A highly convergent, asymmetric synthesis of L-768,673, an I(ks) Class III antiarrhythmic drug candidate, is described. Synthesis of the racemic 1- trifluoroethyl-3-amino-5-phenyl benzodiazepinone [(±)-amine] was achieved by Ru-catalyzed hydrogenation of the corresponding oxime that was derived from commercially available 1-trifluoroethyl-5-phenyl benzodiazepine in 76% overall yield. An efficient one-pot resolution-racemization of (±)-amine provided 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'- 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% overall yield. A modified Schotten-Baumman procedure was developed for coupling of (+)-amine and the acid to produce L-768,673 in 92% yield without racemization.
All Science Journal Classification (ASJC) codes
- Drug Discovery
- Organic Chemistry
- Asymmetric synthesis