CS-682 has been synthesized by several related ways: 1) By acylation of 2'-cyano-2'-deoxy-1-(beta-D-arabinofuranosyl)cytosine (I) with hexadecanoyl chloride (II) and trimethylsilyl chloride in pyridine. 2) By acylation of 2'-cyano-2'-deoxy-1-(beta-D-arabinofuranosyl)cytosine (I) with hexadecanoyl anhydride (III) in hot DMF. 3) The protection of the OH groups of 2'-cyano-2'-deoxy-1-(beta-D-arabinofuranosyl)cytosine (I) with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane in pyridine gives the 3',5'-cyclic disiloxane (IV), which is acylated by means of hexadecanoic acid (V) and DCC in THF, yielding the silylated compound (VI). Finally, this compound is deprotected with tetrabutylammonium fluoride (TBAF) in acetic acid.
4) The acylation of cytidine (VII) with hexadecanoyl anhydride (III) in hot DMF gives N-4-hexadecanoylcytidine (VIII), which is protected with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane in pyridine, yielding the 3',5'-cyclic disiloxane (IX). The oxidation of (IX) with pyridinium dichromate in dichloromethane affords the ketonic derivative (X), which is treated with NaCN in ethyl acetate/phosphate buffer to give 2'-C-cyano-N4-hexadecanoyl-3',5'-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)cytidine (XI). The reaction of (XI) with phenoxythiocarbonyl chloride and DMAP in triethylamine provides the thiocarbonate (XII), which is reduced with AIBN and tributyltin in refluxing toluene to give the 2'-deoxy compound (VI). Finally, this compound is desilylated with TBAF in acetic acid.