Molecular and crystal structure of the hydrochloride monohydrate of (R)-N-[[1-(4-fluorobenzyl)-2-pyrrolidinyl]methyl]-5-bromo-2,3- dimethoxybenzamide, NCQ 115, a novel dopamine D2 receptor antagonist.

Abstract

The structure and absolute configuration of the title compound have been determined by single crystal X-ray diffraction analysis. The space group symmetry is R21; the monoclinic unit cell contains two molecules and has the dimensions a = 12.4291(8), b = 7.4511(5), c = 12.7854(7) angstroms and beta = 102.295(7) degrees. The planar conformation of the benzamide moiety is stabilized by an intramolecular (N)H...O bond. Hydrogen bonds connect the chloride anion to the protonated pyrrolidine N atom, and also the crystal water to the carbonyl oxygen of the amide group. The molecule has a folded conformation in which the N-fluorobenzyl substituent of the pyrrolidine ring and the H-bonded pseudo ring of the benzamide moiety are arranged in a sandwich-like manner. In the crystal, intermolecular hydrogen bonds link the drug molecules via the chloride anion and the hydrate molecule into endless helical chains around the twofold axis. The absolute configuration was determined by comparison of the wRtot values, 0.037 and 0.040, calculated using all measured 2027 unique, non-zero reflections and assuming R and S configuration for the chiral center, respectively. Refinement of the structural model with an R configuration resulted in the final indices of R = 0.031 and wR = 0.033 for 1512 reflections with I/delta(I) greater than 3.