A process for the preparation of a pregabalin intermediate

Abstract

The present application relates to a synthesis method of a pregabalin intermediate, which effectively improves reaction yield and product purity, significantly reduces impurity content, and is suitable for large-scale industrial production.

Description

A preparation method of pregabalin intermediate Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing a pregabalin intermediate. Background Art

[0002] Pregabalin is a novel γ-aminobutyric acid (GABA) receptor agonist used to treat neuropathic pain, focal epilepsy, and anxiety. 3-Isobutylglutarimide (Compound V) is an important intermediate in the preparation of pregabalin. The common preparation route is shown below.

[0003] Patent CN100410242C discloses a method for preparing Compound V: 3-isobutylglutaric acid undergoes a cyclization reaction with a nitrogen-containing reagent in the absence of a solvent at 100-200°C, followed by recrystallization from a mixture of alcohol and water. However, in actual large-scale industrial production, the purity and yield of Compound V obtained by this method are relatively low.

[0004] Summary of the Invention

[0005] In one aspect, the present invention provides a method for preparing compound V, comprising the following steps:

[0006] Step 3: Compound IV reacts with a nitrogen-containing reagent in the presence of acid a to generate compound V.

[0007] In some embodiments of the present invention, the nitrogen-containing reagent in step 3 is any one or more combinations of urea, ammonium bicarbonate, and ammonium chloride;

[0008] The acid a in step 3 is any one or more combinations of organic or inorganic acids, preferably any one or more combinations of phosphoric acid, hydrochloric acid, sulfuric acid, nitric acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, and trifluoroacetic acid, more preferably any one or more combinations of phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, acetic acid, and trifluoroacetic acid;

[0009] The amount of the nitrogen-containing reagent used in step 3 is 0.5 to 1.5 molar equivalents of compound IV;

[0010] The amount of acid a used in step 3 is 0.02 to 0.5 molar equivalents of compound IV.

[0011] In some embodiments of the present invention, the reaction in step 3 is carried out in organic solvent A.

[0012] In some embodiments of the present invention, the organic solvent A in step 3 is a combination of any one or more of toluene, xylene, ethylene glycol dimethyl ether, and ethyl benzoate; preferably, the organic solvent A is toluene or xylene, more preferably, toluene; and the concentration of compound IV in the organic solvent A is 1.2 to 4 mol / L.

[0013] The reaction temperature in step 3 is 105-145° C.; preferably, the reaction temperature in step 3 is 110-130° C. (e.g., 110° C., 115° C., 120° C., 125° C., 130° C., or any value or range therebetween);

[0014] The reaction time in step 3 is 10 to 20 hours, preferably 13 to 18 hours.

[0015] In some embodiments of the present invention, the method for preparing compound V further comprises the following step 4:

[0016] Step 4: After the reaction is completed, cool and crystallize, filter, add solvent to slurry, and filter to obtain compound V.

[0017] In some embodiments of the present invention, the solvent in step 4 is an organic solvent B or a mixed solvent thereof with water; preferably, the organic solvent B is acetone;

[0018] The beating temperature is -5 to 50°C; preferably, the beating temperature is 20 to 50°C.

[0019] In some embodiments of the present invention, the method for preparing compound V further comprises the following steps:

[0020] Step 2: Compound III reacts in the presence of acid b to form compound IV.

[0021] In some embodiments of the present invention, the acid b in step 2 is any one or more of hydrochloric acid, sulfuric acid, and trifluoroacetic acid;

[0022] The reaction temperature in step 2 is 90-130°C;

[0023] The reaction time in step 2 is 8 to 30 hours; preferably, the reaction time in step 2 is 15 to 25 hours;

[0024] The solvent for the reaction in step 2 is water.

[0025] In some embodiments of the present invention, the method for preparing compound V further comprises the following steps:

[0026] Step 1: Compound I reacts with compound II in alkali solution to generate compound III.

[0027] In some embodiments of the present invention, the base in step 1 is an organic base, an inorganic base, or a combination of one or both; preferably, the organic base in step 1 is a combination of any one or more of triethylamine, diethylamine, n-propylamine, diisopropylethylamine, isopropylamine, morpholine, N-methylmorpholine, piperidine, pyridine, and piperazine; preferably, the inorganic base in step 1 is an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide;

[0028] The reaction temperature in step 1 is 0-10°C.

