New polymorphic forms of N-[4-(trifluoromethyl)benzyl]-4-methoxybutyramide
A technology of methoxybutyramide and trifluoromethyl, applied in the field of treatment of alcoholism, can solve the problems of lack of reproducibility, expensive purification, unsuitability and the like, and achieve the effect of reducing spontaneous consumption
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[0057] The above mentioned process for the preparation of polymorph A, i.e. the preferred aspects of the preparation of benzylamine in step (i) and all the advantageous features of steps (i) and (ii) are for the process for the preparation of polymorph B are identical and are hereby incorporated by reference.
[0058] According to the present invention, polymorph A and polymorph B are conveniently obtained by a simple method which also avoids the chromatographic methods used in order to obtain pure crystalline forms and, more advantageously, which has reproducible properties and can selectively obtain the desired crystalline form in a stable form.
[0059] Crystalline polymorphs A and B can be obtained by figure 1 and 2 They are distinguished by their X-ray powder patterns shown, and they can also be distinguished by their infrared spectra in the experimental part.
[0060] Both crystalline polymorphs A and B are thermodynamically stable and cannot be converted from one cry...
Embodiment 1
[0074] Example 1: Preparation of polymorph A of N-[4-(trifluoromethyl)benzyl]-4-methoxybutanamide
[0075] A) Preparation of 4-trifluoromethylbenzylamine
[0076] In the reactor, add 15kg of distilled water, 2.50kg of sodium acetate, 2.30kg of hydroxylamine hydrochloride, and 4.00kg of methanol. At room temperature, 5.0 kg of trifluoromethylbenzaldehyde were added, and the mixture was first stirred for thirty minutes, and then 5 kg of solvent were distilled off under vacuum. Subsequently, 12.0 kg of 80% acetic acid were added and then 4.5 kg of zinc were added in portions, whereby the temperature rose to 60-80° C. due to the exotherm. Subsequently, this temperature is maintained by cooling. At the end of this reaction, 10.0 kg of toluene and 15.0 kg of 30% ammonia were added to remove zinc salts. The material obtained was stirred at 50-60° C. and then the lower aqueous phase was removed.
[0077] After distillation under vacuum to half volume, the toluene solution containi...
Embodiment 2
[0083] In the reactor, 3.8 kg of crude N-[4-(trifluoromethyl)benzyl]-4-methoxybutanamide (the corresponding wet product), 3.8 kg of ethyl acetate and 11.4 kg of n-Hexane. The substance is heated to 40-60°C until a fully dissolved solution is obtained, and then the solution is cooled to 25-35°C. 0.038 kg of polymorph A of N-[4-(trifluoromethyl)benzyl]-4-methoxybutanamide crystallized out. The mass is kept at 25-35°C for at least 1 hour, and then cooled to 10-20°C and held at this temperature again for at least 1 hour. Subsequently, the material was centrifuged by washing with a mixture prepared previously and containing 0.76 kg of ethyl acetate, 2.28 kg of n-hexane. The product obtained is dried at 40-50°C. 3.4 kg of polymorph A of N-[4-(trifluoromethyl)benzyl]-4-methoxybutanamide are obtained. Yield: 89.5% Example 2: Preparation of polymorph B of N-[4-(trifluoromethyl)benzyl]-4-methoxybutanamide
[0084]Crude N-[4-(trifluoromethyl)benzyl]-4-methoxybutyramide was obtained ...
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