Process Development and Scale-Up of the PPAR Agonist NNC 61-4655

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.