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Preparation method for preparing intermediate body of Pramipexole dihydrochloride

A technology for pramipexole hydrochloride and intermediates, which is applied in the field of preparation of pramipexole hydrochloride, and can solve the problems of low yield, unsuitability for industrial production, and high reagent prices

Inactive Publication Date: 2009-11-25
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] 1) Borane is a colorless toxic gas, flammable, explosive, easy to hydrolyze, poor stability, difficult to store and transport, easy to cause safety accidents, not suitable for industrial production
[0006] 2) The homemade method of THF solution of borane is complicated, and the repeatability is poor, and the content of the solvent borane prepared in different batches is inconsistent, and it is difficult to industrialize a large amount of preparation
[0007] 3) At present, foreign pharmaceutical companies sell better-quality borane THF solutions, but the price is very expensive. If you buy this reagent for testing, the cost of raw materials will increase greatly
The disadvantage of this method is that the price of reagent sodium borohydride is higher, while BF 3 Ethyl ether is highly toxic, and it will be hydrolyzed immediately when it encounters moisture in the air, producing highly toxic fluoride, which is not conducive to labor protection, low reaction yield, and high production cost
[0009] In summary, the two reported methods for synthesizing 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole have the disadvantages that the reagents are not easily available, the reaction safety is low or the price of the reagents is high, and the yield is high. Low efficiency and high production costs are not conducive to industrial production

Method used

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  • Preparation method for preparing intermediate body of Pramipexole dihydrochloride
  • Preparation method for preparing intermediate body of Pramipexole dihydrochloride
  • Preparation method for preparing intermediate body of Pramipexole dihydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 Preparation of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole

[0032] In the reaction flask, add THF150ml, ZnCl 2 (17.95g, 0.132mol) and KBH 4 (14.25g, 0.264mol), under nitrogen protection, stirred at room temperature for 2 hours;

[0033] Add 2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole (15g, 0.066mol) and 70ml of toluene, heat slowly, evaporate part of the solvent, make the internal temperature reach 98°C, keep warm Stir for 4 hours. Cool to room temperature, pour into 150ml weight concentration of 10% HCl, the pH value of the reaction system is about 2, filter, the filtrate is extracted with chloroform, and alkalized to pH 12 with 20% weight concentration of sodium hydroxide solution. Extract with chloroform 75ml×3, combine the extracts with NaSO 4 Dry and recover chloroform to obtain 13.2 g of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole, yield 95%, m.p.>280°C, MS (m / z): 211.11, HPLC: 98.5%.

Embodiment 2

[0034] Example 2 Preparation of S-(-)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole

[0035] In the reaction flask, add 150ml of 2-methyltetrahydrofuran, ZnCl 2 (8.97g, 0.066mol) and KBH 4 (7.13g, 0.132mol), under nitrogen protection, stirred at room temperature for 4 hours. Add S-(-)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole (15g, 0.066mol) and 70ml of toluene, heat slowly, evaporate part of the solvent, and make the inner temperature reached 93°C, and kept stirring for 6 hours. Cool to room temperature, pour into 150ml of sulfuric acid with a weight concentration of 10%, the pH value of the reaction solution is between about 1, filter, and after the filtrate is extracted with dichloromethane, it is alkalized with a 20% potassium hydroxide solution by weight to The pH is 13. Extract with dichloromethane 80ml×3, combine the extracts with NaSO 4 Dry and recover dichloromethane to obtain 10.4 g of S-(-)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiaz...

Embodiment 3

[0036] Example 3 Preparation of R-(+)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole

[0037] In the reaction flask, add THF200ml, ZnCl 2 (6.8g, 0.05mol) and KBH 4(15.4 g, 0.1 mol), under nitrogen protection, stirred at room temperature for 2 hours. Add R-(+)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole (7.5g, 0.033mol) and 100ml of benzene, heat slowly, evaporate part of the solvent, and make When the internal temperature reached 85° C., the mixture was kept stirring for 4 hours. Cool to room temperature, pour into 200ml of 10% HCl by weight, the pH value of the reaction solution is 1, filter, and after the filtrate is extracted with chloroform, basify with 20% sodium hydroxide solution by weight until the pH is 12. Extract with chloroform 50ml×3, combine the extracts with NaSO 4 Dry and recover chloroform to obtain 8.5 g of R-(+)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole, yield 61%, m.p.>280°C, MS (m / z): 211.11, HPLC: 98%.

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Abstract

The invention discloses a preparation method for preparing intermediate body of Pramipexole dihydrochloride, which includes the following steps: in the dissolvent, under the exist of Zn(BH4)2, carrying out reduction reaction of (R, S) configuration, (R) configuration or (S) configuration 2-amino-6-propionamido-4, 5, 6, 7-tetrahydro benzopyrene, and then collecting (R, S) configuration, (R) configuration or (S) configuration 2-amino-6-propylamine-4, 5, 6, 7-tetrahydro benzopyrene from the reaction product. The method provided by the invention uses (R, S) configuration, (R) configuration or (S) configuration 2-amino-6-propionamido-4, 5, 6, 7-tetrahydro benzopyrene as raw material, and Zn(BH4)2 as reducing reagent, and has advantages of high reaction yield, easily obtained raw material and low production cost, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to a preparation method of pramipexole hydrochloride, in particular to a preparation method for the preparation of pramipexole hydrochloride key intermediates, in particular to 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzo The preparation method of thiazole. Background technique [0002] 2-Amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole is an important intermediate for the preparation of anti-Parkinson's drug pramipexole hydrochloride. [0003] At present, the document J.Med.Chen.1987,30,494-498 publicly reports a preparation method of pramipexole hydrochloride, which uses S-(-)-2-amino-6-propionamido-4, 5,6,7-Tetrahydrobenzothiazole is used as raw material, under the protection of nitrogen in tetrahydrofuran (THF), react with THF borane solution to obtain S-(-)-2-amino-6-propylamino-4 , 5,6,7-Tetrahydrobenzothiazole. The specific content of the preparation method is, at room temperature and under the protection of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/60
Inventor 李建其金华
Owner SHANGHAI INST OF PHARMA IND CO LTD
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