The key compound 5-(alpha-hydroxybenzyl)-1-methyl-1H-pyrazole [(?-I] was obtained by two related ways: 1) by condensation of N-methylpyrazole with benzonitrile and butyl lithium in tetrahydrofuran and reduction of the obtained ketone with sodium borohydride in methanol or 2) by condensation of N-methylpyrazole with benzaldehyde and butyl lithium in THF/toluene. The alkylation of [(?-I] with 2-(dimethylamino)ethyl chloride hydrochloride was carried out using phase transfer conditions and reaction with citric acid using propanone as solvent.
Asymmetric reduction of ketone (III) with catecholborane or borane璵ethyl sulfide complex and CBS-oxazaborolidene as catalyst afforded [(R)-(+)-I] or [(S)-(?-I].
The transesterification of [(?-I] with vinyl acetate enzymatically catalyzed (lipase) allowed the selective recovery of the enatiomer [(R)-(+)-I] and the hydrolysis and racemization of the undesired enantiomer [(S)-(?-II] with hydrochloric acid.
The optical resolution of (?-cizolirtine was accomplished by recrystallizing diastereoisomeric salts formed with the antipodes of di-p-toluoyltartaric acid in isopropanol.
Resolution of alcohol [(?-I] as its diastereomeric O-acetylmandelate esters and saponification of each of them in ethanol in the presence of catalytic amounts of sodium cyanide yielded the enantiomerically pure alcohols [(R)-(+)-I] and [(S)-(?-I].
Ethyl (R)-mandelate [(R)-IV] was protected as its tert-butyldimethylsilyl ether and reduced with DIBAL to [(R)-V], which was treated with ethoxycarbonylmethyl-enetriphenylphosphorane, followed by reduction to give [(R)-VI]. Subsequent oxidation to [(R)-VII] and cyclization by reaction with methylhydrazine afforded a mixture of pyrazolines [(R)-VIII]. Oxidation to pyrazole and deprotection yielded [(R)-(+)-I].