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Crystalline form of butlutamide and preparation method thereof

A technology of bulutamide and crystal form, which is applied in the directions of medical preparations containing active ingredients, pharmaceutical formulations, organic chemistry, etc., can solve the problem of not providing information on the crystal form of bulutamide, etc., and achieves easy storage and processing. , good processability, good stability effect

Active Publication Date: 2020-02-21
BEIJING HOPE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, CN104341351A and CN201510015415.0 provide no information on the crystalline form of buglutamide

Method used

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  • Crystalline form of butlutamide and preparation method thereof
  • Crystalline form of butlutamide and preparation method thereof
  • Crystalline form of butlutamide and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Preparation of bulutamide β-crystal form

[0045] The preparation method of bulutamide refers to N-methyl-5-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo in Example 41 of CN104341351 -2-thiotetrahydroimidazol-1-yl-butyl]-3-fluorobenzamide, namely the method of bulutamide, to obtain bulutamide.

[0046] At 25°C, 5g of bulutamide was added to a mixed solvent of 48ml of acetone and water (2:1 v / v), the reaction system was heated to reflux, stirred for 15 minutes, cooled to room temperature naturally, and stirred at room temperature 6 hours.

[0047] After filtration, the filter cake was washed with 5 ml of acetone and water (2:1 v / v), and the filter cake was dried in a vacuum blast drying oven at 60°C for 8 hours to obtain 4.2 g of white needle crystals with a yield of 84%.

Embodiment 2

[0048] Example 2: Preparation of the amorphous form of bulutamide

[0049] Under the condition of 25°C, 5 g of bulutamide β-crystal form raw material was put into 60 ml of tetrahydrofuran, the reaction system was heated to reflux for 30 minutes, and stirred for 4 hours under the reflux state. The solution was cooled to 65°C and filtered while hot through a pad of celite.

[0050] The obtained filtrate was cooled to 50° C., under vigorous stirring, the filtrate was added to 100 ml of n-hexane within 20 minutes, and the stirring was continued at room temperature for 2 hours.

[0051] The suspension was filtered and the filter cake was dried under vacuum at 60°C to give 3.8 g of the title compound in 76% yield.

Embodiment 3

[0052] Example 3: Preparation of bulutamide α-crystal form

[0053] At 25°C, 5 g of bulutamide β-crystalline form or amorphous form was put into 55 ml of methyl tert-butyl ether solvent, the reaction system was heated to reflux for 30 minutes, and stirred for 2 hours under reflux. The reaction system was cooled to 65°C, filtered through a celite layer while hot, and the filter layer was washed with 8 ml of methyl tert-butyl ether.

[0054] The obtained filtrate was cooled to 45°C, and the stirring was continued for 2 hours. The obtained reaction system was rapidly cooled to 5° C. within 5 minutes, and kept stirring for 2 hours to produce off-white slurry, which was kept at 5-10° C. for 18 hours.

[0055]The suspension was filtered, the filter cake was washed with 5 ml of methyl tert-butyl ether, and the filter cake was dried in a vacuum blast drying oven at 60 °C for 8 hours to obtain 3.5 g of the title compound as a white crystalline powder, yield 70% .

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Abstract

The invention relates to a crystallization form of N-methyl-5-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thiotetrahydroimidazol-1-yl-butyl]-3-fluorobenzamide and a preparation method thereof. The invention provides a new crystal form of the N-methyl-5-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thiotetrahydroimidazol-1-yl-butyl]-3-fluorobenzamide. Characteristic peaks are formed at 6.20 degrees, 9.94 degrees, 11.16 degrees, 12.30 degrees, 16.48 degrees, 19.80 degrees, 20.70 degrees, 22.06 degrees, and 27.12+ / -0.2 degrees on an X-ray powder diffraction pattern expressed by a 2<theta> diffraction angle. The new crystal form disclosed by the invention is stable in thermodynamic properties, good in solubility and especially suitable for pharmaceutical preparations.

Description

technical field [0001] The present invention relates to a new crystal form of medicine, specifically N-methyl-5-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo -2-thiotetrahydroimidazol-1-yl-butyl]-3-fluorobenzamide, the α-crystal form of bulutamide with the general name, and a preparation method thereof. Background technique [0002] N-methyl-5-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thiotetrahydroimidazol-1-yl -Butyl]-3-fluorobenzamide (compound of formula I), also known as bulutamide [0003] [0004] The preparation method and use thereof, especially its use as an androgen receptor antagonist for the treatment of hyperproliferative diseases, are described in Example 41 of the CN104341351A patent application published on February 11, 2015. [0005] Chinese patent application NO.201510015415.0 describes a method for preparing key intermediates of diarylthiohydantoin derivatives. [0006] However, CN104341351A and CN201510015415.0 do not prov...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/86A61K31/4174A61P5/28
Inventor 狄维吴滨浮绍东
Owner BEIJING HOPE PHARMA
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