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Method for preparing polymorph-A flupirtine maleate with high bulk density

A technology of flupirtine maleate and flupirtine, applied in the directions of organic chemistry, organic chemistry, etc., can solve the problems of inability to obtain high bulk density A crystal form, unable to meet preparation requirements, and low bulk density of A crystal, Achieve the effect of stable crystal content, suitable for industrial production and low cost

Active Publication Date: 2018-12-21
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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  • Method for preparing polymorph-A flupirtine maleate with high bulk density
  • Method for preparing polymorph-A flupirtine maleate with high bulk density
  • Method for preparing polymorph-A flupirtine maleate with high bulk density

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Experimental program
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Effect test

Embodiment 1

[0036] Under the protection of nitrogen, add 10g of flupirtine white gray refined product into a 1000ml three-necked flask, add 250g of isopropanol, 10g of DMSO, heat the inner temperature to 30°C, stir it mechanically, and dissolve it at a speed of 200rpm / min. Add 4.0g of horse Dissolve the acid with 20.0g of isopropanol and add it dropwise into a three-necked flask, react for 1h, filter, rinse with a small amount of isopropanol, and drain to obtain white crystals, which are then vacuum-dried to obtain pure flupirtine maleate 13.1 g, yield 95%. It was confirmed as pure A crystal form by X powder diffraction.

[0037] The diffraction angle, interplanar spacing and relative intensity of crystal A 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,lH), 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 nearby, and the B crys...

Embodiment 2

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

[0045] X powder diffraction, 1 HNMR and infrared spectrum are consistent with embodiment 1.

Embodiment 3

[0047] Under the protection of nitrogen, add 30g of flupirtine white gray refined product into a 2000ml three-necked flask, add 1200g of acetonitrile, 60g of DMSO, heat the inner temperature to 35°C, stir and dissolve with a speed of 250rpm / min, and dissolve 12.0g of maleic acid Dissolved with 90.0g of acetonitrile and added dropwise into a three-necked flask, reacted for 1h, filtered, rinsed with a small amount of acetonitrile, and dried to obtain white crystals, dried in vacuum to obtain 39.7g of pure flupirtine maleate, with a yield of 96% . It was confirmed as pure A crystal form by X powder diffraction.

[0048] X powder diffraction, 1 HNMR and infrared spectrum are consistent with embodiment 1.

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Abstract

The invention discloses a method for preparing polymorph-A flupirtine maleate with high bulk density. The method comprises the following steps: dissolving flupirtine by adopting a mixed solvent comprising DMSO and a solvent X, adding a maleic acid solution into flupirtine solution, stirring, after crystals are sufficiently and completely precipitated, filtering, washing, and drying, thus obtainingthe polymorph-A flupirtine maleate product with high bulk density. The prepared flupirtine maleate prepared in the method of the invention has high bulk density and stable crystal content, can meet the production requirement of high-quality preparations, and is high in process repetition, simple in process condition requirement, low in cost and more suitable for the industrialized production.

Description

technical field [0001] The invention belongs to the field of chemical industry and pharmacy, and relates to a high-bulk-density preparation method of flupirtine maleate A crystal. Background technique [0002] Flupirtine maleate is a new type of non-opioid analgesic, which was launched in Germany in 1986 for the treatment of postoperative pain, toothache, wound and burn pain, and then re-marketed for the treatment of degenerative joint disease, nerve and Cancer Pain, Migraines, Headaches and Dysmenorrhea. [0003] [0004] US4481205 first described the crystal form of flupirtine maleate, explained the existence of polymorphic forms of flupirtine maleate, disclosed the preparation method of crystal form B, and also disclosed the preparation method of A and B mixtures, However, there is no preparation method and bulk density of Form A. [0005] Chinese patent CN104086481A provides a preparation method of flupirtine maleate A crystal form: rapidly adding flupirtine solutio...

Claims

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Application Information

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Patent Type & Authority Applications(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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