CN116041214A

CN116041214A - Preparation method and application of pregabalin intermediate

Info

Publication number: CN116041214A
Application number: CN202211432317.3A
Authority: CN
Inventors: 谢晓强; 周天喜; 张毅; 许佳鹏; 蒋宇俊; 洪安娜
Original assignee: Aurisco Pharmaceutical Co ltd
Current assignee: Aurisco Pharmaceutical Co ltd
Priority date: 2022-11-15
Filing date: 2022-11-15
Publication date: 2023-05-02

Abstract

The invention discloses a preparation method of a compound shown in a formula I, which comprises the following steps: (1) Ethyl (S) -3-cyano-5-methylhexanoate, carrying out hydrolysis reaction in the presence of alkali in an organic solution, and filtering after the reaction is finished to obtain a compound shown in a formula I, wherein the reaction formula is as follows; (2) Pulping the compound shown in the formula I obtained in the step (1) by using an organic solvent, and filtering. The compound shown in the formula I can be used for preparing pregabalin, and the obtained product has the advantages of simple purification mode, good quality and high yield, and is suitable for industrial mass production.

Description

Preparation method and application of pregabalin intermediate

Technical Field

The invention relates to the technical field of pharmaceutical chemistry, in particular to a preparation method of a pregabalin intermediate and a method for preparing pregabalin by using the intermediate.

Background

Pregabalin is a novel antiepileptic drug having a gamma-aminobutyric acid structure in its molecular structure, and thus having an antispasmodic effect. Pregabalin is a class I drug of the BCS classification system. The pregabalin reaches peak concentration after 1.5 hours of oral administration, the relative bioavailability is more than or equal to 90 percent, and Cmax and AUC are in linear relation with the administration dosage, and the pregabalin is not combined with plasma protein in vivo and has almost no metabolism. Pregabalin has been approved for the adjuvant treatment of partial onset diabetic peripheral neuralgia, postherpetic neuralgia, fibromyalgia, and neuropathic pain caused by spinal cord injury in adults. For 8 months 2003, the first registration application by pyroxs was filed in the united states, for 12 months 2004, and the FDA in the united states approved pregabalin for Diabetic Peripheral Neuralgia (DPN) and postherpetic neuralgia (PHN), which is also the first drug to be co-certified for the treatment of 2 neuralgia in the united states and europe (7 months 2004); pregabalin was also approved as an adjunctive therapeutic drug for the treatment of partial seizures 6 months 2005; pregabalin was continually approved by the us FDA as the first drug to treat fibromyalgia syndrome, 6 months 2007; in year 6 2012, the FDA approved pregabalin as the first drug for the treatment of neuralgia caused by spinal cord injury.

The current methods for preparing pregabalin are mainly two:

1. the chemical resolution method is disclosed for the first time in U.S. patent 5616793, takes 3-isobutyl glutaric acid as a raw material, and obtains pregabalin through dehydration cyclization, ammonolysis, R- (+) -alpha-methylbenzylamine resolution and Hoffmann degradation, wherein the optical purity is 99.8%, but the chemical resolution method has high resolution cost, large three-waste pollution and difficult treatment of a large amount of high-concentration wastewater.

2. The enzymatic resolution method is disclosed for the first time in U.S. patent No. 7838686B2, wherein isovaleraldehyde and diethyl malonate are condensed, and then subjected to cyanidation addition, decarboxylation, enzyme selective hydrolysis, hydrolysis decarboxylation in alkaline water and hydrogenation to prepare pregabalin.

The enzymatic resolution method has relatively low cost, but the intermediates 1,2,3 and 4 are all liquid, have high boiling points and cannot be purified by conventional crystallization distillation and other methods, the intermediate 5 is solid, is dissolved in aqueous solution, is very difficult to separate the intermediate 5 from the aqueous solution, has low recovery rate and consumes a large amount of organic solvent, and is not suitable for industrial mass production. High temperature distillation water removal can crystallize to obtain intermediate 5, but high temperature distillation water removal process can generate a large amount of impurities, and intermediate 5 with high purity cannot be obtained. Thus, enzymatic synthesis of pregabalin is currently essentially a one-pot reaction, i.e. all impurities are removed by crystallization after the final hydrogenation step to form a stable API (the final compound pregabalin is recrystallized from a mixture of isopropanol and water). For pharmaceutical production, the removal of a large amount of impurities by crystallization in the API step is uneconomical and also presents a certain quality risk, considering refining in the previous steps of the API to ensure the stability of the quality of the API production.

