CN116253665A

CN116253665A - Preparation method of gabapentin intermediate

Info

Publication number: CN116253665A
Application number: CN202111453071.3A
Authority: CN
Inventors: 朱晓仁; 朱元勋; 颜峰峰
Original assignee: Zhejiang Huahai Pharmaceutical Co Ltd
Current assignee: Zhejiang Huahai Pharmaceutical Co Ltd
Priority date: 2021-12-01
Filing date: 2021-12-01
Publication date: 2023-06-13

Abstract

The invention relates to a preparation method of a key intermediate 1-cyano-cyclohexyl acetonitrile of gabapentin. The invention adopts a one-pot method, which comprises the following steps: cyclohexanone reacts with alkyl cyanoacetate in an organic solvent in the presence of weak alkali salt and organic acid, after the reaction is completed, the cyclohexanone and the alkyl cyanoacetate are not treated, and then react with an aqueous phase reaction system containing strong alkali, cyanide and a phase transfer catalyst continuously to obtain 1-cyano cyclohexyl acetonitrile. The method has the advantages of simple operation and stable process, further reduces the production cost, improves the yield and quality of the product, and is suitable for industrial production.

Description

Preparation method of gabapentin intermediate

Technical Field

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of a key intermediate 1-cyano-cyclohexyl acetonitrile of gabapentin.

Background

Gabapentin (Gabapentin, alias Neurostatin) is a gamma-aminobutyric acid (GABA) analog, which is used for treating epilepsy, and has the chemical name of 1- (aminomethyl) -1-cyclohexane acetic acid and the molecular formula of C ₉ H ₁₇ NO ₂ The molecular weight is 171.24, and the structure is shown as formula I:

at present, the chemical enzyme method is mainly used for synthesizing gabapentin, wherein cyclohexanone is used as a raw material, 1-cyano-cyclohexyl acetonitrile is firstly prepared, then nitrilase is used for catalyzing and generating 1-cyano-cyclohexyl acetic acid, and finally the gabapentin is obtained through catalytic hydrogenation, and the synthetic route is as follows:

1-cyano-cyclohexyl acetonitrile is used as an important intermediate in the chemical enzymatic synthesis method of gabapentin, the existing preparation method has a certain defect, and the research of the preparation method is also receiving more and more attention.

WO2013190357 discloses a method for preparing 1-cyanocyclohexylacetonitrile by a one-pot method, which comprises the steps of dissolving cyclohexanone and methyl cyanoacetate in methanol, adding ammonium acetate and sodium cyanide for reaction, distilling off part of the methanol after the reaction is finished, wherein the yield of the two-step reaction is 76.0%, and the GC purity is 94.4%.

CN111285782 also discloses a process for the preparation of 1-cyanocyclohexylacetonitrile by the "one pot process", which is carried out in two steps, in the most preferred embodiment cyclohexanone and ethyl cyanoacetate are first reacted in benzene in the presence of sodium acetate and p-toluenesulfonic acid monohydrate, after which 25% aqueous sodium cyanide is directly added without treatment, and the phase transfer catalyst 18-crown-6 is reacted further to give 1-cyanocyclohexylacetonitrile, in an optimal molar yield of 90.1% and GC purity of 99.5%.

Therefore, in order to further reduce the production cost and improve the quality and yield of the product, further optimization research on the prior art is required.

Disclosure of Invention

The invention aims to provide a method for preparing an important intermediate 1-cyano-cyclohexyl acetonitrile of gabapentin with high purity, high yield and low cost. The method comprises the following steps:

(1) Dissolving strong alkali, cyanide and a phase transfer catalyst in water to form a water phase reaction system;

(2) Cyclohexanone reacts with alkyl cyanoacetate in an organic solvent in the presence of weak alkali salt and organic acid, and after the reaction is completed, an organic phase reaction system is obtained without treatment;

(3) Mixing the aqueous phase reaction system in the step (1) with the organic phase reaction system in the step (2) for continuous reaction to prepare 1-cyano-cyclohexyl acetonitrile;

wherein the organic solvent in the step (2) is not miscible with water.

In step (1), the strong base is selected from sodium hydroxide, potassium hydroxide, preferably sodium hydroxide, more preferably sodium hydroxide to cyclohexanone in step (2) in a molar ratio of 0.1 to 0.5:1; the cyanide is selected from potassium cyanide and sodium cyanide, preferably sodium cyanide; the phase transfer catalyst is selected from tetrabutylammonium bromide, tetrabutylammonium chloride, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide, preferably tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydroxide.

