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

Identification and synthesis of potential process-related impurities of trametinib: an anti-cancer drug

J. S. Chakradhar Saladi, Gangadhar Bhima Shankar Nangi, Ramadas Chavakula, Kishore Karumanchi, and Kishore Babu Bonige

Chemical Research Department, APL Research Centre-II, Aurobindo Pharma Ltd, Sangareddy District, India

E-mail: jacobkishore@gmail.com

Received: 16 July 2022  Accepted: 28 October 2022

Abstract:

Trametinib is used to treat patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Two process impurities, namely 5-(2-fluoro-4-iodo phenylamino)-1-(3-aminophenyl)-3-cyclopropyl-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7 (1H,3H,6H)-trione hydrochloride (2) and 4-((3-acetamidophenyl)amino)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (3), are observed during the laboratory optimization of trametinib. These impurities have a definite impact on the quality of the drug product. In this context, the identification, synthesis, origin and the control of these potential impurities are described. This study will be helpful to the generic pharmaceutical industry for obtaining chemically pure trametinib.

Keywords: Trametinib; Impurities; 5-(2-fluoro-4-iodo phenylamino)-1-(3-aminophenyl)-3-cyclopropyl-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7 (1H,3H,6H)-trione hydrochloride; 4-((3-acetamidophenyl)amino)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-o

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-022-02570-w

Chemical Papers 77 (3) 1759–1763 (2023)