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Paper | Regular issue | Vol 85, No. 9, 2012, pp.2213-2229
Published online, 19th July, 2012
DOI: 10.3987/COM-12-12518
An Improved Synthesis of 5-Acylamino-6-oxo-2-phenyl-1(6H)-pyrimidineacetic Acid from Glycine with Readily Removable Protecting Groups

Daisuke Takahashi,* Tatsumi Kashiwagi, Hiromi Onoye, Robert M. Williams, and Kunisuke Izawa*

*Research Institute for Bioscience products and Fine chemicals, Ajinomoto Co., Inc., 1780 Hinaga, Yokkaichi, Mie, 510-0885, Japan

Abstract

Concise synthesis of N-acyl-5-amino-6-oxo-2-phenyl-1(6H)-yrimidineacetic acid was achieved by cyclization reaction of 2-alkyl-4-lkoxymethylene-5(4H)-oxazolone with N-(carboxymethyl)benzamidine, while a similar reaction with sodium salt of 2-alkyl-4-hydroxymethylene-5(4H)-xazolones gave a mixture of regioisomers of the pyrimidinone. N-Acyl groups (acetyl or phenylacetyl) of the pyrimidinone derivatives were readily cleaved under very mild conditions with weak base or enzyme. Thus, the process enabled us to synthesize the drug candidate without exchanging N-protecting group. Since the starting oxazolones were easily prepared from N-acylglycine, the synthetic route can be used for the large scale synthesis of the key intermediate for several enzyme inhibitors.