| 杨柳,谢文博,孙雪,李艳杰.化学通报,2023,86(5):630-634. |
| 维布妥昔单抗关键中间体的合成工艺优化 |
| Improved Synthetic Process of the Key Intermediate of Brentuximab Vedotin |
| 投稿时间：2022-10-16 修订日期：2022-11-08 |
| DOI： |
| 中文关键词: 抗体偶联药物 维布妥昔单抗 中间体 工艺优化 |
| 英文关键词:Antibody-drug conjugates, Brentuximab vedotin, Intermediate, Process optimization |
| 基金项目:吉林省辽源市医药健康产业发展项目(202100010)资助 |
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| 中文摘要: |
| 本研究对维布妥昔单抗关键中间体(1)的合成工艺进行了改进与优化。以芴甲氧羰基-L-缬氨酸琥珀酰亚胺酯(2)为起始原料,先后经酯的氨解反应、酰胺化、Fmoc脱保护、酰胺化与酯交换反应制得目标产品1,总收率11.6%,纯度99.2%,产物结构经1H NMR, 13C NMR和HRMS表征。优化后的工艺路线具有反应条件温和、可操作性强、生产过程更安全的特点。在初步放大试验中,首步投料量达百克级别,并已完成三批工艺验证,适合于工业化生产。 |
| 英文摘要: |
| An improved synthetic process of 1, the key intermediate of antibody-drug conjugates brentuximab vedotin, was reported in this paper. Using fluorene methoxycarbonyl-L-valine succinimide ester(2) as raw material, 1 was prepared via multi-step reactions including ammonolysis of esters, amidation, Fmoc deprotection, amidation and transesterification with an overall yield of 11.6%(based on 2) and a purity of 99.2%. The target compound was identified by 1H NMR, 13C NMR and HRMS. In comparison with literature methods, this optimized process route has the advantage of mild reaction conditions, easy work-up and safe in productive process. In preliminary scale-up experiment, the first step of feeding amount reached the level of 100 grams, and three batches of process validation have been completed, which is more suitable for industrial production. |
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