Ammonia → 3'-Amino-2',3'-dideoxycytidine

Participants

Reaction Steps

The synthesis of several new 3'-azido and 3'-amino nucleosides is outlined above. Tritylation of 2'-deoxyuridine (I) with trityl chloride in pyridine gives the corresponding 5'-O-trityl derivative, (II), which is then converted to the 3'-O-methanesulfonyl analog, (III), with methanesulfonyl chloride in pyridine. The replacement of the mesyloxy group at the 3'-position in (III) with net inversion to yield 1-(2'-deoxy-5'-O-trityl-β-D-lyxosyl)uracil (V), is accomplished by refluxing compound (III) with excess sodium hydroxide solution. Mesylation of compound (V) affords the sulfonate (VI). This compound is then treated with lithium azide in N,N-dimethylformamide followed by detritylation by o refluxing with 80% aqueous acetic acid to yield 3'-azido-2,3'-dideoxyuridine (VIII). Catalytic hydrogenation of compound (VIII) in the presence of 10% palladium on charcoal in ethanol gives 3'-amino-2',3'-dideoxyuridine (IX). Acetylation of compound (VIII) with acetic anhydride in pyridine at 4° C. yields 5'-O-acetyl-3'-azido-2',3'-dideoxyuridine (X). Reaction of compound (X) with thionyl chloride and N,N-dimethylformamide in absolute chloroform at reflux temperature for 6 hours affords the corresponding 4-chloro derivative (XI) which is then converted to 3'-azido-2',3'-dideoxycytidine (XII) by treatment with saturated methanolic ammonia at room temperature for 6 days. Hydrogenation of compound (XII) using 10% palladium on charcoal as a catalyst gives 3'-amino-2',3'-dideoxycytidine (XIII). Compounds (VIII) and (IX) are key intermediates for the synthesis of various 5-substituted 3'-azido and 3'-amino nucleoside analogs.

Provenance & Evidence