are dissolved in 50 ml of methanol and 4 drops of sulfuric acid are added. The reaction mixture is stirred for 16 hours at room temperature. The reaction is stopped by addition of 50 mL of saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 14.9 g of methyl 3-(4-hydroxyphenyl)propanoate are obtained. Yield = 92 %
92%
With sulfuric acid for 24h; Reflux;
89%
With acetyl chloride Heating;
88%
With sulfuric acid at 65℃; for 16h; Sealed tube;
86%
With toluene-4-sulfonic acid for 14h; Reflux;
86%
With thionyl chloride at 20℃; for 2h;
Methyl 3-(4-hydroxyphenyl)propanoate (2).
3-(4-hydroxyphenyl)propanoic acid (1, 3.0 g, 18.1 mmol) was dissolved in methanol (50 mL), and SOCl2 (1.5 mL) was added. The solution was stirred at room temperature for 2 h. Then, the reaction mixture was concentrated in vacuo to afford 3.2 g (17.8 mmol) of crude product 2 as oil. The obtained crude product 2 was purified by silica gel column chromatography (dichloromethane). The process was monitored by TLC on silica gel plates (dichloromethane:ethyl acetate,4:1, Rf 0,79) with compound detection accomplished in an iodine chamber. The eluate was evaporated on a rotary evaporator to give compound 2 (2.8 g, 15.5 mmol, 86%) as an oil and with purity >98% (HPLC, method A, UV 220 nm).
85%
With sulfuric acid for 24h; Reflux;
84%
With boron trifluoride diethyl etherate at 20℃; for 8h;
1 Methyl 3-(4-hydroxyphenyl)propanoate (A).
To a solution of 3-(4-hydroxyphenyl)propanoic acid (3 g, 18.1 mmol) in 50 mL MeOH was added ΒΡ3·Ε20 (0.3 mL). The mixture was stirred at rt for 8 h. The mixture was concentrated, and the residue was purified by flash chromatography (FC) (ethyl acetate (EtOAc) /hexane = 2/8) to give 2.72 g white solid A (yield: 84%): 1HNMR(400 MHz, CDC13) δ: 7.07(d, 2H, J= 8.4 Hz), 6.76(d, 2H, J= 8.4 Hz), 4.72(s, 1H), 3.68(s, 3H), 2.89(t, 2H, J= 7.6 Hz), 2.60(t, 2H, J= 7.6 Hz). HRMS (ESI) calculated for C10H13O3 (M+H+), 181.0865; found, 181.0889
84%
With boron trifluoride diethyl etherate at 20℃; for 6h;
1.1 Synthesis of compound 3 (methyl 3-(4-hydroxyphenyl)propionate):
Adding p-hydroxyphenylpropionic acid to a round bottom flask(3g, 18.1mmol) and 50mL of methanol,Subsequently, boron trifluoride diethyl ether (0.3 mL) was added dropwise to the mixed solution.After stirring at room temperature for 6 hours,The organic phase in the filtrate was removed under reduced pressure using a rotary evaporator using n-hexane/ethyl acetate (v/v, 2/8)Through the silica gel column separation,Collect target components,The solvent was removed under reduced pressure.2.72 g of a white solid were obtained (yield: 84%);
83.5%
With boron trifluoride diethyl etherate at 20℃; for 6h;
70%
Acidic conditions; Reflux;
68%
With hydrogenchloride for 12h; Heating / reflux;
1.AV 32.A EXAMPLES EXAMPLE 1: Synthesis of compounds AV 32
AV 32 [ CNHISNOG] Mol. Wt.: 209.24 A. 0.8 gr 4-hydroxy cinnamic acid in 40 [ML METHANOL] and 10 drops HCI were [REFLUXED] for 12 hours. Workup as above gave 0.6 gr oil, 68% yield. NMR CDCl3 7.02, 6.75 (4H, Abq, J=8.6 Hz), 3.66 (3H, s), 2.86 (2H, t, J=7.4 [HZ),] 2.60 (2H, t, J=7. 4 Hz). B. 0.6 gr, 3.3 mM, ester from step A and 0.26 gr, 4.2 mM, ethanol amine were heated at 100 for 3 hours in an open vessel. Chromatography gave 0.3 gr recovered ester followed by amide. The viscous oil was triturated with acetone-methylene chloride and filtered to give 160 mg white solid, 23% yield, mp-102. NMR acetone d6 8.10 (1H, s, OH), 7. [03,] 6.74 (4H, Abq, J=8. [8 HZ),] 3.90 (1H, t, J=5.2 Hz, NH), 3.54 (2H, q, J=7.1 Hz), 3.28 (2H, t, J=7.1 [HZ),] 2.80 (2H, t, J=8.2 Hz), 2.41 (2H, t, J=8.2 Hz).
68%
With hydrogenchloride for 12h; Heating / reflux;
1.A
0. 8g 4-hydroxy cinnamic acid in 40 ml methanol and 10 drops HCl were refluxed for 12 hours. Workup as above gave 0.6g oil, 68% yield. NMR CDC13 7.02, 6.75 (4H, Abq, J=8.6 Hz), 3.66 (3H, s), 2.86 (2H, t, J=7.4 Hz), 2.60 (2H, t, J=7. 4 Hz).
65%
With hydrogen cation
62%
With sulfuric acid for 24h; Reflux;
General procedure for the synthesis of compounds 9-12 and 21-29
General procedure: After dissolving the carboxylic acid in the alcohol, three drops of H2SO4 95% were added to the solution and the mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure and water was added to the crude mixture. The pH of the aqueous layer was adjusted to 7 adding drops of a saturated solution of NaHCO3 and brine was added in the mixture. The aqueous layer was extracted three times with ethyl acetate; the organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure yielding the final compound. Further purification step was made when it was necessary.
With sulfuric acid at 80℃; unter Druck;
With sulfuric acid In 1,2-dichloro-ethane Heating;
With hydrogenchloride Heating;
With 3 A molecular sieve; sulfuric acid for 72h; Heating;
With boron trifluoride for 0.0333333h; Heating;
With Amberlyst 15 for 8h; Heating;
With sulfuric acid Yield given;
With thionyl chloride at 0 - 20℃; for 2h;
A-1
[Example A-1]; Synthesis of methyl 3- (4-HYDROXYPHENYL) propionate (Intermediate 1); A solution obtained beforehand by adding thionyl chloride (18.3 ml, WAKO) dropwise to methanol (250 ml) and mixing the mixture under ice cooling was added dropwise with a solution of 3- (4-HYDROXYPHENYL) propionic acid (16. 6g, TCI) in methanol (50 ml) under ice cooling, stirred for 30 minutes, warmed to room temperature, and further stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and then extracted with diethyl ether (200 ml). The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate 1,17. 95 g).
