Published as part of the Special Topic Synthesis in Industry

Abstract

The concise early development route to the Nav1.7 inhibitor GDC-0310 is described. The active pharmaceutical ingredient (API) contains one stereocenter, which was obtained with high enantiomeric excess (>99:1) by using an S_N2 displacement approach to connect two intermediates: a chiral benzyl alcohol and a piperidine. The synthesis of the piperidine building block proceeded via a regioselective S_NAr reaction on 1-chloro-2,4-difluorobenzene by N-Boc-4-piperidinemethanol, followed by installation of the methyl ester group by electrophilic aromatic bromination and a palladium-catalyzed alkoxycarbonylation. A subsequent Suzuki–Miyaura cross-coupling reaction was then telescoped directly into cleavage of the Boc group to provide the advanced piperidine intermediate. The key feature of the synthesis is the highly selective S_N2 displacement of the chiral mesylate of (R)-1-(3,5-dichlorophenyl)ethan-1-ol with the piperidine intermediate, followed by a chiral purity upgrade via the corresponding (1S)-(+)-camphorsulfonic acid salt. After standard hydrolysis of the methyl ester and CDI mediated amidation to couple the resulting acid with methanesulfonamide, enantiomerically pure GDC-0310 was obtained in high overall yield (37%) on a 6.5 kilogram scale.

中文翻译：

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Nav1.7抑制剂GDC-0310的实用早期开发合成

作为行业专题综合报告的一部分发布

抽象

描述了向Nav1.7抑制剂GDC-0310的简明早期开发路线。活性药物成分（API）包含一个立体中心，该立体中心通过使用S _N 2置换方法连接两个中间体（手性苄醇和哌啶）而获得高对映体过量（> 99：1）。通过区域选择性小号进行哌啶积木的合成_Ñ由Ar反应于1-氯-2,4-二氟苯Ñ-Boc-4-哌啶甲醇，然后通过亲电芳族溴化反应和钯催化的烷氧羰基化反应安装甲酯基。随后，直接将随后的Suzuki-Miyaura交叉偶联反应伸缩到Boc基团的裂解中，以提供高级的哌啶中间体。合成的关键特征是（R）-1-（3,5-二氯苯基）乙-1-醇的手性甲磺酸酯与哌啶中间体的高选择性S _N 2取代，然后通过对应的（1 S）-（+）-樟脑磺酸盐。在甲酯的标准水解和CDI介导的酰胺化反应中，将所得的酸与甲磺酰胺偶合后，以6.5千克的规模以高总收率（37％）得到对映体纯的GDC-0310。