抗肿瘤药物来那度胺的合成方法

Synthetic method of anticancer drugs lenalidomide

2-甲基-3-硝基苯甲酸甲酯(1)与卤化剂反应,制得2-卤甲基-3-硝基苯甲酸甲酯(2)。L-谷氨酰胺(3)经酯化反应制得谷氨酰胺甲酯(4),在Boc试剂、偶联剂和催化剂的作用下,进行分子内关环,制得Boc保护的3-氨基哌啶-2,6-二酮(7),与2-卤甲基-3-硝基苯甲酸甲酯(2)在弱碱的条件下合环,经硝基还原反应,得到来那度胺(9)。本方法反应条件较温和,反应步骤简单易行,降低了生产成本,并且提高了产率,总收率约为40%。

2-Halomethyl-3-nitrobenzoate （2） was obtained from 2-methyl-3-nitrobenzoate （ 1 ） via haloge- nation reactions. Glutamine methyl ester （4） was obtained from L-glutamine （3） via esterification,3-ami- no-piperidine-2,6-dione （7） was obtained from intramolecular cyclization under Boc reagent,condensing agent and catalyst. Compound （2） and （7） cyclization under weak base condensation, followed by nitro- reduction to give lenalidomide （9）. This synthetic method can shorten reaction steps, reduce production costs and improve yield to about 40% in a mild reaction condition.