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Preparation method of central alpha 2 adrenergic receptor agonist

A solid, organic solvent technology, applied in the field of preparation of tizanidine hydrochloride, which can solve the problems of endangering the health of operators, many impurities of tizanidine hydrochloride, and difficult to meet the quality standards, so as to improve industrial production efficiency and shorten the reaction time Time, the effect of improving product quality and yield

Active Publication Date: 2018-03-09
SICHUAN CREDIT PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But, the tizanidine hydrochloride impurity that above-mentioned route prepares is more, and quality is difficult to up to standard
And, the key reaction in this route, i.e. the condensation reaction of 4-amino-5-chloro-2,1,3-benzothiadiazole and acylated imidazoline, uses phosphorus oxychloride as dehydrating agent and / or Solvent, this substance is extremely corrosive and tear-inducing, and seriously endangers the health of operators. The acidic tail gas produced during the reaction is also very harmful to the human body and the environment; in industrial production, phosphorus oxychloride is harmful to equipment. Extremely corrosive, easy to cause equipment damage, not suitable for large-scale industrial production

Method used

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  • Preparation method of central alpha 2 adrenergic receptor agonist
  • Preparation method of central alpha 2 adrenergic receptor agonist
  • Preparation method of central alpha 2 adrenergic receptor agonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Weigh 5g of 4-amino-5-chloro-2,1,3-benzothiadiazole and 4.85g of imidazoline-2-sulfonic acid, add to 75ml of isopropanol, add 18.76g of maleic acid, heat up to 85 ~90°C for 10 hours. The solvent was recovered under reduced pressure, 96 ml of water was added to the residue, and crystallization was carried out with stirring. After filtration, the filter cake was washed successively with ethyl acetate and dichloromethane. After filtering, the filter cake was added to 50 ml of saturated hydrogen chloride ethanol solution, stirred for 4 hours, filtered, and the filter cake was washed with absolute ethanol and dried.

[0043] Add the filter cake to 50ml of 95% ethanol, reflux until the dissolution is complete, naturally cool down and crystallize, filter, wash the filter cake with absolute ethanol, and dry to obtain 4.63g of solid tizanidine hydrochloride with a yield of 59.2% and a purity of 95.59%. . 1 H-NMR (400MHz, d 6 -DMSO):δ3.69(s,4H,CH 2 CH 2 ),7.92(d,1H,J=9.6Hz,...

Embodiment 2

[0052] Weigh 5g of 4-amino-5-chloro-2,1,3-benzothiadiazole and 4.85g of imidazoline-2-sulfonic acid, add them to 75ml of methanol, and add 7.44g of formic acid. The temperature was raised to 65-70°C, and the reaction was stirred for 12 hours. Add 25 mg of activated carbon, stir for about 30 minutes, and filter while hot. The filtrate was cooled to -5~0°C and stirred for 2 hours. After filtering, add the filter cake to 65 ml of saturated hydrogen chloride ethanol solution, stir for 2 hours, filter, wash the filter cake with absolute ethanol, and dry. Add the filter cake to 60ml of 95% ethanol, reflux until the dissolution is complete, naturally cool down and crystallize, filter, wash the filter cake with absolute ethanol, and dry to obtain 6.84g of solid tizanidine hydrochloride with a yield of 87.5% and a purity of 99.98% .

Embodiment 3

[0054] Weigh 5g of 4-amino-5-chloro-2,1,3-benzothiadiazole and 4.45g of imidazoline-2-sulfonic acid, add to 60ml of ethanol, and add 10.42g of dichloroacetic acid. The temperature was raised to 75-80°C, and the reaction was stirred for 10 hours. Add 25 mg of activated carbon, stir for about 30 minutes, and filter while hot. The filtrate was cooled to 0-5°C and stirred for 3 hours. After filtering, the filter cake was added to 70 ml of saturated hydrogen chloride ethanol solution, stirred for 3 hours, filtered, the filter cake was washed with absolute ethanol, and dried. The filter cake was added into 60ml of methanol, refluxed until it was completely dissolved, the temperature was naturally lowered to crystallize, filtered, the filter cake was washed with anhydrous methanol, and dried to obtain 6.79 g of solid tizanidine hydrochloride with a yield of 86.9% and a purity of 99.97%.

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Abstract

The invention relates to a preparation method of a central alpha 2 adrenergic receptor agonist. The invention discloses a preparation method of tizanidine hydrochloride, which comprises the followingsteps of: (1) taking organic acid A, a compound S1 as shown in the specification and a compound S2 as shown in the specification as raw materials for reaction in an organic solvent, separating out a solid to form tizanidine organic acid salt S3 as shown in the specification, and (2) preparing tizanidine hydrochloride by taking the tizanidine organic acid salt S3 obtained in step (1) as a raw material, wherein the organic acid A is formic acid, dichloroacetic acid, glycolic acid, maleic acid, fumaric acid, tartaric acid, caproic acid or benzoic acid; R1 is hydrogen, methyl, acetyl, propionyl, benzoyl, tertiary butyl methyl carbonyl or COOR2; and R2 is methyl, ethyl, allyl, benzyl, tertiary butyl or phenyl. The method achieves higher productivity and purity, is easy and simple to operate, high in production efficiency, environment-friendly, safe and applicable to industrial mass production and has broad market application prospects.

Description

technical field [0001] The invention relates to the field of medicine preparation methods, in particular to a preparation method of tizanidine hydrochloride. Background technique [0002] Tizanidine is a central skeletal muscle relaxant with imidazoline structure, chemical name is 5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-2,1,3 -Benzothiadiazol-4-amine, its molecular structural formula is as follows: [0003] [0004] Tizanidine is the only novel central skeletal muscle relaxant and central α 2 Adrenergic receptor agonists were first developed by the Swiss company Novartis. They were first launched in Denmark and Switzerland in 1988, and subsequently obtained sales licenses in more than 20 countries including Europe, the United States, and Japan. And spinal cord trauma, cerebral hemorrhage, encephalitis, and multiple sclerosis caused by increased skeletal muscle tone, muscle spasm and muscle rigidity and other diseases. Tizanidine can relieve spasticity, but does not c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12
CPCC07D417/12
Inventor 刘强维傅霖李晓莉陈刚陈功政
Owner SICHUAN CREDIT PHARMA
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