特拉匹韦双环吡咯烷中间体的合成新工艺
A new synthetic process of bicyclic pyrrolidine intermediate in telaprevir
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摘要: 对特拉匹韦的双环吡咯烷中间体开展合成新工艺研究:以3-氮杂双环［3.3.0］辛烷盐酸盐( 9 )为起始原料，通过亚胺基氯代、碱性消除、磺酸化、氰化和酸性水解等一系列反应得到外消旋体(3αR，6αS)-八氢环戊二烯并［c］吡咯-1-羧酸盐酸盐( 4 )。游离化合物( 4 )后，通过对亚胺进行Boc保护、化学拆分、羧基的叔丁酯化、亚胺的脱保护、成草酸盐等反应制得目标产物(1S，3αR，6αS)-八氢环戊二烯并［c］吡咯-1-羧酸叔丁酯草酸盐( 1 )，总收率约26.4%。本合成路线操作简单，光学纯度易于控制，适于进行工业化放大生产。Abstract: This paper described a practical process for the preparation of bicyclic pyrrolidine intermediate of telaprevir. The racemate, (3αR, 6αS)-octahydro-cyclopenta［c］pyrrole-1-carboxylic acid hydrochloride( 4 )was synthesized from 3-azabicyclo［3. 3. 0］nonane hydrochloride( 9 ) via chlorination of an imine, basic elimination, sulfonation, cyanation, and acid hydrolysis. The target product, (1S, 3αR, 6αS)-octahydrocyclopenta［c］pyrrole-1-carboxylic-t-butylester oxalate( 1 )was synthesized in an overall yield of about 26. 4% from the free amino acid of compound 4 via Boc protection of the imino, chemical resolution, t-butyl esterification of the carboxyl group, imino deprotection, and formation of the oxalate salt. The convergent synthetic process of compound 1 highlights the ease of operation and high stereoselectivity, and thus should be applicable for large-scale production.
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Keywords:
- telaprevir /
- bicyclic pyrrolidine /
- synthesis /
- serine protease inhibitor
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[1] Matthews SJ,Lancaster JW.Telaprevir:a hepatitis C NS3/4A protease inhibitor[J].Clin Ther,2012,34(9):1 857-1 882. [2] Ding HX,Liu KKC,Sakya SM,et al.Synthetic approaches to the 2011 new drugs[J].Bioorg Med Chem,2013,21(11):2 795-2 825. [3] Tanoury GJ,Chen M,Cochran JE,et al.Processes and intermediates:US,2010126881[P].2010-04-11. [4] Tanoury GJ,Chen M,Cochran JE.Processes and intermediates:US,2007022459[P].2007-02-22. [5] Berranger T,Demonchaux P.Process for the preparation of 6,6-dimethyl-3-azabicyclo-[3.1.0] -hexane compounds utilizing bisulfite intermediate:US,2008082508[P].2008-07-10.
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