A preparation method and application of pregabalin intermediate

Abstract

The invention discloses a method for preparing a compound shown in formula I, the method comprising the following steps: (1) (S)-3-cyano-5-methylhexanoic acid ethyl ester is subjected to a hydrolysis reaction in an organic solution in the presence of a base, and filtered after the reaction is completed to obtain a compound shown in formula I, and the reaction formula is as follows; (2) the compound shown in formula I obtained in step (1) is pulped with an organic solvent and filtered. The compound shown in formula I can be used to prepare pregabalin, and the obtained product purification method is simple, has good quality, high yield, and is suitable for large-scale industrial production. Wherein M is sodium (Na), potassium (K), calcium (Ca), magnesium (Mg) or lithium (Li).

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and more specifically, to a method for preparing a pregabalin intermediate and a method for preparing pregabalin using the intermediate. Background Art

[0002] Pregabalin is a new type of antiepileptic drug. Its molecular structure has a γ-aminobutyric acid structure, so it has an anticonvulsant effect. Pregabalin is a Class I drug in the BCS classification system. Pregabalin reaches its peak concentration 1.5 hours after oral administration, with a relative bioavailability of ≥90%, and a linear relationship between Cmax and AUC and the dose. It does not bind to plasma proteins in the body and has almost no metabolism. Pregabalin has been approved for the adjuvant treatment of partial-onset diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, and neuropathic pain caused by spinal cord injury in adults. In August 2003, Pfizer first filed a registration application in the United States. In December 2004, the U.S. FDA approved the use of pregabalin for diabetic peripheral neuropathy (DPN) and postherpetic neuralgia (PHN). This was also the first drug jointly certified by the United States and Europe (July 2004) for the treatment of two types of neuralgia. In June 2005, pregabalin was certified as an adjuvant therapy for the treatment of partial epileptic seizures. In June 2007, pregabalin continued to be approved by the U.S. FDA as the first drug to treat fibromyalgia syndrome. In June 2012, the FDA approved pregabalin as the first drug for the treatment of neuralgia caused by spinal cord injury.

[0003] There are two main methods for preparing pregabalin:

[0004] 1. Chemical splitting method: This method was first disclosed in U.S. Pat. No. 5,616,793. It uses 3-isobutylglutaric acid as a raw material, and undergoes dehydration cyclization, aminolysis, R-(+)-α-methylbenzylamine splitting, and Hoffmann degradation to obtain pregabalin with an optical purity of 99.8%. However, the cost of chemical splitting is relatively high, the three wastes are polluted, and a large amount of high-concentration wastewater is difficult to treat.

[0005]

[0006] Second, the enzymatic resolution method, which was first disclosed by U.S. Pat. No. 7,838,686B2, comprises condensing isovaleraldehyde with diethyl malonate, and then subjecting the mixture to cyanide addition, decarboxylation, selective enzymatic hydrolysis, hydrolysis decarboxylation in alkaline water, and hydrogenation to obtain pregabalin.

[0007]

[0008] The cost of enzymatic separation is relatively low, but intermediates 1, 2, 3, and 4 are all liquids with high boiling points, and cannot be purified by conventional methods such as crystallization and distillation. Intermediate 5 is solid and dissolves in an aqueous solution. It is very difficult to separate the intermediate 5 from the aqueous solution, and the recovery rate is relatively low. A large amount of organic solvents are consumed for recovery, which is very inappropriate for industrial large-scale production. High-temperature distillation and water removal can crystallize to obtain intermediate 5, but the high-temperature distillation and water removal process can generate a large amount of impurities, and a high-purity intermediate 5 cannot be obtained. Therefore, the current enzymatic synthesis of pregabalin is basically a one-pot reaction, that is, all impurities are crystallized and removed after the last hydrogenation step to form a stable API (the final compound pregabalin is recrystallized using a mixture of isopropyl alcohol and water). For drug production, a large amount of impurities are not economical to be removed by crystallization of the API step, and there is also a certain quality risk. It should be considered to be refined in the previous step of the API to ensure the stability of the API production quality.

