|
【结 构 式】 
|
【药物名称】Rivoglitazone, R-106056, CI-1037, CS-011 【化学名称】(±)-5-[4-(6-Methoxy-1-methylbenzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione 【CA登记号】185428-18-6 【 分 子 式 】C20H19N3O4S 【 分 子 量 】397.45613 |
【开发单位】Sankyo (Originator) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Sensitizers, PPARgamma Agonists, Thiazolidinediones (Glitazones) |
合成路线1
The intermediate phenylenediamine (VI) was prepared as follows. Reaction of 5-chloro-2-nitroaniline (I) with sodium methoxide afforded 5-methoxy-2-nitroaniline (II), which was subsequently converted to the N-Boc derivative (III). Methylation of (III) with iodomethane and NaH, followed by acidic treatment of the resulting N-methyl carbamate (IV), produced the N-methyl aniline (V). The nitro group of (V) was then reduced with the combination SnCl2-NaBH4 to furnish the diamine (VI).
| 【1】 Fujita, T.; Wada, K.; Oguchi, M.; Yanagisawa, H.; Fujimoto, K.; Fujiwara, T.; Horikoshi, H.; Yoshioka, T. (Sankyo Co., Ltd.); Benzimidazole derivs., their preparation and their therapeutic use. CA 2177858; EP 0745600; JP 1997295970; JP 2000001487; US 5886014 . |
| 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) | 15709 | 5-chloro-2-nitrophenylamine; 5-chloro-2-nitroaniline | 1635-61-6 | C6H5ClN2O2 | 详情 | 详情 |
| (II) | 42920 | 5-methoxy-2-nitrophenylamine; 5-methoxy-2-nitroaniline | 16133-49-6 | C7H8N2O3 | 详情 | 详情 |
| (III) | 46874 | tert-butyl 5-methoxy-2-nitrophenylcarbamate | C12H16N2O5 | 详情 | 详情 | |
| (IV) | 46875 | tert-butyl 5-methoxy-2-nitrophenyl(methyl)carbamate | C13H18N2O5 | 详情 | 详情 | |
| (V) | 46876 | 5-methoxy-N-methyl-2-nitroaniline; N-(5-methoxy-2-nitrophenyl)-N-methylamine | C8H10N2O3 | 详情 | 详情 | |
| (VI) | 46877 | N-(2-amino-5-methoxyphenyl)-N-methylamine; 4-methoxy-N(2)-methyl-1,2-benzenediamine | C8H12N2O | 详情 | 详情 |
合成路线2
Alkylation of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione (VII) with methyl bromoacetate (VIII) in the presence of cesium carbonate gave rise to the aryloxy acetate (IX). Subsequent cleavage of the N-trityl protecting group of (IX) was achieved by treatment with HOAc in aqueous dioxan at 80 C. The resulting ester (X) was finally condensed with phenylenediamine (VI) to produce the target benzimidazole.
| 【2】 Fujita, T.; Fujiwara, T.; Izumi, T. (Sankyo Co., Ltd.); Hydrochloride of fused-heterocycle cpd.. EP 1180519; JP 2001039976; US 2002111373; WO 0071540 . |
| 【1】 Fujita, T.; Wada, K.; Oguchi, M.; Yanagisawa, H.; Fujimoto, K.; Fujiwara, T.; Horikoshi, H.; Yoshioka, T. (Sankyo Co., Ltd.); Benzimidazole derivs., their preparation and their therapeutic use. CA 2177858; EP 0745600; JP 1997295970; JP 2000001487; US 5886014 . |
| 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) | 46877 | N-(2-amino-5-methoxyphenyl)-N-methylamine; 4-methoxy-N(2)-methyl-1,2-benzenediamine | C8H12N2O | 详情 | 详情 | |
| (VII) | 18803 | 5-(4-hydroxybenzyl)-3-trityl-1,3-thiazolidine-2,4-dione | C29H23NO3S | 详情 | 详情 | |
| (VIII) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
| (IX) | 46878 | methyl 2-[4-[(2,4-dioxo-3-trityl-1,3-thiazolidin-5-yl)methyl]phenoxy]acetate | C32H27NO5S | 详情 | 详情 | |
| (X) | 46879 | methyl 2-[4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]acetate | C13H13NO5S | 详情 | 详情 |