Multigram Synthesis of BMS-929075, an Allosteric, Palm Site Inhibitor of HCV NS5B Replicase, Involving the Synthesis of a Highly Functionalized Benzofuran through a Telescoped Process,Organic Process Research & Development

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Multigram Synthesis of BMS-929075, an Allosteric, Palm Site Inhibitor of HCV NS5B Replicase, Involving the Synthesis of a Highly Functionalized Benzofuran through a Telescoped Process
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-05-27 , DOI: 10.1021/acs.oprd.0c00198
Daniel Smith ₁ , Subramaniam Krishnananthan ₁ , Nicholas A. Meanwell ₁ , Arvind Mathur ₁ , Jianqing Li ₂

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An efficient scale-up synthesis of 4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide (BMS-929075), an allosteric, palm site inhibitor of the HCV NS5B replicase, is described. The highlights of the process involve (a) the copper-mediated, one-pot synthesis of 2-(3-bromo-2-fluoro-6-methoxyphenyl)acetic acid (21) from regiospecifically lithiated 1-bromo-2-fluoro-4-methoxybenzene (13) and ethyl 2-bromoacetate (18); and (b) the formation of the highly functionalized benzofuran core 26 through a chromatography-free, telescoped process that proceeds via acylation and a subsequent concomitant demethylation and Boc deprotection using BBr₃, followed by an acid-catalyzed cyclization from Boc-protected 2-(3-bromo-2-fluoro-6-methoxyphenyl)-N-methylacetamide 23. This process was applied to the preparation of 110 g of high-quality BMS-929075 to enable preclinical toxicology studies.

中文翻译：

HCV NS5B复制酶的变构棕榈位抑制剂BMS-929075的多重图合成，涉及通过伸缩过程合成高度功能化的苯并呋喃

有效的按比例放大合成4-氟-2-（4-氟苯基）-N-甲基-5-（2-甲基-5-（1-（嘧啶-2-基）环丙基氨基甲酰基）苯基）苯并呋喃-3-描述了羧酰胺（BMS-929075），其是HCV NS5B复制酶的变构，手掌部位抑制剂。该方法的重点包括（a ）由区域特异性锂化的1-溴-2-氟代铜（2-）介导的一锅合成2-（3-溴-2-氟-6-甲氧基苯基）乙酸（21）。 4-甲氧基苯（13）和2-溴乙酸乙酯（18）；（b）形成高度官能化的苯并呋喃核26通过无色谱的伸缩工艺进行，该工艺通过酰化以及随后伴随的脱甲基化和使用BBr _3的Boc脱保护进行，然后由Boc保护的2-（3-溴-2-氟-6-甲氧基苯基）进行酸催化环化- ñ甲基乙酰胺23。此过程用于制备110 g高质量BMS-929075，以进行临床前毒理学研究。

更新日期：2020-06-19

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