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Preparation method of pramipexole hydrochloride and its intermediate

A pramipexole and intermediate technology, which is applied in the field of preparation of pramipexole hydrochloride and its intermediates, can solve the problems of unsuitability for industrial production, poor product purity, low total molar yield and the like

Active Publication Date: 2020-03-17
SHANGHAI BOCIMED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved by the present invention is in order to overcome the preparation method of pramipexole hydrochloride monohydrate in the prior art, route step is long, needs to use chiral resolution, total molar yield is lower, production cost is high, and obtained A method for preparing pramipexole hydrochloride monohydrate is provided due to defects such as poor purity of the product, which does not meet the standard of the raw material drug, and is not suitable for industrial production.

Method used

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  • Preparation method of pramipexole hydrochloride and its intermediate
  • Preparation method of pramipexole hydrochloride and its intermediate
  • Preparation method of pramipexole hydrochloride and its intermediate

Examples

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Embodiment 1

[0069] Embodiment 1: the preparation of pramipexole intermediate III

[0070]

[0071]Under the protection of nitrogen, add 200g of 1,4-cyclohexanedione to 1.2L of methanol, stir to dissolve and cool to 5°C, add 286g of liquid bromine dropwise within 15 minutes and stir for 15 minutes, add 163g of thiourea, and then ℃~25℃ and stirred for 16 hours. Add 200 mL of concentrated hydrochloric acid (12 mol / L) and 1 L of water, and stir at 65°C to 70°C for 1 hour. After cooling, concentrate in vacuo to remove most of the methanol (temperature 35°C ~ 45°C, vacuum pressure -0.085MPa ~ -0.1MPa), after cooling, extract twice with 500mL of toluene, and use 20% sodium hydroxide aqueous solution for the water phase (the said mass percentage refers to the percentage of the quality of sodium hydroxide in the total mass of sodium hydroxide aqueous solution) adjust the pH value to 12~14, extract three times with dichloromethane 1L, combine the organic phase with a mass percentage of 10% sod...

Embodiment 2

[0072] Embodiment 2: the preparation of pramipexole II

[0073]

[0074] In a 500mL hydrogenation kettle, add methanol 245mL and pramipexole intermediate III 24.5g (HPLC purity 98.20%), then add propylamine 7.79g, (+)-1,2-bis(2S,5S)-diethylcyclo 87 mg of trifluoromethanesulfonate rhodium trifluoromethanesulfonate was hydrogenated at 50° C. and 5-8 atmospheres for 6 hours. Filtrate, concentrate in vacuo (45°C~55°C, -0.085MPa~-0.1MPa) to remove the solvent, add 100mL of dichloromethane, and use a mass percentage of 20% sodium hydroxide aqueous solution (the mass percentage refers to The quality of sodium hydroxide accounts for the percentage of the total mass of sodium hydroxide aqueous solution) to adjust the pH value to 12~14, leave to stand for stratification, the aqueous phase is extracted twice with dichloromethane 100mL, and the organic phase is combined with 10% by mass percentage of carbonic acid Sodium bicarbonate aqueous solution (the described mass percentage comp...

Embodiment 3

[0076] Embodiment 3: the preparation of pramipexole II

[0077] In a 500mL hydrogenation kettle, add methanol 320mL and pramipexole intermediate III 24.5g (HPLC purity 98.20%), then add propylamine 10.5g, (+)-1,2-bis(2S,5S)-diethylcyclo 174 mg of rhodium trifluoromethanesulfonate was hydrogenated at 40° C. and 7 to 10 atmospheres for 10 hours. Filtrate, concentrate in vacuo (45°C~55°C, -0.085MPa~-0.1MPa) to remove the solvent, add 100mL of dichloromethane, and use a mass percentage of 20% sodium hydroxide aqueous solution (the mass percentage refers to The quality of sodium hydroxide accounts for the percentage of the total mass of sodium hydroxide aqueous solution) to adjust the pH value to 12~14, leave to stand for stratification, the aqueous phase is extracted twice with dichloromethane 100mL, and the organic phase is combined with 10% by mass percentage of carbonic acid Sodium bicarbonate aqueous solution (the described mass percentage composition refers to the quality pe...

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Abstract

The invention discloses a preparation method of pramipexole dihydrochloride and an intermediate thereof. The invention provides a preparation of pramipexole II. The preparation method of the pramipexole II comprises the following steps: performing condensation reaction and reduction reaction on a pramipexole intermediate III, propylamine and hydrogen in an organic solvent and under the existence of a chiral catalyst, and performing one-pot method to obtain the pramipexole II. According to the preparation method provided by the invention, the route step is short, chiral resolution is not neededand the total molar yield is high; furthermore, the prepared product has high purity, can reach to the standard of raw material medicines and is suitable for industrialized production. (The formula is shown in the description).

Description

technical field [0001] The invention relates to a preparation method of pramipexole hydrochloride and an intermediate thereof. Background technique [0002] Pramipexole dihydrochloride monohydrate (Pramipexole dihydrochloride monohydrate, I) was developed by Boehringer Ingelheim, first approved by the US Food and Drug Administration on July 1, 1997, and then by the European Medicines Agency on October 14, 1997 Approved, and on December 2, 2003, it was approved for marketing by Japan Pharmaceuticals and Medical Devices Comprehensive Agency. [0003] [0004] Pramipexole hydrochloride is a non-ergot dopamine agonist, which has high relative specificity and complete intrinsic activity to dopamine receptors in vitro, and has a higher affinity to dopamine D3 family receptors than D2 or D4. It is used to improve spontaneous Symptoms and signs of Parkinson's disease and moderate to severe restless legs syndrome. [0005] Pramipexole hydrochloride alleviates the movement disord...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/82C07D277/60
CPCC07D277/60C07D277/82
Inventor 陈健乔岩河应述欢
Owner SHANGHAI BOCIMED PHARMA CO LTD
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