Crystallization-induced asymmetric transformation: Stereospecific synthesis of L-768,673

A highly convergent, asymmetric synthesis of L-768,673, an I-ks Class III a ntiarrythmic drug candidate, is described. Synthesis of the racemic l-trifl uoroethyl-3-amino-5-phenyl benzodiazepinone [(+/-)-amine] was achieved by R u-catalyzed hydrogenation of the corresponding oxime that was derived from commercially available 1-trifluoroethyl-5-phenyl benzodiazepine in 76% over all yield. An efficient one-pot resolution-racemization of (+/-)-amine prov ided the desired (+)-amine as its mandelate salt in 92% yield and 99.4% ee. Regioselective ortho-lithiation of 1,3-bis(trifluoromethyl)benzene with n- BuLi in the presence of a catalytic amount of 2,2',6,6'-tetramethylpiperidi ne afforded its aryl lithium. Subsequent transmetalation and alkylation wit h allyl bromide produced the corresponding olefin. Ru-catalyzed oxidative c leavage of the terminated double bond of the olefin provided the desired 2, 4-bis(trifluoromethyl)phenylacetic acid in 35% overall yield. A modified Sc hotten-Baumman procedure was developed for coupling of (+/-)-amine and the acid to produce L768,673 in 92% yield without racemization. (C) 1999 Elsevi er Science Ltd. All rights reserved.