[0009] In addition, the prior art An Enantioselective Synthesis of (S)-(+)-3-Aminomethyl-5-methylhexanoic Acid via Asymmetric Hydrogenation, Mark J. Burk, et al., J. Org. Chem, 2003, 68, 5731-5734 discloses a method for preparing compound 3c using compound 2a as a raw material, and the reaction formula is as follows:

[0010]

[0011] The specific steps are as follows: 3-cyano-5-methylhexenoic acid ethyl ester (compound 2a) is dissolved in a mixture of methanol and water, a methanol solution of potassium hydroxide is added, and the mixture is heated to 55°C in a nitrogen atmosphere and maintained for 2 hours. Then, [(R,R)-(Me-DuPHOS)Rh(COD)]BF is added in a hydrogen atmosphere. 4 A methanol solution is prepared, the reaction vessel is filled with hydrogen to 60 psi and the reaction solution is stirred at 55°C until the absorption of hydrogen stops, and the solvent is removed under vacuum to obtain a white crystalline solid, namely (S) potassium 3-cyano-5-methylhexanoate (Compound 2c). It can be seen that in the prior art, the first step of hydrolysis product Compound 2b is obtained by using Compound 2a as a raw material in a mixed solution of methanol and water, and Compound 2b is directly reduced by hydrogenation in the solution without separation to obtain Compound 2c. The reaction solution containing Compound 2c is subjected to vacuum conditions to remove the solvent to obtain a crude product of Compound 2c. The purity of such a crude product is not high, and for industrial scale-up production, it is time-consuming and labor-intensive to distill off the aqueous solvent to obtain a crude product.

[0012] Therefore, there is still a need in the art to find a new method for preparing pregabalin intermediates that is easy to operate, has good quality, and is suitable for large-scale industrial production. Summary of the invention

[0013] In view of the above problems existing in the prior art, the object of the present invention is to provide a new method for preparing a pregabalin intermediate, which has high yield and purity, is easy to operate, and is suitable for large-scale industrial production.

[0014] To achieve the above object, the present invention adopts the following technical solutions:

[0015] A method for preparing a compound represented by formula I, comprising the following steps:

[0016] (1) (S)-3-cyano-5-methylhexanoic acid ethyl ester is subjected to hydrolysis reaction in an organic solution in the presence of a base. After the reaction is completed, the compound represented by formula I is obtained by filtering. The reaction formula is as follows:

[0017]

[0018] wherein M is sodium (Na), potassium (K), calcium (Ca), magnesium (Mg) or lithium (Li).

[0019] The above method may further comprise step (2): the compound of formula I obtained in step (1) is slurried with an organic solvent and filtered.

[0020] The organic solvent in step (1) can be selected from methanol, ethanol, isopropanol, acetonitrile, or a combination thereof. In some specific embodiments of the present invention, the organic solvent is selected from isopropanol.

[0021] In step (1), the mass volume ratio of (S)-3-cyano-5-methylhexanoic acid to the organic solvent of ethyl ester is 40 to 120 g / L. In some specific embodiments of the present invention, the mass volume ratio of (S)-3-cyano-5-methylhexanoic acid to the organic solvent is 50 to 100 g / L.

[0022] The base in step (1) can be selected from sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium isopropoxide, calcium acetate, or a combination thereof. In some specific embodiments of the present invention, the base is selected from sodium hydroxide.

[0023] 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 specific embodiments of the present invention, the molar ratio of (S)-3-cyano-5-methylhexanoic acid ethyl ester to the base is 1:1.0-1.5.

[0024] The reaction temperature in step (1) is 0-40° C. In some specific embodiments of the present invention, the reaction temperature in step (1) is 10-15° C.

[0025] In the present invention, the base is preferably added to the reaction system in the form of a solution.

[0026] The concentration of the alkali solution is 50 g / L to 300 g / L.

[0027] The organic solvent used to dissolve the base is preferably the same as the organic solvent of the reaction solution in step (1).

