Dimethyl fumarate preparation method

A technology of dimethyl fumarate and fumaric acid, applied in the field of chemistry, can solve problems such as irritating reactions, cumbersome steps, and great safety risks for workers

Inactive Publication Date: 2017-01-11
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this patent, the crystal form and particle size of dimethyl fumarate are controlled through two operations—recrystallization control and crushing control respectively, and the steps are cumbersome; the dust of dimethyl fumarate in the crushing process has serious harm to the human body Irritant reaction, which may cause harm to the operator, and there is a greater safety risk to the workers in the scale-up production

Method used

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preparation example Construction

[0064] The invention discloses a method for preparing dimethyl fumarate, and those skilled in the art can refer to the content of this article and appropriately improve the process parameters to realize it. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and the relevant personnel can obviously make changes or appropriate changes and combinations to the method and application described herein without departing from the content, spirit and scope of the present invention to realize and Apply the technology of the present invention.

[0065] The content of the present invention is the post-treatment process of dimethyl fumarate and the control process of crystal form and particle size. Through the improvement of the process, the fu...

Embodiment 1

[0090] Embodiment 1: the synthesis of dimethyl fumarate crude product

[0091] Add 70L of methanol into a 100L reactor, slowly add 1.4kg of sulfuric acid, and stir at a speed of about 150±50 rpm; after the sulfuric acid methanol solution is prepared, add 14kg (mol) of fumaric acid, and heat to reflux for more than 8 hours. HPLC detects that raw material reaction is complete and can stop reaction. After the reaction is stopped, the reaction is pumped into a container containing 140L of ice water while it is hot. Stir continuously during the operation. As the temperature decreases, a large amount of white powder solids precipitate out. Continue to stir for 1 hour, and centrifuge with a 400-mesh filter cloth to obtain fuma Crude dimethyl ester. The crude product is subject to further purification.

[0092]

[0093] Synthesis of Crude Dimethyl Fumarate

Embodiment 2

[0094] Embodiment 2: post-treatment of dimethyl fumarate crude product

[0095] The crude dimethyl fumarate obtained in Example 1 was dissolved in 84L of ethyl acetate and then added to a 150L extraction kettle. Added 30L of saturated sodium bicarbonate solution and stirred for 10 minutes at a speed of 150±50 rpm. After stirring, let it stand for stratification, separate the lower aqueous phase, and continue to wash the upper organic phase twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The amount of washing solution is 30L / time to ensure that the pH of the aqueous phase solution is 7. . The organic phase was dried with 5 kg of anhydrous sodium sulfate for 30 minutes, and separated by filtration to obtain an ethyl acetate solution of dimethyl fumarate. The synthetic specific process of dimethyl fumarate crude product is as follows:

[0096]

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Abstract

The invention relates to the chemical field, and especially relates to a dimethyl fumarate preparation method. The method adopts a chemical way to control the crystal form and the granularity of a BG-12 raw agent in a one step manner. The method realizes re-crystallization and crushing operating processes in the prior art only through one operating process in order to obtain pharmaceutical production meeting granularity, so severe irritant reaction brought for operators is avoided, and the production safety is greatly improved. The method has the advantages of simplicity in operation, easiness in control of parameters, stable result, and suitableness for large-scale production. The raw medicine with different granularity ranges can be obtained through adjusting technological parameters in order to avoid dust pollution, difficulty cleaning and allergy brought by crushing.

Description

technical field [0001] The invention relates to the chemical field, in particular to a preparation method of dimethyl fumarate. Background technique [0002] BG-12 (dimethyl fumarate) is an oral therapy indicated for the treatment of adults with relapsing-remitting multiple sclerosis (RRMS), the most common form of MS. BG-12 is manufactured by BiogenIdec. becomes the third disease-modifying oral drug for MS, the others including fingolimod (Gilenya) and teriflunomide (Aubagio). Dimethyl fumarate has a novel mechanism of action relative to existing MS drugs, in that it is thought to activate the nuclear factor-like-2 transcriptional pathway, thereby reducing oxidative stress that leads to demyelination. [0003] According to the research institution, two placebo-controlled phase III clinical trials, DEFINE and CONFIRM, serve as the basis for approval. The two trials enrolled a total of 2700 patients. In addition to comparing the drug to placebo, the CONFIRM trial included...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/08C07C69/60C07C67/48C07C67/52
CPCC07C67/08C07C67/48C07C67/52C07C69/60
Inventor 陈新亮宓鹏程陶安进马亚平袁建成
Owner HYBIO PHARMA
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