Efficient Large-Scale Process for Tecovirimat via Reactive Distillation for the Preparation of Cycloheptatriene,Organic Process Research & Development

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Efficient Large-Scale Process for Tecovirimat via Reactive Distillation for the Preparation of Cycloheptatriene
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2023-09-15 , DOI: 10.1021/acs.oprd.3c00151
Emmanuel Mintah Bonku _{1,

2} , Hongjian Qin _{1,

2,

3} , Abdullajon Odilov _{1,

2} , Feipu Yang ₁ , Xinglong Xing ₄ , Xukun Wang ₄ , Samuel Desta Guma _{1,

2} , Jingshan Shen _{1,

2}

Affiliation

This article describes an effective process for the large-scale synthesis of tecovirimat, an antiviral drug for treating monkeypox. A key intermediate of tecovirimat, cycloheptatriene, was efficiently obtained via a reactive distillation process of 7,7-dichlorobicyclo[4.1.0]heptane to give 82% (91.38% purity by GC) on a 44.8 kg scale. This method avoided the high temperatures (490–520 °C) and low yield that detracted from the previous synthesis. After the subsequent Diels–Alder reaction, the process proceeds with one step via the condensation of anhydride and benzohydrazine intermediates to produce the final compound in a 48% overall yield, resulting in a process mass intensity of 28 kg/kg. While many issues related to the previous reported method were avoided, this improved method has been scaled up to a 60 kg batch size with a satisfactory quality of tecovirimat for clinical investigations.

中文翻译：

通过反应蒸馏制备环庚三烯的高效大规模替科维马工艺

本文描述了大规模合成替科维马（一种治疗猴痘的抗病毒药物）的有效工艺。通过 7,7-二氯双环[4.1.0]庚烷的反应蒸馏过程，有效地获得了替科维马的关键中间体环庚三烯，在 44.8 kg 规模上得到 82%（GC 纯度为 91.38%）。该方法避免了先前合成中的高温（490-520 °C）和低产率。在随后的第尔斯-阿尔德反应之后，该过程通过酸酐和苯并肼中间体的缩合进一步进行一步，以 48% 的总收率生产最终化合物，导致过程质量强度为 28 kg/kg。虽然避免了与先前报道的方法相关的许多问题，但这种改进的方法已扩大至 60 公斤批量，并且替科维马的质量满足临床研究的要求。

更新日期：2023-09-15

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