With hydrogenchloride In 1,4-dioxane
B.67.1 Step 1: 3- (4-Hydroxyphenyl) propionic acid methyl ester.
A solution of HCI in dioxane (4.0 M, 7.4 mL) was added to a solution of 4- hydroxyphenylpropionic acid (15.0 g, 90.3 mmol) in MeOH (500 mL). The reaction mixture was stirred overnight and then evaporated. The residue was evaporated from benzene (2 x 50 mL) to provide the product as an oil, which was used without further purification.
With hydrogenchloride In 1,4-dioxane
B.67.1
A solution of HCl in dioxane (4.0 M, 7.4 mL) was added to a solution of 4-hydroxyphenylpropionic acid (15.0 g, 90.3 mmol) in MeOH (500 mL). The reaction mixture was stirred overnight and then evaporated. The residue was evaporated from benzene (2×50 mL) to provide the product as an oil, which was used without further purification.
With sulfuric acid at 25℃;
With thionyl chloride at 0 - 20℃; for 2h;
1.c Reference Example 1; Synthesis of methyl 3-(4-hydroxyphenyl)Propionate (Intermediate 1) (Step c)
Reference Example 1 Synthesis of methyl 3-(4-hydroxyphenyl)Propionate (Intermediate 1) (Step c) A solution obtained beforehand by adding thionyl chloride (18.3 ml, WAKO) dropwise to methanol (250 ml) under ice cooling was added dropwise with a solution of 3-(4-hydroxyphenyl)propionic acid (16.6 g, TCI) in methanol (50 ml) under ice cooling, stirred for 30 minutes, then warmed to room temperature and further stirred for 1.5 hours.The reaction mixture was concentrated under reduced pressure and then extracted with diethyl ether (200 ml).The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine.The organic layer was dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate 1, 17.95 g).
With hydrogenchloride In 1,4-dioxane
1.1
A solution of HCl in dioxane (4.0 M, 7.4 mL) was added to a solution of 4- hydroxyphenylpropionic acid (15.0 g, 90.3 mmol) in MeOH (500 mL). The reaction mixture was stirred overnight and then evaporated. The residue was evaporated from benzene (2 x 50 mL) to provide the product as an oil, which was used without further purification.
With hydrogenchloride
With sulfuric acid
With chloro-trimethyl-silane at 25℃; for 24h;
4.6 General procedure for the preparation of esters 2a-l
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 25°C. After 24h, the reaction was stopped and evaporated under reduced pressure to afford 2a-l in quantitative yield without the need of purification:
21.2 g
With thionyl chloride at 0℃; Inert atmosphere;
2
To a solution of 3-(4-hydroxyphenyl)propionic acid (20 mg, 120 mmol) in MeOH (300 mL) was added SOCl2 (28.6 g, 240 mmol) at 0° C. under nitrogen. The resulting mixture was stirred overnight then concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (2*50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to yield Compound 1 as a red oil (21.2 g). A solution of Compound 1 (19 g, 106 mmol) in dry THF (200 mL) was slowly added to a suspension of LAH (6 g, 158 mmol) in dry THF (200 mL) at 0° C. under nitrogen. The mixture was allowed to reach room temperature and was then stirred for 2 hours. Then water (6 mL) and 15% aqueous NaOH (24 mL) were added. Additional water (6 mL) was added to quench the reaction. The solids were filtered and the filter cake was washed with EtOAc several times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (hexanes:EtOAc 8:1˜5:1˜2:1) to yield Compound 2 as a yellow oil (10 g).
With sulfuric acid for 10h; Reflux; Inert atmosphere;
Concentrated H2SO4 (40 μl, 0.83 mmol)was added to a solution of 3-(4-hydroxyphenyl)propionic acid (11) (2.76 g, 16.6 mmol) in MeOH (30mL), the resulting solution was heated to reflux and stirred for 10 h. The mixture was cooled to roomtemperature by removal of the oil bath, and the residual solvent was removed under reduced pressure.The crude residue was dissolved in EtOAc (40 mL), washed with saturated aqueous NaHCO3 (1 x 40mL) and the layers were separated. The organic layer was dried (MgSO4) and concentrated underreduced pressure to provide a clear, colorless oil that was dissolved in CH2Cl2 (55 mL) and cooled to 0°C. Imidazole (1.70 g, 24.9 mmol) was added, the solution stirred for 10 min, followed by a portion-wiseaddition of TBSCl (2.76 g, 18.3 mmol). The cooling bath was removed and the resulting heterogeneousmixture was stirred for 10 h. The mixture was diluted with H2O (50 mL), the layers were separated, andthe aqueous phase extracted with CH2Cl2 (3 x 50 mL). The combined organic extracts were washed withsaturated aqueous NaCl (50 mL), dried (MgSO4), and concentrated under reduced pressure to provide4.39 g of methyl 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)propanoate as a clear, colorless crude oil.This crude residue was dissolved in CH2Cl2 ( 75 mL), cooled to -90 °C, and a solution of DIBAL-H (1.0M in hexanes, 16.6 mmol, 15 mL) was then added dropwise while ensuring that the internal reactiontemperature remained below -80 °C. The mixture was stirred for 1 h, then excess DIBAL-H wasquenched by the slow addition of MeOH (15 mL), while again being careful to ensure that the internaltemperature of the solution did not rise above -80 °C. The mixture was allowed to warm to roomtemperature by removal of the cooling bath, diluted with saturated aqueous Rochelle’s salt (70 mL), andstirred vigorously for 10 h. The layers were separated and the aqueous phase was extracted with CH2Cl2(3 x 50 mL). The combined organic extracts were washed with saturated aqueous NaCl (50 mL), dried(MgSO4), and concentrated under reduced pressure. The crude residue was purified by flash columnchromatography eluting with hexanes/EtOAc (7:1) to provide 12 in 76% yield (16.6 mmol scale, 3.36mg) over three steps as a clear colorless oil. 1H and 13C NMR data for 12 was consistent with literature reported values.
365.8 g
With sulfuric acid for 7h; Reflux;
1.1 4-hydroxy-phenylpropionic acid methyl ester preparation
2L three-mouth bottle, is provided with a stirring, thermometer and a condenser. Adding 340.0g the hydroxy phenylpropanoic acid, 3.4g concentrated sulfuric acid and 1500 ml methanol, heating reflux for 7 hours. Cooling to room temperature, using NaHCO 3 solution to neutral, rotary evaporimeter desolventizing, by adding 600 ml of water and 600 ml toluene, liquid separation, the organic phase washed to neutral, and to obtain the product solvent 365.8g, GC purity: 98.4%.
With sulfuric acid at 35℃; for 4h;
1.1 Preparation of methyl 3-(4-hydroxyphenyl)propanoate
3-(4-Hydroxyphenyl)propionic acid (8 g, 48.14 mmol) was dissolved in methanol (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- Hydroxyphenyl)propionic acid methyl ester.
