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

• Karuna Veeramani^a, Manish Shinde^a, Vishnuvardhana Vema Reddy Eda^b, Bala Chennaiah Darapaneni^b, Rama Mohan Hindupur^c, Srinivasa Rao Madarapu^c, Saikat Sen^b, Srinivas Oruganti^b

• ^a10X Chemical Process Automation Laboratory, Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Telangana, India
• ^bCentre for Process Research and Innovation, Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Telangana, India
• ^cAurigene Pharmaceutical Services Limited, JP Nagar Road, Miyapur, Hyderabad 500 049, Telangana, India

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·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·HCl invariably present in 10·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.

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