Pyrimidine nucleoside derivatives and methods for producing them

#1. Field of the Invention

#The present invention relates to novel methods for producing 3'-azido-3'-deoxythymidine (azidothymidine, AZT, zidovudine), which is useful as an antiviral agent, and its related compounds. The present invention also relates to novel intermediates useful in such a method.

#2. Discussion of the Background

#Production of 2'-deoxy-2'-bromo-3',5'-O-diacetyl-5-methyluridine from 5-methyluridine:

#42.5 g (350 mmol) of trimethyl orthoacetate were added to 125 ml of a slurry of acetic acid containing 75.3 g (250 mmol) of 85.7% purity 5-methyluridine and reacted at 50.degree. C. for one hour. The reaction mixture was concentrated under reduced pressure to obtain 2',3'-O-methoxyethylidene-5-methyluridine. To the thus-obtained 2',3'-O-methoxyethylidene-5-methyluridine, were added 207 ml of acetonitrile. The resulting solution was heated to 50.degree. C., and a mixture comprising 202 g (3 equivalents) of 30% hydrogen bromide/acetic acid and 30.8 g (one equivalent) of acetic acid bromide was dropwise added thereto over a period of 2 hours. The reaction mixture was heated to 60.degree. C. and reacted for a further 4 hours. The reaction mixture was then cooled to 10.degree. C., and 125 ml of water were added thereto. Then, the reaction mixture was neutralized with an aqueous 25% sodium hydroxide solution, and the acetonitrile layer was separated. The aqueous layer was extracted with acetonitrile. The organic layers were combined and concentrated under reduced pressure. The resulting residue was recrystallized from methanol to obtain 71.5 g (176 mmol) of 2'-deoxy-2'-bromo-3', 5'-O-diacetyl-5-methyluridine. Its yield was 70.6%, based on 5-methyluridine.

#NMR Analysis (.sup.1 H, CDCl.sub.3)