[0028] In some specific embodiments of the present invention, the alkali solution is an isopropanol solution of sodium hydroxide. In some specific embodiments of the present invention, the concentration of the isopropanol solution of sodium hydroxide is 66 g / L.

[0029] The temperature of the reaction system is preferably maintained at 0-40° C. during the addition of the alkali. In some specific embodiments of the present invention, the temperature of the reaction system is maintained at 10-15° C. during the addition of the alkali.

[0030] In some specific embodiments of the present invention, after the addition of the alkaline solution is completed, the reaction solution is stirred at 0-40° C. for 0-2 hours.

[0031] In some specific embodiments of the present invention, after the reaction is completed, the reaction solution is distilled to dryness at 0-40° C. to obtain a crude product of the compound represented by formula I.

[0032] The organic solvent in step (2) can be selected from methanol, ethanol, isopropanol, and acetonitrile. In some specific embodiments of the present invention, the organic solvent in step (2) is isopropanol.

[0033] The volume mass ratio of the organic solvent to (S)-3-cyano-5-methylhexanoic acid ethyl ester in step (2) can be 1 to 10 mL / g.

[0034] Another aspect of the present invention provides (S)-3-cyano-5-methylhexanoate, the structural formula of which is as follows:

[0035]

[0036] Wherein M is calcium (Ca), magnesium (Mg) or lithium (Li).

[0037] Another aspect of the present invention provides a method for preparing pregabalin, which comprises the step of reducing the compound represented by the above formula I to obtain pregabalin, and the reaction formula is as follows:

[0038]

[0039] wherein M is sodium (Na), potassium (K), calcium (Ca), magnesium (Mg) or lithium (Li).

[0040] The reduction reaction is carried out in an organic solvent, using Ni as a catalyst and hydrogen as a reducing agent, at a reaction temperature of 20 to 60°C.

[0041] The organic solvent can be selected from methanol, ethanol, isopropanol and acetonitrile.

[0042] During the reduction process, the hydrogen pressure can be maintained at 0.7-0.9 MPa.

[0043] Another aspect of the present invention provides a method for preparing pregabalin, the method comprising:

[0044] (1) (S)-3-cyano-5-methylhexanoic acid ethyl ester is subjected to hydrolysis reaction in an organic solution in the presence of a base. After the reaction is completed, the compound represented by formula I is obtained by filtering. The reaction formula is as follows:

[0045]

[0046] Wherein M is sodium (Na), potassium (K), calcium (Ca), magnesium (Mg) or lithium (Li);

[0047] (2) the compound of formula I obtained in step (1) is slurried with an organic solvent and filtered;

[0048] (3) The compound of formula I obtained in step (2) is reduced in an organic solvent using Ni as a catalyst and hydrogen as a reducing agent to obtain pregabalin, and the reaction formula is as follows:

[0049]

[0050] wherein M is sodium (Na), potassium (K), calcium (Ca), magnesium (Mg) or lithium (Li). BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 is the HPLC spectrum of (S)-3-cyano-5-methyl-sodium hexanoate obtained in Example 1;

[0052] Figure 2 This is the HPLC spectrum of pregabalin obtained in Example 1. DETAILED DESCRIPTION

[0053] The inventors have conducted extensive and in-depth research, and through a large number of screenings and tests, have found that (S)-3-cyano-5-methylhexanoic acid ethyl ester is hydrolyzed in an organic solvent under alkaline conditions, and the generated salt is precipitated from the reaction solution, and a high-purity intermediate can be obtained by direct filtration, and the yield is high. In addition, the salt can be used to prepare pregabalin, the operation is simple, the final product is of good quality, and it is suitable for large-scale industrial production. On this basis, the present invention has been completed.

[0054] Preparation of the compound shown in formula I

[0055] In a specific embodiment of the present invention, the preparation method of the compound of formula I in the present invention comprises the steps of: (1) hydrolyzing (S)-3-cyano-5-methylhexanoic acid ethyl ester in an organic solution in the presence of a base, and filtering after the reaction is completed to obtain the compound of formula I, the reaction formula is as follows:

[0056]

[0057] wherein M is sodium (Na), potassium (K), calcium (Ca), magnesium (Mg) or lithium (Li).

