Conformations of some semi-rigid neuroleptic drugs. Part 2. Crystal structures of racemic and of (+)-(S)-octoclothepin{2-chloro-10,11-dihydro-11-(4-methylpiperazin-1-yl)dibenzo[b,f]thiepin} and the absolute configuration of the latter

Abstract

The crystal structures of racemic and of dextrorotatory Octoclothepin, a neuroleptic drug, have been determined from diffractometer data, as has the absolute configuration of the latter. Crystals of racemic Octoclothepin are orthorhombic, space group Pna2₁, a= 1 265(4), b= 1 008(2), c= 1 412(5) pm. The structure was solved by Patterson convolution methods and refined by block-diagonal least-squares to R 0.040 (1 083 significant reflections). Crystals of (+)-Octoclothepin are orthorhombic, space group P2₁2₁2₁, a= 1 758(5), b= 1 260(4), c= 787(2) pm. The structure was solved by multisolution direct methods and refined by block-diagonal leastsquares to R 0.039 (1 079 significant data). The absolute configuration was determined to be S by means of an R-factor ratio test at termination of refinement (significant at <0.005 probability level) and confirmed by measurement of 50 Friedel pairs with Cu-K_α radiation.

The conformations of racemic and dextrorotatory molecules are practically identical despite different crystal packings. The central seven-membered ring folds about a line through S(5) and C(12), whereby atoms C(12) and C(13) are almost coplanar with the chlorine-substituted benzene ring. Despite removal of the constraint of a 10,11-double bond in the seven-membered heterocycle, the overall molecular conformation bears a strong resemblance to those of Loxapine, Clozapine, and HUF-2046, in that the mean plane of the piperazine ring lies roughly parallel to the plane of one of the benzene rings.