In addition, prior art An Enantioselective Synthesis of (S) - (+) -3-Aminomerothyl-5-methylhexanoic Acid via Asymmetric Hydrogenation, mark J.Burk, et al, J.org.chem,2003,68,5731-5734 discloses a process for preparing compound 3c using compound 2a as a starting material, the reaction formula is as follows:

the method comprises the following specific steps: 3-cyano-5-methyl hexenoate (compound 2 a) was dissolved with a mixture of methanol and water, a methanol solution of potassium hydroxide was added, heated to 55℃under a nitrogen atmosphere, and maintained for 2 hours. Then [ (R, R) - (Me-DuPHOS) Rh (COD) was added under hydrogen atmosphere]BF ₄ The reaction vessel was filled with hydrogen to 60psi and the reaction solution was stirred at 55 ℃ until the hydrogen absorption ceased, and the solvent was removed under vacuum to give a white crystalline solid, i.e. (S) 3-cyano-5 methylhexanePotassium acid (compound 2 c). It can be seen that in this prior art, the first step of hydrolysis of compound 2b using compound 2a as a starting material is carried out in a mixed solution of methanol and water, and that compound 2b is directly reduced by hydrogenation in this solution without isolation to give compound 2c. The reaction solution containing the compound 2c is subjected to removal of the solvent under vacuum to obtain a crude product of the compound 2c, which is not high in purity, and for industrial scale-up production, distillation of the aqueous solvent to obtain a crude product is time-consuming and labor-consuming.

Therefore, there is still a need in the art to find a new method for preparing pregabalin intermediates that is convenient to operate, of good quality, and suitable for industrial mass production.

Disclosure of Invention

Aiming at the problems existing in the prior art, the invention aims to provide a novel preparation method of pregabalin intermediate, and the product obtained by the preparation method has high yield and purity, is convenient to operate and is suitable for industrial mass production.

In order to achieve the above purpose, the present invention adopts the following technical scheme:

a process for the preparation of a compound of formula I, comprising the steps of,

(1) Ethyl (S) -3-cyano-5-methylhexanoate, in the presence of alkali, carrying out hydrolysis reaction in an organic solution, and filtering after the reaction is finished to obtain a compound shown in a formula I, wherein the reaction formula is as follows:

wherein M is sodium (Na), potassium (K), calcium (Ca), magnesium (Mg) or lithium (Li).

The above method may further comprise step (2): pulping the compound shown in the formula I obtained in the step (1) by using an organic solvent, and filtering.

The organic solvent in step (1) may be selected from methanol, ethanol, isopropanol, acetonitrile, or a combination thereof. In some embodiments of the invention, the organic solvent is selected from isopropanol.

In the step (1), the mass volume ratio of the (S) -3-cyano-5-methylhexanoic acid to the organic solvent of the ethyl ester is 40-120 g/L. In some embodiments of the invention, the mass to volume ratio of (S) -3-cyano-5-methylhexanoic acid to the organic solvent is 50-100 g/L.

The base in step (1) may be selected from sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium isopropoxide, calcium acetate, or a combination thereof. In some embodiments of the invention, the base is selected from sodium hydroxide.

In step (1), the molar ratio of (S) -3-cyano-5-methylhexanoic acid ethyl ester to the base is 1:1.0-5.0 in some embodiments of the invention, the molar ratio of (S) -3-cyano-5-methylhexanoic acid ethyl ester to the base is 1:1.0-1.5.

The reaction temperature in the step (1) is 0-40 ℃. In some embodiments of the invention, the reaction temperature in step (1) is 10 to 15 ℃.

In the present invention, the base is preferably added to the reaction system in the form of a solution.

The concentration of the alkali solution is 50 g/L-300 g/L.

The organic solvent used for dissolving the base is preferably the same as the organic solvent of the reaction liquid of step (1).

In some embodiments of the invention, the solution of base is an isopropanol solution of sodium hydroxide. In some embodiments of the invention, the concentration of the isopropanol solution of sodium hydroxide is 66g/L.

The temperature of the reaction system is preferably maintained at 0 to 40℃during the addition of the base. In some embodiments of the invention, the temperature of the reaction system is maintained between 10 and 15 ℃ during the addition of the base.

