Process Development of (2-Nitrophenylcarbamoyl)-(<i>S</i>)-prolyl-(<i>S</i>)-3- (2-naphthyl)alanyl-<i>N</i>-benzyl-<i>N</i>-methylamide (SDZ NKT343)

Abstract

(2-Nitrophenylcarbamoyl)-( S )-prolyl-( S )-3-(2-naphthyl)alanyl- N -benzyl- N -methylamide ( 1; SDZ NKT343) is a human NK-1 tachykinin receptor antagonist. The development of a robust process for a multikilogram scale, chromatography-free preparation of this compound is described. The new four-step synthesis was based on a convergent approach, which utilized a peptide coupling of 1-[(2-nitrophenylamino)carbonyl]- l -proline ( 11 ) with free base of ( S )-3-(2-naphthyl)alanyl- N -benzyl- N -methylamide hydrochloride ( 4 ) as the key step in the presence of 1,3-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole as coupling agents. A scale-up of the well-known mixed anhydride coupling method, using isobutyl chloroformate, to produce 4 was found to be problematic due to coupling of the amine at the undesired carbonyl group of the mixed anhydride. This problem was overcome. The drug substance, initially an amorphous powder, was obtained with the desired purity without any chromatography. A process for crystallization of 1 was also developed.