In step (2), the alkyl cyanoacetate is selected from methyl cyanoacetate, ethyl cyanoacetate, preferably methyl cyanoacetate; the weak base salt is selected from ammonium acetate, ammonium benzoate, ammonium succinate, preferably ammonium acetate; the organic acid is selected from benzoic acid, succinic acid, phthalic acid, acetic acid, citric acid, preferably citric acid; the organic solvent is toluene or xylene, preferably toluene.

Further, the step (2) reacts at reflux temperature to separate water until no water is fractionated out; the reaction temperature of the step (3) is 40-110 ℃, preferably 60-80 ℃ and the reaction time is 10-30 hours.

Further, the molar ratio of cyclohexanone to alkyl cyanoacetate, weak alkali salt and organic acid in the step (2) is 1:1.0-1.5:0.1-0.5:0.01-0.1, and the mass volume ratio of cyclohexanone to organic solvent is 1:2-5; the molar ratio of cyclohexanone in the step (2) to the phase transfer catalyst and cyanide in the step (1) is 1:0.01-0.05:1.0-1.5, and the mass volume ratio of cyclohexanone to water in the step (1) is 1:1-3.

The preparation method of the invention further comprises the following steps if necessary:

(4) Layering after the reaction of the step (3), taking an organic phase, optionally washing the organic phase with water, distilling the organic phase under reduced pressure to remove the organic solvent, and then adding an alcohol solvent and water for recrystallization to obtain a 1-cyano-cyclohexyl acetonitrile solid;

wherein the alcohol solvent is selected from methanol, ethanol, isopropanol, preferably ethanol; the volume mass ratio of the alcohol solvent, the crystallization water and the cyclohexanone in the step (2) is 1-5: 2 to 5:1, a step of; the crystallization temperature is-5-10 ℃.

The water of the invention is drinking water.

Another object of the present invention is to provide a high purity composition of 1-cyanocyclohexylacetonitrile, wherein the content of 1-cyanocyclohexylacetonitrile in the composition is not less than 99.5%,99.8%,99.9%; the cyclohexanone content is not more than 0.35%,0.05% and 0.02%; the content of other single impurities is not more than 0.10%,0.05% and 0.03%.

The above-mentioned "composition" refers to a mixture of 1-cyanocyclohexylacetonitrile and impurities, which refer to organic impurities related to the structure of 1-cyanocyclohexylacetonitrile, including raw materials, intermediates, byproducts, and the like in the preparation process.

The above-mentioned high purity composition, the impurities have a great influence on the purification of the subsequent process, the quality and cost control of the final product gabapentin, and thus, it is necessary to control the purity of 1-cyanocyclohexylacetonitrile and the contents of various impurities. The content is measured by Gas Chromatography (GC) area normalization method and is identified by percentage area.

In some embodiments, the high purity composition has a 1-cyanocyclohexylacetonitrile content of no less than 99.5%, a cyclohexanone content of no more than 0.35%, and other individual impurities content of no more than 0.10%.

In some embodiments, the high purity composition has a 1-cyanocyclohexylacetonitrile content of no less than 99.8%, a cyclohexanone content of no more than 0.05%, and other individual impurities content of no more than 0.05%.

In some embodiments, the high purity composition has a 1-cyanocyclohexylacetonitrile content of no less than 99.9%, a cyclohexanone content of no more than 0.02%, and other individual impurities content of no more than 0.03%.

Drawings

FIG. 1 is a GC localization spectrum of 1-cyanocyclohexylacetonitrile, RT16.916 is 1-cyanocyclohexylacetonitrile and RT5.313 is cyclohexanone.

FIG. 2 is a GC analysis chart of 1-cyanocyclohexylacetonitrile of example 10.

Detailed Description

For a further understanding of the present invention, preferred embodiments of the invention are described below in conjunction with the examples, but it should be understood that these descriptions are merely intended to illustrate further features and advantages of the invention, and are not limiting of the claims of the invention.

The invention provides a method for detecting 1-cyano-cyclohexyl acetonitrile by GC gas chromatography, which comprises the following steps:

instrument: gas chromatograph equipped with FID detector and automatic sampler

Chromatographic column: DB-FFAP 30 m0.32mm0.25μm

Column temperature: the initial temperature is 80 ℃, the temperature is kept for 5min, the temperature is increased to 180 ℃ at the heating rate of 20 ℃/min, and the temperature is kept for 5min; then the temperature is raised to 240 ℃ at a rate of 10 ℃/min and maintained for 5min.

Vaporization chamber temperature: 200 DEG C

Detector temperature: 250 DEG C

Carrier gas: n (N) ₂

Linear velocity: 30cm/sec

Split ratio: 10:1

Sample injection amount: 1.0 mu L

Dilution liquid: acetonitrile

Comparative examples: preparation of 1-cyanocyclohexylacetonitrile

1-cyanocyclohexylacetonitrile prepared according to CN111285782 example 1, GC detection: 99.5% of 1-cyanocyclohexyl acetonitrile, 0.45% of cyclohexanone and <0.05% of single impurity.

