GENERAL-METHOD OF PREPARATION OF N-[(S)-(3-HYDROXY-2-PHOSPHONOMETHOXYPROPYL)] DERIVATIVES OF HETEROCYCLIC BASES

Reaction of (R)-1-O-p-toluenesulfonyl-1,2,3-propanetriol (IV) with N-t rimethylacetylimidazole (II) afforded enesulfonyl-3-O-trimethylacetyl- 1.2.3-propanetriol (V) which was reacted with dimethoxymethane in the presence of phosphorus pentoxide to give enesulfonyl-3-O-trimethylacet yl-1.2.3-propanetriol (VI). Compound VI was treated with acetic anhydr ide and boron trifluoride etherate and the obtained 2-acetoxy derivati ve VII reacted with bromotrimethylsilane to give the intermediary brom omethyl ether VIII. Compound VIII on reaction with tris(2-propyl) phos phite afforded enesulfonyl-3-0-trimethylacetyl-1,2,3-propanetriol (IX) . Condensation of synthon IX with sodium salts of adenine, 2,6-diamino purine, or with cytosine, 6-azacytosine or 2-chloroadenine in the pres ence of cesium carbonate, afforded fully protected diesters X and XIII b which on methanolysis and reaction with bromotrimethylsilane gave N- [(S)-(3-hydroxy-2-phosphonomethoxypropyl)] derivatives of adenine (XIa ), 2-chloroadenine (XIb), 2,6-diaminopurine (XIc), cytosine (XIVa) and 6-azacylosine (XIVb). In an analogous reaction, sodium salt of 4-meth oxy-2-pyrimidone reacted with compound IX to give an intermediate XIII a which on treatment with methanolic ammonia and subsequent deblocking under the same conditions also afforded the cytosine derivative XIVa. Sodium salt of 2-amino-6-chloropurine was in this way converted into the corresponding 2-aminopurine derivative XVIII. Deprotection of this compound gave (3-hydroxy-2-phosphonomethoxypropyl)-2-aminopurine (XIX ).