合成路线1

There are two options for the synthesis of lamivudine: In the first approach the intact nucleoside analogue is prepared in racemic form by resolution to afford the required chiral product. This can be effected by an enzyme-mediated enantiospecific reaction. In the second approach synthesis of a chiral sugar component precedes coupling with the cytosine base under conditions where the chirality of the sugar precursor is maintained. The first approach is outlined in Scheme 18435601a. The oxathiolane (III) is obtained as a 1:1 mixture of anomers from reaction of benzoyloxyacetaldehyde (I) with mercaptoacetaldehyde dimethylacetal (II) in the presence of a Lewis acid. Treatment of (III) with silylated cytosine (IV) in the presence of TMS-triflate affords a 1:1 mixture of beta- and alpha-anomers (V) from which the required beta-anomer may be obtained by crystallization. Various alternative coupling conditions have been reported which yield almost exclusively the beta-anomer, notably as a result of the use of SnCl4. Subsequent deprotection affords the racemic nucleoside (VI) (BCH189). The resolution may be effected by a variety of enzymatic processes. Treatment of the nucleoside with phosphorus oxychloride and trimethylphosphate affords the 5'-monophosphate (VII). The natural enantiomer is selectively recognized by the 5'-nucleotidase from Crotalus atrox venom to afford the (+)-beta-D-nucleoside (VIII) and leave the unatural (-)-beta-L-enantiomer as the monophosphate (IX). Facile separation of these two products and subsequent dephosphorylation of (IX) using bacterial alkaline phosphatase affords lamivudine. Selective enzymatic recognition of the natural enantiomer may also be used to advantage in the resolution using cytidine deaminase derived from E. coli. In this case the enzyme is responsible for enantiospecific hydrolysis of the natural form to afford a readily separable mixture of lamivudine and the uridine derivative (X). Other enzymes including esterases and phosphodiesterases have application in the resolution of derivatives of the racemic nucleoside.