当前位置: X-MOL 学术Synthesis › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Practical Early Development Synthesis of Nav1.7 Inhibitor GDC-0310
Synthesis ( IF 2.2 ) Pub Date : 2020-06-22 , DOI: 10.1055/s-0040-1707859
Andreas Stumpf 1 , Frédéric St-Jean 1 , David Lao , Zhigang Ken Cheng , Remy Angelaud , Francis Gosselin
Affiliation  


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 SN2 displacement approach to connect two intermediates: a chiral benzyl alcohol and a piperidine. The synthesis of the piperidine building block proceeded via a regioselective SNAr 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 SN2 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:

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。

更新日期:2020-06-23
down
wechat
bug