R.69
Reference Example 69 4-hydroxybenzenepropanamide 25% Aqueous ammonia (30 mL) was added to methyl 4-hydroxybenzenepropanoate (1.5 g, 8.3 mmol), and the mixture was stirred at room temperature for 15 hrs. Dil. hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.43 g, yield 31%). 1H NMR (CDCl3) δ 2.49 (2H, t, J=7.9 Hz), 2.90 (2H, t, J=7.9 Hz), 4.65 (1H, s), 5.25 (2H, br s), 6.76 (2H, d, J=8.5 Hz), 7.08 (2H, d, J=8.5 Hz).
With hydrogen In ethanol for 24h; Ambient temperature;
99%
In ethanol
16 Methyl 3-(4-hydroxyphenyl)propanoate
Methyl 3-(4-hydroxyphenyl)propanoate To a solution of (E)-methyl 3-(4-hydroxyphenyl)acrylate (1.0 g, 5.6 mmol) in EtOH (20 mL), Pd/C (0.1g) was added. The reaction mixture was vigorously stirred under hydrogen atmosphere (1 bar) at room temperature for 21 h. The suspension was filtered through a Celite pad and evaporated to dryness under vacuum to afford 1.0 g (5.6 mmol, 99% yield) of an oil identified as methyl 3-(4-hydroxyphenyl)propanoate. 1H NMR (400 MHz, CDCl3) δ 7.07 (ddd, J = 8.8, 2.8, 2.0 Hz, 2H), 6.76 (ddd, J = 8.8, 2.8, 2.0 Hz, 2H), 4.72 (br s, 1H), 3.67 (s, 3H), 2.88 (t, J = 7.8 Hz, 2H), 2.60 (t, J = 7.8 Hz, 2H).
99%
With palladium on activated charcoal; hydrogen In ethanol at 20℃; for 21h;
16 Methyl 3-(4-hydroxyphenyl)propanoate
Methyl 3-(4-hydroxyphenyl)propanoate (0413) (0414) To a solution of (E)-methyl 3-(4-hydroxyphenyl)acrylate (1.0 g, 5.6 mmol) in EtOH (20 mL), Pd/C (0.1 g) was added. The reaction mixture was vigorously stirred under hydrogen atmosphere (1 bar) at room temperature for 21 h. The suspension was filtered through a Celite pad and evaporated to dryness under vacuum to afford 1.0 g (5.6 mmol, 99% yield) of an oil identified as methyl 3-(4-hydroxyphenyl)propanoate. (0415) 1H NMR (400 MHz, CDCl3) δ 7.07 (ddd, J=8.8, 2.8, 2.0 Hz, 2H), 6.76 (ddd, J=8.8, 2.8, 2.0 Hz, 2H), 4.72 (br s, 1H), 3.67 (s, 3H), 2.88 (t, J=7.8 Hz, 2H), 2.60 (t, J=7.8 Hz, 2H).
82%
With 5%-palladium/activated carbon; hydrogen In ethyl acetate
80%
With sodium tetrahydroborate; nickel (II) chloride hexahydrate In methanol
Methyl 3-(4-hydroxyphenyl)propanoate (14)
To an ice-bath cooled solution of 13 (0.845 g, 5.1 mmol) and nickeldichloride hexahydrate (0.12 g, 0.5 mmol) in dry methanol (10 mL) asodium borohydride (0.5 g, 13.2 mmol) was added in small portion.After completion of reaction (controlled by GC-MS), saturated ammoniumchloride solution (2.5 mL) was added and methanol was evaporatedunder reduced pressure. Water (5 mL) and aqueous ammonia(10 mL) were added to the residue, and the product was extracted withethyl acetate (3x15 ml). The extracts were combined, dried overNa2SO4, and evaporated. The crude product was purified by columnchromatography (hexane-ethyl acetate 7:3).White solid, 0.67 g 80%. 1H NMR (500 MHz, CDCl3) δ 2.60 (t,J = 7.70 Hz, 2H), 2.88 (t, J = 7.70 Hz, 2H), 3.67 (s, 3H), 5.55 (br.s,1H), 6.70-6.80 (m, 1H), 7.00-7.09 (m, 1H).
71%
With ferrous ammonium sulphate hexahydrate; isopropyl β-D-thiogalactopyranoside In aq. phosphate buffer at 37℃; for 48h;
With hydrogen In methanol for 0.5h; Ambient temperature;
With hydrogen In ethanol for 16h;
With palladium 10% on activated carbon; hydrogen In ethyl acetate at 20℃; for 12h;
36 %Spectr.
With methanol; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate at 20℃; for 16h; Inert atmosphere; Irradiation; Sealed tube;
Stage #1: 3-(4-hydroxyphenyl)propionic acid methyl ester With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 4 - 5h; Heating / reflux;
Stage #2: With sodium hydroxide; water In tetrahydrofuran; ethyl acetate
1.i
Step (i); To a suspension of LAH (22.1 g, 2.5 eq, 583 mmol) in dry THF (1.0 L),was added dropwise a THF (50 mL) solution of methyl 3-(4-hydroxyphenyl)propionate(21 g, 1.0 eq, 116 mmol) at RT. The reaction mixture was refluxed for 4-5 h. It wasworked up by quenching with excess ethyl acetate followed by addition of water (23mL), 15% aq. NaOH (23 mL) and water (70 mL) under controlled stirring andmaintaining RT. To the workup mixture cone. HC1 was added to adjust the pH at 7.0. Itwas then filtered through celite and washed with ethyl acetate. Combined filtrate wasdried QS^SO/t) and condensed. Obtained residue was chromatographed (ethylacetate/hexanes) to obtain 3-(4-hydroxyphenyl)propanol (17 g, 100%) as white solid.Mp: 52-54°C.'H NMR (CDC13, 200 MHz 5: 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, 1505.Massm/z(CI):
100%
Stage #1: 3-(4-hydroxyphenyl)propionic acid methyl ester With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 4 - 5h; Heating / reflux;
Stage #2: With sodium hydroxide In tetrahydrofuran; water; ethyl acetate at 20℃;
Stage #3: With hydrogenchloride In tetrahydrofuran; water; ethyl acetate
1.i
To a suspension of LAH (22.1 g, 2.5 eq, 583 mmol) in dry THF (1.0 L), was added dropwise a THF (50 mL) solution of methyl 3-(4-hydroxyphenyl)propionate (21 g, 1.0 eq, 116 mmol) at RT. The reaction mixture was refluxed for 4-5 h. It was worked up by quenching with excess ethyl acetate followed by addition of water (23 mL), 15% aq. NaOH (23 mL) and water (70 mL) under controlled stirring and maintaining RT. To the workup mixture conc. HCl was added to adjust the pH at 7.0. It was then filtered through celite and washed with ethyl acetate. Combined filtrate was dried (Na2SO4) and condensed. Obtained residue was chromatographed (ethyl acetate/hexanes) to obtain 3-(4-hydroxyphenyl)propanol (17 g, 100%) as white solid. Mp: 52-54° C. 1H NMR (CDCl3, 200 MHz δ: 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, 1505. Mass m/z (CI): 152 [M+1].