[0058] (2) The compound of formula I obtained in step (1) is slurried with an organic solvent and filtered.

[0059] The organic solvent used in step (1) includes but is not limited to methanol, ethanol, isopropanol, and acetonitrile. The organic solvent is used to provide a medium for the reaction, and its amount is not particularly limited. Its amount is the conventional amount in the art, preferably the minimum amount that allows the raw materials to be completely dissolved.

[0060] 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 an alkaline environment for the hydrolysis of the ester, and its amount is the conventional amount used in the art. Preferably, the molar ratio of (S)-3-cyano-5-methylhexanoic acid ethyl ester to the base is 1:1.0 to 5.0, such as 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 using an organic dissolving base to obtain a solution, and the organic solvent used to dissolve the base is preferably the same as the organic solvent of the reaction solution.

[0061] The alkali is preferably added to the reaction system in the form of a solution. The concentration of the alkali solution is not particularly limited. As long as a clear solution is formed, it can be used in the present invention. During the addition of the alkali solution, the temperature of the reaction system is preferably maintained at 0 to 40° C., more preferably maintained at 10 to 15° C. After the alkali solution is added dropwise, the reaction system is heated to room temperature, and stirring is continued for 0.5 to 2 hours. The crude product of the compound represented by formula I is obtained by filtration.

[0062] In step (2), both the slurrying and the filtration can be carried out at room temperature. The solvent used for slurrying is preferably the same as the solvent in the reaction solution.

[0063] Preparation of pregabalin

[0064] The preparation method of pregabalin comprises the step of subjecting the compound represented by the above formula I to hydrogenation reduction to obtain pregabalin, and the reaction formula is as follows:

[0065]

[0066] wherein M is sodium (Na), potassium (K), calcium (Ca), magnesium (Mg) or lithium (Li).

[0067] The reduction reaction is carried out in an organic solvent, using Ni as a catalyst, and the reaction temperature is a conventional temperature for such reactions, such as 20-60° C. The organic solvent used in the reaction is a commonly used solvent in the art, including but not limited to methanol, ethanol, isopropanol, and acetonitrile.

[0068] Compared with the prior art, the advantages of the present invention are:

[0069] In the present invention, (S)-3-cyano-5-methylhexanoic acid ethyl ester is hydrolyzed in an organic solvent in the presence of a base, and the hydrolysis product has a low solubility in the organic solvent and is directly precipitated from the reaction solution, and a crude product can be obtained by filtration, and then a high-purity (S)-3-cyano-5-methylhexanoate is obtained by slurrying and filtering. And the high-purity (S)-3-cyano-5-methylhexanoate is subjected to conventional Raney nickel catalytic hydrogenation to obtain pregabalin, and the obtained pregabalin is simply slurried 1 to 2 times and filtered to obtain a pregabalin product with a purity of not less than 99.8%. The method for preparing pregabalin of the present invention is simple to operate, has good final product quality, and is suitable for large-scale industrial production.

[0070] The present invention will be explained in more detail below in conjunction with the examples, which are only used to illustrate the technical solutions of the present invention, and the essence and scope of the present invention are not limited thereto. Unless otherwise specified, percentages and parts are weight percentages and weight parts.

[0071] In the following examples, the HPLC detection conditions of the pregabalin intermediate, the compound represented by Formula I and pregabalin are shown in Table 1 below:

[0072] Table 1

[0073]

[0074]

[0075] Example 1

[0076] The reaction formula for preparing pregabalin in this embodiment is as follows:

[0077]

