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Nesting method for pregabalin intermediate mother liquor

A technology of intermediates and mother liquors, applied in the field of application of pregabalin intermediate mother liquors

Active Publication Date: 2014-08-13
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] But at present there is no patent literature report that the mother liquor of the free process has been applied mechanically, that is, (R)-3-(carbamoylmethyl)-5-methylhexanoic acid compound II is reclaimed, therefore, find a kind of highly feasible It is necessary to recycle the above mother liquor

Method used

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  • Nesting method for pregabalin intermediate mother liquor
  • Nesting method for pregabalin intermediate mother liquor
  • Nesting method for pregabalin intermediate mother liquor

Examples

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example 1

[0029] Add (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid-(R)-(+)-α-phenethylamine salt 200g into a 1000ml four-neck flask, free mother liquor 600g and 40g water, heat up to 40°C and stir mechanically. When the internal temperature of the system reaches 40°C, keep stirring for 10 minutes, cool down to 25°C, start to slowly add 77g of concentrated hydrochloric acid, adjust the pH to 1.5, start to cool down to 5°C, and keep warm Stir for 3 hours, filter with suction and dry to obtain 132.6 g of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid with a yield of 109.2% and a purity of 99.6%. 0.11%.

example 2

[0031] Add (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid-(R)-(+)-α-phenethylamine salt 200g into a 1000ml four-neck flask, free mother liquor 640g and 40g methanol, heat up to 35°C and stir mechanically, when the internal temperature of the system reaches 35°C, keep stirring for 10 minutes, start to slowly add 77g concentrated hydrochloric acid dropwise, adjust the pH to 1.0, start to cool down to 8°C, keep stirring for 4 hours, shake Filtration and drying gave 127.5 g of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid, with a yield of 105.0%, a purity of 99.6%, and an isomer of 0.12%.

example 3

[0033] Add (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid-(R)-(+)-α-phenethylamine salt 200g into a 1000ml four-neck flask, free mother liquor 550g and 40g isopropanol, heat up to 45°C and stir mechanically. When the internal temperature of the system reaches 45°C, keep stirring for 10 minutes, then cool down to 30°C, start to slowly add 77g of concentrated hydrochloric acid dropwise, adjust the pH to 1.0, and start to cool down to 5 ℃, heat preservation and stirring for 3.5 hours, rejection filtration, and drying to obtain (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid 126.4g, yield 104.1%, purity 99.4%, Isomer 0.15%.

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Abstract

The invention discloses a nesting method for a mother liquor of a free pregabalin intermediate (R)-(-)-3-(carbamyl methyl)-5-methylhexanol-(R)-(+)-alpha-phenethylamine salt. The method comprises the following steps: (1) feeding a phenethylamine salt (R)-(-)-3-(carbamyl methyl)-5-methylhexanol-(R)-(+)-alpha-phenethylamine salt to the mother liquor filtered by dissociation in the procedure, and adding a certain amount of solvent to agitate, heat and dissolve; (2) cooling, dropwise adding an acid to adjust the pH; (3) devitrifying at certain temperature, filtering, wherein the filtrate is the mother liquor, and baking the filter cake to obtain (R)-(-)-3-(carbamyl methyl)-5-methylhexanol. The atom utilization rate of the reaction is improved, environmental pollution caused by direct emission of the material in the mother liquor is avoided, the nesting method is mild in reaction condition, has no demands on special equipment and instrument and has green chemistry characteristics, and the production cost is greatly reduced.

Description

technical field [0001] The invention relates to a method for mechanically applying a pregabalin intermediate mother liquor, and belongs to the field of medicine and chemical industry. Background of the invention [0002] (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid-(R)-(+)-α-phenethylamine salt compound I and (R)-3-(ammonia Formylmethyl)-5-methylhexanoic acid compound II is two important intermediates of pregabalin, and obtains pregabalin through one-step hoffmann degradation, and its structural formula is as follows: [0003] [0004] The chemical name of pregabalin is (3S)-3-aminomethyl-5-methylhexanoic acid. It is a GBAB receptor agonist developed by Pfizer. Pain, postherpetic neuralgia, and localized seizures in adults. S-pregabalin is the first drug approved by the FDA for the treatment of more than two types of neuropathic pain. It has the characteristics of less frequent administration and fewer adverse reactions. [0005] Currently, there are two main type...

Claims

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Application Information

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IPC IPC(8): C07C233/05C07C231/12
Inventor 刘幕松张文灵姜建新王鹏
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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