100%
With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 4 - 5h; Heating / reflux;
i Step (i)
To a suspension of LAH (22.1 g, 2.5 eq, 583 mmol) in dry THF (1.0 L), was added dropwise a THF (50 mL) solution of methyl 3-(4-hydroxyphenyl)propionate (21 g, 1.0 eq, 116 mmol) at RT. The reaction mixture was refluxed for 4-5 h. It was worked up by quenching with excess ethyl acetate followed by addition of water (23 mL), 15% aq. NaOH (23 mL) and water (70 mL) under controlled stirring and maintaining RT. To the workup mixture conc. HCl was added to adjust the pH at 7.0. It was then filtered through celite and washed with ethyl acetate. Combined filtrate was dried (Na2SO4) and condensed. Obtained residue was chromatographed (ethyl acetate/hexanes) to obtain 3-(4-hydroxyphenyl)propanol (17 g, 100%) as white solid. Mp: 52-54° C. [0183] 1H NMR (CDCl3, 200 MHz δ: 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, 1505. [0184] Mass m/z (CI): 152 [M+1].
84.2%
With sodium tetrahydroborate In methanol at 20℃; for 3h; Cooling with ice;
16.a (a) 4-(3-hydroxypropyl) phenol
[0241] 45.0 g (0.25 mol) of methyl p-hydroxyphenylpropionate was dissolved in 200 mL of methanol, cooled in an ice bath. 14.2 g (0.375 mol) of sodium borohydride was added in batches, and the addition was completed within about 1 hour. The reaction was continued with stirring at room temperature for 2 hours. Thin layer detection showed that the raw materials was reacted completely. The solvent was removed under reduced pressure. The residue was dissolved in water which is adjusted to be with the pH 2 by adding 2M hydrochloric acid. The solution was extracted with dichloromethane three times (200 mL3). The extracts were combined, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, the solvent was removed under reduced pressure, and the residue was crystallized with dichloromethane and petroleum ether (1/5). 32.0g of the target compound was obtained with a yield of 84.2%.
32%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
Preparation of 1k [2]
A solution of compound 62 (9.0 g, 50 mmol) in anhydrous THF (100 ml) was slowly added to a well stirred suspension of LiAlH4 (3 g, 79 mmol, 1.6 equiv.) in anhydrous THF (300 ml) at 0 °C under argon atmosphere. The mixture was allowed to reach room temperature and then stirred for 2 hours. Then water (3 ml), 15% NaOH aqueous (3 ml) and water (3 ml) were added sequentially. Then the mixture was filtered, washed with EtOAc (100 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified flash silica gel (300-400 mesh) chromatography to afford 63 as a white solid (2.45 g, 32% yield). To a well-stirred solution of 63 (2.45 g, 16.1 mmol) in anhydrous DCM (300 ml) was added PBr3 (2.25 ml, 19 mmol, 1.2 equiv.) dropwise at 0 °C under argon atmosphere, then stirred for 1 hour, then allowed tostirred in room temperature for 5 hours. The resulting mixture was washed with water (50 ml×2) and saturated aqueous of NaHCO3 (100 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified flash silica gel (300-400 mesh) chromatography to afford 64 as a yellow oil (1.7 g, 53% yield). A well stirred solution of compound 64 (1.7 g, 7.9 mmol) in 5 ml of propargyl alcohol was cooled to 0 °C and treated with phenyliodine(III) diacetate (PIDA, 3.0 g, 12 mmol, 1.5 equiv.) in several portions. The resulting mixture was warmed to room temperature and stirred overnight. Then the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography using hexane / ethyl acetate eluent to afford the desired product 1k (600 mg, 39.7% yield) as a yellow oil.
With lithium borohydride In diethyl ether; toluene for 0.25h; Heating;
10 g
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere;
2
To a solution of 3-(4-hydroxyphenyl)propionic acid (20 mg, 120 mmol) in MeOH (300 mL) was added SOCl2 (28.6 g, 240 mmol) at 0° C. under nitrogen. The resulting mixture was stirred overnight then concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (2*50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to yield Compound 1 as a red oil (21.2 g). A solution of Compound 1 (19 g, 106 mmol) in dry THF (200 mL) was slowly added to a suspension of LAH (6 g, 158 mmol) in dry THF (200 mL) at 0° C. under nitrogen. The mixture was allowed to reach room temperature and was then stirred for 2 hours. Then water (6 mL) and 15% aqueous NaOH (24 mL) were added. Additional water (6 mL) was added to quench the reaction. The solids were filtered and the filter cake was washed with EtOAc several times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (hexanes:EtOAc 8:1˜5:1˜2:1) to yield Compound 2 as a yellow oil (10 g).
Methyl 3-(4-benzyloxyphenyl)propanoate To a suspension of sodium hydride in DMF (50 ml) at 0 C. was added dropwise a solution of methyl 3-(4-hydroxyphenyl)propionate (10.0 g, 55.5 mmol) and benzyl bromide (7.93 ml, 66.7 mmol) dissolved in DMF (100 ml). The mixture was stirred at room temperature for 16 hours, cooled to 0 C., quenched with aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (2*150 ml). The combined organic layers were washed with aqueous ammonium chloride (50 ml), brine (3*60 ml), dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from hexane-ethyl acetate to give the title compound (13.7 g, 91%) as a white solid.
91%
In N,N-dimethyl-formamide;
Methyl 3-(4-benzyloxyphenyl)propanoate To a suspension of sodium hydride in DMF (50 ml) at 0 C. was added dropwise a solution of methyl 3-(4-hydroxyphenyl)propionate (10.0 g, 55.5 mmol) and benzyl bromide (7.93 ml, 66.7 mmol) dissolved in DMF (100 ml). The mixture was stirred at room temperature for 16 hours, cooled to 0 C., quenched with aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (2*150 ml). The combined organic layers were washed with aqueous ammonium chloride (50 ml), brine (3*60 ml), dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from hexane-ethyl acetate to give the title compound (13.7 g, 91%) as a white solid. Anal. Calcd. for C17H18O3: C, 75.53%; H, 6.71%; Found: C, 75.48%; H, 6.68%.
