Process development and scale-up of PPAR α/γ Dual agonist lobeglitazone sulfate (CKD-501)

Hong Woo Lee, Joong Bok Ahn, Sung Kwon Kang, Soon Kil Ahn, Deok Chan Ha

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

A scaleable synthetic route to the potent PPARα/γ dual agonistic agent, lobeglitazone (1), used for the treatment of type-2 diabetes was developed. The synthetic pathway comprises an effective five-step synthesis. This process involves a consecutive synthesis of the intermediate, pyrimidinyl aminoalcohol (6), from the commercially available 4,6-dichloropyrimidine (3) without the isolation of pyrimidinyl phenoxy ether (4). Significant improvements were also made in the regioselective 1,4-reduction of the intermediate, benzylidene-2,4-thiazolidinedione (10), using Hantzsch dihydropyridine ester (HEH) with silica gel as an acid catalyst. The sulfate salt form of lobeglitazone was selected as a candidate compound for further preclinical and clinical study. More than 2 kg of lobeglitazone sulfate (CKD-S01, 2) was prepared in 98.5% purity after the GMP batch. Overall yield of 2 was improved to 52% from 17% of the original medicinal chemistry route.

Original languageEnglish
Pages (from-to)190-199
Number of pages10
JournalOrganic Process Research and Development
Volume11
Issue number2
DOIs
Publication statusPublished - 2007 Mar

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry

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