LDM256 CB1 receptor antagonist: The story unfolds from CSP to Phase 1

ORGN 634

Kevin Vargas, Kevin.Vargas@novartis.com, Michael Girgis, Jessica Liang, Zhengming Du, Edwin Villhauer, Lech Ciszewski, Yansong Lu, and Wen Shieh. Chemical and Analytical Development, Novartis Pharmaceuticals, One Health Plaza, East Hanover, NJ 07936
LDM256 is a selective, orally bio-available cannabinoid-1 antagonist with potential to regulate food intake. This drug has potential to help reduce weight gain. However, the research synthesis had a high complexity with eight chromatographies, an osmium tetroxide oxidation, azide addition, microwave at 200 °C urea formation, use of methylene chloride, and a diazotization. In addition, a long lead time and expensive chiral amine is required in the first step. So, the CSP stage gained some improvement over the research phase. An achiral approach is followed. The expensive chiral amine was eliminated by using a cheaper starting material. Methylene chloride was removed as a solvent. Two normal phase and one chiral simulated moving bed (SMB) chromatographies were still needed in this phase. The chiral SMB was done on the final step. The FSC synthesis included the chiral center early as a mandelic acid derivative. Several intermediates were outsourced “at risk” for this campaign. The complexity improved from 87 to 53. The Phase I synthesis completed the list of improvements and made it ready for the plant scale. Compound A1 had a S/R enantiomer ratio of 97/3 as an outsourced item. The S/R was monitored at A4 as 95/5. This was tentatively believed to be improved at A11 but an ethanol recrystallization was needed to increase to 99.7% S/R. The overall plant yield was 14%.