88%
With potassium carbonate; In acetonitrile; for 1h;Reflux;
Methyl 3-[4-(benzyloxy)phenyl]propanoate; BnBr (4.39 g, 25.64 mmol) was added to a suspension of K2CO3 (3.55 g, 25.64 mmol) and methyl 3-(4-hydroxyphenyl)propanoate (1.54 g, 8.55 mmol) in CH3CN (40 ml_). The reaction mixture was warmed up to reflux, and allowed to react for 1 h. It was poured into H2O (120 ml_), taken up to pH = 2 with HCI (10% aqueous solution) and extracted with EtOAc (2x100 ml_). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (0?5% EtOAc/hexanes) to give 2.01 g of methyl 3-[4- (benzyloxy)phenyl]propanoate (white solid, yield: 88%).1 H NMR (CDCI3, 250 MHz) delta ppm: 7.51 -7.29 (m, 5H), 7.14 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.05 (s, 2H), 3.69 (s, 3H), 2.92 (t, J = 7.6 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H).
In acetone; for 40h;Heating / reflux;
Benzyl bromide (12.9 mL, 108 MMOL), K2C03 (15.0 G, 109 mmol) and the 3- (4- hydroxyphenyl) propionic acid methyl ester from Step 1 above were combined in acetone (300 mL) and refluxed 40 h. The crude reaction mixture was filtered and the cake washed with acetone (2 x 100 mL). The filtrate was evaporated and the residue was triturated with MeOH (50 mL, 6 mL, 4 mL) to provide the product as a solid which was used without further purification.
With potassium carbonate; In acetone; for 40h;Heating / reflux;
Benzyl bromide (12.9 mL, 108 mmol), K2CO3 (15.0 g, 109 mmol) and the 3-(4-hydroxyphenyl)propionic acid methyl ester from Step 1 above were combined in acetone (300 mL) and refluxed 40 h. The crude reaction mixture was filtered and the cake washed with acetone (2×100 mL). The filtrate was evaporated and the residue was triturated with MeOH (50 mL, 6 mL, 4 mL) to provide the product as a solid which was used without further purification.
With potassium carbonate; In acetone; for 40h;Heating / reflux;
Benzyl bromide (12.9 mL, 108 mmol), K2C03 (15.0 g, 109 mmol) and the 3- (4- hydroxyphenyl) propionic acid methyl ester from step 1 above were combined in acetone (300 mL) and refluxed 40 h. The crude reaction mixture was filtered and the cake washed with acetone (2 x 100 mL). The filtrate was evaporated and the residue was triturated with MeOH (50 mL, 6 mL, 4 mL) to provide the product as a solid, which was used without further purification.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3.5h;
A mixture of methyl 3-(4-hydroxyphenyl) propionate (1.57 g), benzyl bromide (1.24 mL), potassium carbonate (1.44 g) and N,N-dimethylformamide (30 mL) was stirred for 3.5 hours at room temperature. Water was added to the reaction solution, which was then extracted with diethyl ether. The extract was washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from hexane to obtain methyl 3-[4-(benzyloxy)phenyl] propionate (1.98 g) as colorless crystals. 1H-NMR (300MHz, CDCl3); delta 2.60 (2H, t, J=7.8Hz), 2.89 (2H, t, J=7.8Hz), 3.66 (3H, s), 5.04 (2H, s), 6.90 (2H, d, J=8.4Hz), 7.11 (2H, d, J=8.4Hz), 7.28-7.45 (5H, m)
With caesium carbonate; In dimethyl sulfoxide; at 20℃; for 2.5h;
Methyl 3-(4-((phenylmethyI)oxy)phenyl)propanoate (23.1).; A reaction mixture of methyl 3-(4-hydroxyphenyl)propanoate (commercially available, from Aldrich) (4.0 g, 22 mmol), l-(bromomethyl)benzene (3.8 g, 22 mmol (commercially available from Aldrich)) and cesium carbonate (14.30 g, 44 mmol) in DMSO (20.0 mL) was stirred at room temperature for 2.5 hours. The reaction mixture was poured into water (50.0 mL) and extracted with EtOAc (100.0 mL), and the organic layer was washed with water (3 x 30 mL) and brine (30 mL), and dried with MgSO4. The crude product was recrystalized with hexane/EtOAc (98/2) to the title compound 23.1. 1H NMR (500 MHz, CDCl3) delta ppm 2.65 (t, J=7.83 Hz, 2 H) 2.94 (t, J=7.83 Hz, 2 H) 3.71 (s, 3 H) 5.08 (s, 2 H) 6.95 (d, J=8.56 Hz, 2 H) 7.16 (d, J=8.56 Hz, 2 H) 7.34 - 7.50 (m, 5 H).
With potassium hydrogencarbonate In N,N-dimethyl-formamide at 40℃;
95.9%
Stage #1: 4-hydroxyphenylpropionic acid With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: methyl iodide In N,N-dimethyl-formamide at 0 - 20℃; for 3h;
1
Intermediate 2: Methyl 3-(4-hydroxyphenyl) propanoateTo a 1000 mL RB flask fitted with magnetic stirrer was charged 250 mL of DMF, 3-(4- Hydroxy-phenyl)-propanoic acid (25.0 g, 150.43 mmol) and K2C03 (41.58 g, 300.87 mmol). The resulting mixture was stirred at RT for 30 minutes. Methyl Iodide (25.627 g, 180.51 mmol) was added to the resulting mixture which was precooled to 0 ¾. The resulting mixture was stirred at RT for 3 h. After completion of the reaction (reaction monitored by TLC), the solvent was removed under reduced pressure and the crude mass was dissolved in ethyl acetate (250 mL). The organic layer was washed with water (250 mL), saturated sodium bicarbonate solution (250 mL X 2), and saturated brine solution (250 mL). The organic layer was dried over anhydrous Na2S04 and the solvent was removed under reduced pressure. The product was obtained as yellow color oil (26 g, Yield: 95.9 %): MS (ESI, 120 eV) : m/z = 178.9 (M- H)+; 1H NMR (300MHz, CDCI3): δ 6.97-7.00(d, 2H), 6.66-6.69(d, 2H), 4.94(s, 1 H), 3.59(s, 3H), 2.78-2.83(t, 2H), 2.50-2.55(t, 2H).
With potassium hydroxide In dimethyl sulfoxide at 40℃;
132.1
Add benzylamine (32.0 mL, 293 mmol) to methyl 3- (4-HYDROXYPHENYL) propionate (7.01 g, 38.9 mmol) and heat to 150 C FOR 18 h under nitrogen. Cool to room temperature and pour the reaction mixture into 5 N hydrochloric acid (200 mL) and extract with ethyl acetate (3 X 150 mL). Wash the ethyl acetateextracts with 5 N hydrochloric acid (200 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 9.74 g (98%) of N-benzyl-3- (4-hydroxy- PHENYL)-PROPIONAMIDE : mass spectrum (ion spray): M/Z = 256.2 (M+1) ;'H NMR (DMSO-d6) : 9.15 (s, 1H), 8.28 (t, 1H), 7.39-6. 96 (m, 7H), 6.66-6. 63 (m, 2H), 4.23 (d, 2H), 2.72 (t, 2H), 2.37 (t, 2H).
