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【结 构 式】 
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【分子编号】10303 【品名】(2R)-2-Hydroxy-2-phenylethanoic acid; R-(-)-Mandelic acid 【CA登记号】611-71-2 |
【 分 子 式 】C8H8O3 【 分 子 量 】152.14972 【元素组成】C 63.15% H 5.3% O 31.55% |
合成路线1
该中间体在本合成路线中的序号：(XI)3) The methylation of 3-(2-oxo-1,2-dihydroquinolin-4-yl)-(R,S)-alanine (IX) with SOCl2 and methanol yields the corresponding methyl ester (X), which is submitted to optical resolution with D-(-)-mandelic acid, affording adducts (XII) and (XIII). The hydrolytic treatment of (XII) and (XIII) with HCl and propylene oxide finally yields isomers (VIIr) and (VIIs), already obtained. Racemic OPC-12759 can also be resolved into its optical isomers by treatment with brucine and fractionated crystallization.
| 【1】 Morita, S.; Yamasaki, K.; Shimizu, T.; Uchida, M.; Otsubo, K.; Kanbe, T.; Synthesis and antiulcer activity of optical isomers of 2-(4-chlorobenzoy lamino)-3-[2(1H)-quinolinon-4-yl]propionic acid (rebamipide). Chem Pharm Bull 1991, 39, 11, 2906. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII-S) | 10299 | (2S)-2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid | C12H12N2O3 | 详情 | 详情 | |
| (VIIR) | 10306 | (2R)-2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid | C12H12N2O3 | 详情 | 详情 | |
| (IX) | 10301 | 2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid | C12H12N2O3 | 详情 | 详情 | |
| (X) | 10302 | methyl 2-amino-3-(2-chloro-4-quinolinyl)propanoate | C13H13ClN2O2 | 详情 | 详情 | |
| (XI) | 10303 | (2R)-2-Hydroxy-2-phenylethanoic acid; R-(-)-Mandelic acid | 611-71-2 | C8H8O3 | 详情 | 详情 |
| (XII) | 10304 | compound with hydroxy-phenyl-acetic acid; 2-Amino-3-(2-oxo-1,2-dihydro-quinolin-4-yl)-propionic acid methyl ester | C13H14N2O3.C8H8O3 | 详情 | 详情 | |
| (XIII) | 10305 | 2-Amino-3-(2-oxo-1,2-dihydro-quinolin-4-yl)-propionic acid methyl ester; compound with hydroxy-phenyl-acetic acid | C13H14N2O3.C8H8O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)4) The reaction of racemic omeprazole (VII) with formaldehyde in dichloromethane gives, after crystallization in acetonitrile, 1-(hydroxymethyl)-6-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinylmethylsulfinyl)-1H-benzimidazole (VIII), which is treated with SOCl2 in dichloromethane to afford, after crystallization in acetonitrile, the corresponding chloromethyl derivative (IX). The condensation of (IX) with (R)-2-hydroxy-2-phenylacetic acid (X) by means of NaOH and tetrabutylammonium hydrogen sulfate in water gives the corresponding ester (XI) as a diastereomeric mixture, which is resolved by reverse phase chromatography. Finally, the suitable isomer is hydrolyzed to esomeprazole by treatment with NaOH in methanol. (Scheme 27259802a) Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water. (Schemes 27259801a and 27259802a)
| 【1】 Castañer, R.M.; Castañer, J.; Graul, A.; Esomeprazole Magnesium. Drugs Fut 1999, 24, 11, 1178. |
| 【2】 Alminger, T.B.; Bergman, R.A.; Bundgaard, H.; Lindberg, P.L.; Sunden, G.E. (Hassle Lakemedel AB); Benzimidazole derivs.. AU 8783302; EP 0279149; EP 0332647; EP 0510719; JP 1990500744; US 5215974; WO 8803921 . |
| 【3】 Von Unge, S. (AstraZeneca plc); Novel ethoxycarbonyloxymethyl derivs. of substd. benzimidazoles. WO 9532957 . |
| 【4】 Lindberg, P.L.; Von Unge, S. (AstraZeneca plc); Optically pure salts of pyridinylmethyl sulfinyl-1H-benzimidazole cpds.. EP 1020460; EP 1020461; US 5693818; US 5714504; WO 9427988 . |
| 【5】 Bergstrand, P.J.A.; Lovgren, K.I. (AstraZeneca plc); Multiple unit tableted dosage form I. WO 9601623 . |
| 【6】 Mattson, A.; Hogberg, J.-A.; Ioannidis, P. (AstraZeneca plc); Process for the preparation of a magnesium salt of a substd. sulphinyl heterocycle. JP 2000509067; WO 9741114 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 29926 | 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole; 5-methoxy-1H-benzimidazol-2-yl (4-methoxy-3,5-dimethyl-2-pyridinyl)methyl sulfoxide | 73590-58-6 | C17H19N3O3S | 详情 | 详情 |
| (VIII) | 29928 | (6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazol-1-yl)methanol | C18H21N3O4S | 详情 | 详情 | |
| (IX) | 29929 | 1-(chloromethyl)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole; 1-(chloromethyl)-6-methoxy-1H-benzimidazol-2-yl (4-methoxy-3,5-dimethyl-2-pyridinyl)methyl sulfoxide | C18H20ClN3O3S | 详情 | 详情 | |
| (X) | 10303 | (2R)-2-Hydroxy-2-phenylethanoic acid; R-(-)-Mandelic acid | 611-71-2 | C8H8O3 | 详情 | 详情 |
| (XI) | 29930 | (6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazol-1-yl)methyl (2R)-2-hydroxy-2-phenylethanoate | C26H27N3O6S | 详情 | 详情 | |
| (XII) | 29931 | (6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazol-1-yl)methyl (2R)-2-hydroxy-2-phenylethanoate | C26H27N3O6S | 详情 | 详情 | |
| (XIII) | 29927 | 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole; 5-methoxy-1H-benzimidazol-2-yl (4-methoxy-3,5-dimethyl-2-pyridinyl)methyl sulfoxide | C17H19N3O3S | 详情 | 详情 |