In some embodiments of the invention, the reaction solution is stirred at 0-40 ℃ for 0-2 hours after the addition of the base solution is completed.

In some embodiments of the invention, after the reaction is completed, the reaction solution is distilled to dryness at 0-40 ℃ to obtain a crude product of the compound shown in the formula I.

The organic solvent in step (2) may be selected from methanol, ethanol, isopropanol, acetonitrile. In some embodiments of the invention, the organic solvent in step (2) is isopropanol.

The volume-mass ratio of the organic solvent in the step (2) to the ethyl (S) -3-cyano-5-methylhexanoate can be 1-10 mL/g.

In another aspect of the invention, there is provided (S) -3-cyano-5-methylhexanoic acid salt having the structural formula:

wherein M is calcium (Ca), magnesium (Mg) or lithium (Li).

In another aspect, the present invention provides a method for preparing pregabalin, which includes a step of reducing a compound shown in the formula I to obtain pregabalin, where the reaction formula is as follows:

In the organic solvent, ni can be used as a catalyst, hydrogen is used as a reducing agent, and the reaction temperature is 20-60 ℃.

The organic solvent can be selected from methanol, ethanol, isopropanol, and acetonitrile.

In the reduction process, the hydrogen pressure can be kept between 0.7 and 0.9MPa.

In another aspect, the present invention provides a process for the preparation of pregabalin, comprising,

wherein M is sodium (Na), potassium (K), calcium (Ca), magnesium (Mg) or lithium (Li);

(2) Pulping the compound shown in the formula I obtained in the step (1) by using an organic solvent, and filtering;

(3) In an organic solvent, the compound shown in the formula I and obtained in the step (2) is reduced by taking Ni as a catalyst and hydrogen as a reducing agent to obtain pregabalin, wherein the reaction formula is as follows:

Drawings

FIG. 1 is an HPLC chart of sodium (S) -3-cyano-5-methyl-hexanoate obtained in example 1;

FIG. 2 is an HPLC chart of pregabalin obtained in example 1.

Detailed Description

Through extensive and intensive studies, the inventors of the present invention have found that (S) -3-cyano-5-methylhexanoic acid ethyl ester is hydrolyzed in an organic solvent under alkaline conditions, and the resulting salt is precipitated from the reaction solution, and the intermediate with high purity can be obtained by direct filtration, and the yield is high, through extensive screening and testing. The salt can be used for preparing pregabalin, is simple to operate, has good quality of the final product, is suitable for industrial mass production, and completes the invention on the basis.

Preparation of Compounds of formula I

In one embodiment of the present invention, the method for preparing the compound of formula I of the present invention comprises the steps of: (1) Ethyl (S) -3-cyano-5-methylhexanoate, in the presence of alkali, carrying out hydrolysis reaction in an organic solution, and filtering after the reaction is finished to obtain a compound shown in a formula I, wherein the reaction formula is as follows:

(2) Pulping the compound shown in the formula I obtained in the step (1) by using an organic solvent, and filtering.

The organic solvents used in step (1) include, but are not limited to, methanol, ethanol, isopropanol, acetonitrile. The organic solvent is used to provide a medium for the reaction, and the amount thereof is not particularly limited, and is a conventional amount in the art, preferably a minimum amount to completely dissolve the raw materials.

The base used in step (1) includes, but is not limited to, sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium isopropoxide, and calcium acetate. The base is used to provide a basic environment for the hydrolysis of the ester in amounts conventional in the art, preferably in a molar ratio of ethyl (S) -3-cyano-5-methylhexanoate to base of 1:1.0 to 5.0, e.g., 1:1.2,1:1.5,1:2.0, etc. The base is preferably added to the reaction system in the form of a solution, preferably an organic solvent for dissolving the base is preferably the same as the organic solvent of the reaction solution, to obtain a solution.

The alkali is preferably added into the reaction system in the form of a solution, the concentration of the alkali solution is not particularly limited, the alkali solution can be used in the invention as long as a solution of a solution is formed, the temperature of the reaction system is preferably kept at 0-40 ℃, more preferably kept at 10-15 ℃ in the process of adding the alkali solution, after the alkali solution is added dropwise, the reaction system is heated to room temperature, stirring is continued for 0.5-2 hours, and the crude product of the compound shown in the formula I is obtained after filtering.