Multi-step reaction with 2 steps
1: aq. HCl / 6 h / Heating
2: H2 / 10percent Pd/C / methanol / 0.5 h / 760 Torr / Ambient temperature
With sulfuric acid In methanol
1.1 Step 1:
Step 1: Preparation of Methyl 3-(4-Hydroxyphenyl) Propionate A solution of p-hydroxycinnamic acid (32.8 g) in methanol (200 ml) is hydrogenated over 5% palladium on carbon (0.5 g) until hydrogen uptake ceases. The catalyst is removed by filtration and sulfuric acid (1 ml) added to the filtrate and the resulting solution stirred at reflux for about 18 hours. The solution is concentrated in vacuo, the residue dissolved in ether and the solution washed with water, saturated sodium bicarbonate solution, and brine. The organic solution is concentrated in vacuo to give the desired product.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0℃; for 2h;
Reference Example 1 Methyl 4-(phenylmethoxy)benzenepropanoate To a solution of ice-cooled methyl 4-hydroxybenzenepropanoate (0.70 g, 3.9 mmol), benzyl alcohol (0.48 mL, 4.7 mmol) and triphenylphosphine (1.2 g, 4.7 mmol) in tetrahydrofuran (5 mL) was added dropwise diethyl azodicarboxylate (0.73 mL, 4.7 mmol), and the mixture was stirred for 2 hours with ice cooling. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate = 17: 3) to give the title compound (0.62 g, yield 59%) as powders. 1H NMR (CDC13) delta 2.59 (2H, t, J=7.5 Hz), 2.89 (2H, t, J=7.5 Hz), 3.66 (3H, s), 5.04 (2H, s), 6.90 (2H, d, J=8.6 Hz), 7.11 (2H, d, J=8.6 Hz), 7.29-7.44 (5H, m).
59%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0℃; for 2h;
Reference Example 1 methyl 4-(phenylmethoxy)benzenepropanoate To an ice-cooled solution of methyl 4-hydroxybenzenepropanoate (0.70 g, 3.9 mmol), benzyl alcohol (0.48 mL, 4.7 mmol) and triphenylphosphine (1.2 g, 4.7 mmol) in tetrahydrofuran (5 mL) was added dropwise diethyl azodicarboxylate (0.73 mL, 4.7 mmol), and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=17:3) to give the title compound (0.62 g, yield 59%) as a powder. 1H NMR (CDCl3) delta 2.59 (2H, t, J=7.5 Hz), 2.89 (2H, t, J=7.5 Hz), 3.66 (3H, s), 5.04 (2H, s), 6.90 (2H, d, J=8.6 Hz), 7.11 (2H, d, J=8.6 Hz), 7.29-7.44 (5H, m).
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 20℃; for 12h;
To a mixture of 4-(chloromethyl)benzyl alcohol (9.66 g, 61.1 mmol), methyl 3-(4-hydroxyphenyl)propanoate (10 g, 55.5 mmol), triphenylphosphine (18.9 g, 72.1 mmol) and tetrahydrofuran (200 mL) was added dropwise diethyl azodicarboxylate (40% toluene solution, 32.8 mL, 72.3 mmol) with stirring at 0C, and the mixture was stirred at room temperature for 12 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=4/1) to give the title compound (9.89 g, yield 56%) as colorless crystals. 1H NMR (CDCl3) delta: 2.60(2H, t, J=7. 8Hz), 2.89(2H, t, J=7. 8Hz), 3.66(3H, s), 4.60(2H, s), 5.04(2H, s), 6.89(2H, d, J=8.7Hz), 7.11(2H, d, J=8.7Hz), 7.34-7.45(4H, m).
54%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 35℃; for 1h;
Reference Example 9 methyl 3-(4-[4-(chloromethyl)benzyl]oxy}-phenyl)propanoate 4-(Chloromethyl)benzyl alcohol (4.68 g), methyl 3-(4-hydroxyphenyl)propanoate (5.40 g) and triphenylphosphine (9.20 g) were dissolved in a mixed solvent of toluene (60 mL)-tetrahydrofuran (30 mL), cooled to 0C and diethyl azodicarboxylate (40% toluene solution, 15.2 g) was added dropwise with stirring. After completion of the dropwise addition, the reaction mixture was allowed to warm to room temperature and further stirred for 1 hr. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:19-1:1 in volume ratio) to give the title compound (5.19 g, yield 54%) as colorless crystals. 1H NMR (300 MHz, CDCl3) delta: 2.59(2H,t,J=7.7Hz), 2.89(2H,t,J=7.7Hz), 3.66(3H,s), 4.59(2H,s), 5.04(2H,s), 6.89(2H,d,J=8.7Hz), 7.11(2H,d,J=8.7Hz), 7.35-7.45(4H,m).
54%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 20℃;
Reference Example 180 methyl 3-(4-[4-(chloromethyl)benzyl]oxy}phenyl)propanoate 4-(Chloromethyl)benzyl alcohol (4.68 g), methyl 3-(4-hydroxyphenyl)propanoate (5.40 g) and triphenylphosphine (9.20 g) were dissolved in a mixed solvent of toluene-tetrahydrofuran (60-30 mL) and cooled to 0C, and diethyl azodicarboxylate (40% toluene solution, 15.2 g) was added dropwise with vigorously stirring. After the completion of the dropwise addition, the temperature of the reaction mixture was allowed to return to room temperature and the mixture was further stirred for 1 hr. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography with ethyl acetate-hexane (gradient of 1:19 to 1:1 by volume ratio) to give the title compound (5.19 g, yield 54%) as colorless crystals. 1H NMR (300 MHz, Chloroform-D) delta: 2.59 (2 H, t, J=7.7 Hz), 2.89 (2 H, t, J=7.7 Hz), 3.66 (3 H, s), 4.59 (2 H, s), 5.04 (2 H, s), 6.89 (2 H, d, J=8.7 Hz), 7.11 (2 H, d, J=8.7 Hz), 7.35 - 7.45 (4 H, m).
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 15h;
27
Example 27 methyl 4-[(4-benzoylphenyl)methoxy]benzenepropanoate To a solution of methyl 4-hydroxybenzenepropanoate (0.65 g, 3.6 mmol) in N,N-dimethylformamide (20 mL) were added 4-(bromomethyl)benzophenone (1.0 g, 3.6 mmol) and potassium carbonate (0.50 g, 3.6 mmol), and the mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:1) to give the title compound (1.3 g, yield 96%) as a powder. 1H NMR (CDCl3) δ 2.60 (2H, t, J=8.0 Hz), 2.90 (2H, t, J=8.0 Hz), 3.67 (3H, s), 5.17 (2H, s), 6.91 (2H, d, J=8.7 Hz), 7.13 (2H, d, J=8.7 Hz), 7.46-7.60 (5H, m), 7.79-7.84 (4H, m).