[0078] 4(S)-3-cyano-5-methyl-hexanoic acid ethyl ester was prepared according to the synthesis method disclosed in Chinese patent application number CN200580020494.9: 2.55 Kg (10 mol) of (1-cyano-3-methylbutyl) diethyl malonate (intermediate 2) was added to a 5 L glass reactor, 80 g of calcium acetate and 600 ml of purified water were added, 300 g of Lipolase enzyme was added, and the reaction was stirred at room temperature. The pH was controlled to be 6.8-7.2 by dropwise addition of 30% sodium hydroxide solution. After 24 hours of reaction, HPLC detection was completed, 5.0 L of toluene was added for extraction and stratification, 20 g of sodium chloride and 1000 ml of toluene were added to the water layer, the temperature was raised to reflux, stirred for 20 h, and stratified again. The water layer was extracted once with 500 ml of toluene, and the mixture was concentrated under reduced pressure until all the toluene was evaporated to obtain intermediate 4, 823.5 g of (S)-3-cyano-5-methyl-hexanoic acid ethyl ester, with a purity of 98.6% and a yield of 45.0%.

[0079] 198g (4.95mol, 1.1equiv) of sodium hydroxide was added to 3L of isopropanol in batches, stirred to dissolve, and then cooled to room temperature for use. 823.5 (4.95mol) g of the distilled intermediate 4(S)-3-cyano-5-methyl-hexanoic acid ethyl ester was added to a 50L glass kettle, and 17L of isopropanol was added. After stirring evenly, the temperature was lowered to 10-15°C, and the pre-prepared sodium hydroxide isopropanol solution was slowly added dropwise. When 1 / 4 of the solution was added, a large amount of solids precipitated. After the addition was completed, the mixture was heated to room temperature and stirred for one hour. The filter cake was slurried with 3L of isopropanol and filtered. The purity was 99.8%. The wet cake was put into a 20L hydrogenation kettle, 5L of methanol was added to dissolve, 41g of Raney nickel was slowly added under nitrogen protection (Raney nickel was pre-eluted with methanol, be careful of explosion), the temperature was raised to 40°C after displacement hydrogenation, the hydrogen pressure was maintained at 0.5-0.7MPa for hydrogenation reaction, the reaction was stopped after 6h, Raney nickel was filtered out (be careful of explosion), acetic acid was added to adjust the pH to about 7, filtered, the filter cake was slurried with 300ml of ice methanol, filtered, and dried to obtain 681.1g of pure pregabalin, with a yield of 95.2% (the yield was calculated based on (S)-3-cyano-5-methyl-hexanoic acid ethyl ester as raw material), and the HPLC purity was 100.0%. The structure was confirmed to be pregabalin by nuclear magnetic resonance, 1 H-NMR (500 MHz, D 2 Od 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 =5 Hz, 1H). 13 C-NMR (500 MHz, D 2 Od 2 )δ: 21.51, 21.98, 24.37, 31.68, 40.57, 40.74, 43.67, 181.18.

[0080] The HPLC results of (S)-3-cyano-5-methyl-sodium hexanoate and pregabalin obtained in this example are shown in Table 1. Figure 1 and Figure 2 .

[0081] Example 2

[0082] The reaction formula for preparing pregabalin in this embodiment is as follows:

[0083]

[0084] Add 12.3g (0.22mol, 1.1equiv) of potassium hydroxide to 100mL of ethanol in batches, stir to dissolve, and then cool to room temperature for use. Add 37.0g (0.20mol) of the intermediate 4(S)-3-cyano-5-methyl-hexanoic acid ethyl ester to a 1000mL glass bottle, add 400mL of ethanol, stir evenly, cool to 10-15°C, slowly drop the pre-prepared potassium hydroxide ethanol solution, and when 3 / 4 of the solution is added, a large amount of solid precipitates. After the addition is completed, warm to room temperature and continue stirring for one hour, heat to <40°C, remove about 300mL of ethanol by vacuum distillation, and then cool to 0-5°C and keep warm for one hour for filtration. The filter cake is slurried with 50mL of ice ethanol and filtered, and the purity is ≥99.5%. The wet cake was put into a 1000mL hydrogenation kettle, 500L of ethanol was added to dissolve it, and 2.0g of Raney nickel was slowly added under nitrogen protection (Raney nickel was pre-washed with ethanol, be careful of deflagration), and the temperature was raised to 40°C after displacement hydrogenation, and the hydrogen pressure was maintained at 0.5-0.7MPa for hydrogenation reaction. The reaction was stopped after 4h of reaction, and Raney nickel was filtered out (be careful of deflagration), and acetic acid was added to adjust the pH to about 7, filtered, and the filter cake was slurried with 50ml of ice ethanol, filtered, and dried to obtain 29.6g of pure pregabalin (the yield is calculated based on (S)-3-cyano-5-methyl-hexanoic acid ethyl ester as raw material), with a yield of 93.3% and a HPLC purity of 99.9%.

