Patent ID: 7994310

Claim:
A method for preparing 2′-deoxy-2′,2′-difluorocytidine represented by Formula I and a salt thereof from an optically pure intermediate prepared by optically resolving an ethyl 3-hydroxypropionic acid ester compound as a mixture of R- and S-enantiomers with an optically active amine, which comprises: (1) reacting an ethyl 3-hydroxypropionic acid ester of Formula IX with an amine selected from an optically pure (S)-1-phenylethanamine, (S)-1-(4-methylphenyl)ethanamine, (S)-1-phenyl-1-propanamine, (S)-1-(4-methoxyphenyl)ethanamine and (S)-1-(4-chlorophenyl)ethanamine, to prepare an optically pure 3-(R)-hydroxy propane amide of Formula VIII; (2) protecting the hydroxyl group of the compound of Formula VIII to prepare a compound of Formula VII; (3) hydrolyzing the compound of Formula VII to prepare a D-erythro-1-oxoribose of Formula VI; (4) protecting the 5-hydroxyl group of the D-erythro-1-oxoribose of Formula VI to prepare a D-erythro-1-oxoribose of Formula V; (5) reducing the D-erythro-1-oxoribose of Formula V to prepare a lactol of Formula IV; (6) reacting the lactol of Formula IV with methanesulfonyl chloride in the presence of a base such as triethylamine, pyridine or diisopropyl ethylamine to prepare a D-erythro-1-methanesulfonyloxy ribofuranose of Formula III; (7) glycosylating the D-erythro-1-methanesulfonyloxy ribofuranose of Formula III and a nucleobase, while mixing with an organic solvent such as toluene, 1,2-dichloroethane, anisole or xylene, to obtain a nucleoside of Formula II; and (8) deprotecting the nucleoside of Formula II with a strong base or a strong acid; wherein the noted Formulas I-IX are identified as follows: wherein R 1 and R 2 are a protecting group, and when R 1 is 1-naphthoyl or 2-naphthoyl, R 2 is benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl or 4-t-butylbenzoyl, and when R 2 is 1-naphthoyl or 2-naphthoyl, R 1 is benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, or 4-t-butylbenzoyl; R 3 , R 4 and R 7 are each independently C 1 -C 3 alkyl; R 5 is methyl or ethyl; R 6 is hydrogen, methyl or methoxy; R 7 is ethyl; and P′ is acetyl or hydrogen.