Pulping in the step (2), and filtering can be carried out at room temperature. The solvent used for beating is preferably the same as the solvent in the reaction solution.

Preparation of pregabalin

The preparation method of pregabalin comprises the step of carrying out hydrogenation reduction on the compound shown in the formula I to obtain pregabalin, wherein the reaction formula is as follows:

The reduction reaction uses Ni as a catalyst in an organic solvent at a conventional temperature for such reaction, for example, 20 to 60 ℃. The organic solvents used in the reaction are solvents commonly used in the art, including but not limited to methanol, ethanol, isopropanol, acetonitrile.

Compared with the prior art, the invention has the advantages that:

in the invention, (S) -3-cyano-5-methyl ethyl caproate is hydrolyzed in an organic solvent in the presence of alkali, the solubility of a hydrolysis product in the organic solvent is small, the hydrolysis product is directly separated out from a reaction solution, a crude product is obtained after filtration, and then the crude product is pulped and filtered to obtain the high-purity (S) -3-cyano-5-methyl caproate. And the high-purity (S) -3-cyano-5-methylhexanoate is subjected to conventional Raney nickel catalytic hydrogenation to prepare pregabalin, and the obtained pregabalin is subjected to simple pulping for 1-2 times and filtering to obtain the pregabalin product with the purity of not less than 99.8%. The method for preparing pregabalin has the advantages of simple operation, good quality of the final product and suitability for industrial mass production.

The present invention will be explained in more detail with reference to the following examples, which are only for illustrating the technical aspects of the present invention, and the spirit and scope of the present invention are not limited thereto. Percentages and parts are weight percentages and parts unless otherwise indicated.

In the following examples, the HPLC detection conditions for pregabalin intermediates, compounds of formula I and pregabalin are shown in Table 1 below:

TABLE 1

Example 1

The reaction formula for the preparation of pregabalin in this example is as follows:

preparation of ethyl 4 (S) -3-cyano-5-methyl-hexanoate according to the synthetic method disclosed in chinese patent application No. CN 200580020494.9: 2.55Kg (10 mol) of diethyl (1-cyano-3-methylbutyl) malonate (intermediate 2) is added into a 5L glass reaction kettle, 80g of calcium acetate and 600ml of purified water are added, 300g of Lipolase enzyme is added, the mixture is stirred at normal temperature for reaction, the PH is controlled to be 6.8-7.2 by dropwise adding 30% sodium hydroxide solution, after 24 hours of reaction, HPLC detection is finished, 5.0L of toluene is added for extraction layering, 20g of sodium chloride and 1000ml of toluene are added into a water layer, the mixture is heated to reflux and stirred for 20 hours, layering is carried out again, the water layer is extracted once by 500ml of toluene, and the mixture is concentrated under reduced pressure until the toluene is completely distilled off to obtain 823.5g of intermediate 4, (S) -3-cyano-5-methyl-hexanoic acid ethyl ester, the purity is 98.6%, and the yield is 45.0%.

198g (4.95 mol,1.1 equiv) of sodium hydroxide is added in portions to 3L of isopropanol, and the solution is stirred and cooled to room temperature for use. 823.5 (4.95 mol) g of distilled intermediate 4 (S) -3-cyano-5-methyl-hexanoic acid ethyl ester is added into a 50L glass kettle, 17L of isopropanol is added, the temperature is reduced to 10-15 ℃ after uniform stirring, a sodium hydroxide isopropanol solution prepared in advance is slowly added dropwise, a large amount of solid is separated out after 1/4 of the solution is added dropwise, the solution is stirred for one hour after the solution is cooled to room temperature, the solution is filtered, and a filter cake is filtered after 3L of isopropanol is pulped, and the purity is 99.8%. Adding the wet filter cake into a 20L hydrogenation kettle, adding 5L methanol for dissolution, slowly adding 41g of Raney nickel (the Raney nickel is leached by methanol in advance, taking care of deflagration) under the protection of nitrogen, heating to 40 ℃ after replacement hydrogenation, maintaining the hydrogen pressure at 0.5-0.7 MPa for hydrogenation reaction, stopping the reaction after 6 hours, filtering to remove the Raney nickel (taking care of deflagration), adding acetic acid to adjust the pH to about 7, filtering, pulping the filter cake by 300ml of ice methanol, filtering and drying to obtain 681.1g of pure pregabalin, wherein the yield is 95.2% (calculated by taking (S) -3-cyano-5-methyl-ethyl caproate as a raw material), and the HPLC purity is 100.0 percent. The nuclear magnetic confirmation structure is pregabalin, ¹ H-NMR(500MHz，D ₂ O-d ₂ )δ：0.779(t，J＝6Hz，6H)，1.108(t，J＝7Hz，2H)，1.506～1.587(m，1H)，2.009～2.089(m，1H)，2.101(q，J＝7.5Hz，1H)，2.190(dd，J ₁ ＝15Hz，J ₂ ＝6Hz，1H)，2.815(q，J＝7Hz，1H)，2.881(dd，J ₁ ＝12.5Hz，J ₂ ＝5Hz，1H)。 ¹³ C-NMR(500MHz，D ₂ O-d ₂ )δ：21.51，21.98，24.37，31.68，40.57，40.74，43.67，181.18。

