Alternate end-game strategies towards Nirmatrelvir synthesis: Defining a continuous flow process for the preparation of an anti-COVID drug

被引：2

作者：

Veeramani, Karuna ^{[1
]}

Shinde, Manish ^{[1
]}

Eda, Vishnuvardhana Vema Reddy ^{[2
]}

Darapaneni, Bala Chennaiah ^{[2
]}

Hindupur, Rama Mohan ^{[3
]}

Madarapu, Srinivasa Rao ^{[3
]}

Sen, Saikat ^{[2
]}

Oruganti, Srinivas ^{[2
]}

机构：

[1] Univ Hyderabad Campus, Dr Reddys Inst Life Sci, Chem Proc Automation Lab 10X, Hyderabad 500046, Telangana, India

[2] Univ Hyderabad Campus, Dr Reddys Inst Life Sci, Ctr Proc Res & Innovat, Hyderabad 500046, Telangana, India

[3] Aurigene Pharmaceut Serv Ltd, JP Nagar Rd, Hyderabad 500049, Telangana, India

来源：

TETRAHEDRON LETTERS | 2023年 / 116卷

关键词：

Nirmatrelvir; Continuous flow synthesis; Mixed anhydride; Amidation; Nitrile formation; 1-Propanephosphonic acid anhydride (T3P); INGREDIENT;

D O I：

10.1016/j.tetlet.2023.154344

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

Scalable alternate end-game strategies for the synthesis of the anti-COVID drug molecule Nirmatrelvir (1, PF-07321332) have been described. The first involves a direct synthesis of 1 via amidation of the carboxylic acid 7 (suitably activated as a mixed anhydride with either pivaloyl chloride or T3P) with the amino-nitrile 10 center dot HCl. T3P was found to be a more practical choice since the reagent promoted efficient and concomitant dehydration of the amide impurity 9 (derived from the amino-amide contaminant 8 center dot HCl invariably present in 10 center dot HCl) to 1. This observation allowed for the development of the second strategy, namely a continuous flow synthesis of 1 from 9 mediated by T3P. Under optimized conditions, this conversion could be achieved within 30 min in flow as opposed to 12-16 h in a traditional batch process. The final API had quality attributes comparable to those obtained in conventional flask processes.(c) 2023 Elsevier Ltd. All rights reserved.

引用

页数：5