Chiral Discrimination at the Solid State of Methyl 2-(Diphenylmethylsulfinyl)acetate Ludovic Renou, † Thomas Morelli, † Servane Coste, † Marie-Noe ¨lle Petit, † Benjamin Berton, ‡ Jean-Jacques Malandain, # and Gerard Coquerel* ,† Sciences et Me ´ thodes Se ´ paratiVes, UPRES EA 3233, IRCOF, UniVersite ´ de Rouen, 76821 Mont-Saint Aignan Cedex, France, Sciences et Me ´ thodes Se ´ paratiVes, UPRES EA 3233, UniVersite ´ de Rouen, 27002 EVreux Cedex, France, and Groupe de Physique des Mate ´ riaux UMR 6634 CNRS, UniVersite ´ de Rouen, 76801 Saint-E Ä tienne du RouVray, France ReceiVed January 23, 2007; ReVised Manuscript ReceiVed June 14, 2007 ABSTRACT: The present paper reports a study on the chiral discrimination at the solid state of methyl 2-(diphenylmethylsulfinyl)- acetate (hereafter, DMSAM) as a key intermediate in the synthesis of an acetamide derivative (modafinil). A partial solid solution (i.e., stable “racemic conglomerate” with partial miscibility at the solid state) between enantiomers was characterized by X-ray single crystal analyses and high performance liquid chromatography (HPLC). Binary and ternary phase diagrams of DMSAM were investigated by HPLC measurements, differential scanning calorimetry (DSC), discontinuous isoperibolic thermal analysis (DITA), and Raman spectroscopy. Finally, the distribution of the two enantiomers inside single crystals was studied by dissolution and Raman microspectroscopy. Introduction The development of chiral drugs is an important issue for pharmaceutical companies 1 because each enantiomer has its specific biological activity (and side effects). At the end of the 1990s, guidelines from the Food and Drug Administration (FDA) changed the strategy of pharmaceutical industries toward chiral drugs. 2 Since then, the commercialization of single active enantiomers is preferred. 3 The access to a single enantiomer can result from a stereoselective synthesis or from a preparative resolution followed by purification. Nevertheless, enantiomeric purification performances by means of selective crystallization are strongly dependent on the nature of the solid phases that can be crystallized out of a mixture of enantiomers. In the case of crystallization of chiral molecules, “racemic compounds” 4 represent 90-95% and the “racemic conglomerates” 4,5 represent 10-5%. The formation of solid solutions 4 is a much more uncommon phenomenon (less than 1% of the cases lead to mixed crystals 4 ). 6 Complete solid solutions among enantiomers were first classified by Rozeboom: 7 type I corresponds to an ideal solid solution, types II and III correspond, respectively, to solid solution with a maximum and a minimum melting point at the racemic composition. 8 Type I of solid solutions corre- sponds to liquid crystals or plastic crystals with static and/or dynamic disorders. These compounds have usually a molecular shape nearly spherical (i.e., camphor). 9,10 Type II or III can also be metastable and connected to polymorphism. 8,11 The chiral discrimination at the solid state can therefore exhibit sharp differences from one crystal lattice to another. 8,9,12-14 In a more recent review, partial solid solutions (i.e., stable “racemic conglomerates” with partial miscibility at the solid state) with and without polymorphism and critical points have been discussed in detail. 15 Several types of local orders up to superstructures have been presented and will be examined in this study. Methyl 2-(diphenylmethylsulfinyl)acetate (DMSAM) 16 (Fig- ure 1) is an intermediate in the synthesis of the drug modafinil. As illustrated in this study, it is a new example of limited chiral discrimination at the solid state. This paper aims at understand- ing the formation of mixed crystals. This study is also focused on the possible existence of a local order (i.e., the existence of clusters) inside single crystals. Experimental Section Materials. DMSAM as an R enantiomer (R(-)DMSAM) and racemic mixture ((()DMSAM) were supplied by Cephalon France (Mitry Mory, France). Differential Scanning Calorimetry (DSC). DSC was performed on a Setaram DSC 141 instrument. Samples (15-20 mg) were put in a 30 µL open aluminum crucible and melted under a fixed heating rate (2 or 1 °C/min). No purging gas was used. The system was calibrated with indium (mp 156.6 °C) and benzoic acid (secondary standard). Crystal Growth. Single crystals of batches I, II, III, IV, V, VI, and VII (Figure 2) were grown at room temperature by the slow evaporation of ethanolic solutions with enantiomeric excesses (hereafter e.e. 4 ) of 100% (I), 80% (II), 75% (III), 60% (IV), 40% (V), 20% (VI), and 0% (VII). Single crystals of batch VIII were obtained in a thermostated vial by lowering the temperature of ethanolic solutions with 0% e.e. from 20((0.2) °C to 5((0.2) °C. Single crystals of batch IX were grown by a slow evaporation of saturated ethanolic solutions (0% e.e.) in a thermostated vial at 20((0.2) °C. Single crystals of batch X were grown in a gel composed of 0.8 g of (()DMSAM, 1 mL (12.5%(v/v)) of tetramethoxysilane (TMOS), 3 mL of N,N-dimethyl- formamide (DMF), 4 mL of water, and two drops of 0.5 N NaOH. The gel was then formed at 40 °C in a drying oven. The crystallization occurred by lowering the temperature to 20 °C. 17 Crystal Structure Determination. Selected single crystals were stuck on a glass fiber. Data collections were performed on a Bruker * Corresponding author. E-mail: gerard.coquerel@univ-rouen.fr. † Sciences et Me ´thodes Se ´paratives, UPRES EA 3233, IRCOF. ‡ Sciences et Me ´thodes Se ´paratives, UPRES EA 3233. # Groupe de Physique des Mate ´riaux UMR 6634 CNRS. Figure 1. Formula and properties of methyl 2-(diphenylmethylsulfi- nyl)acetate (DMSAM). CRYSTAL GROWTH & DESIGN 2007 VOL. 7, NO. 9 1599 - 1607 10.1021/cg070075f CCC: $37.00 © 2007 American Chemical Society Published on Web 08/01/2007