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

Development of a multigram synthetic process to clinical candidate TMP195, a class IIa histone deacetylase selective inhibitor

Siyuan Wang, Wenchao Zhang, Han Qin, Meidi Luo, Rui Lin, Jiachen Wen, and Dan Liu

Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China

E-mail: jiachen.a.wen@outlook.com

Received: 11 May 2024  Accepted: 24 October 2024

Abstract:

TMP195 is a highly profiled clinical candidate demonstrating class IIa histone deacetylase (HDAC) selective inhibition. Current preparation of TMP195 is limited to subgram-scale due to the requirement of tedious (post-)experimental procedures and the uses of hazardous reagents. To fulfill the unmet need for the bulky synthesis of TMP195 for the future clinical study, we have carried out its synthetic research. The present study provides a novel synthetic process suitable for the multigram-scale synthesis of TMP195. Its overall yield has increased significantly from the literature to the present, with respective values of 9% and 45%. Notably, the proposed process is more efficient and facile, characterized by accelerated reaction rates from 40 h to within 19 h and a streamlined post-reaction column chromatography purification from five reactions to just one. Additionally, the proposed process is more environmentally friendly, featured by the solvent-free synthesis of key intermediate 4-(chloromethyl)-2-phenyloxazole and replacement of non-toxic cyanide source. This newly proposed synthetic process is highly stable and repeatable under 10 gramme scale counted by benzamide as starting material.

Graphical abstract

Keywords: TMP195; Scale-up synthesis; Clinical candidate; IIa HDAC inhibitor

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-024-03769-9

Chemical Papers 78 (18) 9559–9568 (2024)