Industrial preparation method of pramipexole dihydrochloride

Inactive Publication Date: 2014-03-12
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The main disadvantage of this method is that the BF 3 Diethyl ether solution is easy to decompose when it meets water, forming highly toxic fluoride, wh

Method used

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  • Industrial preparation method of pramipexole dihydrochloride

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Experimental program
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Effect test

Embodiment 1

[0022] (1) Preparation of (S)-(-)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole

[0023] Add (S)-(-)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (42.3g, 0.25mol) into methanol (500mL), stir and cool to -20°C , temperature control at -15 ~ -20 ° C dropwise added n-propanal (26.75g, 0.46mol). After the addition is complete, stir and react at this temperature for 1.5 hours, then add NaBH dropwise at -15 to -20°C under temperature control 4 (6.65g, 0.18mol) in 80mL of methanol solution, after addition, stirred and reacted at natural temperature for 2 hours. Then cool to below 0°C, add 70mL of concentrated hydrochloric acid dropwise to adjust pH=2~3, then evaporate methanol, dissolve the residue in 150mL water, adjust pH=7 with 25% sodium hydroxide solution, stir and analyze at 0°C crystallized for 2 hours, filtered to obtain a white scaly solid, refined twice with a mixed solvent of ethanol / water (volume ratio 5:1), and air-dried to obtain a white powdery solid (S)-(-)-2...

Embodiment 2

[0027] (1) Preparation of (S)-(-)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole

[0028] Add (S)-(-)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (42.3g, 0.25mol) into methanol (500mL), stir and cool to -10°C , temperature control at -5 ~ -10 ° C dropwise added n-propanal (29.04g, 0.50mol). After the addition is complete, stir the reaction at this temperature for 1.5 hours, and add NaBH dropwise at -5~-10°C under temperature control. 4 (7.76g, 0.21mol) in methanol solution in 100mL, after the addition, stirred and reacted at natural temperature for 0.5 hours. Then cool to below 0°C, add 79mL of concentrated hydrochloric acid dropwise to adjust the pH=2~3, then evaporate the methanol, dissolve the residue in 150mL of water, adjust the pH=9 with 25% sodium hydroxide solution, stir and analyze at 0°C crystallized for 2 hours, filtered to obtain a white scaly solid, refined with a mixed solvent of ethanol / water (volume ratio 10:3), and air-dried to obtain a white powdery ...

Embodiment 3

[0032] (1) Preparation of (S)-(-)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole

[0033] Add (S)-(-)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (42.3g, 0.25mol) into methanol (500mL), stir and cool to -30°C , temperature control at -25 ~ -30 ° C dropwise added n-propanal (26.75g, 0.46mol). After the addition is complete, stir and react at this temperature for 1.5 hours, then add NaBH dropwise at -25~-30°C under temperature control 4 (18.90g, 0.5mol) in 200mL of methanol solution, after the addition, stirred and reacted at natural temperature for 3 hours. Then cool to below 0°C, add 180mL of concentrated hydrochloric acid dropwise to adjust the pH=2~3, then evaporate the methanol, dissolve the residue in 150mL water, adjust the pH=5 with 25% sodium hydroxide solution, stir and analyze at 0°C crystallized for 2 hours, filtered to obtain a white scaly solid, refined twice with a mixed solvent of ethanol / water (volume ratio 5:1), and air-dried to obtain a white powdery ...

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Abstract

The invention relates to an industrial preparation method of pramipexole dihydrochloride, belonging to the technical field of drug synthesis. The industrial preparation method is characterized by using (S)-(-)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole as a raw material to react with n-propanal to generate Schiff base, then carrying out NaBH4 reduction and recrystallization to obtain (S)-(-)-2-amino-6-propylamine-4,5,6,7-tetrahydrobenzothiazole, and finally preparing pramipexole dihydrochloride monohydrate through salifying and recrystallization. The industrial preparation method of pramipexole dihydrochloride avoids using toxic reagents and has the advantages of accessible raw materials, simplicity in operation and high reaction safety.

Description

technical field [0001] The invention relates to an industrialized preparation method of pramipexole hydrochloride, which belongs to the technical field of medicine synthesis. Background technique [0002] Parkinson's disease is a progressive neurodegenerative disorder with increasing prevalence with age. Pramipexole is a fully synthetic non-ergot alkaloid dopamine receptor agonist, which can highly selectively stimulate dopamine receptors, thereby improving symptoms of patients. It is a new generation of drugs superior to ergot derivatives. Its main chemical composition is (S)-(-)-2-amino-4,5,6,7-tetrahydro-6-propylamine benzothiazole dihydrochloride monohydrate, where (S) stands for pramoxine hydrochloride Pramipexole is in S configuration, (-) means pramipexole hydrochloride is left-handed. [0003] At present, its synthesis methods mainly include: [0004] 1. J.Med.Chem.1987,30,494-498 discloses a preparation method of pramipexole hydrochloride, which uses (-)-2,6-diam...

Claims

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Application Information

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IPC IPC(8): C07D277/60
CPCC07D277/60
Inventor 郑忠辉曹丽丽潘西海李兴泰
Owner SHANDONG XINHUA PHARMA CO LTD
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