220892-17-1Relevant academic research and scientific papers
Crystallization-induced asymmetric transformation: stereospecific synthesis of L-768,673
Shi, Yao-Jun,Wells, Kenneth M.,Pye, Philip J.,Choi, Woo-Baeg,Churchill, Hywyn R. O.,et al.
, p. 909 - 918 (1999)
A highly convergent, asymmetric synthesis of L-768,673, an Iks Class III antiarrythmic drug candidate, is described. Synthesis of the racemic 1-trifluoroethyl-3-amino-5-phenyl benzodiazepinone was achieved by Ru-catalyzed hydrogenation of the corresponding oxime that was derived from commercially available 1-trifluoroethyl-5-phenyl benzodiazepine in 76 percent overall yield. An efficient one-pot resolution-racemization of (+/-)-amine provided the desired (+)-amine as its mandelate salt in 92 percent yield and 99.4 percent 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'-tetramethylpiperidine afforded its aryl lithium. Subsequent transmetalation and alkylation with allyl bromide produced the corresponding olefin. Ru-catalyzed oxidative cleavage of the terminated double bond of the olefin provided the desired 2,4-bis(trifluoromethyl)phenylacetic acid in 35 percent overall yield. A modified Schotten-Baumman procedure was developed for coupling of (+)-amine and the acid to produce L-768,673 in 92 percent yield without racemization. - Keywords: Asymmetric synthesis; Benzodiazepines; Oximes; Resolution-racemization