[0029] In some embodiments of the present invention, after the reaction of step 1 is completed, the reaction of step 2 is directly carried out without post-treatment.

[0030] In some embodiments of the present invention, after the reaction in step 2 is completed, organic solvent A is added to extract the reaction solution, the organic phase is separated, and 40% to 60% (e.g., 40%, 50%, 60% or any value or range therebetween) of organic solvent A is distilled off before proceeding to the next step of the reaction.

[0031] The organic solvent A removed by distillation can be recycled.

[0032] Another aspect of the present invention provides a method for preparing pregabalin, comprising the following steps:

[0033] Compound IV reacts with a nitrogen-containing reagent in the presence of acid a to produce compound V

[0034] Compound V was further prepared into pregabalin.

[0035] In the present invention, under acid catalysis, the cyclization reaction of compound IV is carried out in an organic solvent A (such as toluene, xylene, ethylene glycol dimethyl ether, ethyl benzoate). The reaction can be effectively carried out at 110°C, the reaction is mild, and a high temperature of 150 to 180°C is not required. The energy, temperature or pressure accumulation caused by the solvent-free reaction at high temperature is avoided, and the local overheating of the system causes the material to coke and the content and type of reaction impurities to increase. The method of the present invention not only improves the yield of the reaction, but also facilitates safe production. The solvent can be recycled and reused after distillation, which is more economical and environmentally friendly.

[0036] After the reaction of steps 1 and 2 is completed, only simple processing is required, and no separation or purification is required to proceed to the next reaction. The reactions of steps 1 to 3 can be carried out in a single reactor, simplifying the production process. After the reaction of step 3 is completed, only the solid needs to be precipitated by cooling, and then the crude product needs to be purified by beating to obtain a high-purity product. The total yield of the three-step reaction can reach up to 88.9%. The overall process route is simple to operate and is conducive to industrial production.

[0037] The preparation method provided by the present invention effectively improves the reaction yield and product purity, significantly reduces the impurity content, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0038] Unless otherwise specified, the terms in this invention have the following meanings:

[0039] In the present invention, the terms "organic solvent A" and "organic solvent B" actually refer to organic solvents, and A and B are only used to distinguish them as organic solvents used in different reactions.

[0040] In the present invention, the terms "acid a" and "acid b" actually refer to acids, wherein a and b are only used to distinguish them as acids used in different reactions.

[0041] In the present invention, nuclear magnetic resonance spectroscopy ( 1 H-NMR) was measured by a Bruker nuclear magnetic resonance spectrometer.

[0042] In the present invention, unless otherwise specified, % concentration refers to mass percentage concentration.

[0043] In the present invention, "concentrated hydrochloric acid" refers to a hydrochloric acid aqueous solution with a concentration of 36 to 38%.

[0044] In the present invention, "the yield relative to compound IV" refers to the yield of step 3 alone.

[0045] The impurity content in the embodiments of the present invention was detected using high performance liquid chromatography (HPLC) under the following HPLC detection conditions:

[0046] Chromatographic column: XBridge Premier BEH C18 150*4.6mm

[0047] Mobile phase A: 1.0 mL phosphoric acid to 1000 mL water

[0048] Mobile phase B: 1.0 mL phosphoric acid to 1000 mL acetonitrile

[0049] Wavelength: 210nm

[0050] Flow rate: 0.8 mL / min

[0051] In the present invention, "RRT" is relative retention time, which generally refers to the ratio of the retention time of the component to be analyzed to the retention time of the main component.

[0052] In order to make the technical problems, technical solutions and beneficial effects solved by the present invention more clearly understood, the present invention is further described below in conjunction with specific embodiments. However, it should be understood that the embodiments do not limit the scope of this application.

[0053] The reagents and solvents used in this application were purchased from commercial sources and were used directly without further treatment unless otherwise specified.

[0054] Example 1

[0055] Step 1: Dissolve 58.0 g of sodium hydroxide solid in 255 ml of water, cool to 3°C, slowly add 142.5 g of 70% cyanoacetic acid dropwise, maintain the temperature at 5°C, add 50.0 g of isovaleraldehyde dropwise, and react for 1 hour.

