Multistep sepn. for preparing optically pure hetrazepine enantiomers - using liq. chromatography to separate mixt. of both enantiomers, dissolving obtd. mixt. enriched in specific and racemising other enantiomer

摘要

In the multistep sepn. process optically pure enantiomers of formula (I) are prepd. In (I) R1 = H, opt. branched 1-4C alkyl (pref. Me), cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R2 = a residue of formula -A-C(O)-N(R5)(R6); A = opt. branched alkyl with n C atoms, where n = 0-8; R5 and R6 = H, phenyl (opt. substd.), 3-6C cycloalkyl (opt. substd.), opt. branched alkyl, alkenyl or alkynyl gp. with 1-10 (1-4) C opt. substd. by OH, (substd.) phenyl or (substd.) amino gp.; R5 or R6 may form a 5-, 6- or 7-membered heterocyclic ring which is opt. unsatd. and opt. substd. by one or more 1-4C alkyl or R5 and R6 may together with the N atom form a 5, 6 or 7-membered ring which is opt. unsatd. and opt. substd. by one or more 1-4C alkyl and which further can contain another heteroatom comprising N, O or S with the N atom opt. substd. by 1-C alkyl esp. Me; R3 = phenyl opt. substd. by one or more halogen, nitro and/or trifluoromethyl and R4 = H or Me. Process comprises (1) sepg. the mixt. of both enantiomers (S(-) and R(-), by liq. chromatography until the desired enantiomer has an optical purity of at least 60%; (2) dissolving the obtd. mixt. enriched in the desired enantiomer in a polar solvent pref. a 1-4C alcohol, followed by crystallising the enantiomer of higher optical purity, and (3) racemising the other enantiomer obtd. in step (1) in a polar solvent in presence of a base, followed by crystallising and recycling it to step (1). USE - The optically active (I) enantiomer is used for the synthesis of medical prods..