ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Design and development of efficient synthetic strategies for the chiral synthesis of novel ketolide antibiotic, nafithromycin (WCK 4873)

Satish Bhavsar, Ravikumar Tadiparthi, Sunil Gupta, Shivaji Pawar, Ravindra Yeole, Abhijeet K. Kayastha, Prasad Deshpande, Sachin Bhagwat, and Mahesh Patel

Wockhardt Research Center, Aurangabad, India

E-mail: sbhavsar@wockhardt.com

Received: 9 November 2022  Accepted: 10 February 2023

Abstract:

In structure activity relationship-driven novel ketolide drug development program at Wockhardt, the reaction between racemic 2-[5-(1-bromoethyl)-1,3,4-thiadiazol-2-yl]pyridine and novel amidoxime ketolide core concluded the synthesis of WCK 4871 as a diastereomeric mixture. This mixture of compounds, when subjected for initial microbiological evaluation, exhibited desired activities against resistant Gram-positive Streptococcus pneumoniae and Streptococcus pyogenes. In order to attain further improvements in microbiological activities, diastereomeric separation of WCK 4871 was essential. Initially, development of chiral preparative HPLC method helped to achieve the separation of diastereomeric mixture by giving out two compounds, WCK 4872 and WCK 4873. Here, WCK 4873 (nafithromycin) was found potent in preclinical studies and chosen for advance clinical developments as suitable drug candidate. In order to accomplish the chiral synthesis of nafithromycin, in the first attempt, chiral auxiliary, (S)-mandelic acid gave us undesired isomer, (S)-1-(5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl)ethanol, leading into the synthesis of WCK 4872. Upon altering the chiral auxiliary, (R)-mandelic acid furnished the synthesis of nafithromycin, although associated problems in the recrystallization through chiral auxiliary approach prompted us in finding the alternate routes. Finally, the chiral synthesis of nafithromycin was achieved through the chiral pool approach where the side chain, (R)-1-(5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl)ethyl 4-nitrobenzenesulfonate, was prepared in 5 steps, starting from methyl d-lactate.

Graphical abstract

Keywords: Nafithromycin; WCK 4873; Ketolides; Amidoxime; Methyl d-lactate

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-023-02725-3

Chemical Papers 77 (7) 3629–3640 (2023)