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Preparation method and application of high-purity dimethyl 3-isobutylglutarate

A technology of isobutylglutaric acid dimethyl ester and isobutyl glutaric acid, applied in the preparation of high-purity 3-isobutylglutaric acid dimethyl ester, high-purity 3-isobutylglutaric acid dimethyl The application field of methyl ester in the further preparation of pregabalin can solve the problems of many impurities, low purity of dimethyl 3-isobutylglutarate, and removal of impurities

Active Publication Date: 2019-11-22
HUANGGANG LUBAN PHARM
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  • Claims
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AI Technical Summary

Problems solved by technology

[0012] However, although the existing method two has a high yield, the restrictive factor is that the purity of 3-isobutylglutaric acid dimethyl ester (formula 2) is not high, and there are many impurities, and wherein the impurities are difficult to remove by simple separation (such as rectification)

Method used

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  • Preparation method and application of high-purity dimethyl 3-isobutylglutarate
  • Preparation method and application of high-purity dimethyl 3-isobutylglutarate
  • Preparation method and application of high-purity dimethyl 3-isobutylglutarate

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[0084] The preparation method of pregabalin

[0085] One object of the present invention is to provide a method for preparing high-purity pregabalin.

[0086] In a specific embodiment, the invention provides a kind of preparation method of pregabalin, it comprises steps:

[0087] (1) In methanol, in the presence of potassium permanganate and concentrated sulfuric acid, 3-isobutylglutaric acid (formula 1) is reacted to obtain 3-isobutylglutaric acid dimethyl ester (formula 2),

[0088] with

[0089] (2) Pregabalin was prepared from the dimethyl 3-isobutylglutarate (formula 2) obtained in step (1).

[0090] In another preference, step (2) includes the steps of:

[0091] 3-isobutylglutaric acid dimethyl ester (formula 2) obtains the formula 9 compound through enzymatic selective hydrolysis; The formula 9 compound obtains the formula 10 compound with ammoniacal liquor ammonia solution; And the formula 10 compound carries out Hoffman degradation with sodium hypochlorite to ob...

Embodiment 2

[0133] Example 2: Preparation of 2-cyano-5-methyl-2-enhexanoic acid methyl ester (formula 6) (preparation of impurity 6 reference substance)

[0134] Add isovaleraldehyde (43g, 0.5mol), cyanoacetamide (84g, 1mol) and water (500ml) into the reaction flask at one time, slowly add piperazine (15g, 0.17mol) at a low temperature of 10°C, keep warm after adding After the reaction, a white solid was gradually formed, and toluene (250ml) was added and stirred for 10-12h to obtain 2,6-dicyano-3-isobutylglutaramide (Formula 5). In order to obtain more impurity 6 as a reference substance, the compound of formula 5 was prepared in a way that is more likely to form the impurity of formula 7 in this example.

[0135] The 2,6-dicyano-3-isobutylglutaramide (formula 5) generated in the previous step reaction was added dropwise to concentrated sulfuric acid (300 g). After the dropwise addition, the temperature was slowly raised to reflux for 12 hours, cooled to 80°C, the organic phase was sepa...

Embodiment 3

[0140] Example three: Preparation of dimethyl 3-isobutylglutarate (formula 2) (research on the amount of potassium permanganate)

[0141] Get 6 reaction flasks of 500ml, add 18.8g of 3-isobutylglutaric acid (formula 1) respectively, then respectively add 188g of methanol, after stirring and dissolving, add potassium permanganate 0.94g, potassium permanganate 0.94g, 1.88g, 3.76g, 5.64g, 9.4g. After the addition, 1.88g of concentrated sulfuric acid was added dropwise to the 6 reaction flasks, and the temperature was raised to reflux for 10-12 hours. The reaction liquid was cooled to room temperature, then methanol was distilled off, the residual liquid was extracted with n-hexane, washed with sodium bicarbonate solution until neutral, the organic layer was dried, filtered, and concentrated to obtain the crude product of 3-isobutylglutaric acid dimethyl ester (Formula 2) Detect product and impurity formula 6 data with high performance liquid phase as shown in table 1:

[0142] T...

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Abstract

The invention provides a preparation method and application of high-purity dimethyl 3-isobutylglutarate. Specifically, the invention provides the method for preparing dimethyl 3-isobutylglutarate shown as a formula 2, and the method comprises the step of enabling 3-isobutylglutaric acid to react in methanol in the presence of potassium permanganate and concentrated sulfuric acid, so as to obtain the high-purity dimethyl 3-isobutylglutarate. The method is simple, easy to control, high in product conversion rate, mild in reaction condition, convenient for industrial production and low in cost, the product is easy to purify, and the purity is up to 99% or above.

Description

technical field [0001] The invention belongs to the fields of medicine and fine chemical industry, and in particular relates to a method for preparing high-purity dimethyl 3-isobutylglutarate (Formula 2), and the prepared high-purity 3-isobutylglutaric acid Application of dimethyl ester (formula 2) in the further preparation of pregabalin. Background technique [0002] Pregabalin is approved for the adjunctive treatment of partial-onset diabetic peripheral neuralgia, postherpetic neuralgia, fibromyalgia, and neuropathic pain due to spinal cord injury in adults. In August 2003, Pfizer first filed an application for registration in the United States. In December 2004, the U.S. FDA approved the use of pregabalin for diabetic peripheral neuralgia (DPN) and postherpetic neuralgia (PHN). It is also the first drug jointly certified by the United States and Europe (July 2004) for the treatment of two types of neuralgia; in June 2005, pregabalin was certified as an adjuvant drug for...

Claims

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Application Information

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IPC IPC(8): C07C227/18C07C229/08C07C67/08C07C69/42C07C67/313C07C231/02C07C233/05C07C253/30C07C255/22C07C51/08C07C55/02G01N1/28
CPCC07C227/18C07C229/08C07C67/08C07C69/42C07C67/313C07C231/02C07C253/30C07C51/08G01N1/28C07C233/05C07C255/22C07C55/02
Inventor 杨小龙裴啤兵张建军杨铁波陈潜
Owner HUANGGANG LUBAN PHARM
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