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摘要：卡非佐米(Carfilzomib,商品名Kyprolis)是新型、选择性高、不可逆的第二代蛋白酶体抑制剂。该药可以诱导骨髓瘤细胞的凋亡，且单药治疗时对MM细胞具有高效持久作用，毒性作用较小，可长期使用。该药是以一个四胜肽结合一个环氧酮基团，并以不可逆的方式结合至20s蛋白酶体的含苏氨酸N-末端活性位点达到抑制癌细胞增殖，它属于环氧甲酮四肽蛋白酶体抑制剂类抑制剂。本次实验研究主要是Carfilzomib的制备方法以及工艺优化，本文着重研究卡非佐米制备的重要中间体(R)-2-氨基-4-甲基-1-((S)-2-甲基环氧乙烷-2-基)戊-1-酮 三氟乙酸盐的合成及工艺优化。但在实际路线设计中，根据情况优化路线选择合成环氧化物(R)-2-氨基-4-甲基-1-((S)-2-甲基环氧乙烷-2-基)戊-1-酮 三氟乙酸盐，以达到较优的制备方案。最终确定了以N,O-二甲基羟基盐酸盐与Boc-L-亮氨酸为原料，分别经过氮酰化、格式反应、环氧化、去Boc保护基的制备合成路线，同时在反应过程中讨论各个步骤的操作要点以及实验温度、投料量、反应时间等因素对反应的影响，确定了较佳的工艺条件。通过一系列的工艺优化最终确定了一条具有商业可行性的方法制备低成本、高产量、高纯度、绿色安全的工艺路线。20360
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关键词：卡非佐米；蛋白酶体抑制剂；(R)-2-氨基-4-甲基-1-((S)-2-甲基环氧乙烷-2-基)戊-1-酮 三氟乙酸盐
Carfilzomib intermediates in (R)-2-amino-4-methyl-1-((S)-2-methyloxiran-2-yl)pentan-1-one trifluoroacetate acid salt Synthesis and process optimization
Abstract：Carfilzomib is a novel, highly selective, irreversible inhibitor of proteasome second generation. The drug can induce apoptosis of myeloma cells , and the single agent for the treatment of MM cells with high efficiency long-lasting effect, less toxicity, long-term use. The drug is a combination of four peptides one epoxy ketone group, and irreversibly binds to the 20s proteasome-containing N-terminal threonine active site to inhibit the proliferation of cancer cells. It belongs to the epoxy ketone tetrapeptide inhibitors of proteasome inhibitors.This experimental study synthesis process of carfilzomib and process optimization, and the paper focuses on an important intermediate in the preparation of carfilzomib (R)-2-amino-4-methyl-1-((S)-2-methyloxiran-2-yl)pentan-1-one trifluoroacetate acid salt and process optimization. Ultimately using N, O- dimethylhydroxylamine hydrochloride and Boc-L- leucine as the raw material, 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine was prepared through acylation, Grignard reaction, epoxidation, last of the Removal of the Boc protecting group. In the reaction process the best reaction condition was determined by discussing the various steps of operating points,changing feed ratio, reaction temperature and time to optimum technology conditions. Through a series of process optimization and ultimately determine low-cost, high- yield, high purity , green and safe process route with the method of preparation of a commercially viable.
Keywords：
Carfilzomib; proteasome inhibitor;
(R)-2-amino-4-methyl-1-((S)-2-methyloxiran-2-yl)pentan-1-one trifluoroacetate acid salt
目 录
1 绪论 1
1.1 Carfilzomib的简介 1
1.1.1 Carfilzomib的应用价值 2
1.1.2 Carfilzomib的相关化学信息 2
1.1.3 Carfilzomib的制备合成方法 3
1.2 本课题主要研究内容 7
1.2.1 Carfilzomib中间体环氧酮合成路线的现状 7
1.2.2 Carfilzomib中间体环氧酮合成路线改进 9
1.2.3 合成路线的确定 10
1.3 反应原理 11
1.3.1 酰化反应 11
1.3.2 格林尼亚反应 12