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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 involving a reverse addition of 2 and the base to the coupling agent isobutyl chloroformate, followed by the addition of the amine, was developed that minimized the symmetrical anhydride formation. A novel, water-assisted N-methylation of 5 with dimethyl sulfate in the presence of sodium hydride in THF was also developed that eliminated the use of methyl iodide, silver oxide, and KCN. Deprotection of the BOC group in 6 with sulfuric acid circumvented the formation of diketopiperazine and tetrapeptide observed with HCl and trifluoroacetic acid, respectively.
Prashad et al. (Wed,) studied this question.