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一种基于硫酰氯的连续流反应——恩曲他滨和拉米夫定新合成路线中关键中间体的合成。

A Continuous Flow Sulfuryl Chloride-Based Reaction-Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine.

作者信息

de Souza Juliana M, Berton Mateo, Snead David R, McQuade D Tyler

机构信息

Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, Virginia 23284-3068, United States.

Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos-SP, Brazil.

出版信息

Org Process Res Dev. 2020 Oct 16;24(10):2271-2280. doi: 10.1021/acs.oprd.0c00146. Epub 2020 May 13.

DOI:10.1021/acs.oprd.0c00146
PMID:33100813
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7574626/
Abstract

We demonstrate a continuous two-step sequence in which sulfenyl chloride is formed, trapped by vinyl acetate, and chlorinated further via a Pummerer rearrangement. These reactions produce a key intermediate in our new approach to the oxathiolane core used to prepare the antiretroviral medicines emtricitabine and lamivudine. During batch scale-up to tens of grams, we found that the sequence featured a strong exotherm and evolution of hydrogen chloride and sulfur dioxide. Keeping gaseous byproducts in solution and controlling the temperature led to better outcomes. These reactions are ideal candidates for implementation in a continuous mesoscale system for the sake of superior control. In addition, we found that fast reagent additions at controlled temperatures decreased byproduct formation. Herein we discuss the flow implementation and the final reactor design that led to a system with a 141 g/h throughput.

摘要

我们展示了一个连续的两步反应序列，其中次磺酰氯形成后被乙酸乙烯酯捕获，然后通过普默勒重排进一步氯化。这些反应在我们用于制备抗逆转录病毒药物恩曲他滨和拉米夫定的氧硫杂环戊烷核心的新方法中产生了一个关键中间体。在批量放大到几十克的过程中，我们发现该反应序列具有强烈的放热现象，并伴有氯化氢和二氧化硫的释放。将气态副产物保留在溶液中并控制温度可获得更好的结果。为了实现更好的控制，这些反应是在连续中试规模系统中实施的理想选择。此外，我们发现，在控制温度下快速添加试剂可减少副产物的形成。在此，我们讨论了流动实施和最终反应器设计，该设计导致了一个吞吐量为141 g/h的系统。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/75c08bf0a3b8/op0c00146_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/7e492c6404cc/op0c00146_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/14ebc64aa684/op0c00146_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/1ac37c599e21/op0c00146_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/27541d87dd01/op0c00146_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/b78c663312ce/op0c00146_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/f43130f273eb/op0c00146_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/beff4da448fe/op0c00146_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/75c08bf0a3b8/op0c00146_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/7e492c6404cc/op0c00146_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/14ebc64aa684/op0c00146_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/1ac37c599e21/op0c00146_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/27541d87dd01/op0c00146_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/b78c663312ce/op0c00146_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/f43130f273eb/op0c00146_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/beff4da448fe/op0c00146_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7696/7574626/75c08bf0a3b8/op0c00146_0005.jpg

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本文引用的文献

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2
Impact of continuous flow chemistry in the synthesis of natural products and active pharmaceutical ingredients.连续流动化学在天然产物及活性药物成分合成中的影响
An Acad Bras Cienc. 2018;90(1 Suppl 2):1131-1174. doi: 10.1590/0001-3765201820170778.
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Twenty-Five Years of Lamivudine: Current and Future Use for the Treatment of HIV-1 Infection.
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J Acquir Immune Defic Syndr. 2018 Jun 1;78(2):125-135. doi: 10.1097/QAI.0000000000001660.
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The Hitchhiker's Guide to Flow Chemistry ∥.《流动化学漫游指南》。
Chem Rev. 2017 Sep 27;117(18):11796-11893. doi: 10.1021/acs.chemrev.7b00183. Epub 2017 Jun 1.
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Continuous-flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients.连续流技术——一种用于安全制造活性药物成分的工具。
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Continuous flow organic synthesis under high-temperature/pressure conditions.在高温/高压条件下的连续流动有机合成。
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Emtricitabine (FTC) for the treatment of HIV infection.
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Emtricitabine: an antiretroviral agent for HIV infection.恩曲他滨：一种用于治疗HIV感染的抗逆转录病毒药物。
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