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A kind of preparation method of pregabalin

A technology of pregabalin and reaction, applied in the field of preparation of pregabalin, can solve problems such as difficulty in removing impurities, side reactions, and low product yield

Active Publication Date: 2021-12-24
CHANGZHOU PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, when reproducing the patented method, it was found that the above-mentioned patented method has a low product yield, and it is easy to introduce unknown impurities that are difficult to remove, which cannot meet the standards for pharmaceutical raw materials
[0004] Patent CN106748850A has also reported that (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid carries out Hoffman rearrangement reaction under the effect of sodium hydroxide, sodium hypochlorite, also can A side reaction occurs, resulting in impurity X and impurity Y that are difficult to remove

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  • A kind of preparation method of pregabalin
  • A kind of preparation method of pregabalin
  • A kind of preparation method of pregabalin

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[0019] The embodiment of the present invention provides a kind of preparation method of pregabalin, comprises the following steps:

[0020] In an alkaline solution, (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and sodium hypochlorite were subjected to a Hoffman rearrangement reaction to obtain a reaction solution, and the reaction solution was added to the acid -In the organic solvent system, extract and combine the organic phases, add alkali for alkali analysis, beating and washing with water to obtain high-purity pregabalin.

Embodiment 1

[0056] Add 32kg (0.8mol) of sodium hydroxide to 80L of water, stir and dissolve, lower to 0-10°C, add 40kg of (R)-(-)-3-(carbamoylmethyl)-5-methylhexyl in batches Acid, control 0-10°C, stir for 10 minutes after adding, add dropwise sodium hypochlorite solution (9.7% 164kg), control temperature 0-10°C, keep warm for 30 minutes after adding, slowly heat up to 80°C for 1h, cool to room temperature for later use.

[0057] Add 80L of methyl ethyl ketone and 50L of sulfuric acid into the reaction kettle, cool down to about 15°C, add the above-mentioned spare reaction solution dropwise, control it within 25°C, add sulfuric acid to adjust the pH to 2, raise the temperature to 25°C-30°C, and let it stand for stratification. Extract the aqueous layer with 40L*3 butanone, combine the organic layers (the combined organic layer includes 80L*3 butanone), adjust the pH to 8 with ammonia water, raise the temperature to 85°C and stir for 10min, press filter to the crystallization tank Cool to ...

Embodiment 2

[0071] Add 32kg (0.8mol) of sodium hydroxide into 80L of water, stir and dissolve, lower to 0°C, add 40kg of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid in batches, Control 0-10°C, stir for 10 minutes after adding, add sodium hypochlorite solution (9.7% 164kg) dropwise, control temperature 0-10°C, keep warm for 30 minutes after adding, slowly heat up to 80°C for 1h, cool to room temperature for later use.

[0072] Add 80L of toluene and sulfuric acid to the reaction kettle to cool down to about 15°C, add the above-mentioned spare reaction solution dropwise, control it within 25°C, add sulfuric acid to adjust the pH to 3, raise the temperature to 25°C-30°C, let the layers stand still, and the water layer Extract with 40L*3 toluene, combine the organic layers (the combined organic layer includes 80L toluene and 40L*3 toluene), adjust the pH to 7.5 with ammonia water, raise the temperature to 85°C and stir for 10min, press filter into the crystallization kettle, cool down to...

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Abstract

The present invention relates to a kind of preparation method of pregabalin, and this preparation method comprises the following steps: in alkaline solution, (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and Hoffman rearrangement reaction is carried out under the action of sodium hypochlorite. After the rearrangement reaction is completed, the reaction solution is added to the acid-organic solvent system, the organic phase is extracted and combined, and alkali is added for alkali analysis, beating and washing to obtain high-purity common Ribalin. The above-mentioned preparation method has the advantages of simple process route, high product yield and high product purity, can meet the pharmaceutical quality standard without recrystallization, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of pharmacy, and in particular to a preparation method of pregabalin. Background technique [0002] Pregabalin is used to treat partial epilepsy in adult patients. In June 2005, it was approved by the US Food and Drug Administration (FDA). In March 2006, a variety of new indications were added. One of the world's best-selling drugs. [0003] Existing many papers patent reports the preparation synthetic method of pregabalin at present, and patent CN101500985A records with (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid in sodium hydroxide, Under the action of sodium hypochlorite, the Hofmann rearrangement reaction is carried out, and then the pH is adjusted by hydrochloric acid to obtain pregabalin. However, when the patented method was reproduced, it was found that the above-mentioned patented method had a low product yield, easily introduced unknown impurities that were difficult to remove, and could no...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C227/10C07C229/08
CPCC07C227/10C07C229/08
Inventor 周付潮于立国金晓峰郭乙杰邵志春
Owner CHANGZHOU PHARMA FACTORY