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Preparation method of high-purity pramipexole dihydrochloride

A high-purity technology for pramipexole hydrochloride, which is applied in the field of preparation of high-purity pramipexole hydrochloride, can solve problems such as low reaction yield, cumbersome process, and loss of crystal water, and achieve simple reaction steps, high safety, water a stable effect

Active Publication Date: 2021-01-29
珠海润都制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In this method, acetone is used as a solvent, concentrated hydrochloric acid is formed into a salt, the yield is low, and multiple refining is required
[0018] The synthesis method of pramipexole hydrochloride in the prior art has the following disadvantages: 1) the reaction conditions are harsh, the reaction safety is low, it needs to be carried out under the protection of an inert gas, the post-treatment is complicated, and the solvent needs to be removed, resulting in a low product yield; 2) Multiple recrystallizations are required, the yield is low, the intermediate treatment process is complicated, and the process is cumbersome, and it is not suitable for industrial production; 3) The reaction yield is low and the purity is not high; 4) Single polar solvents such as acetone and ethanol are used Recrystallization will cause the loss of crystal water, resulting in unqualified moisture

Method used

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  • Preparation method of high-purity pramipexole dihydrochloride

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Experimental program
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Effect test

Embodiment 1

[0042] Add 50 g of (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole, 300 ml of tetrahydrofuran, and 20 g of sodium borohydride into the reaction flask. 94.5 g of boron trifluoride was added dropwise at a temperature of 10 degrees Celsius, and after the drop was completed, the temperature was raised to reflux for 2 hours of reaction. After cooling down to room temperature, dilute hydrochloric acid was added to terminate the reaction. Add 20% sodium hydroxide aqueous solution, adjust the pH to 14, add ethyl acetate for extraction, and separate layers. The organic layer was concentrated until 4-5V of solvent remained, then 2V of methanol was added, 0.75V of concentrated hydrochloric acid was added dropwise to form a salt, and the temperature was lowered to 10°C for crystallization. After filtration and drying, 60.3 g of pramipexole hydrochloride dihydrochloride monohydrate was obtained, with a molar yield of 89.9% and a purity of 99.92%.

[0043] Add 50g of pramipexol...

Embodiment 2

[0045] Add 50 g of (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole, 400 ml of tetrahydrofuran, and 24 g of sodium borohydride into the reaction flask. 113.4 g of boron trifluoride was added dropwise at a temperature of 10 degrees Celsius, and after the drop was completed, the temperature was raised to reflux for 2 hours of reaction. After cooling down to room temperature, dilute hydrochloric acid was added to terminate the reaction. Add 20% sodium hydroxide aqueous solution, adjust the pH to 14, add ethyl acetate for extraction, and separate layers. The organic layer was concentrated until 4-5V of solvent remained, and then 2V of methanol was added, and 0.8V of concentrated hydrochloric acid was added dropwise to form a salt, and the temperature was lowered to 10°C for crystallization. After filtration and drying, 61.5 g of pramipexole hydrochloride dihydrochloride monohydrate was obtained, with a molar yield of 91.7% and a purity of 99.91%.

[0046] Add 50g of pr...

Embodiment 3

[0048] Add 50 g of (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole, 500 ml of tetrahydrofuran, and 22 g of sodium borohydride into the reaction flask. 104 g of boron trifluoride was added dropwise at a temperature of 10 degrees Celsius, and after the drop was completed, the temperature was raised to reflux for 2 hours of reaction. After cooling down to room temperature, dilute hydrochloric acid was added to terminate the reaction. Add 20% sodium hydroxide aqueous solution, adjust the pH to 14, add ethyl acetate for extraction, and separate layers. The organic layer was concentrated until 4-5V of solvent remained, and then 2V of methanol was added, and 0.8V of concentrated hydrochloric acid was added dropwise to form a salt, and the temperature was lowered to 10°C for crystallization. After filtration and drying, 61.1 g of pramipexole hydrochloride dihydrochloride monohydrate was obtained, with a molar yield of 91.1% and a purity of 99.91%.

[0049] Add 50g of pram...

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Abstract

The invention provides a preparation method of high-purity pramipexole dihydrochloride, which comprises the following steps: (a) by using (S)-2-amino- 6-propionamido 4, 5, 6, 7-tetrahydrobenzothiazoleas a raw material and tetrahydrofuran as a solvent, reacting in the presence of a reducing agent, and adding diluted hydrochloric acid to terminate the reaction after the reaction is completed; (b) adding a sodium hydroxide solution to adjust the pH value, adding an extraction agent for extraction, adding an alcohol reagent, dropwise adding concentrated hydrochloric acid for salifying, cooling for crystallization, filtering and drying to obtain pramipexole dihydrochloride monohydrate; and (c) refining the pramipexole dihydrochloride monohydrate obtained in the step (b) through a ternary system of water, an alcohol reagent and an ester reagent, filtering and drying to obtain a pramipexole dihydrochloride finished product. The novel synthetic method of pramipexole dihydrochloride is simplein reaction steps, high in safety, high in yield, stable in water content and suitable for industrial production, and the purity of pramipexole dihydrochloride reaches 99.95% or above. The pramipexoledihydrochloride has stable water content and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a preparation method of high-purity pramipexole hydrochloride. Background technique [0002] Pramipexole hydrochloride is a drug for the treatment of Parkinson's syndrome. It is a selective non-ergot dopamine receptor agonist. It was successfully developed by Boehringer Ingelheim in Germany. It is currently the most prescribed dopamine receptor agonist in the world. In May 1997, it was first approved by the US FDA for the treatment of idiopathic Parkinson's disease. It can alleviate the symptoms and signs of patients. It can be used alone or in combination with levodopa. It is marketed in the United States under the trade name Mirapex, which is The FDA approved the drug for Parkinson's disease for the first time in the past 6 years. It was launched in China in 2007 under the trade name Senfulo. It is used to treat the signs and symptoms of idiopathic Parkins...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/60
CPCC07D277/60
Inventor 殷超刘杰商俊兵胡敏兰柳琴
Owner 珠海润都制药股份有限公司
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