Preparation method of pramipexole dihydrochloride

A technology of pramipexole hydrochloride and camphorsulfonic acid, which is applied in the field of medicine, can solve the problems of low pramipexole hydrochloride content, low solubility, and low yield, and achieve the effects of less impurities, high solubility, and low cost

Active Publication Date: 2015-04-08
葛亚伯
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In view of this, the present invention provides a preparation method of pramipexole hydrochloride, which solves the problem that the content of pramipexole h...

Method used

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  • Preparation method of pramipexole dihydrochloride
  • Preparation method of pramipexole dihydrochloride
  • Preparation method of pramipexole dihydrochloride

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Embodiment 1

[0025] A preparation method of pramipexole hydrochloride, comprising the steps of:

[0026] Step 1: Preparation of (-)-(6s)-2,6-diamino4,5,6,7-tetrahydrobenzothiazole

[0027] In 2mol / L dichloromethane organic solvent, take 1mol 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole as raw material, add 0.9mol resolving agent brominated camphorsulfonic acid, heat and reflux for 5h , the reaction temperature is 20°C, cooled to 5°C, suction filtered, adjusted to pH 11 for alkalization, and (-)-(6s)-2,6-diamino 4,5,6,7-tetrahydro Benzothiazole.

[0028] Step 2: Preparation of (-)-(6s)-2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole

[0029] In 1.8mol / L ethanol solution, react 1mol(-)-(6s)-2,6-diamino 4,5,6,7-tetrahydrobenzothiazole with 1mol propionic anhydride, the reaction temperature is 50℃ , After heating to reflux for 5h, the (-)-(6s)-2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole was obtained.

[0030] Step 3: Preparation of pramipexole

[0031] 1mol(-)-(6s)-2-...

Embodiment 2

[0035] A preparation method of pramipexole hydrochloride, comprising the steps of:

[0036] Step 1: Preparation of (-)-(6s)-2,6-diamino4,5,6,7-tetrahydrobenzothiazole

[0037] In 2.2mol / L dichloromethane organic solvent, take 1mol 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole as raw material, add 1mol resolving agent brominated camphorsulfonic acid, heat and reflux for 8h , the reaction temperature is 30°C, cooled to 10°C, filtered with suction, adjusted the pH value to 11 for alkaline treatment, and obtained (-)-(6s)-2,6-diamino 4,5,6,7-tetrahydro Benzothiazole.

[0038] Step 2: Preparation of (-)-(6s)-2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole

[0039] In 2mol / L ethanol solution, react 1mol(-)-(6s)-2,6-diamino 4,5,6,7-tetrahydrobenzothiazole with 1.1mol propionic anhydride, the reaction temperature is 60℃ , After heating to reflux for 7h, the (-)-(6s)-2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole was obtained.

[0040] Step 3: Preparation of pramip...

Embodiment 3

[0045] A preparation method of pramipexole hydrochloride, comprising the steps of:

[0046] Step 1: Preparation of (-)-(6s)-2,6-diamino4,5,6,7-tetrahydrobenzothiazole

[0047] In 2.1mol / L dichloromethane organic solvent, take 1mol 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole as raw material, add 1.2mol resolving agent camphorsulfonic acid bromide, heat to reflux 5h, the reaction temperature was 35°C, cooled to 15°C, filtered with suction, adjusted the pH value to 11 for alkaline treatment, and obtained (-)-(6s)-2,6-diamino-4,5,6,7-tetra Hydrobenzothiazole.

[0048] Step 2: Preparation of (-)-(6s)-2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole

[0049]In 2.1mol / L ethanol solution, react 1mol(-)-(6s)-2,6-diamino 4,5,6,7-tetrahydrobenzothiazole with 0.9mol propionic anhydride, the reaction temperature is 70 ℃, after heating and refluxing for 5h, (-)-(6s)-2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole was obtained.

[0050] Step 3: Preparation of pramipexole...

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Abstract

The invention discloses a preparation method of pramipexole dihydrochloride. The preparation method comprises the following steps: 1) in an organic solvent, by taking 2,6-diamido-4,5,6,7-tetrahydrobenzothiazole as a raw material, adding a resolving agent, heating for reflux and carrying out cooling, suction filtration and alkalization to prepare (-)-(6s)-2,6-diamido-4,5,6,7-tetrahydrobenzothiazole; 2) in an ethyl alcohol solution, carrying out reaction on (-)-(6s)-2,6-diamido-4,5,6,7-tetrahydrobenzothiazole and propionic anhydride and heating for reflux to prepare (-)-(6s)-2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole; 3) carrying out reduction reaction on (-)-(6s)-2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole in a methylbenzene solution by red aluminum, heating for reflux and carrying out stirring and crystallization to prepare pramipexole; 4) dissolving the pramipexole in an isopropanol solution, reacting with hydrochloric acid after stirring and crystallization and carrying out decompression and drying to obtain pramipexole dihydrochloride. The preparation method is low in requirements for reaction equipment; the prepared pramipexole dihydrochloride is high in content, high in purity, high in solubility, high in output and less in impurity.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of pramipexole hydrochloride. Background technique [0002] Pramipexole is a non-ergot derivative that acts highly selectively on DA-2 receptors. It can be used alone to treat Parkinson's disease in the early stage, and it can be used together with dopamine to treat Parkinson's disease in the late stage. Pramipexole was developed by Boehringer Ingelheim in Germany. On May 10, 1997, the FDA approved Pramipexole to go on the market. The trade name was Mirapex, and it was jointly sold by Boehringer Ingelheim and Pharmacia in the United States. It is the first drug approved by the FDA for the treatment of Parkinson's disease in the 1990s. The drug has been used in more than 50 countries around the world, and it was launched in my country in 2007. [0003] After nearly two decades of development, there are various preparation methods of pramipexole hydrochloride...

Claims

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Application Information

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IPC IPC(8): C07D277/60
CPCC07D277/60
Inventor 葛亚伯苏东晓
Owner 葛亚伯
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