| Autor: |
Deussen, H.-J., Jeppesen, L., Scharer, N., Junager, F., Bentzen, B., Weber, B., Weil, V., Mozer, S. J., Sauerberg, P. |
| Zdroj: |
Organic Process Research & Development; May 2004, Vol. 8 Issue: 3 p363-371, 9p |
| Abstrakt: |
A scalable synthetic route of the nonselective but PPARα-preferring potent PPAR agonist NNC 61-4655 aimed for treatment of type 2 diabetes was developed. The synthetic pathway comprises the convergent synthesis and coupling of the two key intermediates E-5-(chloropent-3-en-1-ynyl)benzene 8 (prepared in a five-step synthesis in 18% overall yield) and (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid isopropyl ester 9. The 2-aminoethanol salt of NNC 61-4655 was selected in a preclinical salt selection program as the appropriate salt form for further development. More than 900 g of NNC 61-4655, 2-aminoethanol was finally synthesized under GMP in 98.7% purity. In comparison to the original medicinal chemistry route, starting from phenylpropargyl aldehyde 1, the overall yield towards NNC 61-4655 could be enhanced from 24 to 37%. An improved scalable two-step synthesis for 8 was developed on a laboratory scale (≥33−35% overall yield) shortly after the GMP batch. |
| Databáze: |
Supplemental Index |
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