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Method for synthesizing hydrochloric acid baclofen

A technology of baclofen hydrochloride and synthetic method, which is applied in the field of drug synthesis, can solve the problems of expensive phase transfer catalyst, high toxicity of solvent toluene, and long synthetic process route, achieve good industrial prospects, simple reaction process, and avoid low temperature reaction Effect

Inactive Publication Date: 2012-02-15
HEBEI UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] This method has disadvantages: (1) the synthesis process route is long; (2) 3-p-chlorophenyl acrylate and nitromethane need to carry out Michael addition reaction in toluene under 0 ℃ and under the catalysis of phase transfer catalyst to prepare 3 -Nitro-3-p-chlorophenylpropionate, low temperature reaction requires high equipment and large investment; phase transfer catalyst is expensive, and the use of phase transfer catalyst brings trouble to the separation and purification of products; solvent toluene is more toxic , it is not safe to use

Method used

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  • Method for synthesizing hydrochloric acid baclofen
  • Method for synthesizing hydrochloric acid baclofen
  • Method for synthesizing hydrochloric acid baclofen

Examples

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Embodiment 1

[0029] First prepare the used ultrafine potassium carbonate of the present invention, 100g potassium carbonate, 500g dehydrated alcohol are added grinder, seal all grinder openings, grind 5h under normal temperature, sampling, the average particle diameter of testing potassium carbonate by particle size distribution is 500nm , pour out spare. Wherein, the grinding time length, and the input amount of potassium carbonate, the input amount of dehydrated alcohol etc. all can affect the particle diameter of the ultrafine potassium carbonate prepared at last, the required potassium carbonate particle diameter of following embodiment is at 100~1000nm All have better performance.

[0030] Add 4-chlorophenylacetonitrile, ethyl bromoacetate, and superfine potassium carbonate into the reactor at a molar ratio of 1.00:1.05:1.3, and at the same time add 5 times the mass of absolute ethanol to superfine potassium carbonate, and react at 30°C for 10 hours , filtered, and the filtrate was c...

Embodiment 2

[0034] Add 200g of potassium carbonate and 1200g of absolute ethanol into the grinder, close all the openings of the grinder, grind for 6 hours at room temperature, take a sample, test the average particle size of potassium carbonate by particle size distribution to be 200nm, and pour it out for later use.

[0035] Add 4-chlorophenylacetonitrile, ethyl bromoacetate, and superfine potassium carbonate into the reactor at a molar ratio of 1.00:1.20:2.0, and at the same time add methanol 10 times the mass of superfine potassium carbonate, react at 70°C for 4 hours, and filter , the filtrate was concentrated to give white solid 3-(4-chlorophenyl)-3-cyanopropionic acid ethyl ester, yield 95%, mp56~57°C.

[0036] The white solid 3-(4-chlorophenyl)-3-cyanopropionic acid ethyl ester and Raney nickel obtained in the above reaction were mixed in 3-(4-chlorophenyl)- Put the methanol of ethyl cyanopropionate into the dry hydrogenation kettle in turn, start stirring after sealing, first rep...

Embodiment 3

[0039] Add 300g of potassium carbonate and 1500g of absolute ethanol into the grinder, close all the openings of the grinder, grind for 8 hours at room temperature, take a sample, and test the average particle size of potassium carbonate by particle size distribution to be 230nm, pour it out for later use.

[0040] Add 4-chlorophenylacetonitrile, ethyl bromoacetate, and superfine potassium carbonate into the reactor at a molar ratio of 1.00:1.20:1.7, and at the same time add methanol 10 times the mass of superfine potassium carbonate, react at 60°C for 6 hours, and filter , and the filtrate was concentrated to obtain ethyl 3-(4-chlorophenyl)-3-cyanopropionate (II) as a white solid, yield 96%, mp 56-57°C.

[0041]Add 20 g of 3-(4-chlorophenyl)-3-cyanopropionic acid ethyl ester (II) and 100 ml of water obtained by the above reaction into a reactor equipped with a reflux device, stir carefully in batches at room temperature Add 12g of sodium borohydride (NaBH 4 ), continue to st...

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Abstract

The invention relates to a novel method for synthesizing medicament hydrochloric acid baclofen. The method comprises the following steps of: adding 4-chlorobenzene acetonitrile, bromoacetate and ultrafine potassium carbonate into C1-C4 low carbon alcohol, reacting at the temperature of 30-70 DEG C, filtering and removing a potassium salt, and concentrating the filtrate to obtain a white solid, i.e., 3-(4-chlorphenyl)-3-cyan ethyl propionate (II) of which the melting point is 56-57 DEG C; undergoing a hydrogenation reduction reaction on the white solid (II) to obtain a white solid, i.e., 4-(4-chlorphenyl)-2-pyrrolidone (III) of which the melting point is 109-111 DEG C; and refluxing the white solid (III) in a hydrochloric acid aqueous solution for 8-30 hours, concentrating under reduced pressure to obtain hydrochloric acid baclofen when finishing the reaction , and recrystallizing by using isopropanol to obtain refined hydrochloric acid baclofen of which the melting point is 178-179 DEG C. Raw materials used in the method are readily available, the process is easy and reliable, and the total yield of the hydrochloric acid baclofen is up to 59 percent; and the method has a good industrial prospect.

Description

technical field [0001] The invention relates to a medicine synthesis method, in particular to a medicine baclofen hydrochloride synthesis method. Background technique [0002] Baclofen hydrochloride (baclofen hydrochloride, 1), the chemical name is β-(aminomethyl) p-chlorophenylpropionate hydrochloride, is the first selective GABAβ receptor agonist used in clinical practice. The drug was developed by Medtronic of the United States and first launched in the United States in 1992. It is clinically used for skeletal muscle spasm, bone marrow infection, degenerative muscle spasm, spinal cord injury caused by multiple sclerosis, and cerebral palsy, stroke and cerebral palsy. Muscle spasm caused by vascular accident can relieve symptoms and help rebuild residual function. [0003] In recent years, it has been found that baclofen hydrochloride has a good effect in the treatment of intractable hiccups, neuropathic pain, hemiplegia after stroke, etc., as well as in reducing dependen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/34C07C227/22
Inventor 李军章王家喜刘守信
Owner HEBEI UNIV OF TECH
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