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Utilize the method for directly synthesizing gabapentin with 1-cyano cyclohexyl acetic acid

A technology of gabapentin and acetic acid, which is applied in chemical instruments and methods, preparation of organic compounds, preparation of cyanide reactions, etc., can solve the problems of lack of a lot of research, cumbersome, cumbersome steps, etc., and achieves good atomic economy and is conducive to recovery and circulation. The effect of utilizing and reducing pollution

Active Publication Date: 2019-07-26
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] At present, most scholars use chemical methods to synthesize gabapentin, which requires the use of a large number of reagents, and the conditions and steps are lengthy and cumbersome; Xue et al. previously used chemical-enzymatic methods to synthesize gabapentin, which required three main steps: enzymatic catalysis, direct hydrogenation and chemical hydrolysis. , the steps are still relatively cumbersome
[0014] Therefore, through comparative studies, it was found that predecessors did not have a lot of research on the direct one-step hydrogenation catalytic synthesis of gabapentin, and the previous process was to directly hydrogenate 1-cyanocyclohexylacetic acid to synthesize cyclized products, and then hydrolyze to obtain gabapentin

Method used

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  • Utilize the method for directly synthesizing gabapentin with 1-cyano cyclohexyl acetic acid
  • Utilize the method for directly synthesizing gabapentin with 1-cyano cyclohexyl acetic acid
  • Utilize the method for directly synthesizing gabapentin with 1-cyano cyclohexyl acetic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: a kind of method of chemical-enzymatic synthesis of gabapentin, the steps are as follows:

[0040] (1) Preparation of seed liquid: the engineered bacteria E.coli BL21(DE3) / pET28b(+)-F168V (same as patent application CN104911225A Example 1) Inoculate on LB plate medium containing a final concentration of 5g / L kanamycin, cultivate overnight at 37°C, pick a single colony and inoculate it into 100mL of LB liquid containing a final concentration of 5g / L kanamycin culture medium at 37°C and 150 rpm overnight to obtain seed liquid.

[0041] (2) Fermentation culture: inoculate seed liquid in the 5L fermentor of the 3L fermented medium that contains final concentration 5g / L kanamycin, inoculum size is 3% (v / v), and regulating aeration ratio is 1.3vvm, in Fermentation culture was carried out at 37°C and 500rpm. During the fermentation process, ammonia water with a volume concentration of 8% and an aqueous solution of phosphoric acid with a volume concentration of 1...

experiment example 2

[0047] Experimental Example 2: Direct hydrogenation of conversion solution catalyzed by immobilized cells containing 1-cyanocyclohexylacetic acid to produce gabapentin

[0048] (1) Synthesis of gabapentin: get the immobilized cell catalyzed filtrate a containing 1-cyanocyclohexylacetic acid in step (4) in embodiment 1 after diluting 4 times with distilled water (1-cyanocyclohexylacetic acid concentration is 250mM ) 100mL into the hydrogenation reactor, add about 1.0g Raney Ni, add 1mL 98% triethylamine and 0.5mL 98% formic acid; replace the air with nitrogen, after 3 times, introduce 1MPa hydrogen at 30°C, 500rpm After keeping at low temperature for 12 hours, remove the hydrogen gas, raise the temperature to 40°C, keep at 500rpm for 12 hours, then remove the hydrogen gas, heat up to 50°C, then pass in the hydrogen gas, keep for 12 hours, remove the hydrogen gas, raise the temperature to 60°C, pass in the hydrogen gas, keep for 12 hours, and pass Inject hydrogen at 70°C, keep a...

experiment example 3

[0050] Experimental example 3: Direct hydrogenation of conversion solution catalyzed by immobilized cells containing 1-cyanocyclohexylacetic acid to produce gabapentin

[0051](1) Synthesis of gabapentin: get the filtrate a catalyzed by immobilized cells containing 1-cyanocyclohexylacetic acid in the step (4) of Example 1 after diluting 4 times with distilled water (the concentration of 1-cyanocyclohexylacetic acid is 250mM ) 100mL to the hydrogenation reactor, add about 1.0g Pd / C (Pd mass load 10%), 1mL 98% triethylamine and 0.5mL 98% formic acid; Inject 1MPa hydrogen at 40°C, keep at 500rpm for 12 hours, then remove the hydrogen, heat up to 50°C, then pass in hydrogen, leave for 12 hours, remove the hydrogen, raise the temperature to 60°C, pass in hydrogen, and hold for 12 hours. After degassing, the reaction liquid is filtered to obtain filtrate b and filter cake b, the filter cake b is the recovered catalyst, and the filtrate b is cooled to room temperature.

[0052] (2) ...

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Abstract

The invention discloses a method for directly synthesizing gabapentin by virtue of 1-cyanocyclohexyl acetic acid. The method comprises the following steps: dispersing immobilized cells of nitrilase genetically engineered bacteria into deionized water, adding 1-cyanocyclohexyl acetonitrile, stirring the completely react at 20-50 DEG C and 10rpm-350rpm, and carrying out suction filtration, so as to obtain filtrate a; adding the filtrate a into a hydrogenation reaction kettle, adding a catalyst and an aid, introducing nitrogen to completely react at 20-150 DEG C and 300rpm-1100rpm, and separating and purifying reaction liquid, so as to obtain gabapentin. By adding the aid and changing a heating strategy, the reaction is carried out for one batch under the optimal condition, and then the yield of gabapentin reaches 53.3%; 1-cyanocyclohexyl acetic acid is recycled and hydrogenated for five cycles, the yield of gabapentin reaches above 80% and is increased by 20% than that of a reported chemical process.

Description

[0001] (1) Technical field [0002] The invention relates to a synthesis process of gabapentin, that is, a synthesis process of 1-(aminomethyl)cyclohexylacetic acid, in particular to a method for directly synthesizing gabapentin with 1-cyanocyclohexylacetic acid, which belongs to the technical field of drug synthesis. [0003] (2) Background technology [0004] Gabapentin (Gabapentin), the trade name is Neurontin, the chemical name is 1-(aminomethyl)cyclohexylacetic acid, and the structure is similar to γ-aminobutyric acid (GABA). first launched in the UK. Gabapentin is a new generation of antiepileptic drugs, and it is also suitable for various types of neuralgia. It has the characteristics of mild adverse reactions, short duration, and no hepatic metabolism. Since its listing, sales have continued to rise, and it has a large share in the antiepileptic drug market. [0005] Since gabapentin contains a cyclohexane group structure, in the existing reports, cyclohexane compound...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C227/10C07C229/28C07C227/40C12P13/00
CPCC07C227/10C07C227/40C12P13/002C07C229/28
Inventor 薛亚平郑裕国钟胡军徐喆
Owner ZHEJIANG UNIV OF TECH
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