[0085] Example 3

[0086] The reaction formula for preparing pregabalin in this embodiment is as follows:

[0087]

[0088] At room temperature, add 37.0 g (0.20 mol) of the intermediate 4(S)-3-cyano-5-methyl-hexanoic acid ethyl ester into a 1000 mL glass bottle, add 300 mL of methanol, and add 47.4 g (0.3 mol, 1.5 equiv) of calcium acetate in four batches. After the addition is completed, raise the temperature to 50°C and continue stirring for 3 hours, then reduce the temperature to 10-15°C and keep warm for one hour for filtration. The filter cake is slurried with 50 mL of methanol and then filtered, with a purity of ≥98%. The wet filter cake was put into a 1000mL hydrogenation kettle, 300mL of methanol was added, and 3.0g of Raney nickel was slowly added under nitrogen protection (Raney nickel was pre-eluted with methanol, be careful of deflagration), and the temperature was raised to 40°C after displacement hydrogenation, and the hydrogen pressure was maintained at 0.7-0.9MPa for hydrogenation reaction. The reaction was stopped after 7h of reaction, and Raney nickel was filtered out (be careful of deflagration), and acetic acid was added to adjust the pH to about 7, filtered, and the filter cake was slurried with 50ml of ice water, filtered, and dried to obtain 27.3g of pure pregabalin, with a yield of 88.2% (the yield was calculated based on (S)-3-cyano-5-methyl-hexanoic acid ethyl ester as raw material), and the HPLC purity was 99.3%.

[0089] Example 4

[0090] The reaction formula for preparing pregabalin in this embodiment is as follows:

[0091]

[0092] 32.1 g (0.22 mol, 1.1 equiv) of magnesium isopropoxide was added in batches to 200 L of isopropanol, stirred until dissolved, and then cooled to room temperature for use. 37.0 g (0.20 mol) of the intermediate 4(S)-3-cyano-5-methyl-hexanoic acid ethyl ester was added to a 1000 mL glass bottle, and 500 mL of isopropanol was added. After stirring evenly, the temperature was lowered to 10-15°C, and the pre-prepared magnesium isopropoxide solution was slowly added dropwise. After the addition was completed, the temperature was raised to room temperature and continued to stir for three hours, and then filtered. The filter cake was slurried with 200 mL of isopropanol and filtered. The purity was ≥99.5%. The wet cake was put into a 1000mL hydrogenation kettle, 500mL of methanol was added to dissolve it, 1.5g of Raney nickel was slowly added under nitrogen protection (Raney nickel was pre-eluted with methanol, be careful of deflagration), the temperature was raised to 40°C after displacement hydrogenation, the hydrogen pressure was maintained at 0.5-0.7MPa for hydrogenation reaction, the reaction was stopped after 6h, the Raney nickel was filtered out (be careful of deflagration), acetic acid was added to adjust the pH to about 7, filtered, the filter cake was slurried twice with 300ml of ice methanol, filtered, and dried to obtain 28.4g of pure pregabalin, with a yield of 89.2% (the yield is calculated based on (S)-3-cyano-5-methyl-hexanoic acid ethyl ester as raw material), and the HPLC purity was 99.8%.

