Process Development and Scale-Up of PPAR / Dual Agonist Lobeglit
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- 作者：Hong Woo Lee ; Joong Bok Ahn ; Sung Kwon Kang ; Soon Kil Ahn ; Deok-Chan Ha
- 刊名：Organic Process Research & Development
- 出版年：2007
- 出版时间：March 2007
- 年：2007
- 卷：11
- 期：2
- 页码：190 - 199
- 全文大小：164K
- 年卷期：v.11,no.2(March 2007)
- ISSN：1520-586X
文摘
A scaleable synthetic route to the potent PPAR
/
dualagonistic agent, lobeglitazone (1), used for the treatment oftype-2 diabetes was developed. The synthetic pathway comprisesan 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 silicagel as an acid catalyst. The sulfate salt form of lobeglitazonewas selected as a candidate compound for further preclinicaland clinical study. More than 2 kg of lobeglitazone sulfate(CKD-501, 2) was prepared in 98.5% purity after the GMPbatch. Overall yield of 2 was improved to 52% from 17% ofthe original medicinal chemistry route.
/ dualagonistic agent, lobeglitazone (1), used for the treatment oftype-2 diabetes was developed. The synthetic pathway comprisesan 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 silicagel as an acid catalyst. The sulfate salt form of lobeglitazonewas selected as a candidate compound for further preclinicaland clinical study. More than 2 kg of lobeglitazone sulfate(CKD-501, 2) was prepared in 98.5% purity after the GMPbatch. Overall yield of 2 was improved to 52% from 17% ofthe original medicinal chemistry route.