HPLC of (S) -sodium 3-cyano-5-methyl-hexanoate and pregabalin obtained in this example are shown in FIGS. 1 and 2, respectively.

Example 2

12.3g (0.22 mol,1.1 equiv) of potassium hydroxide was added in portions to 100mL of ethanol, and the solution was stirred and cooled to room temperature for use. Adding 37.0g (0.20 mol) of intermediate 4 (S) -3-cyano-5-methyl-ethyl caproate into a 1000mL glass bottle, adding 400mL of ethanol, uniformly stirring, cooling to 10-15 ℃, slowly dropwise adding a pre-prepared potassium hydroxide ethanol solution, precipitating a large amount of solid when the dropwise addition is completed to 3/4, heating to room temperature for continuously stirring for one hour, heating to <40 ℃, distilling under reduced pressure to remove about 300mL of ethanol, cooling to 0-5 ℃, preserving heat for one hour, filtering, pulping a filter cake with 50mL of ice ethanol, and filtering, wherein the purity is more than or equal to 99.5%. Adding the wet filter cake into a 1000mL hydrogenation kettle, adding 500L ethanol for dissolution, slowly adding 2.0g of Raney nickel (the Raney nickel is leached by ethanol in advance and is carefully deflagrated) under the protection of nitrogen, heating to 40 ℃ after replacement hydrogenation, maintaining the hydrogen pressure at 0.5-0.7 MPa for hydrogenation reaction, stopping the reaction after 4 hours, filtering to remove the Raney nickel (the deflagration is noticed), adding acetic acid to adjust the pH to about 7, filtering, pulping the filter cake by 50mL of glacial ethanol, filtering and drying to obtain 29.6g of pregabalin pure product (the yield is calculated by taking (S) -3-cyano-5-methyl-ethyl caproate as a raw material), and obtaining 93.3 percent of pregabalin pure product with the HPLC purity of 99.9 percent.

Example 3

37.0g (0.20 mol) of intermediate 4 (S) -3-cyano-5-methyl-ethyl hexanoate is added into a 1000mL glass bottle at room temperature, 300mL of methanol is added, 47.4g (0.3 mol,1.5 equiv) of calcium acetate is added into the bottle in four batches, after the material feeding is finished, stirring is continued for 3 hours at 50 ℃, the temperature is reduced to 10-15 ℃ for heat preservation and one hour for filtration, 50mL of methanol is used for pulping the filter cake, and the purity is more than or equal to 98 percent. Adding the wet filter cake into a 1000mL hydrogenation kettle, adding 300mL of methanol, slowly adding 3.0g of Raney nickel (the Raney nickel is leached by methanol in advance, careful deflagration is taken), heating to 40 ℃ after replacement hydrogenation, maintaining the hydrogen pressure at 0.7-0.9 MPa for hydrogenation reaction, stopping the reaction after 7h, filtering to remove the Raney nickel (the deflagration is taken), adding acetic acid to adjust the pH to about 7, filtering, pulping the filter cake by 50mL of ice water, filtering and drying to obtain 27.3g of pregabalin pure product, and obtaining 88.2% of yield (the yield is calculated by taking (S) -3-cyano-5-methyl-ethyl caproate as a raw material), wherein the HPLC purity is 99.3%.

