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【结 构 式】 
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【分子编号】29926 【品名】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 【CA登记号】73590-58-6 |
【 分 子 式 】C17H19N3O3S 【 分 子 量 】345.42228 【元素组成】C 59.11% H 5.54% N 12.16% O 13.9% S 9.28% |
合成路线1
该中间体在本合成路线中的序号：(VII)Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. 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.
| 【1】 Isaksson, R.; Pettersson, C.; Erlandsson, P.; Marle, I.; Pettersson, G.; Separation of enantiomers using cellulase (CBH I) silica as a chiral stationary phase. J Chromatogr 1991, 586, 2, 233. |
| 【2】 Hakusui, H.; Yamazaki, H.; Tanaka, M.; Direct HPLC separation of enantiomers of pantoprazole and other benzimidazole sulfoxides using cellulose-based chiral stationary phases in reversed-phase mode. Chirality 1995, 7, 8, 612. |
| 【3】 Isaksson, R.; Lorentzon, P.; Lindberg, P.; Erlandsson, P.; Resolution of the enantiomers of omeprazole and some of its analogues by liquid chromatography on a trisphenylcarbamoylcellulose-based stationary phase. The effect of the enantiomers of omeprazole on gastric glands. J Chromatogr 1990, 532, 305. |
| 【4】 Balmer, K.; Persson, B.-A.; Lagerstrom, P.-O.; Stereoselective effects in the separation of enantiomers of omeprazole and other substituted benzimidazoles on different chiral stationary phases. J Chromatogr 1994, 660, 1-2, 269. |
| 【5】 Castañer, R.M.; Castañer, J.; Graul, A.; Esomeprazole Magnesium. Drugs Fut 1999, 24, 11, 1178. |
| 【6】 Steiner, U.; Lindner, W.; Uray, G.; (S,S)-Diphenylethylethanediamine derivatives as chiral selectors. II. Gasparrini-type bound chiral stationary phase with high enantioselectivity for naphthylamides. J Chromatogr 1991, 553, 1-2, 373. |
| 【7】 Isaksson, R.; Pettersson, G.; Marle, I.; Jonsson, S.; Pettersson, C.; Chiral stationary phases based on intact and fragmented cellobiohydrolase I immobilized on silica. J Chromatogr 1993, 648, 2, 333. |
| 【8】 Niederreiter, K.S.; Maier, N.M.; Spitaler, M.M.; Uray, G.; Diphenylethanediamine derivatives as chiral selectors. VIII. Influence of the second amido function on the high-performance liquid chromatographic enantioseparation characteristics of (N-3,5-dinitrobenzoyl)-diphenylethanediamine based chiral stationary ph. J Chromatogr 1998, 799, 1-2, 67. |
| 【9】 Uray, G.; Kleidernigg, O.P.; Maier, N.M.; Lindner, W.; Diphenylethanediamine (DPEDA) derivatives as chiral selectors: IV. A comparison of 3,5-dinitrobenzoylated (S,S)- and (S,R)-DPEDA-derived chiral stationary phases with Pirkle's standard (R)-phenylglycine-derived phase in normal phase HPLC. Chirality 1994, 6, 2, 116. |
| 【10】 Junggren, U.K.; Sjöstrand, S.E. (Hässle Läkemedel AB); Substd. pyridylsulfinylbenzimidazoles having gastric acid secretion properties, pharmaceutical preparations containing same, and intermediates for their preparation. CA 1129417; EP 0005129; US 4255431 . |
| 【11】 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 . |
| 【12】 Taylor, S.; Holt, R.; Graham, D.; Lindberg, P. (AstraZeneca plc); Enantioselective preparation of pharmaceutically active sulfoxides by bioreduction. WO 9617077 . |
| 【13】 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 . |
| 【14】 Von Unge, S. (AstraZeneca plc); A process for the optical purification of enantiomerically enriched benzimidazole derivs.. WO 9702261 . |
| 【15】 Holt, R.; Lindberg, P.; Taylor, S.; Reeve, C. (AstraZeneca plc); Enantioselective preparation of pharmaceutically active sulfoxides by biooxidation. WO 9617076 . |
| 【16】 Bergstrand, P.J.A.; Lovgren, K.I. (AstraZeneca plc); Multiple unit tableted dosage form I. WO 9601623 . |
| 【17】 Von Unge, P.O.S.; Larsson, E.M.; Cotton, H.K.; Sorensen, H.; Stenhede, U.J. (AstraZeneca plc); Process for synthesis of substd. sulphoxides. WO 9602535 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 18785 | (4-methoxy-3,5-dimethyl-2-pyridinyl)methanol | C9H13NO2 | 详情 | 详情 | |
| (II) | 16521 | 2-(chloromethyl)-3,5-dimethyl-4-pyridinyl methyl ether; 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine; 2-Chloromethyl-3,5-dimethyl-4-methoxypyridine | 86604-75-3 | C9H12ClNO | 详情 | 详情 |
| (III) | 29922 | 2-amino-4-methoxyphenylamine; 4-methoxy-1,2-benzenediamine | 102-51-2 | C7H10N2O | 详情 | 详情 |
| (IV) | 29923 | o-Ethylxanthic acid potassium salt; Potassium ethyl xanthogenate; potassium 1-(carbodithioatooxy)ethane | 140-89-6 | C3H5KOS2 | 详情 | 详情 |
| (V) | 29924 | 5-Methoxy-1H-benzimidazol-2-ylhydrosulfide; 2-Mercapto-5-methoxybenzimidazole; 5-Methoxy-1H-benzimidazole-2-thiol; 5-Methoxy-2-mercaptbenzimidazole; 5-Methoxy-2-Benzimidazolethiol | 37052-78-1 | C8H8N2OS | 详情 | 详情 |
| (VI) | 29925 | 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfanyl]-1H-benzimidazole; 2-[[(5-methoxy-1H-benzimidazol-2-yl)sulfanyl]methyl]-3,5-dimethyl-4-pyridinyl methyl ether | 73590-85-9 | C17H19N3O2S | 详情 | 详情 |
| (VII) | 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 |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(VI)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 |