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.
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.
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.
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.
The reaction of Lovastatin (I) with refluxing butylamine gives the N-butylamide (II), which is silylated with TBDMS-Cl and imidazole to yield the bis(silyl) ether (III). The careful methylation of (III) with MeI (only 1.5 mol) and lithium pyrrolidide in THF at -10 C affords a high yield of 2,2-dimethylbutyrate (IV) avoiding the methylation of the amide nitrogen. The desilylation of (IV) with MsOH in methanol gives the dihydroxyamide (V), which is treated successively with NaOH in methanol/water, with HCl, and finally with ammonia in methanol to give the ammonium salt (VI). Finally, this compound is cyclized by heating at 100 C in toluene to afford the target simvastatin.
The reaction of lovastatin (I) with benzoyl chloride (II) and pyridine gives the expected benzoate (III), which is treated with ethyleneglycol (IV), triethyl orthoformate and H2SO4 to yield the cyclic orthoformate (V). The methylation of (V) by means of MeI and BuLi in pyrrolidine affords the 2,2-dimethylbutyrate ester (VI), which is finally deprotected with HCl in THF to provide the target simvastatin.