Process for the production of crystals of a benzoic acid derivative

#The present invention relates to a method for selective preparation of a particular crystal of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid useful as an active ingredient of a medicament.

#4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid has retinoid activity, and its use as an active ingredient of a medicament has been expected. Conventionally, this compound is known to exist at least as two kinds of crystal polymorphs, that is, (1) a crystal melting at 193° C. and (2) a crystal melting at 233° C. [see, Japanese Patent No. 3001632 as for (1), and Japanese Patent Unexamined Publication (Kokai) No. 61-76440 as for (2). (3) A crystal melting at 205.5° C. to 206.5° C. is disclosed in Chem. Pharm. Bull., 32, p.4209, 1984. However, this crystal was later reported to actually have the melting point of 231° C. to 232° C. and thus revealed to be identical to the crystal (2) (J. Cellular Physiology, 135, pp.179-188, 1988)].

#The crystal described in Japanese Patent No. 3001632, which melts at 193° C., is prepared by using a mixture of methanol and water as a recrystallization solvent. The crystal that melts at 233° C. is prepared by using a mixture of ethyl acetate and hexane as a recrystallization solvent. The latter crystal (melting point: 233° C.) contains 1200 ppm and 190 ppm of residual ethyl acetate and hexane, respectively, and thus has a problem that the crystal can hardly satisfy the standard values of residual solvents provided by the Ministry of Health and Welfare (ethyl acetate: 5000 ppm or less; hexane: 290 ppm). Whilst, the crystal that melts at 193° C. has a characteristic feature that a residual methanol level can be significantly lowered.

#The present invention will be explained more specifically with reference to the following examples. However, the scope of the present invention is not limited to these examples.

#4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid (10.0 g) was added to a mixture of ethanol (130 mL) and water (120 mL) and dissolved with heating, and then the solution was gradually cooled and the precipitated crystals were collected by filtration. The resulting wet crystals were dried at 110° C. to 120° C. under reduced pressure to obtain crystals. The resulting crystals were subjected to differential scanning calorimetry, and as a result, the crystals gave a single endothermic peak approximately at 233° C. Further, the powder X-ray diffraction pattern of the crystals was identical to the powder X-ray diffraction pattern shown in FIG. 6 of Japanese Patent No. 3001632, which verified that the crystals were type-II crystals.

#Crystals were obtained in the same manner as in Example 1 except that the recrystallization solvent was changed to a mixture of ethanol (150 mL) and water (100 mL). The resulting crystals were subjected to differential scanning calorimetry, and as a result, the crystals gave a single endothermic peak approximately at 233° C. Further, the powder X-ray diffraction pattern of these crystals was identical to the powder X-ray diffraction pattern shown in FIG. 6 in Japanese Patent No. 3001632, which verified that the crystals were type-II crystals.