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Synthetic method of pramipexole dihydrochloride related substance B

A technology for the synthesis of pramipexole hydrochloride and its synthesis method, which is applied in the field of synthesis of related substance B of pramipexole hydrochloride, which can solve the problems that the synthesis of pramipexole hydrochloride has not been reported, etc., and achieves easy-to-obtain raw materials, good repeatability, and mild reaction conditions Effect

Active Publication Date: 2014-04-16
SICHUAN KELUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] At present, some related substances of pramipexole hydrochloride have been reported on the synthesis, but there is no report on the synthesis of related substance B of pramipexole hydrochloride

Method used

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  • Synthetic method of pramipexole dihydrochloride related substance B
  • Synthetic method of pramipexole dihydrochloride related substance B
  • Synthetic method of pramipexole dihydrochloride related substance B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: Synthesis of related substance B (i.e. compound of formula I)

[0030] (1) Synthesis of (S)-2,6-dipropionylamino-4,5,6,7-tetrahydrobenzothiazole (IV)

[0031] Suspend 1.0g of (S)-(-)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (III) in 15ml of anhydrous tetrahydrofuran, add 1.3g of triethylamine, and A mixture of 1.2 g of propionyl chloride and 5 ml of anhydrous tetrahydrofuran was added dropwise with stirring, and stirred at room temperature for 3.5 hours. After the reaction was completed, add 10ml of water to quench the reaction, distill THF under reduced pressure, adjust the pH to 9-10 with 25% NaOH, stir for 30min, and precipitate a solid, filter, wash the filter cake with water to 7-8, and dry to obtain 1.23g of white solid , proceed directly to the next reaction.

[0032] (2): Synthesis of (S)-2,6-dipropylamino-4,5,6,7-tetrahydrobenzothiazole (I)

[0033] Suspend 1.0 g of compound (IV) in 30 ml of anhydrous tetrahydrofuran, add 0.8 g of lithium al...

Embodiment 2

[0038] Embodiment 2: Synthesis of related substance B (i.e. compound of formula I)

[0039] (1) Synthesis of (S)-2,6-dipropionylamino-4,5,6,7-tetrahydrobenzothiazole (IV)

[0040] Suspend 2.3g of (S)-(-)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (III) in 35ml of anhydrous tetrahydrofuran, add 3.0g of triethylamine, and A mixture of 2.5 g of propionyl chloride and 12 ml of anhydrous tetrahydrofuran was added dropwise with stirring, and stirred at room temperature for 3.5 hours. After the reaction was completed, add 25ml of water to quench the reaction, distill off THF under reduced pressure, adjust the pH to 9-10 with 25% NaOH, stir for 30min, precipitate a solid, filter, wash the filter cake with water to 7-8, and obtain 2.67g of white solid after drying , proceed directly to the next reaction.

[0041] (2): Synthesis of (S)-2,6-dipropylamino-4,5,6,7-tetrahydrobenzothiazole (I)

[0042] Suspend 1.5g of compound (IV) in 45ml of anhydrous tetrahydrofuran, add 1.53g of lithi...

Embodiment 3

[0043] Embodiment 3: Synthesis of related substance B (i.e. compound of formula I)

[0044] (1) Synthesis of (S)-2,6-dipropionylamino-4,5,6,7-tetrahydrobenzothiazole (IV)

[0045] Suspend 1.3g of (S)-(-)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (III) in 20ml of anhydrous tetrahydrofuran, add 2.2g of triethylamine, and A mixture of 1.8 g of propionyl chloride and 6.5 ml of anhydrous tetrahydrofuran was added dropwise with stirring, and stirred at room temperature for 3.5 hours. After the reaction was completed, add 13ml of water to quench the reaction, distill off THF under reduced pressure, adjust the pH to 9-10 with 25% NaOH, stir for 30min, precipitate a solid, filter, wash the filter cake with water to 7-8, and obtain 1.61g of white solid after drying , proceed directly to the next reaction.

[0046] (2): Synthesis of (S)-2,6-dipropylamino-4,5,6,7-tetrahydrobenzothiazole (I)

[0047] Suspend 1.0 g of compound (IV) in 30 ml of anhydrous tetrahydrofuran, add 0.68 g of l...

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Abstract

The invention provides a synthetic method of a pramipexole dihydrochloride related substance B shown by a formula I. The pramipexole dihydrochloride related substance B synthesized by the synthetic method is high in purity and can be directly used for quality control of related substances in pramipexole dihydrochloride; moreover, the synthetic method provided by the invention is simple and convenient in operation, readily-available in raw material, mild in reaction condition, good in repeatability, and suitable for production of the related substance B.

Description

technical field [0001] The invention relates to a synthesis method of pramipexole hydrochloride related substance B. Background technique [0002] Pramipexole hydrochloride (Pramipexole dihydrochloride, II), chemical name is (S)-2-amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole dihydrochloride monohydrate, molecular formula C 10 h 17 N 3 S 2HCl H 2 O, trade name Senfulo. Clinically used to treat the signs and symptoms of idiopathic Parkinson's disease. At present, China has no legal sources of APIs. [0003] [0004] There are 5 related substances of pramipexole hydrochloride mentioned in the European Pharmacopoeia: related substances A, B, C, D, E. The structures are: [0005] [0006] The existence of related substances directly affects the quality and safety of products, so it is of great significance to the quality control of main components and related substances in products. [0007] At present, there have been reports on the synthesis of some relate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/60
CPCC07D277/60
Inventor 吴松童元峰杨庆云邓愉凤王朝阳葛建华姜晓艳赵同华赵栋胡思玉王利春王晶翼程志鹏刘革新刘思川
Owner SICHUAN KELUN PHARMA CO LTD
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