Dimethylaminomicheliolide fumarate crystal form C and preparation method thereof

A technology of fumarate and dimethylamine, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of small particle size, easy aggregation, and small bulk density of crystal form A, and achieve high product yield and repeatability Good performance and easy preparation

Active Publication Date: 2020-06-19
ACCENDATECH +1
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Problems solved by technology

[0005] Patent CN103724307B discloses crystal form A of dimethylamine mignalactone fumarate and its preparation method. Although crystal form A has many advantages over amorphous dimethylamine mignalactone fumarate, crystal form A is more The density is small, only reaching 0.270g/mL, the particle size is small, the main particle size is 35.8μm, the coalescence is serious, the angle of repose is 62°, the fluidity is poor, and it is not convenient for post-production into medicine
In addition, crystal form A is prone to crystal transformation in a solvent environment, which affects storage and transportation, and will cause many problems in later processing and handling
[0006] In order to overcome the disadvantages of the existing technology and solve the problems of current crystal form A prod

Method used

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  • Dimethylaminomicheliolide fumarate crystal form C and preparation method thereof
  • Dimethylaminomicheliolide fumarate crystal form C and preparation method thereof
  • Dimethylaminomicheliolide fumarate crystal form C and preparation method thereof

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Experimental program
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Effect test

Embodiment 1

[0029]Put 0.03g of dimethylamine michelolactone fumarate raw material in a 4mL sample bottle, add 3g of acetone solvent to make it dissolved and in a supersaturated state, stir at 35°C, and perform solvent-mediated crystallization. After 24h The suspension was filtered to obtain a white solid, which was dried under normal pressure at 30°C for 6 hours to obtain crystals of dimethylaminomildolide fumarate. The X-ray powder diffraction pattern of the product is represented by 2θ at 6.4°, 7.4°, 11.6°, 12.1°, 13.1°, 14.5°, 15.1°, 15.5°, 15.9°, 18.3°, 18.6°, 19.3°, 20.5° , 22.0°, 26.9°, and 27.4° have characteristic peaks, of which 6.4° is the initial peak, and the relative intensity of the characteristic peak at 7.4° is 100%. In addition, the X-ray powder diffraction pattern of the product is represented by 2θ angle Angle also has characteristic peaks at 19.8°, 22.5°, 22.9°, 23.9°, 24.4°, 25.5°, 26.2°, 28.1°, 29.3°, 29.5°, 30.6°, 31.0°, 31.5°, and figure 1 unanimous. The DSC spec...

Embodiment 2

[0031] Put 3g of dimethylamine michelolactone fumarate raw material in a 150mL crystallizer, add 100g of acetonitrile solvent to dissolve it and make it in a supersaturated state, stir at 50°C, and perform solvent-mediated crystallization. After 48h, the The suspension was filtered to obtain a white solid, which was dried under normal pressure at 40°C for 10 h to obtain crystals of dimethylamine michelactone fumarate. The X-ray powder diffraction pattern of the product is represented by 2θ, at 6.6°, 7.6°, 11.8°, 12.3°, 13.3°, 14.7°, 15.3°, 15.6°, 16.0°, 18.5°, 18.8°, 19.5°, 20.7 °, 22.2°, 27.1°, and 27.6° have characteristic peaks, of which 6.6° is the initial peak, and the relative intensity of the characteristic peak at 7.6° is 100%. In addition, the X-ray powder diffraction pattern of the product is represented by 2θ angle Diffraction angles also have characteristic peaks at 20.0°, 22.7°, 23.1°, 24.1°, 24.6°, 25.7°, 26.4°, 28.3°, 29.5°, 30.7°, 31.2°, 31.7°, and figure 1 un...

Embodiment 3

[0033] Put 0.2g of dimethylamine michelolactone fumarate raw material in a 20mL sample bottle, add 10g of tetrahydrofuran solvent to dissolve and make it in a supersaturated state, stir at 45°C, and perform solvent-mediated crystallization. After 30h The suspension was filtered to obtain a white solid, which was dried under normal pressure at 35°C for 8 hours to obtain crystals of dimethylaminomildolactone fumarate. The X-ray powder diffraction pattern of the product is represented by 2θ, at 6.3°, 7.3°, 11.4°, 12.0°, 13.0°, 14.4°, 15.0°, 15.4°, 15.8°, 18.1°, 18.5°, 19.2°, 20.4 °, 21.9°, 26.9°, and 27.3° have characteristic peaks, of which 6.3° is the initial peak, and the relative intensity of the characteristic peak at 7.3° is 100%. In addition, the X-ray powder diffraction pattern of the product is represented by 2θ angle Diffraction angles also have characteristic peaks at 19.8°, 22.5°, 22.8°, 23.8°, 24.4°, 25.5°, 26.2°, 28.0°, 29.2°, 29.5°, 30.6°, 31.0°, 31.5°, and figure...

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Abstract

The invention relates to a dimethylaminomicheliolide fumarate crystal form C and a preparation method thereof, wherein X-ray powder diffraction results show that the crystal form C has characteristicpeaks at 2[theta] of 6.4+/-0.2 DEG, 7.4+/-0.2 DEG, 11.6+/-0.2 DEG, 12.1+/-0.2 DEG, 13.1+/-0.2 DEG, 14.5+/-0.2 DEG, 15.1+/-0.2 DEG, 15.5+/-0.2 DEG, 15.9+/-0.2 DEG, 18.3+/-0.2 DEG, 18.6+/-0.2 DEG, 19.3+/-0.2 DEG, 19.8+/-0.2 DEG, 20.5+/-0.2 DEG, 22.0+/-0.2 DEG, 22.5+/-0.2 DEG, 22.9+/-0.2 DEG, 23.9+/-0.2 DEG, 24.4+/-0.2 DEG, 25.5+/-0.2 DEG, 26.2+/-0.2 DEG, 26.9+/-0.2 DEG, 27.4+/-0.2 DEG, 28.1+/-0.2 DEG, 29.3+/-0.2 DEG, 29.5+/-0.2 DEG, 30.6+/-0.2 DEG, 31.0+/-0.2 DEG and 31.5+/-0.2 DEG, wherein the characteristic peak at 6.4+/-0.2 DEG is an initial peak, and the relative intensity of the characteristic peak at 7.4+/-0.2 DEG is 100%. According to the invention, the preparation process is constant-temperature suspension crystal transformation preparation, the process method is simple, easy to operate and good in reproducibility, the purity of the obtained product is 99% or above, the yield is higher than 90%, the stability is good, the bulk density is high, the surface is smooth, the completerod-like crystal habit is achieved, and the method is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical crystallization, and in particular relates to crystal form C of dimethylaminomimicrolactone fumarate and a preparation method thereof. Background technique [0002] Tumors, especially malignant tumors have caused serious harm to human health. At present, cytotoxic anticancer drugs are widely used clinically. This type of drug is like a double-edged sword. It has poor selectivity and strong toxic side effects, and it is also easy to develop drug resistance. More and more scientific studies have found that cancer stem cells are the source of most cancers' generation, development, recurrence, drug resistance and metastasis. The current clinical drug therapy and radiotherapy methods only target common cancer cells, but cannot selectively kill cancer stem cells. [0003] In recent years, the research and development of anticancer drugs has focused on finding compounds with anticancer activity...

Claims

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Application Information

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IPC IPC(8): C07D307/93
CPCC07D307/93C07B2200/13
Inventor 李中华龚俊波侯宝红吴送姑陈悦邱传将朱兴华齐杰王桂燕
Owner ACCENDATECH
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