合成路线:Two new related proceases to synthesize simvastatin have been described:1) The reduction of the lactone function of lovastatin (I) with diisobutylaluminum hydride (DIBAL) in THF/dichoromethane gives the hemiacetal (II),which by reaction with acetyl chloride in methanol yields the acetal (III).The methylation of (III) with methyl iodide by means of BuLi and pyrrolidine in THF affords the 2,2-dimethylbutyric acid ester (IV),which is treated with HCl in THF to give the hemiacetal (V).Finally,this compound is oxidized with Ag2CO3 in refluxing toluene.2) The direct methylation of hemiacetal (II) with methyl iodide by means of BuLi and pyrrolidine in THF directly yields the methylated herniacetal (V) although with a little bit less purity.
参考文献标题:Process to manufacture simvastatin and intermediates
文献作者:Doucette,G.; Tam,T.F.; Tao,Y.; Karimian,K.; Li,Y.(Apotex Inc.)
参考来源:WO 9965892
合成路线:The deacylation of lovastatin (I) with aqueous LiOH gives the free diol (II),which is partially protected with tert-butyldimethylsilyl chloride as usual,yielding the monosilylated derivative (III).The acylation of (III) with 2,2-dimethylbutyryl chloride (IV) by means of 4-pyrrolidino pyridine (py-py) in pyridine affords the silylated ester (V),which is finally deprotected with tetrabutylammonium fluoride and acetic acid in THF.
参考文献标题:Process for the preparation of simvastatin and analogs thereof
文献作者:Zlicar,M.(LEK Pharmaceutical and Chemical Co.)
参考来源:WO 0032585
合成路线:The esterification of 6(R)-[2-(8(S)-hydroxy-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydro-1(S)-naphthyl)ethyl]-4(R)-(tert-butyldimethylsilyloxy)tetrahydropyran-2-one (I) with 2,2-dimethylbutyric acid (II) by means of PPh3 and hexachloroethane in dichloromethane gives the protected intermediate (III),which is finally desilylated by means of Me-SO3H in water to yield the target simvastatin.
参考文献标题:A process for producing simvastatin
文献作者:Kim,J.W.; Bae,H.; Lee,K.H.; Choi,K.D.(Cheil Jedang Corp.)
参考来源:WO 0172734
合成路线:The deacylation of lovastatin (I) with aqueous LiOH gives the free diol (II),which is partially protected with tert-butyldimethylsilyl chloride as usual,yielding the monosilylated derivative (III).The acylation of (III) with 2,2-dimethylbutyryl chloride (IV) by means of 4-pyrrolidino pyridine (py-py) in pyridine affords the silylated ester (V),which is finally deprotected with tetrabutylammonium fluoride and acetic acid in THF.
参考文献标题:Simvastatin
文献作者:Prous,J.; Castar,J.
参考来源:Drugs Fut 1988,13(6),531
合成路线:The deacylation of lovastatin (I) with aqueous LiOH gives the free diol (II),which is partially protected with tert-butyldimethylsilyl chloride as usual,yielding the monosilylated derivative (III).The acylation of (III) with 2,2-dimethylbutyryl chloride (IV) by means of 4-pyrrolidino pyridine (py-py) in pyridine affords the silylated ester (V),which is finally deprotected with tetrabutylammonium fluoride and acetic acid in THF.
参考文献标题:3-Hydroxy-3-methylglutaryl-coenzyme A reductase in
文献作者:Hoffman,W.F.; Alberts,A.W.; Anderson,P.S.; Smith,R.L.; Chen,J.S.; Willard,A.K.
参考来源:J Med Chem 1986,29(5),849
合成路线:A cost-efficient synthesis of simvastatin has been reported:1) The reaction of lovastatin (mevinolin) (I) with cyclopropylamine (II) gives the corresponding amide (III),which is methylated by means of BuLi,methyl iodide and pyrrolidine in THF yielding the dimethylbutyryl derivative (IV).Hydrolysis of (IV) with NaOH in refluxing methanol,followed by a treatment with NH4OH in methanol affords the ammonium salt (V),which is finally lactonized in acidic medium.2) The cyclopropylamide (III) can also be obtained by reaction of mevinolinic acid ammonium salt (VI) with cyclopropylamine in hot toluene.
参考文献标题:A cost-efficient synthesis of simvastatin via high-conversion methylation of an alkoxide ester enolate
文献作者:Thaper,R.K.; Misra,S.; Kumar,Y.; Kumar,S.M.D.; Khanna,J.M.
参考来源:Org Process Res Dev 1999,3(6),476
产品链接: CAS No. 79902-63-9››