合成路线:The reaction of 3-cyclopentyloxy-4-methoxybenzaldehyde (I) with LiBr,trimethylsilyl chloride (TMS-Cl) and 1,1,3,3-tetramethyldisiloxane in acetonitrile gives the corresponding benzyl bromide (II),which by reaction with NaCN in DMF affords 2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (III).The condensation of (III) with methyl acrylate (IV) by means of Triton B in refluxing acetonitrile yields the 4-cyanopimelate (V),which is cyclized by means of NaH in refluxing DME,giving the 2-oxocyclohexanecarboxylic ester (VI).The decarboxylation of (VI) by means of NaCl in DMSO/water at 150 C yields the cyclohexanone (VII),which is condensed with 2-(trimethylsilyl)-1,3-dithiane (VIII) by means of BuLi in THF,affording the cyclohexylidene-dithiane (IX).The methanolysis of (IX) catalyzed by HgCl2 and HClO4 in refluxing methanol gives a mixture of the cis- and trans-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexanecarboxylic acid methyl ester which is submitted to flash chromatography to obtain the cis-isomer (XII).Finally,this compound is hydrolyzed with KOH in methanol/THF/water.
参考文献标题:Cyano cpds.and preparation thereof
文献作者:Bordas-Nagy,J.; Gorycki,P.; Webb,K.S.(SmithKline Beecham plc)
参考来源:JP 1997510213; WO 9524381
合成路线:The reaction of 3-cyclopentyloxy-4-methoxybenzaldehyde (I) with LiBr,trimethylsilyl chloride (TMS-Cl) and 1,1,3,3-tetramethyldisiloxane in acetonitrile gives the corresponding benzyl bromide (II),which by reaction with NaCN in DMF affords 2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (III).The condensation of (III) with methyl acrylate (IV) by means of Triton B in refluxing acetonitrile yields the 4-cyanopimelate (V),which is cyclized by means of NaH in refluxing DME,giving the 2-oxocyclohexanecarboxylic ester (VI).The decarboxylation of (VI) by means of NaCl in DMSO/water at 150 C yields the cyclohexanone (VII),which is condensed with 2-(trimethylsilyl)-1,3-dithiane (VIII) by means of BuLi in THF,affording the cyclohexylidene-dithiane (IX).The methanolysis of (IX) catalyzed by HgCl2 and HClO4 in refluxing methanol gives a mixture of the cis- and trans-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexanecarboxylic acid methyl ester which is submitted to flash chromatography to obtain the cis-isomer (XII).Finally,this compound is hydrolyzed with KOH in methanol/THF/water.
参考文献标题:SB-207499
文献作者:Graul,A.; Castar,J.; Silvestre,J.S.
参考来源:Drugs Fut 1998,23(6),607
合成路线:The reaction of 3-cyclopentyloxy-4-methoxybenzaldehyde (I) with LiBr,trimethylsilyl chloride (TMS-Cl) and 1,1,3,3-tetramethyldisiloxane in acetonitrile gives the corresponding benzyl bromide (II),which by reaction with NaCN in DMF affords 2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (III).The condensation of (III) with methyl acrylate (IV) by means of Triton B in refluxing acetonitrile yields the 4-cyanopimelate (V),which is cyclized by means of NaH in refluxing DME,giving the 2-oxocyclohexanecarboxylic ester (VI).The decarboxylation of (VI) by means of NaCl in DMSO/water at 150 C yields the cyclohexanone (VII),which is condensed with 2-(trimethylsilyl)-1,3-dithiane (VIII) by means of BuLi in THF,affording the cyclohexylidene-dithiane (IX).The methanolysis of (IX) catalyzed by HgCl2 and HClO4 in refluxing methanol gives a mixture of the cis- and trans-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexanecarboxylic acid methyl ester which is submitted to flash chromatography to obtain the cis-isomer (XII).Finally,this compound is hydrolyzed with KOH in methanol/THF/water.
参考文献标题:1,4-Cyclohexanecarboxylates: Potent and selective inhibitors of phosphodiesterase 4 for the treatment of asthma
文献作者:Christensen,S.B.; Guider,A.; Forster,C.J.; Gleason,J.G.; Bender,P.E.; Karpinski,J.M.; DeWolf ,W.E.Jr.; Barnette,M.S.; Underwood,D.C.; Griswold,D.E.; Cieslinski,L.B.; Burman,M.; Bochnowicz,S.; Osborn,R.R.; Manning,C.D.; Grous,M.; et al.
参考来源:J Med Chem 1998,41(6),821-35
合成路线:The reaction of cyclohexanone (I) with chloroacetonitrile,KOH and benzyltriethylammonium chloride in THF gives the cyanoepoxide (II),which is treated with LiBr and LiOH in DMF/acetonitrile/water to yield the lithium salt (III) of the title product.Finally,this salt is treated with HCl in ethyl acetate to afford the target Cilomilast.
参考文献标题:A practical synthesis of the PDE4 inhibitor,SB-207499,from a cyclohexanone precursor
文献作者:Badham,N.F.; Chen,J.-H.; Cummings,P.G.; Dell'Orco,P.C.; Diederich,A.M.; Eldridge,A.M.; Mendelson,W.L.; Mills,R.J.; Novack,V.J.; Olsen,M.A.; Rustum,A.M.; Webb,K.S.; Yang,S.
参考来源:Org Process Res Dev 2003,7(1),101
产品链接: CAS No. 153259-65-5››