A method for preparing flupirtine maleate with a crystal form high bulk density

A technology of flupirtine maleate and flupirtine, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of inability to obtain high bulk density crystal form A, failure to meet preparation requirements, serious electrostatic adsorption, etc., and achieve crystal The effect of stable type content, low cost and high bulk density

Active Publication Date: 2022-05-27
SICHUAN QINGMU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Chinese patent CN102850264A provides a method for preparing flupirtine maleate crystal A, in which maleic acid methanol solution is added dropwise into flupirtine methanol solution, the method prepares crystal A with a small bulk density, serious electrostatic adsorption, and a flocculent shape. Difficult to crush, unable to meet the requirements of subsequent formulations
Unable to obtain crystal form A with high bulk density

Method used

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  • A method for preparing flupirtine maleate with a crystal form high bulk density
  • A method for preparing flupirtine maleate with a crystal form high bulk density
  • A method for preparing flupirtine maleate with a crystal form high bulk density

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Under nitrogen protection, add 10 g of flupirtine white partial ash refined product into a 1000 m3 three-necked flask, add 250 g of isopropanol, 10 g of DMSO, heat the internal temperature to 30 ° C, mechanically stir to dissolve, the rotating speed is 200 rpm / min, 4.0 g of horse The acid was dissolved in 20.0 g isopropanol and added dropwise to a three-necked flask, reacted for 1 h, filtered, rinsed with a small amount of isopropanol, and drained to obtain white crystals, which were dried in vacuum to obtain pure flupirtine maleate 13.1 g, the yield is 95%. It was confirmed to be pure A crystal form by X powder diffraction.

[0037] The diffraction angle, interplanar spacing and relative intensity of A crystal are shown in the following table:

[0038]

[0039] 1 HNMR (500MHz, DMSO-d6) δ:

[0040] 8.342(s,1H), 7-8(m,5H), 6.152(s,2H), 5.79(d,1H), 4.385(s,2H), 4.03(t,2H), 1.193(m,3H) .

[0041] A crystal infrared spectrum at 1170cm -1 There is an absorption peak...

Embodiment 2

[0044] Under nitrogen protection, add 20 g of flupirtine white partial ash refined product into a 2000 ml three-necked flask, add 830 g of propanol, 40 g of DMSO, heat the internal temperature to 50 ° C, mechanically stir to dissolve, rotate at 400 rpm / min, and add 9.1 g of Malay The acid was dissolved in 50.0 g of propanol and added dropwise to a three-necked flask, reacted for 1 h, filtered, rinsed with a small amount of propanol, and drained to obtain white crystals, which were dried in vacuum to obtain 26.2 g of pure flupirtine maleate. rate 95%. It was confirmed to be pure A crystal form by X powder diffraction.

[0045] X-Powder Diffraction, 1 HNMR and infrared spectra were consistent with Example 1.

Embodiment 3

[0047] Under nitrogen protection, add 30 g of flupirtine white partial ash refined product into a 2000 ml three-necked flask, add 1200 g of acetonitrile, 60 g of DMSO, heat the internal temperature to 35 ° C, mechanically stir to dissolve, rotate speed 250 rpm / min, add 12.0 g of maleic acid Dissolve with 90.0 g of acetonitrile and add dropwise into a three-necked flask, react for 1 h, filter, rinse with a small amount of acetonitrile, and drain to obtain white crystals, which are dried in vacuum to obtain 39.7 g of pure flupirtine maleate, with a yield of 96% . It was confirmed to be pure A crystal form by X powder diffraction.

[0048] X-Powder Diffraction, 1 HNMR and infrared spectra were consistent with Example 1.

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Abstract

The invention discloses a method for preparing flupirtine maleate with crystal form A and high bulk density, specifically dissolving flupirtine in a mixed solvent containing DMSO and solvent X, and then adding the maleic acid solution into the flupirtine solution , stirred, and after the crystals are fully separated, filtered, washed, and dried to obtain the high bulk density crystal A flupirtine maleate product. The flupirtine maleate prepared by the method of the invention has high bulk density, stable crystal form content, can meet the requirements of high-quality preparation production, has strong process repeatability, simple process condition requirements, low cost, and is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy and relates to a high bulk density preparation method of flupirtine maleate A crystal. Background technique [0002] Flupirtine maleate is a novel non-opioid pain reliever that was marketed in Germany in 1986 for the treatment of postoperative pain, toothache, wound and burn pain, and was later re-marketed for the treatment of degenerative joint disease, neurological and Cancer pain, migraines, headaches and dysmenorrhea. [0003] [0004] US4481205 first described the crystal form of flupirtine maleate, explained the existence of polymorphism of flupirtine maleate, and disclosed the preparation method of crystal form B, and also disclosed the preparation method of the mixture of A and B, However, there is no preparation method and bulk density of A crystal form. [0005] Chinese patent CN104086481A provides a method for preparing a crystal form of flupirtine maleate A: the flupirtine solutio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/89
CPCC07D213/89C07B2200/13
Inventor 任良卢铁刚李晓迅邵波王颖
Owner SICHUAN QINGMU PHARMA CO LTD
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