[0056] Step 2: Add 353 g of concentrated hydrochloric acid to the reaction system, raise the temperature to 110° C., and keep the reaction for 24 hours. Extract the reaction solution with 800 mL of toluene, let it stand for stratification, remove the aqueous phase, retain the organic phase, and distill off about 400 ml of toluene to obtain a toluene solution of compound IV. The content of compound IV therein is measured by high performance liquid chromatography (HPLC).

[0057] Step 3: Add 35 g of urea and 8 g of p-toluenesulfonic acid to the above toluene solution, raise the temperature to 110 ° C, reflux for 18 hours, and after the reaction is completed, cool to 5 ° C to precipitate a solid, filter, then add 15 ml of acetone and 150 ml of pure water, slurry at 40 ° C, cool to room temperature, filter and dry to obtain 85.3 g of compound V with a purity of 99.8%. The yield relative to compound IV is 96%, and the total yield of the three-step reaction is 86.9%.

[0058] Characterization of Compound IV

[0059] 1 H-NMR(CDCl3): δ8.37(s,1H), 2.69-2.24(dd,4H), 2.22(m,1H), 1.27(m,1H), 1.26(t,2H), 0.91-0.90(s,6H).

[0060] Example 2

[0061] Step 1: Dissolve 220g of sodium hydroxide solid in 1L of water, cool to 5°C, slowly add 500g of 70% cyanoacetic acid dropwise, maintain the temperature at 5°C, add 145g of isovaleraldehyde dropwise, and keep the reaction warm for 1h.

[0062] Step 2: Add 920 g of concentrated sulfuric acid to the reaction system, raise the temperature to 110°C, and keep the reaction for 20 hours. Extract the reaction solution with 2 L of xylene, let it stand for stratification, remove the aqueous phase, retain the organic phase, and distill off about 1 L of xylene to obtain a xylene solution of compound IV. The content of compound IV therein is measured by HPLC.

[0063] Step 3: Add 320 g of urea and 20 g of concentrated hydrochloric acid to the above xylene solution, raise the temperature to 130 ° C, reflux for 20 hours, and after the reaction is completed, cool to 10 ° C to precipitate a solid, filter, then add 180 ml of acetone and 1500 ml of pure water, slurry at 30 ° C, cool to room temperature, filter and dry to obtain 250.1 g of compound V with a purity of 99.8%. The yield relative to compound IV is 96.5%, and the total yield of the three-step reaction is 87.8%.

[0064] Example 3

[0065] Step 1: Dissolve 240 g of potassium carbonate solid in 400 ml of water, cool to 7°C, slowly add 145 g of 70% cyanoacetic acid dropwise, maintain the temperature at 7°C, add 55 g of isovaleraldehyde dropwise, and keep the reaction warm for 3 hours.

[0066] Step 2: Add 420 g of concentrated hydrochloric acid to the reaction system, raise the temperature to 110°C, and keep the reaction for 17 hours. Extract the reaction solution with 1.4 L of xylene, let it stand for stratification, remove the aqueous phase, retain the organic phase, and distill off about 0.7 L of xylene to obtain a xylene solution of compound IV. The content of compound IV therein is measured by HPLC.

[0067] Step 3: 76 g of urea and 18 g of acetic acid were added to the above xylene solution, the temperature was raised to 130°C, and the reaction was refluxed for 15 h. After the reaction was completed, the temperature was lowered to 10°C to precipitate a solid, which was filtered. 150 ml of acetone and 1.2 L of pure water were added, and the mixture was slurried at 35°C. The mixture was cooled to room temperature, filtered, and dried to obtain 93.6 g of compound V with a purity of 99.8%. The yield relative to compound IV was 95.8%, and the total yield of the three-step reaction was 86.7%.

[0068] Example 4

[0069] Step 1: Dilute 180g of morpholine with 200ml of water, cool to 5°C, slowly add 100g of cyanoacetic acid dropwise while maintaining the temperature at 5°C, add 60g of isovaleraldehyde dropwise, and keep the reaction warm for 5h.

