瑞来巴坦及其中间体的合成研究进展

doi:10.16085/j.issn.1000-6613.2024-1151

摘要/Abstract

摘要：

瑞来巴坦是新一代的β-内酰胺酶抑制剂，可以重新恢复或增强β-内酰胺类抗生素活性，从而缓解全球细菌耐药性对公众健康构成的威胁。本文介绍了7个已上市的β-内酰胺酶抑制剂，以瑞来巴坦为例引出此类原料药合成上的难点，对瑞来巴坦进行逆合成分析。根据起始原料不同，合成瑞来巴坦关键中间体11-PG的工艺路线共4条，本文阐述了以L-焦谷氨酸、(2S, 5S)-5-羟基哌啶-2-甲酸、L-谷氨酸和4-羟基-2-丁酮为起始原料合成11-PG的优缺点。重点介绍了原研默沙东公司用11-PG合成瑞来巴坦的工艺改进策略，实现规模化制备瑞来巴坦的思路。同时指出此类化合物的双手性和脲环的构建是关键，高效设计并构建手性哌啶是缩短瑞来巴坦合成路线最有效的方式，在温和条件下清洁高效地成脲环和脱Boc将成为今后的研究方向。

关键词: 瑞来巴坦, 逆合成工艺, β-内酰胺酶抑制剂, 手性哌啶, 成脲环, 脱Boc

Abstract:

Relebactam is a new class of β-lactamase inhibitors that can restore or enhance the activity of β-lactam antibiotics, thereby mitigating the threat to public health posed by bacterial resistance globally. In this paper, the seven marketed β-lactamase inhibitors are introduced, and relebactam is analysed by retrosynthetic analysis, taking relebactam as an example to introduce the difficulties in the synthesis of such active pharmaceutical ingredients (APIs). Depending on the starting materials, there are four process routes to synthesize the key intermediate 11-PG of relebactam, and the advantages and disadvantages of using L-pyroglutamic acid, (2S,5S)-5-hydroxypiperidine-2-carboxylic acid, L-glutamic acid, and 4-hydroxy-2-butanone as the starting materials are illustrated. The process improvement strategies of the original researcher Merck & Co. for the synthesis of relebactam from 11-PG are emphasized to achieve the concept of large-scale preparation of relebactam. Simultaneously, it is pointed out that the construction of the double chirality and urea ring of such compounds is the key. The efficient design and construction of chiral piperidine are the most effective manner for shortening the synthetic route of relebactam. The formation of the urea ring and the deprotection of Boc under mild conditions and in a clean and efficient manner will become the research direction in the future.

Key words: relebactam, retrosynthetic process, β-Lactamase inhibitor, chiral piperidine, formation of the urea ring, deprotection of Boc

中图分类号:

TQ463

王帅, 张得意, 李超, 乔仁忠. 瑞来巴坦及其中间体的合成研究进展[J]. 化工进展, 2025, 44(9): 5224-5233.

WANG Shuai, ZHANG Deyi, LI Chao, QIAO Renzhong. Progress on synthesis of relebactam and its key intermediates[J]. Chemical Industry and Engineering Progress, 2025, 44(9): 5224-5233.

图/表 12

图1 β-内酰胺酶抑制剂的结构式

图2 瑞来巴坦的逆合成分析

图3 以L-焦谷氨酸（1）为起始原料的关键中间体11-Cbz合成[19]

图4 默沙东2014年以(2S, 5S)-5-羟基哌啶-2-甲酸（12）为起始原料合成关键中间体11-Boc[20]

图5 默沙东2020年以(2S, 5S)-5-羟基哌啶-2-甲酸（12）为起始原料合成关键中间体11-Boc的工业化路线[27]

图6 以L-谷氨酸（23）为起始原料合成关键中间体11-Boc[21]

图7 以4-羟基-2-丁酮（31）为起始原料合成关键中间体11-Boc[24]

图8 以L-谷氨酸（23）为起始原料合成关键中间体11-Boc[32]

图9 以二氮杂双环辛烷羧酸钠盐（46）为原料合成关键中间体11-Boc[34]

图10 原研默沙东公司以11-Cbz合成瑞来巴坦的第一代工艺（1psi=6.89kPa）

图11 原研默沙东公司以11-Boc合成瑞来巴坦的第二代工艺

图12 原研默沙东公司以11-Boc合成瑞来巴坦的生产工艺

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