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In tetrahydrofuran; at -30℃; for 23h;
Example 38 methyl (S)-4-[(2,3-dihydro-1H-inden-1-yl)oxy]benzenepropanoate Methyl 4-hydroxybenzenepropanoate (4.1 g, 22 mmol) was dissolved in tetrahydrofuran (50 mL) and the mixture was stirred at -30C. (R)-1-Indanol (98% ee) (3.0 g, 22 mmol), 1,1'-(azodicarbonyl)dipiperidine (5.66 g, 22 mmol) and tributylphosphine (5.6 mL, 22 mmol) were added and the mixture was stirred at -30C for 23 hrs. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The mixture was concentrated under reduced pressure and the obtained oil was purified by silica gel chromatography (hexane to hexane/ethyl acetate=10:1) to give the title compound (4.4 g, yield 66%) as a yellow oil.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Step 1 3-[4-(Pyridin-4-ylmethoxy)-phenyl]-propionic acid To a solution of Methyl 3-(4-hydroxyphenyl)propanoate (0.5 g, 2.77 mmol) in dry DMF (10 ml) is added potassium carbonate (0.76 g, 5.55 mmol) followed by <strong>[73870-24-3]4-(bromomethyl)pyridine hydrobromide</strong> (0.7 g, 2.77 mmol). The reaction mixture is stirred at room temperature overnight then poured into water (80 ml) and extracted with EtOAc (40 ml). The organic phase is washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield a dark brown oil. Chromatography (SiO2, EtOAc) yields 3-[4-(Pyridin-4-ylmethoxy)-phenyl]-propionic acid methyl ester as a colourless oil; [M+H]+ 272.0
With potassium carbonate; In N,N-dimethyl-formamide;
Step 1 3-[4-(Pyridin-4-ylmethoxy)-phenyl]-propionic acid To a solution of Methyl 3-(4-hydroxyphenyl)propanoate (0.5 g, 2.77 mmol) in dry DMF (10 ml) is added potassium carbonate (0.76 g, 5.55 mmol) followed by <strong>[73870-24-3]4-(bromomethyl)pyridine hydrobromide</strong> (0.7 g, 2.77 mmol). The reaction mixture is stirred at room temperature overnight then poured into water (80 ml) and extracted with EtOAc (40 ml). The organic phase is washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield a dark brown oil. Chromatography (SiO2, EtOAc) yields 3-[4-(Pyridin-4-ylmethoxy)-phenyl]-propionic acid methyl ester as a colorless oil; [M+H]+ 272.0.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
To a solution of Methyl 3-(4-hydroxyphenyl)propanoate (0.5 g, 2.77 mmol) in dry DMF (10 ml) is added potassium carbonate (0.76 g, 5.55 mmol) followed by <strong>[73870-24-3]4-(bromomethyl)pyridine hydrobromide</strong> (0.7 g, 2.77 mmol). The reaction mixture is stirred at room temperature overnight then poured into water (80 ml) and extracted with EtOAc (40 ml). The organic phase is washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield a dark brown oil. Chromatography (SiO2, EtOAc) yields 3-[4-(Pyridin-4-ylmethoxy)-phenyl]-propionic acid methyl ester as a colorless oil; [M+H]+ 272.0.
methyl 3-(4-(2,6-dichlorobenzyloxy)-phenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89.8%
With potassium carbonate; In acetone; for 24h;Reflux;
To a solution of methyl 3-(4-hydroxyphenyl)propanoate2 (18 g, 0.1 mol) and K2CO3 (20.7 g, 0.15 mol) in acetone(200 mL), 2, 6-dichlorobenzyl chloride 1 (19.6 g, 0.1 mol)was added. The mixture was stirred vigorously, and heated to reflux for 24 h. On cooling the reaction mixture down to room temperature, the mixture was concentrated and diluted with water (200 mL) and then extracted with AcOEt (2 x 100mL). The organic layers were washed with 10% NaOH solution,dried with Na2SO4 and then concentrated in vacuo to afford 3 (30.45 g, 89.8%) as a yellow oil. 1H-NMR (300MHz, CDCl3): 2.58-2.63 (2H, t, J = 7.5 Hz, J = 8.1 Hz, -CH2), 2.88-2.93 (2H, t, J = 7.5 Hz, J=8.1 Hz, -CH2), 3.66(3H, s, -CH3), 5.23 (2H, s, -CH2), 6.93-6.96 (2H, d, J = 8.7Hz, AA?BB?, Ar-H), 7.11-7.12 (2H, d, J = 6.6 Hz, Ar-H),7.19-7.22 (1H, t, J = 6.6 Hz, Ar-H), 7.32-7.35 (2H, d,J = 8.7Hz, AA?BB?, Ar-H) ppm. EI-MS (m/z) 338 (M)+.
methyl 3-(4-((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)phenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77.6%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;
General procedure: A solution of the substituted pyridazinone and either a benzylic alcohol or benzylic bromide in dimethylformamide was treated with cesium carbonate then optionally heated to 55-80 C. After cooling to ambient temperature, the crude product was isolated as a solution in ethyl acetate, washed with water and aqueous sodium chloride then dried, filtered and concentrated. Subsequent purification by chromatography on silica afforded the title compound.
methyl 3-(4-((2-phenyloxazol-4-yl)methoxy)phenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate In N,N-dimethyl-formamide at 70℃; for 16h;
General method to prepare compounds 7 and 8.
General procedure: General method to prepare compounds 7 and 8. Cs2CO3 (1.47 g, 4.5 mmol) and the corresponding chloromethyl azoles 5 (3 mmol) were addedsequentially to a solution of methyl 3-(4-hydroxyphenyl)propanoate (0.54 g, 3 mmol) or methyl3-(3-chloro-4-hydroxyphenyl)propanoate (0.64 g, 3 mmol) in DMF (10 mL). The resultingmixture was stirred at 70 oC for 16 h. Then it was cooled to r. t. and treated with water (50 mL).The precipitate formed was filtered off, washed with water (4×20 mL) and air-dried. The esterthus obtained was used for the next step without purification. The entire amount of the esterintermediate was dissolved in MeOH (30 mL) and treated with 5% aqueous NaOH (5 mL). Theresulting mixture was heated for 3h at 60 oC. It was cooled to 5 oC and then aqueous 5% HCl (5-10 mL) was added dropwise (to bring the pH to <5). Water (50 mL) was added and theprecipitate formed was filtered off, washed with water and air-dried. Purification by flashchromatography on silica gel using an appropriate gradient of methanol in DCM furnishedcompounds 7 and 8 in yield (over two steps) shown in Tables 1 and 2.
methyl 3-(4-((3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate In N,N-dimethyl-formamide at 70℃; for 16h;
General method to prepare compounds 7 and 8.
