B细胞淋巴瘤因子-2抑制剂维耐托克的合成新方法

A New Method for the Synthesis of Venetoclax,a B-cell Lymphoma Factor-2(BCL-2)Inhibitor

本研究设计一条新路线合成B细胞淋巴瘤因子-2(BCL-2)抑制剂维耐托克(ABT-199)。4-氟水杨酸甲酯(2)和1-叔丁氧羰基哌嗪(3)在相转移催化剂四丁基溴化铵(TBAB)和盐酸的作用下取代、脱保护得到化合物2-羟基-4-(哌嗪-1-基)苯甲酸甲酯盐酸盐(4)。3,3-二甲基-1-环己烷酮(10)在DMF和三氯氧磷作用下取代、Vilsmeier-Haack“一锅法”生成化合物2-氯-4,4-二甲基环己-1-烯-1-甲醛(11)。11与4-氯苯硼酸(12)无需过渡金属在TBAB和微波条件下经Suzuki-Miyaura反应制得化合物4′-氯-5,5-二甲基-3,4,5,6-四氢-[1,1′-联苯]-2-甲醛(5)。5与4在选择性还原剂三乙酰氧基硼氢化钠(STAB)作用下经还原氨化反应得到甲基4-[4-[(4′-氯-5,5-二甲基-3,4,5,6-四氢-[1,1′-联苯]-2-基)甲基]哌嗪-1-基]-2-羟基苯甲酸甲酯(6)。6与5-溴-4-氮杂吲哚(7)在碘化亚铜和碳酸铯作用下取代得到[2–(1H-吡咯并[2,3-b]吡啶-5-基)氧基]-4-[4-[4′-氯-5,5-二甲基3,4,5,6-四氢(1,1′-联苯基)-2-基)甲基]哌嗪-1-基]苯甲酸(8)。8与3-硝基-4-[[(四氢-2H-吡喃-4-基)甲基]氨基]苯磺酰胺(9)在酰化催化剂4-二甲氨基吡啶(DMAP)和脱水剂二环己基碳二亚胺(DCC)作用下酰胺化得到目标产物维耐托克(1),总收率49.7%(以2计)。本法中由2和3制备化合物4的方法,由11和12制备5的方法均未见文献报道。

A novel synthetic route for Venetoclax(ABT-199),a B-cell lymphoma factor-2(BCL-2)inhibitor was reported.Methyl 4-fluorosalicylate(2)reacted with 1-tert-butoxycarbonyl piperazine(3)to give 2-hydroxy-4-(piperazine-1-yl)benzoate hydrochloride(4)by catalyst TBAB and hydrochloric acid.2-chloro-4,4-dimethylcyclohexanone-1-ene-1-formaldehyde(11)was synthesized from 3,3-dimethyl-1-cyclohexanone(10),DMF and phosphorus oxychloride by“One-pot”which was reacted by substitution and Vilsmeier-Haack at the same time.Compound 4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-formaldehyde(5)was synthesized by Suzuki-Miura reaction between 11 and 4-chlorophenylboric acid(12)with the catalyst TBAB and microwave.Methyl4-[4-[(4′-chloro-4′-chloro-5,5-dimethyl-3,4,5,5,5,5,6-tetrahydro-[1,1′-biphphphphen]-2-methyl)methyl]piperazine-piperazine-1-yl]-2-hydroxbenzoate methyl ester(6)was obtained by the reduction and ammoniation of 5 and 4 under the action of selective reductant sodium triacetoxyborohydride(STAB).6 and 5-bromo-1H-pyrrolo[2,3-b]pyridine(7)reacted via cuprous iodide and cesium carbonate to obtain(2-(1H-(1H-pyrrole[1 H-pyrrole[2,1,pyrrole 4-(4-(4′-chlorine)-5,5,5,6-tetrahydro(1,1′-biphenyl)-2-methyl)piperazine-1-yl)benzoic acid(8).Compound 8 was amidated with 3-nitro-4-[(tetrahydro-2H-pyran-4-yl)methyl]amino]benzenesulfonamide(9)via DMAP and DCC to obtain the target product Venetoclax with a total yield of 49.7%(based on 2).In this process,compound 4 from 2 and 3 and compound 5 from 11 and 12 have not yet been reported in literatures.