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The method for high-purity industrialized production of tizanidine hydrochloride

A tizanidine hydrochloride, high-purity technology, applied in the field of drug synthesis, can solve the problems of low yield, unfavorable industrial production, unsuccinct reaction and the like, and achieve the effect of high product purity

Active Publication Date: 2019-09-06
ANHUI HEALSTAR PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] Although this method has no impurity B and impurity C, the reaction is not simple and the yield is low, which is unfavorable for industrialized production

Method used

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  • The method for high-purity industrialized production of tizanidine hydrochloride
  • The method for high-purity industrialized production of tizanidine hydrochloride
  • The method for high-purity industrialized production of tizanidine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] a. Preparation of Intermediate II:

[0051] 310g (3.6mol) of 2-imidazolidinone, 930ml of a 50% aqueous solution of methacryloylpropyltrimethylammonium chloride, stirred at 15-25°C, and 520g (3.6mol) of dimethyl chlorophosphate was added thereto , keep stirring and react for 3 hours, then add 278g (1.5mol) of 4-amino-5-chloro-2,1,3-benzothiadiazole, maintain the temperature and stir the reaction, and identify the end point of the reaction by TLC (developer: dichloro Methane-methanol-triethylamine=1:1:0.1), the reaction was completed, filtered, the solid was washed with a small amount of water, and then washed with an appropriate amount of methanol, and dried in vacuum at 50-55°C for 6 hours to obtain 369g (1.454mol) of light yellow powder The yield of solid intermediate II (tizanidine) is 97.0%, mp: 221-222°C, and the HPLC content is 99.1%.

[0052] b, the preparation of compound I (tizanidine hydrochloride):

[0053] Intermediate II 360g (1.42mol), 95% ethanol 2160ml,...

Embodiment 2

[0060] Replace the 50% aqueous solution of methacryloylpropyltrimethylammonium chloride in the embodiment one step a with the 40% aqueous solution of tetrabutylammonium fluoride trihydrate, all the other steps are the same, make tizanidine hydrochloride 407g, total yield 95.5%, mp: 289~290°C (decomposition), HPLC content 99.9%, impurity A, impurity B and impurity C were not detected.

Embodiment 3

[0062] Diethyl chlorophosphate was used instead of dimethyl chlorophosphate in step a of Example 1, and the rest of the steps were the same to obtain 405 g of tizanidine hydrochloride, with a total yield of 95.3%, mp: 289-290°C (decomposition), HPLC The content is 99.8%, and impurity A, impurity B and impurity C are not detected.

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Abstract

The invention discloses a method for industrial production of high-purity tizanidine hydrochloride. The method comprises the following steps: by taking 4-amino-5-chlorine-2,1,3-diazosulfide and 2-imidazolidone as initial raw materials, implementing a reaction with chlorine phosphate in a quaternary ammonium type ionic liquid so as to obtain tizanidine, and further implementing a salting reaction in a 95% alcohol solvent, so as to obtain the tizanidine hydrochloride. The method is novel in process route, gentle in process condition, simple to operate and free of multiple times of recrystallization operation, a qualified product of which the purity is greater than or equal to 99.5% can be prepared at one time, the problem of impurities of the tizanidine hydrochloride can be solved, raw material medicine requirements of criterions of the United States Pharmacopeia and the European Pharmacopoeia can be completely met, and relatively good practical values and social economic benefits can be made.

Description

technical field [0001] The invention relates to a method for producing a central skeletal muscle relaxant of imidazole derivatives, in particular to a method for high-purity industrial production of tizanidine hydrochloride, which belongs to the technical field of drug synthesis. Background technique [0002] Tizanidine hydrochloride, an imidazole derivative, can selectively inhibit the polysynaptic mechanism related to muscle hypertonicity and reduce the release of excitatory amino acids from interneurons. This product does not affect the transmission of nerves and muscles, and is well tolerated, and can reduce the resistance of passive movement, relieve spasticity and clonus, and enhance the intensity of voluntary movement. It is effective for both acute painful muscle spasms and chronic tonic states originating in the spinal cord and brain. This product can also increase the anti-inflammatory effect of non-steroidal anti-inflammatory drugs (NSAIDs) and prevent NSAID-indu...

Claims

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Application Information

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IPC IPC(8): C07D417/12
Inventor 徐奎王陈曽飞
Owner ANHUI HEALSTAR PHARM CO LTD
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