Process and methods for the preparation of optically active cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane or pharmaceutically acceptable salts thereof

A method for resolving a compound of formula III, in the cis configuration:

• wherein:
• R1 is H, C1-6 alkyl, C6-12 aryl, C6-12 arylalkyl, (CO)C1-6 alkyl, (CO)O—C1-6 alkyl, (CO)C6-12 aryl, or (CO)C6-12 arylalkyl;
• R2 is H, C1-6 alkyl or CO—R5;
• R3 is H, C1-6 alkyl, bromide, chloride, fluoride, iodide or CF3;
• and
• R5 is H or C1-6 alkyl;
• said process comprising:
• a) reacting said compound of formula III with a chiral acid to produce two diastereomeric salts, wherein said chiral acid is (1R)-(−)-10-camphorsulfonic acid, (−)-2,3-dibenzoyl-L-tartaric acid, (+)-L-tartaric acid or (−)-L-malic acid;
• b) recovering a mixture of said two diastereomeric salts containing an excess of one of said two diastereomeric salts;
• c) converting said one of said two diastereomeric salts into a compound of formula I or II:

A process for producing an optically active compound of formula I or formula II:

• wherein:
• R1 is H, C1-6 alkyl, C6-12 aryl, C6-12 arylalkyl, (CO)C1-6 alkyl, (CO)O—C1-6 alkyl, (CO)C6-12 aryl, or (CO)C6-12arylalkyl;
• R2 is H, C1-6 alkyl or CO—R5;
• R3 is H, C1-6 alkyl, bromide, chloride, fluoride, iodide or CF3;
• and
• R5 is H or C1-6 alkyl;
• said process comprising:
• a) reacting a compound of formula III in the cis configuration:
• with a chiral acid and an achiral acid to produce a mixture of two diastereomeric salts and an enantiomeric salt, wherein said chiral acid is (1R)-(−)-10-camphorsulfonic acid, (−)-2,3-dibenzoyl-L-tartaric acid, (+)-L-tartaric acid or (−)-L-malic acid;
• b) recovering a mixture of said two diastereomeric salts containing an excess of one of said two diastereomeric salts;
• c) converting said one of said two diastereomeric salts into said optically active compound of formula I or formula II.