Example 4

32.1g (0.22 mol,1.1 equiv) of magnesium isopropoxide was added in portions to 200L of isopropanol, and the solution was stirred and cooled to room temperature for use. 37.0g (0.20 mol) of intermediate 4 (S) -3-cyano-5-methyl-hexanoic acid ethyl ester is added into a 1000mL glass bottle, 500mL of isopropanol is added, the temperature is reduced to 10-15 ℃ after uniform stirring, a pre-prepared magnesium isopropoxide solution is slowly added dropwise, after the dropwise addition is finished, the temperature is raised to room temperature, stirring is continued for three hours, filtering is carried out, and filter cake is filtered after being pulped with 200mL of isopropanol, wherein the purity is more than or equal to 99.5%. Adding the wet filter cake into a 1000mL hydrogenation kettle, adding 500mL of methanol for dissolution, slowly adding 1.5g of Raney nickel under the protection of nitrogen, eluting with methanol in advance, taking care of deflagration, heating to 40 ℃ after replacement hydrogenation, maintaining the hydrogen pressure at 0.5-0.7 MPa for hydrogenation reaction, stopping the reaction after 6 hours, filtering to remove Raney nickel (taking care of deflagration), adding acetic acid to adjust the pH to about 7, filtering, pulping the filter cake with 300mL of glacial methanol twice, filtering, and drying to obtain 28.4g of pure pregabalin with the yield of 89.2% (calculated by taking (S) -3-cyano-5-methyl-ethyl caproate as a raw material) and the HPLC purity of 99.8 percent.

Example 5

37.0g (0.20 mol) of intermediate 4 (S) -3-cyano-5-methyl-ethyl caproate is added into a 1000mL glass bottle at room temperature, 500mL of isopropanol is added, the temperature is reduced to 0-5 ℃ after uniform stirring, 11.9g (0.22 mol,1.1 equiv) of sodium methoxide is added in four batches, stirring is continued for 3 hours after the material feeding is finished, filtering is carried out, and the filter cake is filtered after being pulped with 50mL of isopropanol, wherein the purity is more than or equal to 99.5%. Adding the wet filter cake into a 1000mL hydrogenation kettle, adding 500mL of methanol, slowly adding 37.0g of immobilized Raney nickel under the protection of nitrogen, heating to 40 ℃ after hydrogen replacement, keeping the hydrogen pressure between 0.7 and 0.9MPa for hydrogenation, stopping the reaction after 7 hours, filtering to remove the immobilized Raney nickel, adding acetic acid to adjust the pH to about 7, filtering, pulping the filter cake with 50mL of methanol, filtering, drying to obtain 28.8g of pregabalin pure product with the yield of 90.6% (the yield is calculated by taking (S) -3-cyano-5-methyl-hexanoic acid ethyl ester as a raw material), and the HPLC purity is 99.9%.

Comparative example 1

The reaction formula for the preparation of pregabalin in this comparative example is as follows:

12.3g (0.22 mol,1.1 equiv) of potassium hydroxide was added in portions to 50mL of water, and the solution was stirred and cooled to room temperature for use. Adding 37.0g (0.20 mol) of intermediate 4 (S) -3-cyano-5-methyl-ethyl caproate into a 500mL glass bottle at room temperature, adding 200mL of water, uniformly stirring, cooling to 0-5 ℃, slowly dropwise adding a potassium hydroxide aqueous solution, continuously stirring for 1 hour, adding the feed liquid into a 500mL hydrogenation kettle, slowly adding 3.7g of wet Raney nickel under the protection of nitrogen, heating to 40 ℃ after replacing hydrogen, keeping the hydrogen pressure at 0.7-0.8 MPa, carrying out hydrogenation reaction for 7 hours, stopping the reaction, filtering to remove the solid Raney nickel, adding acetic acid to adjust the pH to about 7, filtering, adding 100mL of isopropanol and 100mL of water into a filter cake, heating to reflux to dissolve clear, cooling and crystallizing to obtain 24.5g of pregabalin pure product, wherein the yield is 77.0% (calculated by taking (S) -3-cyano-5-methyl-ethyl caproate as a raw material), and the HPLC purity is 99.8%.

