Process for the Preparation of an Amorphous, Peptide-like Diabetes Drug: Approach to a Chromatography-Free Process

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• 作者：Yasuhiro Sawai ; Taihei Yamane ; Motoki Ikeuchi ; Shinji Kawaguchi ; Masatoshi Yamada ; Mitsuhisa Yamano
• 刊名：Organic Process Research & Development
• 出版年：2010
• 出版时间：September 17, 2010
• 年：2010
• 卷：14
• 期：5
• 页码：1110-1117
• 全文大小：307K
• 年卷期：v.14,no.5(September 17, 2010)
• ISSN：1520-586X

文摘

A manufacturing process suitable for large-scale production of the peptide-like amorphous compound N-((2R)-1-{(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl}-3-(1H-indol-3-yl)-1-oxopropan-2-yl)-1-[(1-methyl-1H-indol-2-yl)carbonyl]piperidine-4-carboxamide (1) as a drug for treating diabetes has been developed. The first kilogram quantities of 1 were prepared via a single-chromatography process that employed recyclable cation-exchange resin chromatography for an amorphous intermediate (2R)-2-amino-1-[(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl]-3-(1H-indol-3-yl)-propan-1-one (syn-3a). We have also developed a chromatography-free process that involves a combination purification of extraction of syn-3a with crystallization of syn-3a·0.25H₃PO₄·0.5H₂O. The latter process afforded amorphous compound 1 with >98% purity by HPLC area analysis, the same quality as that provided by the former process.