Example 1: preparation of 1-cyanocyclohexylacetonitrile

An aqueous reaction system was prepared by dissolving 5.7g of sodium hydroxide, 69.9g of sodium cyanide and 4.60g of tetrabutylammonium bromide in 140ml of water.

140.0g of cyclohexanone, 141.2g of methyl cyanoacetate, 11.0g of ammonium acetate and 2.7g of citric acid are added into 280ml of toluene, heated, refluxed and distributed until no water is generated in the system, then added into the water phase reaction system prepared in the previous step, the temperature of the system is controlled to 80 ℃, and the reaction is carried out for 15 hours with heat preservation. After the reaction, separating the water layer, washing the organic layer with 140ml of water for 2 times, distilling under reduced pressure to remove the solvent, then adding 140ml of ethanol and 280ml of water, stirring to dissolve, cooling to-5 ℃ for crystallization, filtering to obtain 191.3g of 1-cyanocyclohexyl acetonitrile, and detecting by GC with the yield of 90.5 percent: 99.9% of 1-cyano-cyclohexyl acetonitrile, less than 0.01% of cyclohexanone and less than or equal to 0.02% of single impurity.

Examples 2 to 7: preparation of 1-cyanocyclohexylacetonitrile

The different bases were selected to prepare 1-cyanocyclohexylacetonitrile as described in example 1, with the results shown in the following table:

numbering device	Alkali screening	Purity of	Cyclohexanone	Single impurity	Yield is good
						Example 1	Sodium hydroxide	99.9％	<0.01％	≤0.02％	90.5％
Example 2	Potassium hydroxide	99.8％	0.01％	≤0.03％	88.5％
						Example 3	Lithium hydroxide	99.0％	0.85％	≤0.1％	80.5％
Example 4	Sodium carbonate	97.0％	2.5％	≤0.3％	65.5％
						Example 5	Potassium carbonate	96.5％	3.0％	≤0.2％	63.0％
Example 6	Triethylamine	92.0％	6.5％	≤1.3％	51.0％
						Example 7	Control group (alkali-free)	90.0％	7.5％	≤1.5％	45.0％

From the above experimental results, it can be seen that the addition of the base can promote the reaction, and can reduce the occurrence of side reactions, thereby reducing the generation of impurities. And the strong alkali reaction effect is better than weak alkali. Wherein, the sodium hydroxide has the optimal effect, and the yield and purity of the 1-cyano-cyclohexyl acetonitrile prepared by the method are higher.

Example 8: preparation of 1-cyanocyclohexylacetonitrile

28.5g of sodium hydroxide, 104.9g of sodium cyanide and 19.8g of tetrabutylammonium chloride were dissolved in 420ml of water to prepare an aqueous reaction system.

140g of cyclohexanone, 211.8g of methyl cyanoacetate, 55.0g of ammonium acetate and 27.4g of citric acid are added into 700ml of dimethylbenzene, the temperature is raised, water is returned and separated until no water is generated in the system, and then the mixture is added into a water phase reaction system prepared in the previous step, the temperature of the system is controlled to be 110 ℃, and the reaction is carried out for 10 hours under the condition of heat preservation. After the reaction, the aqueous layer was separated, the organic layer was washed 1 time with 280ml of water, the solvent was distilled off under reduced pressure, 280ml of methanol and 560ml of water were added, the mixture was stirred and dissolved, the temperature was lowered to 5℃for crystallization, 189.2g of 1-cyanocyclohexyl acetonitrile was obtained by filtration, the yield was 89.5%, and GC detection: 99.8 percent of 1-cyano-cyclohexyl acetonitrile, 0.05 percent of cyclohexanone and less than or equal to 0.05 percent of single impurity.

Example 9: preparation of 1-cyanocyclohexylacetonitrile

11.4g of sodium hydroxide, 111.5g of potassium cyanide and 13.8g of tetrabutylammonium bromide were dissolved in 280ml of water to prepare an aqueous reaction system.

140.0g of cyclohexanone, 193.6g of ethyl cyanoacetate, 21.7g of ammonium succinate and 1.68g of succinic acid are added into 280ml of dimethylbenzene, the temperature is raised and the mixture is refluxed until no water is generated in the system, and then the mixture is added into the water phase reaction system prepared in the previous step, the temperature of the system is controlled to be 80 ℃, and the reaction is carried out for 30 hours under the condition of heat preservation. After the reaction, the aqueous layer was separated, the organic layer was washed 2 times with 140ml of water, the solvent was distilled off under reduced pressure, 420ml of isopropyl alcohol and 700ml of water were added and stirred to dissolve, the temperature was lowered to 0 ℃ for crystallization, 193.5g of 1-cyanocyclohexyl acetonitrile was obtained by filtration, the yield was 91.5%, and GC detection: 99.9% of 1-cyano-cyclohexyl acetonitrile, less than 0.01% of cyclohexanone and less than or equal to 0.02% of single impurity.

