CYC-682, CS-682

N-[1-[(2R,3S,4S,5R)-3-氰基-4-羟基-5-(羟甲基)氧杂环戊-2-基]-2-氧代嘧啶-4-基]十六酰胺Chemical Name: 2'-Cyano-2'-deoxy-1-(beta-D-arabinofuranosyl)-N4-palmitoylcytosine; N-[1-(2-Cyano-2-deoxy-beta-D-arabinofuranosyl)-1,2-dihydro-2-oxo-4-pyrimidinyl]hexadecanamide
CAS No. 151823-14-2
项目整合开发状态: Phase I/II
项目研究机构: Sankyo (Originator), Cyclacel (Licensee)
合成路线: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.

合成路线: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.