Process Development of a Large-Scale Synthesis of TKA731: A Tachykinin Receptor Antagonist

An efficient and chromatography-free large-scale synthesis of a tachykinin receptor antagonist TKA731 (1), utilizing the coupling of dipeptide 7 and 2-chloro-4(3H)-quinazolinone (13) as the key step, is described. The overall yield of 1 from BOC-l-3-(2-naphthyl)alanine (2) in six linear steps (total of eight steps) is 63%. This new convergent approach avoided the use of methyl iodide and the formation of methanethiol byproduct in the last step involving the construction of the quinazolinone ring in the original discovery synthesis. Four chromatographies were also eliminated. The main cause of the side reaction, leading to the urethane byproduct (I) formation and starting amino acid (2) liberation during the coupling of 2 with N-benzylmethylamine using well-known isobutyl chloroformate mediated mixed carboxylic-carbonic anhydride method, was found to be the symmetrical anhydride (III) formation from 2 as determined by the CO2 offgas formation. A new procedure for the coupling of 2 with N-benzylmethylamine ...