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Crystallization is usually a highly selective process, and this selectivity is exploited in the pharmaceutical and other industries as a method of chemical purification. Relatively little is known about how polymorphism and solvate formation can influence the selectivity of crystallizations. We describe a piperidene pharmaceutical intermediate that can crystallize as either a hydrate or an anhydrous form, with very different purities. The exploitation of this effect is described, and an explanation in terms of the crystal structures is proposed.

Keywords: α-Amino acid / Cycloadditions / Nitrogen heterocycles 3-Spiro[pyrrolidino-oxindoles] were prepared in high yields from a three-component reaction between isatin, an α-amino acid, and a dipolarophile. Both N-substituted and N-unsubstituted α-amino acids were used as the amine component.

The structure of the potent dopamine-D2 antagonist, raclopride, (S)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamid e (+)-tartrate, has been determined by X-ray crystallography. The benzamide moiety of raclopride is planar in accordance with other salicylamides (FLA 797 and eticlopride). The planar conformation is stabilized by two intramolecular hydrogen bonds, i.e. one between the amide hydrogen and the methoxy group and one between the phenol hydrogen and the carbonyl group. The side-chain of raclopride has an extended conformation in contrast to the solid state conformations of FLA 797 and eticlopride. The side-chain conformations were studied by rigid rotations followed by MM2PI relaxations of the eight local minima found. Small energy differences (less than 4.0 kcal mol-1) exist between the various extended and folded conformations. Based on modelling studies with piquindone as template, it is suggested that the salicylamides with N-ethyl-2-pyrrolidinylmethyl side-chains interact with the dopamine-D2 receptor in a folded or a half-folded conformation.