Comparative example 2

8.8g (0.22 mol,1.1 equiv) of sodium hydroxide was added in portions to 50mL of water, and the solution was stirred and cooled to room temperature for use. Adding 37.0g (0.20 mol) of intermediate 4 (S) -3-cyano-5-methyl-ethyl caproate into a 500mL glass bottle at room temperature, adding a mixed solution of 125mL of water and 125mL of methanol, uniformly stirring, cooling to 0-5 ℃, slowly dropwise adding a potassium hydroxide aqueous solution, continuously stirring for 1 hour after the dropwise addition, adding 3.7g of wet Raney nickel into a 500mL hydrogenation kettle under the protection of nitrogen, heating to 40 ℃ after hydrogen replacement, keeping the hydrogen pressure at 0.7-0.8 MPa for hydrogenation reaction, stopping the reaction after 7 hours, filtering to remove the solid Raney nickel, adding acetic acid to adjust the pH to about 7, filtering, adding 100mL of isopropanol and 100mL of water into a filter cake, heating to reflux for dissolving, cooling for crystallization to obtain 23.1g of pregabalin pure product, and obtaining the yield of 72.6% (the yield is calculated by taking (S) -3-cyano-5-methyl-ethyl caproate as a raw material), wherein the purity of HPLC is 99.7%.

As can be seen from comparative examples 1 and 2, the first reaction step was carried out using water or an aqueous solvent as a reaction medium, and the obtained 3-cyano-5-methylhexanoate was dissolved in the reaction medium, and the reaction solution containing 3-cyano-5-methylhexanoate was directly subjected to hydrogenation reduction without treatment, to obtain pregabalin having lower yield and purity than examples 1 to 5.

All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims

1. A process for the preparation of a compound of formula I, comprising the steps of:

2. The method of manufacturing according to claim 1, further comprising the step (2): pulping the compound shown in the formula I obtained in the step (1) by using an organic solvent, and filtering.

3. The preparation method according to claim 1 or 2, wherein step (1) has one or more of the following features:

(i) The organic solvent is selected from methanol, ethanol, isopropanol, acetonitrile, or a combination thereof;

(ii) In the step (1), the mass volume ratio of the (S) -3-cyano-5-methylhexanoic acid to the organic solvent of the ethyl ester is 40-120 g/L.

(iii) The base is selected from sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium isopropoxide, calcium acetate, or a combination thereof;

(iv) The molar ratio of the (S) -3-cyano-5-methyl ethyl caproate to the alkali is 1:1.0-5.0;

(v) The reaction temperature is 0-40 ℃.

4. A method of preparation according to claim 3, wherein step (1) has one or more of the following features:

(i) The organic solvent is selected from isopropanol;

(ii) The mass volume ratio of the (S) -3-cyano-5-methyl caproic acid to the ethyl ester is 50-100 g/L.

(iii) The base is selected from sodium hydroxide;

(iv) The mol ratio of the (S) -3-cyano-5-methyl ethyl caproate to the alkali is 1:1.0-1.5;

(v) The reaction temperature is 10-15 ℃.

5. A method according to claim 3, wherein in step (1):

the base is added to the reaction system in the form of a solution, and/or

Maintaining the temperature of the reaction system at 0 to 40 ℃, more preferably 10 to 15 ℃, and/or during the addition of the base

After the addition of the alkali solution is completed, the reaction solution is stirred for 0 to 2 hours at a temperature of between 0 and 40 ℃, and/or

After the reaction is completed, the reaction solution is distilled to dryness at 0-40 ℃ to obtain a crude product of the compound shown in the formula I.

6. The method according to claim 1 or 2, wherein in step (2):

the organic solvent is selected from methanol, ethanol, isopropanol, acetonitrile, more preferably isopropanol; and/or

The volume mass ratio of the organic solvent to the (S) -3-cyano-5-methyl ethyl caproate is 1-10 mL/g.

7. (S) -3-cyano-5-methyl hexanoate has the following structural formula:

wherein M is sodium calcium (Ca), magnesium (Mg) or lithium (Li).

8. A process for the preparation of pregabalin, comprising the step of hydrodereducing a compound of formula I prepared by the process according to any one of claims 1 to 6 to pregabalin, the reaction being as follows:

9. The preparation method of pregabalin according to claim 8, characterized in that the hydrogenation reduction reaction is carried out in an organic solvent at a reaction temperature of 20-60 ℃ by using Ni as a catalyst and hydrogen as a reducing agent,

preferably, the organic solvent is selected from methanol, ethanol, isopropanol, acetonitrile.

10. A method for preparing pregabalin, characterized in that the method comprises,