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Method for preparing 3-isobutylglutaric acid

A technology of isobutylglutaric acid and isovaleraldehyde, which is applied in the preparation of carboxylic acid esters, chemical instruments and methods, and the preparation of organic compounds, and can solve problems such as low experimental yield, large steric hindrance, and long time consumption , to achieve the effect of ensuring the total yield, small steric hindrance, and simple reaction route

Pending Publication Date: 2019-09-20
CHANGZHOU VOCATIONAL INST OF ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The method takes a long time, the reaction time alone exceeds 70h, and the empirical yield is very low, because the condensation product of isovaleraldehyde and cyanoacetate: 5-methyl-2-cyano-2-hexenoate carbon The carbon double bond has a large steric hindrance, which hinders the addition reaction with diethyl malonate

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0026] Adopt the inventive method to prepare 3-isobutyl diethyl glutarate, comprise the steps:

[0027] S1: Add diethyl malonate (16g, 0.1mol), isovaleraldehyde (8.6g, 0.1mol), cyclohexane (300mL), glacial acetic acid (30mL), hexahydropyridine (1mL ), install a water separator, and heat to reflux for 3h. Cool the reaction solution to room temperature, add saturated NaCl solution and stir for 0.5 h, let stand to separate layers, take the organic layer, and distill off most of the cyclohexane under reduced pressure to obtain a brown oil (compound A solution);

[0028] S2: Add the compound A solution, NaCl (11.3g, 0.194mol), DMSO (200mL) and water (5mL) in step S1 into the reaction flask, heat to 185°C under nitrogen protection, and stir for 3h. The reaction solution was cooled to room temperature, acidified by adding dilute hydrochloric acid, extracted with dichloromethane (200 mL / time x 3 times), washed with water, anhydrous Na 2 SO 4 After drying, most of the dichloromethan...

Embodiment 2

[0035] Adopt the inventive method to prepare 3-isobutyl diethyl glutarate, comprise the steps:

[0036] S1: Add diethyl malonate (20.8g, 0.13mol), isovaleraldehyde (10.3g, 0.12mol), cyclohexane (300mL), glacial acetic acid (30mL), hexahydropyridine ( 1mL), install a water trap, and heat to reflux for 3h. Cool the reaction solution to room temperature, add saturated NaCl solution and stir for 0.5 h, let stand to separate layers, take the organic layer, and distill off most of the cyclohexane under reduced pressure to obtain a brown oil (compound A solution);

[0037]S2: Add the compound A solution, NaCl (11.3g, 0.194mol), DMSO (200mL) and water (5mL) in step S1 into the reaction flask, heat to 185°C under nitrogen protection, and stir for 3h. The reaction solution was cooled to room temperature, acidified by adding dilute hydrochloric acid, extracted with dichloromethane (200 mL / time x 3 times), washed with water, anhydrous Na 2 SO 4 After drying, most of the dichloromethane...

Embodiment 3

[0044] Adopt the inventive method to prepare 3-isobutyl diethyl glutarate, comprise the steps:

[0045] S1: Add diethyl malonate (16g, 0.1mol), isovaleraldehyde (8.6g, 0.1mol), cyclohexane (300mL), glacial acetic acid (30mL), hexahydropyridine (1mL ), install a water separator, and heat to reflux for 3h. Cool the reaction solution to room temperature, add saturated NaCl solution and stir for 0.5 h, let stand to separate layers, take the organic layer, and distill off most of the cyclohexane under reduced pressure to obtain a brown oil (compound A solution);

[0046] S2: Add the compound A solution, NaCl (11.3g, 0.194mol), DMSO (200mL) and water (5mL) in step S1 into the reaction flask, heat to 185°C under nitrogen protection, and stir for 3h. The reaction solution was cooled to room temperature, acidified by adding dilute hydrochloric acid, extracted with dichloromethane (200 mL / time x 3 times), washed with water, anhydrous Na 2 SO 4 After drying, most of the dichloromethan...

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Abstract

The invention discloses a method for preparing 3-isobutylglutaric acid. The method includes the following steps: carrying out a Knoevenagel condensation reaction on isovaleraldehyde and diethyl malonate with hexahydropyridine acetate as a catalyst in a cyclohexane solvent; carrying out a heating decarboxylation reaction on a product obtained by the first step in a solution composed of sodium chloride, DMSO and water; carrying out a Michael addition and decarboxylation reaction on a product obtained by the second step and diethyl malonate in an alcohol solvent of an alkali; and carrying out a hydrolysis reaction on a product obtained by the third step under an acidic condition to obtain the 3-isobutylglutaric acid product. The method of the invention uses the cheap and easily available isovaleraldehyde and diethyl malonate as raw materials, overcomes the defect of large steric hindrance of carbon-carbon a double bond in 5-methyl-2-cyano-2-hexenoate in the prior art, shortens the reaction time, and increases the reaction conversion rate of the isovaleraldehyde, thereby ensuring the overall yield of the 3-isobutylglutaric acid product.

Description

technical field [0001] The invention relates to the technical field of a drug synthesis method, in particular to a method for preparing 3-isobutylglutaric acid. Background technique [0002] Pregabalin (Pregabalin) chemical name: (3S)-3-aminomethyl-5-methylhexanoic acid, trade name Lyrica (Lyrica), is a new type of γ-aminobutyric acid (GABA) receptor Antagonist was approved for marketing by the European Union for the first time in July 2004, and was approved by the US Food and Drug Administration (FDA) for marketing in the United States in June 2005. It is the first drug approved by the FDA for the treatment of more than two types of neuropathic pain. It can be used to treat pain caused by postherpetic neuralgia, peripheral neuralgia, and diabetic peripheral neuropathy, has good antiepileptic therapeutic effect, less administration times, and less adverse reactions. As the key intermediate of pregabalin - 3-isobutylglutaric acid, the main synthesis method reported in the li...

Claims

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Application Information

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IPC IPC(8): C07C51/09C07C55/02C07C51/42
CPCC07C51/09C07C51/42C07C67/00C07C67/343C07C69/593C07C69/533C07C69/34C07C55/02
Inventor 祁秀秀陈文华尤海烽陈闻起王菲张乔乔
Owner CHANGZHOU VOCATIONAL INST OF ENG
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