[0093] Example 5

[0094] The reaction formula for preparing pregabalin in this embodiment is as follows:

[0095] At room temperature, add 37.0 g (0.20 mol) of the intermediate 4(S)-3-cyano-5-methyl-hexanoic acid ethyl ester into a 1000 mL glass bottle, add 500 mL of isopropanol, stir evenly and then cool to 0-5°C, add 11.9 g (0.22 mol, 1.1 equiv) of sodium methoxide in four batches, continue stirring for 3 hours after the feeding is completed, filter, and slurry the filter cake with 50 mL of isopropanol and filter, with a purity of ≥99.5%. The wet filter cake was put into a 1000mL hydrogenation kettle, 500mL of methanol was added, and 37.0g of immobilized Raney nickel was slowly added under nitrogen protection. After replacing hydrogen, the temperature was raised to 40°C, and the hydrogen pressure was maintained at 0.7-0.9MPa for hydrogenation reaction. The reaction was stopped after 7h of reaction. After filtering to remove the immobilized Raney nickel, acetic acid was added to adjust the pH to about 7, and filtered. The filter cake was slurried with 50ml of methanol, filtered, and dried to obtain 28.8g of pure pregabalin with a yield of 90.6% (the yield was calculated based on (S)-3-cyano-5-methyl-hexanoic acid ethyl ester as raw material), and the HPLC purity was 99.9%.

[0096] Comparative Example 1

[0097] The reaction formula for preparing pregabalin in this comparative example is as follows:

[0098]

[0099] Add 12.3 g (0.22 mol, 1.1 equiv) of potassium hydroxide in batches to 50 mL of water, stir to dissolve, and then cool to room temperature for use. Add 37.0 g (0.20 mol) of the intermediate 4 (S) -3-cyano-5-methyl-hexanoic acid ethyl ester to a 500 mL glass bottle at room temperature, add 200 mL of water, stir evenly, cool to 0-5 ° C, slowly add potassium hydroxide aqueous solution, and continue stirring for 1 hour after the addition is completed. Put the feed liquid into a 500 mL hydrogenation kettle, slowly add 3.7 g of wet Raney nickel under nitrogen protection, replace the hydrogen, and heat to 40 ° C, maintaining the hydrogen pressure The reaction was hydrogenated at a pressure of 0.7-0.8 MPa. The reaction was stopped after 7 hours. After filtering to remove the immobilized Raney nickel, acetic acid was added to adjust the pH to about 7, and the mixture was filtered. 100 ml of isopropanol and 100 ml of water were added to the filter cake, and the mixture was heated to reflux to dissolve. The mixture was cooled and crystallized to obtain 24.5 g of pure pregabalin with a yield of 77.0% (the yield was calculated based on (S)-3-cyano-5-methyl-hexanoic acid ethyl ester as raw material) and a HPLC purity of 99.8%.

[0100] Comparative Example 2

[0101] The reaction formula for preparing pregabalin in this comparative example is as follows:

[0102]

[0103] 8.8g (0.22mol, 1.1equiv) of sodium hydroxide was added to 50mL of water in batches, stirred to dissolve and then cooled to room temperature for use. At room temperature, 37.0g (0.20mol) of the intermediate 4(S)-3-cyano-5-methyl-hexanoic acid ethyl ester was added to a 500mL glass bottle, and a mixture of 125mL of water and 125mL of methanol was added. After stirring evenly, the temperature was lowered to 0-5°C, and potassium hydroxide aqueous solution was slowly added dropwise. After the addition was completed, stirring was continued for 1 hour, and the feed liquid was put into a 500mL hydrogenation kettle. 3.7g of wet Raney nickel was slowly added under nitrogen protection, and the temperature was raised to 40°C after replacing the hydrogen. , maintain the hydrogen pressure at 0.7-0.8 MPa for hydrogenation reaction, stop the reaction after 7 hours, filter to remove the immobilized Raney nickel, add acetic acid to adjust the pH to about 7, filter, add 100 ml of isopropanol and 100 ml of water to the filter cake, raise the temperature to reflux to dissolve, cool and crystallize to obtain 23.1 g of pure pregabalin, with a yield of 72.6% (the yield is calculated based on (S)-3-cyano-5-methyl-hexanoic acid ethyl ester as raw material), and the HPLC purity is 99.7%.