Example 10: preparation of 1-cyanocyclohexylacetonitrile

An aqueous reaction system was prepared by dissolving 5.7g of sodium hydroxide, 69.9g of sodium cyanide and 3.7g of tetrabutylammonium hydroxide in 140ml of water.

140g of cyclohexanone, 141.2g of methyl cyanoacetate, 39.7g of ammonium benzoate and 11.8g of phthalic acid are added into 420ml of toluene, the temperature is raised until no water is generated in the system, and then the mixture is added into the water phase reaction system prepared in the previous step, the temperature of the system is controlled to be 60 ℃, and the reaction is carried out for 24 hours with heat preservation. After the reaction, the aqueous layer was separated, the organic layer was washed 2 times with 140ml of water, the solvent was distilled off under reduced pressure, 140ml of methanol and 280ml of water were added, the mixture was stirred and dissolved, the temperature was lowered to-5℃for crystallization, 192.4g of 1-cyanocyclohexylacetonitrile was obtained by filtration, the yield was 91.0%, and GC detection: 99.9% of 1-cyano-cyclohexyl acetonitrile, less than 0.01% of cyclohexanone and less than or equal to 0.03% of single impurity.

Claims

1. The preparation method of the 1-cyano-cyclohexyl acetonitrile is characterized by comprising the following steps:

wherein the organic solvent in the step (2) is not miscible with water.

2. The process according to claim 1, wherein the strong base in step (1) is selected from sodium hydroxide, potassium hydroxide, preferably sodium hydroxide, more preferably sodium hydroxide to cyclohexanone in step (2) in a molar ratio of 0.1 to 0.5:1.

3. The process according to claim 1, wherein the cyanide in step (1) is selected from potassium cyanide, sodium cyanide, preferably sodium cyanide; the phase transfer catalyst is selected from tetrabutylammonium bromide, tetrabutylammonium chloride, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide, preferably tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydroxide.

4. The process according to claim 1, wherein in step (2) the alkyl cyanoacetate is selected from the group consisting of methyl cyanoacetate, ethyl cyanoacetate, preferably methyl cyanoacetate; the weak base salt is selected from ammonium acetate, ammonium benzoate, ammonium succinate, preferably ammonium acetate; the organic acid is selected from benzoic acid, succinic acid, phthalic acid, acetic acid, citric acid, preferably citric acid; the organic solvent is selected from toluene, xylene, preferably toluene.

5. The process of claim 1 wherein step (2) is carried out at reflux temperature until anhydrous fractionation; the reaction temperature of the step (3) is 40-110 ℃, preferably 60-80 ℃ and the reaction time is 10-30 hours.

6. The preparation method according to claim 1, wherein the molar ratio of cyclohexanone to alkyl cyanoacetate, weak alkali salt and organic acid in the step (2) is 1:1.0-1.5:0.1-0.5:0.01-0.1, and the mass-volume ratio of cyclohexanone to organic solvent is 1:2-5.

7. The preparation method according to claim 1, wherein the molar ratio of cyclohexanone in the step (2) to the phase transfer catalyst and cyanide in the step (1) is 1:0.01-0.05:1.0-1.5, and the mass-volume ratio of cyclohexanone in the step (1) to water is 1:1-3.

8. The preparation method according to claim 1, further comprising the steps of:

(4) And (3) layering after the reaction in the step (3), taking an organic phase, optionally washing the organic phase with water, distilling the organic phase under reduced pressure to remove the organic solvent, and then adding an alcohol solvent and water for recrystallization to obtain the 1-cyano-cyclohexyl acetonitrile solid.

9. The process according to claim 8, wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol, preferably ethanol; the volume mass ratio of the alcohol solvent, the crystallization water and the cyclohexanone in the step (2) is 1-5: 2 to 5:1, the crystallization temperature is-5-10 ℃.

10. A 1-cyanocyclohexylacetonitrile composition obtainable by the process according to claims 1-9, wherein the 1-cyanocyclohexylacetonitrile content of the composition is not less than 99.5%, the cyclohexanone content is not more than 0.35%, and the content of other individual impurities is not more than 0.10%; preferably, the content of 1-cyanocyclohexyl acetonitrile is not less than 99.8%, the content of cyclohexanone is not more than 0.05%, and the content of other single impurities is not more than 0.05%; the content is measured by Gas Chromatography (GC) area normalization method.