[0070] Step 2: Add 320 g of trifluoroacetic acid to the reaction system, raise the temperature to 110° C., and keep the reaction for 16 hours. Extract the reaction solution with 1.2 L of ethyl benzoate, let it stand for stratification, remove the aqueous phase, retain the organic phase, and distill off about 0.6 L of ethyl benzoate to obtain an ethyl benzoate solution of compound IV, and measure the content of compound IV therein by HPLC.

[0071] Step 3: 85 g of urea and 42 g of methanesulfonic acid were added to the above ethyl benzoate solution, the temperature was raised to 130 ° C, and the reaction was refluxed for 10 h. After the reaction was completed, the temperature was cooled to 0 ° C to precipitate a solid, which was filtered. 200 ml of acetone and 1.9 L of pure water were added, and the mixture was slurried at 25 ° C. The mixture was cooled to room temperature, filtered and dried to obtain 102.7 g of compound V with a purity of 99.7%. The yield relative to compound IV was 96.6%, and the total yield of the three-step reaction was 87.1%.

[0072] Example 5

[0073] Step 1: Dissolve 65 kg of sodium hydroxide solid in 240 L of water, cool to 5°C, slowly add 100 kg of 70% cyanoacetic acid dropwise, maintain the temperature at 5°C, add 52 kg of isovaleraldehyde dropwise, and keep the reaction warm for 1.5 hours.

[0074] Step 2: Add 390 kg of concentrated hydrochloric acid to the reaction system, raise the temperature to 115 ° C, and keep the reaction for 16 hours. Extract the reaction solution with 1100 L of xylene, let it stand for stratification, remove the aqueous phase, retain the organic phase, and distill off about 550 L of xylene to obtain a xylene solution of compound IV. The content of compound IV therein is measured by HPLC.

[0075] Step 3: Add 38 kg of urea and 8 kg of phosphoric acid to the above xylene solution, raise the temperature to 130 ° C, reflux for 13 hours, and after the reaction is completed, cool to 8 ° C to precipitate the solid, filter, then add 100 L of acetone and 1300 L of pure water, slurry at 25 ° C, cool to room temperature, filter and dry to obtain 90.3 kg of compound V with a purity of 99.8%. The yield relative to compound IV is 97%, and the total yield of the three-step reaction is 88.3%.

[0076] Example 6

[0077] Step 1: Dissolve 200g of sodium hydroxide solid in 1L of water, cool to 5°C, slowly add 500g of 70% cyanoacetic acid dropwise, maintain the temperature at 5°C, add 145g of isovaleraldehyde dropwise, and keep the reaction warm for 1h.

[0078] Step 2: Add 1030 g of concentrated sulfuric acid to the reaction system, raise the temperature to 110°C, and keep the reaction for 20 hours. Extract the reaction solution with 2 L of toluene, let it stand for stratification, remove the aqueous phase, retain the organic phase, and distill off about 1 L of toluene to obtain a toluene solution of compound IV. The content of compound IV therein is measured by HPLC.

[0079] Step 3: Add 360 g of ammonium bicarbonate and 40 g of p-toluenesulfonic acid to the above toluene solution, raise the temperature to 120 ° C, reflux for 16 hours, and after the reaction is completed, cool to 10 ° C to precipitate a solid, filter, then add 180 ml of acetone and 1500 ml of pure water, slurry at 20 ° C, cool to room temperature, filter and dry to obtain 248.6 g of compound V with a purity of 99.8%, a yield of 95.9% relative to compound IV, and a total yield of 87.3% for the three-step reaction.

[0080] Example 7

[0081] Step 1: Dissolve 200g of sodium hydroxide solid in 1L of water, cool to 5°C, slowly add 500g of 70% cyanoacetic acid dropwise while maintaining the temperature at 5°C, add 145g of isovaleraldehyde dropwise, and allow to react for 1h after the addition is complete.

[0082] Step 2: Add 920 g of concentrated sulfuric acid to the reaction system, raise the temperature to 110°C, and keep the reaction for 20 hours. Extract the reaction solution with 2 L of xylene, let it stand for stratification, remove the aqueous phase, retain the organic phase, and distill off about 1 L of xylene to obtain a xylene solution of compound IV. The content of compound IV therein is measured by HPLC.

