Telescoped Two-Step Continuous-Flow Synthesis of Nevirapine Enabled by the On-Demand Generation of NaHMDS

IF 3.3 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2026-10-16 Epub Date: 2026-10-01 DOI:10.1021/acs.oprd.6c00277

Maksim Vasilev, Rajasekar Reddy Annapureddy, Chengfeng Ye, Sridhar Regati, Praveen Kumar Gajula, Jonathan Bietsch, Zhirui Wang, Jack D. Brown, Gopal Sirasani, Aravind S. Gangu, Paul Guo, Bo Qu, Chris H. Senanayake

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Abstract

A telescoped two-step fully continuous-flow process for the synthesis of nevirapine (trade name: Viramune), a key therapeutic agent for the prevention and treatment of HIV-1 infection, has been developed. The process employs, for the first time, sodium bis(trimethylsilyl)amide (NaHMDS) as a homogeneous, process-friendly base for both reaction stages and enables direct conversion of methyl 2-(cyclopropylamino)nicotinate and 2-chloro-3-amino-4-picoline to nevirapine without isolation of the cyclization intermediate. The optimized process operates with a total residence time of 10 min and delivers crude nevirapine in 91.9% overall isolated yield across two reaction steps, with a space-time yield of ∼365 g/h/L and 99.6 A% HPLC purity. Furthermore, we developed an on-demand continuous generation of NaHMDS in diglyme (up to ∼2.0 M) using a sodium packed-bed column reactor. Using on-demand generated NaHMDS, the telescoped synthesis yielded crude nevirapine in 90.7% isolated yield (∼340 g/h/L space-time yield and 99.5 A% purity), providing a scalable and cost-effective alternative to NaH applied in the current commercial synthesis.

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由NaHMDS按需生成的奈韦拉平的伸缩两步连续流合成

摘要建立了一种两步全连续流程合成奈韦拉平（商品名：Viramune）的缩缩式工艺。奈韦拉平是预防和治疗HIV-1感染的关键药物。该工艺首次采用双（三甲基硅基）酰胺钠（NaHMDS）作为两个反应阶段的均质，工艺友好的碱，并且可以直接将2-（环丙胺）烟酸甲酯和2-氯-3-氨基-4-吡啶转化为奈维拉平，而无需分离环化中间体。优化后的工艺总停留时间为10 min，两个反应步骤的总分离率为91.9%，空时产率为~ 365 g/h/L，高效液相色谱纯度为99.6 a %。此外，我们开发了一种按需连续生成NaHMDS在二磷酸（高达~ 2.0 M）使用钠填充床柱反应器。使用按需生成的NaHMDS，伸缩式合成以90.7%的分离收率（约340 g/h/L时空收率和99.5%纯度）获得奈韦拉平粗品，为目前商业合成中应用的NaH提供了一种可扩展且具有成本效益的替代品。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.