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Gabapentin synthesis method

A synthetic method, gabapentin technology, applied in the field of gabapentin synthesis, can solve the problems of low yield and low product purity, achieve high yield, simple reaction route, and ensure the effect of total yield and purity

Inactive Publication Date: 2015-11-18
TAICANG YUNTONG BIOCHEM ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method comprises cyclohexanone and ethyl fat through Knoevenagel reaction, Michael addition reaction, Pd-C catalytic hydrogenation reduction and hydrolysis reaction to prepare 2-hydroxyl-2-azaspiral[4,5]decane-3 ketone, Then through RaneyNi catalyzed hydrogenation reduction and hydrolysis, salt formation, the total yield of antiepileptic drug gabapentin is 14%, but the yield of this step reaction is low, and the purity of the product is low

Method used

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Examples

Experimental program
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Embodiment 1

[0028] Put cyclohexanone in the reaction vessel, cool to -10°C, add 1.05 times the molarity of ethyl cyanoacetate in cyclohexanone, and add -10°C 4wt% liquid ammonia in anhydrous isopropanol solution at constant temperature while stirring , The amount of anhydrous isopropanol solution is 5 times that of cyclohexanone. At this temperature, let it stand for 9h, filter, wash with ether, and dry to obtain 2,4-dioxo-3-aza-spiro[5,5]undecane-1,5-dinitrile ammonium salt. Named as Compound A.

[0029] Put the above-mentioned compound A, 2 times the deionized water of compound A quality, the concentrated sulfuric acid (its consumption is so that the mass concentration of sulfuric acid in the reaction solution is 5% in the high-pressure reactor, adjust the pressure of the reactor so that the reaction solution The temperature is 205°C. Stop the reaction after the hydrolysis reaction for 3 hours, cool down, and cool down. Wash the solid twice with water, and recrystallize with a mixture ...

Embodiment 2

[0034] Put cyclohexanone in the reaction vessel, cool to -5°C, add ethyl cyanoacetate with 1.2 times the molarity of cyclohexanone, and add 16wt% liquid ammonia in anhydrous isopropanol solution at -5°C at constant temperature while stirring , The amount of anhydrous isopropanol solution is twice that of cyclohexanone. At this temperature, let it stand for 15h, filter, wash with ether, and dry to obtain 2,4-dioxo-3-aza-spiro[5,5]undecane-1,5-dinitrile ammonium salt. Named as Compound A.

[0035] Put the above-mentioned compound A, 10 times the deionized water of compound A quality, the vitriol oil (its consumption is so that the mass concentration of sulfuric acid in the reaction solution is 20% in the high-pressure reactor, adjust the pressure of the reactor so that the reaction solution The temperature is 235°C. Stop the reaction after the hydrolysis reaction for 1 hour, cool down, and cool down. Wash the solid twice with water, and recrystallize with a mixture of methanol:...

Embodiment 3

[0040] Put cyclohexanone in the reaction vessel, cool to -7°C, add 1.12 times the molarity of ethyl cyanoacetate in cyclohexanone, and add -7°C 10wt% liquid ammonia in anhydrous isopropanol solution at constant temperature while stirring , The amount of anhydrous isopropanol solution is 3.5 times that of cyclohexanone. At this temperature, let it stand for 12 hours, filter, wash with ether, and dry to obtain 2,4-dioxo-3-aza-spiro[5,5]undecane-1,5-dinitrile ammonium salt. Named as Compound A.

[0041] Put above-mentioned compound A, deionized water, concentrated sulfuric acid (its consumption is so that the mass concentration of sulfuric acid in the reaction solution is 12% in the reaction kettle of high pressure, 6 times of compound A quality, adjust the pressure of reaction kettle so that the reaction solution The temperature is 220°C. Stop the reaction after the hydrolysis reaction for 2 hours, cool down, and cool down. Wash the solid twice with water, and recrystallize wit...

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Abstract

The invention discloses a gabapentin synthesis method which comprises the following steps: enabling addition cyclization reaction on cyclohexanone and ethyl cyanoacetate in an anhydrous isopropanol solution of liquid ammonia; enabling hydrolysis reaction on 2,4-dioxo-3-aza-spiro[5,5]undecane-1,5-dinitrile ammonium salt in high temperature liquid water by using H2SO4 as a catalyst; enabling dehydration reaction in a dichloroethane solvent by adding phosphorus pentoxide into 1,1-cyclohexyl diacetic acid; enabling ammonolysis reaction on 1,1-cyclohexyl diacetic anhydride in ammonia water; conducting Hofmann degradation reaction on 1,1-cyclohexyl diacetic acetamide. Cyclohexanone which is cheap and easy to obtain is used as a raw material to obtain gabapentin through addition cyclization reaction, hydrolysis, dehydration, ammonolysis and Hofmann degradation reaction, the reaction route is simple, and the yield of each step of reaction is relatively high, so that the final total yield and purity of gabapentin are ensured.

Description

technical field [0001] The invention relates to the technical field of gabapentin, in particular to a synthesis method of gabapentin. Background technique [0002] Gabapentin, the chemical name is 1-(aminomethyl)cyclohexaneacetic acid; 1-(methylamino)cyclohexaneacetic acid. [0003] Its structural formula is Gabapentin was developed by Warner-Lamber and was first launched in the UK in 1993. Gabapentin is designed to pass through the blood-brain barrier. It is a combined treatment drug for adult refractory epilepsy and partial seizures. It is clinically used for patients with epilepsy and localized seizures that cannot be satisfactorily controlled or tolerated by conventional antiepileptic drugs. Add-on therapy in patients with seizures and subsequent generalization of epilepsy. [0004] "Synthesis of Gabapentin, Xi Caiming et al., China Pharmaceutical Industry" reported a synthesis method of gabapentin. The method comprises cyclohexanone and ethyl fat through Knoevenage...

Claims

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Application Information

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IPC IPC(8): C07C229/28C07C227/04
Inventor 张卫东
Owner TAICANG YUNTONG BIOCHEM ENG
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