Hydrate of micheliolide dimethylamine fumarate, preparation method and application thereof

A technology of dimethylamine fumarate and hydrate, which is applied in the field of microlactone dimethylamine fumarate hydrate, which can solve the problems of small particle size, poor stability and poor fluidity of crystal form A , to achieve the effect of solving small bulk density, increasing particle size and good fluidity

Active Publication Date: 2020-06-19
ACCENDATECH +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Chinese patent CN103724307B discloses mimilactone dimethylamine fumarate crystal form A and its preparation method. The patent uses XRPD to characterize crystal form A, expressed in 2θ at 7.10°, 7.58°, 11.72°, 12.26° , 13.30°, 14.24°, 15.70°, 16.38°, 17.04°, 19.02°, 19.86°, 20.14°, 20.66°, 21.20°, 21.78°, 22.64°, 23.58°, 23.8°, 24.48°, 25.08°, 26.24 °, 27.08°, 27.60°, 28.40°, 28.94°, 34.48°, 34.82°, 36.12°, 38.72°, and 45° have characteristic peaks, and crystal form A is prepared by recrystallization in ethyl acetate solvent. In this method Natural cooling is used to prepare products, and the crystallization process is controlled by thermodynamics and kineti

Method used

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  • Hydrate of micheliolide dimethylamine fumarate, preparation method and application thereof
  • Hydrate of micheliolide dimethylamine fumarate, preparation method and application thereof
  • Hydrate of micheliolide dimethylamine fumarate, preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Preparation of Hydrate of Milactone Dimethylamine Fumarate

[0043] Under the action of stirring, 0.293g of dimethylamine michelolactone and 0.116g of fumaric acid were added to the mixed solvent system of solvent S1 and solvent S2 whose temperature was constant at 30°C. The quality of solvent S1 was the same as that of solvent S2. Among them, solvent S1 is composed of 1.598g of acetone solvent and 0.16g of water, and solvent S2 is composed of 0.879g of ethyl acetate and 0.879g of diethyl ether. After reacting for 5 hours, filter and dry at 25°C for 6 hours under normal pressure to obtain michelactone dimethylamine Fumarate D crystal product. Thermogravimetric analysis / differential scanning calorimetry of the product and additional figure 1 Consistently, thermogravimetric analysis showed a 4.22% weight loss before decomposition, and differential scanning calorimetry showed a dehydration endothermic peak at 75°C and a characteristic melting peak at 148°C. The X-ray po...

Embodiment 2

[0045] Preparation of Hydrate of Milactone Dimethylamine Fumarate

[0046] Under the action of stirring, 1.758g of dimethylamine michelolactone and 0.58g of fumaric acid were added to the mixed solvent system of solvent S1 and solvent S2 whose temperature was constant at 50°C. The quality of solvent S2 was 2 times that of solvent S1. times, the solvent S1 is composed of 12.306g tetrahydrofuran solvent and 1.758g water, and the solvent S2 is composed of 21.096g isopropyl acetate and 7.032g methyl tert-butyl ether. After reacting for 8 hours, filter and dry under normal pressure at 30°C for 10 hours. A crystal form D product of mimilactone dimethylamine fumarate was obtained. Thermogravimetric analysis / differential scanning calorimetry of the product and additional figure 1 Consistently, thermogravimetric analysis showed a 4.20% weight loss before decomposition, and differential scanning calorimetry showed a dehydration endothermic peak at 78°C and a characteristic melting pea...

Embodiment 3

[0048] Preparation of Hydrate of Milactone Dimethylamine Fumarate

[0049] Under the action of stirring, 4.688g of dimethylamine michelolactone and 1.16g of fumaric acid were added to the mixed solvent system of solvent S1 and solvent S2 whose temperature was constant at 70°C. The quality of solvent S2 was 3 times that of solvent S1. times, the solvent S1 is composed of 39g 1,4-dioxane solvent and 7.88g water, and the solvent S2 is composed of 93.76g methyl acetate and 46.88g methyl ethyl ether. After reacting for 10h, filter and store under normal pressure at 45°C After drying for 8 hours, the crystal form D product of mimilactone dimethylamine fumarate was obtained. Thermogravimetric analysis / differential scanning calorimetry of the product and additional figure 1 Consistently, thermogravimetric analysis showed a 3.97% weight loss before decomposition, and differential scanning calorimetry showed a dehydration endothermic peak at 75°C and a characteristic melting peak at 1...

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Abstract

The invention relates to a hydrate of micheliolide dimethylamine fumarate, a preparation method and application thereof, wherein the hydrate is a crystal form D, is high in crystallinity, smooth in particle surface, free of coalescence, high in bulk density and good in flowability, and has good stability and good reproducibility. The preparation method comprises the following steps: under stirringeffect, adding dimethylamine micheliolide and fumaric acid into a mixed solvent system with a constant temperature of 30-70 DEG C, carrying out reaction crystallization; and filtering after the reaction is finished, and drying the filtered solid at normal pressure to obtain the micheliolide dimethylamine fumarate crystal form D. The preparation method is simple, the product yield is high, and themethod is suitable for later preparation of patent medicines, and is beneficial to large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicine crystallization, and in particular relates to a hydrate of mimilactone dimethylamine fumarate, a preparation method and application thereof. Background technique [0002] Parthenolide is a main active ingredient extracted from the Compositae herb Chamomile and Tansy. It is a natural sesquiterpene lactone compound. Traditionally, Parthenolide is mainly used for fever , rheumatoid arthritis, migraine, toothache and other diseases. In recent years, domestic and foreign studies have found that parthenolide also has anti-tumor effects, but this compound is unstable under acidic or alkaline conditions. [0003] In order to improve its stability, the compound parthenolide was modified to obtain Micheliolide. The English name is Micheliolide (MCL), which belongs to the guaiacane-type sesquiterpene lactone compound. There are relevant literature and patent reports on Micheliolide Esters have the effect o...

Claims

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Application Information

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IPC IPC(8): C07D307/93A61K31/343A61P35/02A61P35/00
CPCC07D307/93A61P35/02A61P35/00C07B2200/13
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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