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药物详细合成路线

Name CYC-682;CS-682
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 151823-14-2
Related CAS
Formula C26H42N4O5
Structure
Formula Weight 490.64844
Stage I/II 期临床
Company Sankyo (Originator), Cyclacel (Licensee)
Activity/Mechanism ONCOLYTIC DRUGS, Antimetabolites, DNA Polymerase Inhibitors
Syn. Route 2
Route 1
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.
List of intermediates No.
7-fluoro-3-methyl-1-benzothiophen-5-amine (ii)
5-fluoro-3-(4-piperidinyl)-1h-indole (i)
4,5-bis(benzyloxy)-2-fluorobenzaldehyde (iii)
dichloromethyl phenyl sulfoxide; (dichloromethyl)(oxo)phenyl-lambda(4)-sulfane (iv)
1-[4,5-bis(benzyloxy)-2-fluorophenyl]-2,2-dichloro-2-(phenylsulfinyl)-1-ethanol (v)
1-[4,5-bis(benzyloxy)-2-fluorophenyl]-2-chloro-1-ethanone (vi)
Reference 1:
    castaner, j.; hoshi, a.; cs-682. drugs fut 1999, 24, 9, 957.
Reference 2:
    kaneko, m.; hotoda, h.; shibata, t.; kobayashi, t.; mitsuhashi, y.; matsuda, a.; sasaki, t. (sankyo co., ltd.); pyrimidine nucleoside derivs. having anti-tumor activity, their preparation and use. ep 0536936; jp 1993194497; us 5691319 .

Route 2
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.
List of intermediates No.
4,5-bis(benzyloxy)-2-fluorobenzaldehyde (viii)
1-[4,5-bis(benzyloxy)-2-fluorophenyl]-2-chloro-1-ethanone (vi)
(3ar)-1-methyl-3,3-diphenylhexahydro-1h-pyrrolo[2,1-e][1,2]azaborole (vii)
(1r)-1-[4,5-bis(benzyloxy)-2-fluorophenyl]-2-chloro-1-ethanol (ix)
(1r)-2-azido-1-[4,5-bis(benzyloxy)-2-fluorophenyl]-1-ethanol (x)
3,4-bis(benzyloxy)-2-fluorobenzaldehyde (xi)
1-[3,4-bis(benzyloxy)-2-fluorophenyl]-2,2-dichloro-2-(phenylsulfinyl)-1-ethanol (xii)
(xiii)
Reference 1:
    castaner, j.; hoshi, a.; cs-682. drugs fut 1999, 24, 9, 957.
Reference 2:
    kaneko, m.; hotoda, h.; shibata, t.; kobayashi, t.; mitsuhashi, y.; matsuda, a.; sasaki, t. (sankyo co., ltd.); pyrimidine nucleoside derivs. having anti-tumor activity, their preparation and use. ep 0536936; jp 1993194497; us 5691319 .

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名CS-682;英文名CYC-682;CS-682;CAS[151823-14-2]

 
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