Patent FR-2849029-A1 (FR)
Title: Production of new or known crystalline forms of enantiomers of modafinil, useful e.g. for treating hypersomnia and stimulating cognition, by crystallization from solvents other than ethanol
Inventor: NECKEBROCK OLIVIER
IPC: A61P25/00
Filed: 2002-12-20
Abstract: Production of crystalline forms (specifically polymorphic forms or solvates) of enantiomers of modafinil (A) involves dissolving an enantiomer of (A) (preferably the levorotatory isomer, (-)-(A)) in a solvent other than ethanol, crystallizing the enantiomer and recovering the obtained crystalline form. Some polymorphic forms and solvates of (-)-(A) are new.  Independent claims are included for: (a) the following new polymorphic forms of (-)-(A): (i) Form II, having an X-ray diffraction pattern with maxima corresponding to interplanar spacings of 8.54 Angstrom, 7.57 Angstrom, 7.44 Angstrom, 4.56 Angstrom, 3.78 Angstrom and 3.71 Angstrom; (ii) Form III, having an X-ray diffraction pattern with maxima corresponding to interplanar spacings of 12.58 Angstrom, 8.54 Angstrom, 5.01 Angstrom, 4.10 Angstrom, 3.97 Angstrom and 3.20 Angstrom; and (iii) Form IV, having an X-ray diffraction pattern with maxima corresponding to interplanar spacings of 12.38 Angstrom, 8.58 Angstrom, 7.34 Angstrom, 5.00 Angstrom and 4.09 Angstrom;  (b) a new dimethyl carbonate solvate of (-)-(A), having an X-ray diffraction pattern with maxima corresponding to interplanar spacings of 12.31 Angstrom, 9.69 Angstrom, 9.09 Angstrom, 8.54 Angstrom, 7.27 Angstrom, 6.21 Angstrom, 5.45 Angstrom, 5.10 Angstrom, 5.00 Angstrom, 4.83 Angstrom, 4.63 Angstrom, 4.46 Angstrom, 4.22 Angstrom, 4.21 Angstrom, 4.09 Angstrom, 3.78 Angstrom, 3.62 Angstrom, 3.53 Angstrom, 3.42 Angstrom, 3.32 Angstrom, 3.24 Angstrom, 3.21 Angstrom and 3.10 Angstrom;  (c) a method for converting a first crystalline form of an enantiomer of (A) (specifically Form I of (-)-(A)) into another crystalline form, involving suspending the first crystalline form in a suitable solvent and recovering the second form (the solvate specifically being acetonitrile, with the product being recovered as acetonitrile solvate);  (d) a new acetonitrile solvate of (-)-(A), having an X-ray diffraction pattern with maxima corresponding to interplanar spacings of 16.17 Angstrom, 14.14 Angstrom, 12.32 Angstrom, 10.66 Angstrom, 9.79 Angstrom, 9.29 Angstrom, 8.54 Angstrom, 8.15 Angstrom, 7.80 Angstrom, 7.09 Angstrom, 6.31 Angstrom, 5.83 Angstrom, 5.62 Angstrom, 5.41 Angstrom, 5.10 Angstrom, 4.90 Angstrom, 4.66 Angstrom, 4.58 Angstrom, 4.46 Angstrom, 4.33 Angstrom, 4.20 Angstrom, 4.02 Angstrom, 3.92 Angstrom, 3.835 Angstrom, 3.72 Angstrom, 3.60 Angstrom, 3.57 Angstrom, 3.45 Angstrom, 3.33 Angstrom, 3.24 Angstrom, 3.19 Angstrom, 3.0 Angstrom and 3.03 Angstrom;  (e) the preparation of optically active (A) from modafinic acid (B) by: (i) optically resolving (+/-)-(B) and recovering at least one of the enantiomers; (ii) contacting one of the enantiomers with a lower alkyl haloformate in presence of alcohol and organic base; and (iii) converting the obtained ester into the amide; and  (f) the preparation of an enantiomer of (A) by optically resolving (+/-)-(B) (or its salt) by preferential crystallization and converting the obtained enantiomer into (A) (optionally via a lower alkyl ester).