General procedure: General method to prepare compounds 7 and 8. Cs2CO3 (1.47 g, 4.5 mmol) and the corresponding chloromethyl azoles 5 (3 mmol) were addedsequentially to a solution of methyl 3-(4-hydroxyphenyl)propanoate (0.54 g, 3 mmol) or methyl3-(3-chloro-4-hydroxyphenyl)propanoate (0.64 g, 3 mmol) in DMF (10 mL). The resultingmixture was stirred at 70 oC for 16 h. Then it was cooled to r. t. and treated with water (50 mL).The precipitate formed was filtered off, washed with water (4×20 mL) and air-dried. The esterthus obtained was used for the next step without purification. The entire amount of the esterintermediate was dissolved in MeOH (30 mL) and treated with 5% aqueous NaOH (5 mL). Theresulting mixture was heated for 3h at 60 oC. It was cooled to 5 oC and then aqueous 5% HCl (5-10 mL) was added dropwise (to bring the pH to <5). Water (50 mL) was added and theprecipitate formed was filtered off, washed with water and air-dried. Purification by flashchromatography on silica gel using an appropriate gradient of methanol in DCM furnishedcompounds 7 and 8 in yield (over two steps) shown in Tables 1 and 2.
methyl 3-(4-((3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate In N,N-dimethyl-formamide at 70℃; for 16h;
General method to prepare compounds 7 and 8.
General procedure: General method to prepare compounds 7 and 8. Cs2CO3 (1.47 g, 4.5 mmol) and the corresponding chloromethyl azoles 5 (3 mmol) were addedsequentially to a solution of methyl 3-(4-hydroxyphenyl)propanoate (0.54 g, 3 mmol) or methyl3-(3-chloro-4-hydroxyphenyl)propanoate (0.64 g, 3 mmol) in DMF (10 mL). The resultingmixture was stirred at 70 oC for 16 h. Then it was cooled to r. t. and treated with water (50 mL).The precipitate formed was filtered off, washed with water (4×20 mL) and air-dried. The esterthus obtained was used for the next step without purification. The entire amount of the esterintermediate was dissolved in MeOH (30 mL) and treated with 5% aqueous NaOH (5 mL). Theresulting mixture was heated for 3h at 60 oC. It was cooled to 5 oC and then aqueous 5% HCl (5-10 mL) was added dropwise (to bring the pH to <5). Water (50 mL) was added and theprecipitate formed was filtered off, washed with water and air-dried. Purification by flashchromatography on silica gel using an appropriate gradient of methanol in DCM furnishedcompounds 7 and 8 in yield (over two steps) shown in Tables 1 and 2.
methyl 3-(4-((2-bromopyridin-3-yl)methoxy)phenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With diethyl diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃;
21.a Synthesis of methyl 3-(4-((2-bromopyridin-3-yl)methoxy)phenyl)propanoate
A mixture of (2-bromopyridin-3-yl)methanol (0.500 g, 2.66 mM), methyl 3-(4- hydroxyphenyl)propanoate (0.479 g, 2.66 mM) , PPI13 (0.697 g, 2.66 mM) was dissolved in THF (5 ml), cooled to 0 °C. (E)-diethyl diazene-l,2-dicarboxylate (0.463 g, 2.66 mM) was added slowly into the reaction mixture. The reaction mixture was stirred at RT for overnight and THF was removed under vacuum and then reaction mass was quenched with water. The aqueous layer was extracted by ethyl acetate, combined the organic layer, dried over Na2S04, concentrated and purified by column chromatography to give the title compound. Yield: 0.60 g, 64%; JH (DMSOd6, 300 MHz): δ 8.36-8.34 (m, 1H), 7.95(d, J=6 Hz, 1H), 7.49 (q, J=4.5 Hz, J=7.2 Hz, 1H), 7.16 (d, J=8.7 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 5.07 (s, 2H), 3.56 (s, 3H), 2.77 (t, J=7.5 Hz, J=15 Hz, 2H), 2.55 (t, J=7.5 Hz, J=14.1 Hz, 2H). MS (e/z): 352 [M + 2].
A mixture of 292 g (1 mol) of 3,5-di-tert-butyl-4-hydroxyphenylpropionic acid was addedMethyl esterWith 8.8 g of catalyst p-toluenesulfonic acid was added to the reactor,Heating up to 90 C reaction.HPLC monitoring reaction,When the raw material content is less than 20%When the intermediate content reaches 80%, the reaction is terminated.Step-dealkylation The high performance liquid chromatogram is shown in Fig.1Among them, impurity 1: tr = 3.208, content of 4.14%;Impurity 3: tr = 3.493, content 1.60%;Intermediate: tr = 5.385, content 80.08%;Raw materials: tr = 12.470, content of 10.96%;Impurity 2: tr = 16.067, content 2.35%.
With oxide catalyst; at 149.84℃; for 4h;Microwave irradiation;
2 g (20 mmol) of methyl p-hydroxyphenylpropionate, 3.5 g (50 mmol) of t-butanol and 1.6 g of a catalyst were added to the reactor vessel, and magnetic stirring was carried out to control the stirring speed at 500 r/min, and the mixture was stirred for 10 min. The raw materials and the catalyst were uniformly mixed, and after uniformly mixing, the microwave heating device was turned on, and the reaction mixture was subjected to microwave irradiation at 423 K for 4 hours. After completion of the reaction, the condensing unit was turned on to cool the reaction mixture, and the mixture was extracted with 10 mL of cyclohexanol, and the catalyst was filtered off. The organic phase obtained by extraction is dried over anhydrous sodium sulfate and concentrated to dryness to give an antioxidant 3,5-methyl ester. Among them, the mixture after the reaction was sampled, and the conversion rate of methyl p-hydroxyphenylpropionate was 99.2%, and the purity of the antioxidant 3,5-methyl ester was 98.7% by quantitative analysis by gas chromatography.
methyl 3-{4-[(13,13-dimethyl-11-oxo-3,6,9,12-tetraoxatetradecan-1-yl)oxy]phenyl}propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
698 mg
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1.0h;
Cesium carbonate (10.8 g) was added to a solution of methyl 3-(4-hydroxyphenyl) propanoate (300 mg) and Example Compound 1-3 (836 mg) in N, N-dimethylformamide (8.3 mL) at 80 C. was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 90: 10-50: 50) to give the title compound (698 mg) as a colorless oil.
3-(4-(2-hydroxypropoxy)phenyl)propanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
Stage #1: 1,2-propylene cyclic carbonate; 3-(4-hydroxyphenyl)propionic acid methyl ester With potassium carbonate In neat (no solvent) at 160℃; for 1h; Inert atmosphere;
Stage #2: With sodium hydroxide Reflux;
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