Crystallization-Induced Asymmetric Transformation in the Synthesis of

A second example of crystallization-induced asymmetric transformation of a 3-amino-l,4-benzodiazepine derivative is illustrated by the key step in the highly convergent synthesis of 4 (L-768,673), an anti-arrhythmic drug candidate [30, 31]. 

Compound 4 is an inhibitor of the slowly activating delayed rectifier K(+) current which repolarizes the cardiac ventricular cell membrane. As a result, the refractory period of the spontaneously contracting heart muscle is prolonged and the cardiac action potential is delayed. This helps to reduce the potentially fatal cardiac ventricular fibrillation which can result from ischaemic heart damage, leading to myocardial infarction. 

Structurally, compound 4 is a l-trifluoroethyl-(3/ )-amino-1,4-benzodiazepine derivative, N-acylated by the strongly lipophilic 1,4-bis-trifluoromethyl-phenyla-cetyl group. It is interesting to observe that the (3S) enantiomer of 1-trilluoroethyl-3-amino-l,4-BZD is present in 4, whereas the (3R) enantiomers of its N-alkyl congeners are preferred in the y-secretase inhibitors 1-3  

Comparison of the conditions for crystallization-induced asynunetric transformation of 4 and 13, which differ in the CH3 and CH2CF3 group at N(l), reveals how considerable serendipity and experience must be invested in solving specific, non-trivial problems on the path to chiral drugs in an optically pure form. 

In the final step, acylation of (3/ )-16 by 2,4-trifluoromethyl-phenylacetic acid was completed under standard conditions, in 92% yield and, more importantly, without any significant racemization the e.e of the final product, (3/ )-4, was 99% [31]. 

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