该文报道了新型凝血酶抑制剂阿加曲班关键中间体 (2R,4R) -4- 甲基 -2- 哌啶甲酸乙酯 (1) 的合成新工艺。以 4- 甲基环己酮 (2) 为起始原料，与盐酸羟胺反应制得 4- 甲基环己酮肟 (3)，3 在对甲苯磺酸 / 二氯化锌作用下经 Beckmann 重排生成 5- 甲基氮杂环庚 -2- 酮 (4)，4 经溴化铜溴代得到 3- 溴 -5- 甲基氮杂环庚 -2- 酮 (5)，5 经 Favorski 重排制得 4- 甲 基 -2- 哌啶甲酸乙酯 (6)，6 经减压分馏获得反 -4- 甲基 -2- 哌啶甲酸乙酯 (7)，最后 7 经 L-(+)- 酒石酸拆分，得目标产品 1，纯度 99.58％，光学纯度 99.13％，总收率约 9％(以 2 计 )。改进后的新工艺操作简便，生产过程更安全，适合工业化生产。
Abstract
A novel synthetic process of ethyl (2R,4R)-4-methylpiperidine-2-carboxylate(1), the key intermediate of thrombin inhibitor argatroban, was reported in this paper. 4-Methylcyclohexan-1-one(2) was reacted with hydroxylamine hydrochloride to obtain 4-methylcyclohexan-1-one oxime(3). Compound 3 transformed into 5-methylazepan-2-one(4) through Beckmann rearrangement under p-toluenesulfonamide(p-TSA)/ZnCl2 condition. Compound 4 was treated with cupric bromide to prepare 3-bromo-5-methylazepan-2-one(5). Ethyl 4-methylpiperidine- 2-carboxylate(6) was available from 5 via Favorski rearrangement on exposure to sodium ethoxide. Fractionation of 6 under reduced pressure to separate ethyl trans-4-methylpiperidine-2-carboxylate(7). Finally, the target compound 1 was obtained from 7 through resolution by L-(+)-tartaric acid with a purity of 99.58％, a chiral purity of 99.13％ and an overall yield of about 9％(based on 2). The new route was easy to operate, safe in production process, which was suitable for industrial production.
关键词
阿加曲班 /
凝血酶抑制剂 /
(2R,4R)-4- 甲基 -2- 哌啶甲酸乙酯 /
中间体 /
合成工艺
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Key words
argatroban /
thrombin inhibitor /
ethyl (2R,4R)-4-methylpiperidine-2-carboxylate /
intermediate /
synthetic process
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