[0104] It can be seen from Comparative Examples 1 and 2 that the first step reaction is carried out using water or a water-containing solvent as the reaction medium, the obtained 3-cyano-5-methylhexanoate is dissolved in the reaction medium, and the reaction solution containing 3-cyano-5-methylhexanoate is directly subjected to hydrogenation reduction without treatment, and the yield and purity of pregabalin are lower than those of Examples 1 to 5.

[0105] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing a compound of formula I, characterized in that: The preparation method comprises the following steps: (1) (S)-3-cyano-5-methylhexanoic acid ethyl ester is subjected to hydrolysis reaction in an organic solvent in the presence of a base. After the reaction is completed, the compound represented by formula I is obtained by filtering. The reaction formula is as follows: Where M is sodium, The base is selected from sodium hydroxide, The organic solvent is selected from isopropanol, The preparation method further comprises step (2): the compound of formula I obtained in step (1) is slurried with an organic solvent, filtered, The organic solvent used for pulping is isopropanol.

2. The preparation method according to claim 1, characterized in that: Step (1) has one or more of the following characteristics: (i) in step (1), the mass volume ratio of the organic solvent of (S)-3-cyano-5-methylhexanoic acid and ethyl ester is 40 to 120 g / L, (ii) the molar ratio of (S)-3-cyano-5-methylhexanoic acid ethyl ester to the base is 1:1.0 to 5.0, (v) The reaction temperature is 0 to 40°C.

3. The preparation method according to claim 2, characterized in that: Step (1) has one or more of the following characteristics: (i) the molar ratio of (S)-3-cyano-5-methylhexanoic acid ethyl ester to the base is 1:1.0-1.5, (ii) The reaction temperature is 10-15°C.

4. The preparation method according to claim 2, characterized in that: In step (1), The base is added to the reaction system in the form of a solution, and / or During the addition of alkali, the temperature of the reaction system is maintained at 0-40°C, and / or After the addition of the alkali solution is completed, the reaction solution is stirred at 0-40°C for 0-2 hours, and / or After the reaction is completed, the reaction solution is distilled to dryness at 0-40° C. to obtain a crude product of the compound represented by formula I.

5. The preparation method according to claim 4, characterized in that: In step (1), the temperature of the reaction system is maintained at 10-15° C. during the addition of the base.

6. The preparation method according to claim 1, characterized in that: In step (2), the volume mass ratio of the organic solvent to (S)-3-cyano-5-methylhexanoic acid ethyl ester is 1 to 10 mL / g.

7. A method for preparing pregabalin, characterized in that: The preparation method comprises the following steps: (1) preparing the compound of formula I according to the preparation method according to any one of claims 1 to 6; (2) The product obtained in step (1) is subjected to hydrogenation reduction to obtain pregabalin, and the reaction formula is as follows: Wherein M is sodium.

8. The method for preparing pregabalin according to claim 7, characterized in that: The hydrogenation reduction reaction is carried out in an organic solvent, using Ni as a catalyst and hydrogen as a reducing agent, and the reaction temperature is 20 to 60°C.

9. The method for preparing pregabalin according to claim 8, characterized in that: The organic solvent is selected from methanol, ethanol, isopropanol and acetonitrile.

10. A method for preparing pregabalin, characterized in that: The preparation method comprises: (1) (S)-3-cyano-5-methylhexanoic acid ethyl ester is subjected to hydrolysis reaction in an organic solvent in the presence of a base. After the reaction is completed, the compound represented by formula I is obtained by filtering. The reaction formula is as follows: wherein M is sodium, the base is sodium hydroxide, The organic solvent is isopropanol; (2) the compound of formula I obtained in step (1) is slurried with an organic solvent and filtered. The organic solvent is isopropanol; (3) The compound of formula I obtained in step (2) is reduced in an organic solvent using Ni as a catalyst and hydrogen as a reducing agent to obtain pregabalin, and the reaction formula is as follows: Wherein M is sodium.

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