[0083] Step 3: Add 270 g of ammonium chloride and 35 g of acetic acid to the above xylene solution, raise the temperature to 130 ° C, reflux for 15 hours, and after the reaction is completed, cool to 5 ° C to precipitate a solid, filter, then add 180 ml of acetone and 1500 ml of pure water, slurry at 20 ° C, cool to room temperature, filter and dry to obtain 250.6 g of compound V with a purity of 99.7%, which is 96.7% relative to compound IV, and the total yield of the three-step reaction is 88.0%.

[0084] Example 8

[0085] Step 1: Dissolve 110 kg of sodium hydroxide solid in 500 L of water, cool to 5°C, slowly add 250 kg of 70% cyanoacetic acid dropwise, maintain the temperature at 5°C, add 73 kg of isovaleraldehyde dropwise, and keep the temperature for 1 hour.

[0086] Step 2: Add 460 kg of concentrated sulfuric acid to the reaction system, raise the temperature to 110°C, and keep the reaction warm for 20 hours. Extract the reaction solution with 1000 L of xylene, let it stand for stratification, remove the aqueous phase, retain the organic phase, and distill off about 500 L of xylene to obtain a xylene solution of compound IV. The content of compound IV therein is measured by HPLC.

[0087] Step 3: Add 160 kg of urea and 11 kg of concentrated hydrochloric acid to the above xylene solution, raise the temperature to 130 ° C, reflux for 20 hours, and after the reaction is completed, cool to 10 ° C to precipitate solids, filter, then add 90 L of acetone and 750 L of pure water, slurry at 25 ° C, cool to room temperature, filter and dry to obtain 126.1 kg of compound V with a purity of 99.7%, a yield of 97.3% relative to compound IV, and a total yield of 88.5% for the three-step reaction.

[0088] Example 9

[0089] Step 1: Dilute 170 kg of morpholine with 200 L of water, cool to 5°C, slowly add 100 kg of 70% cyanoacetic acid dropwise, maintain the temperature at 5°C, add 60 kg of isovaleraldehyde dropwise, and keep the reaction warm for 5 hours.

[0090] Step 2: Add 320 kg of trifluoroacetic acid to the reaction system, raise the temperature to 110 ° C, and keep the reaction for 15 hours. Take the reaction solution with 1200 L of toluene, let it stand for stratification, remove the aqueous phase, retain the organic phase, and distill off about 600 L of toluene to obtain a toluene solution of compound IV. The content of compound IV therein is measured by HPLC.

[0091] Step 3: Add 85 kg of urea and 42 kg of methanesulfonic acid to the above toluene solution, raise the temperature to 130 ° C, reflux for 10 hours, and after the reaction is completed, cool to 0 ° C to precipitate the solid, filter, then add 200 L of acetone and 1900 L of pure water, slurry at 20 ° C, cool to room temperature, filter and dry to obtain 103.5 kg of compound V with a purity of 99.8%. The yield relative to compound IV is 97.4%, and the total yield of the three-step reaction is 87.8%.

[0092] Example 10

[0093] Step 1: Dissolve 1100 kg of sodium hydroxide solid in 5000 L of water, cool to 0°C, slowly add 2500 kg of 70% cyanoacetic acid dropwise, maintain the temperature at 10°C, add 730 kg of isovaleraldehyde dropwise, and keep the reaction warm for 2 hours.

[0094] Step 2: Add 4600 kg of concentrated sulfuric acid to the reaction system, raise the temperature to 110 ° C, keep the reaction for 24 hours, extract the reaction solution with 8000 L of toluene, let it stand for stratification, remove the aqueous phase, retain the organic phase, and distill off about 3000 L of toluene to obtain a toluene solution of compound IV, and measure the content of compound IV therein by HPLC.

[0095] Step 3: Add 700 kg of urea and 80 kg of trifluoroacetic acid to the above toluene solution, raise the temperature to 115 ° C, reflux for 15 hours, and after the reaction is completed, cool to 10 ° C to precipitate the solid, filter, then add 900 L of acetone and 6000 L of pure water, slurry at 20 ° C for 2 hours, filter and dry to obtain 1275.0 kg of compound V with a purity of 99.8%. The yield relative to compound IV is 97.7%, and the total yield of the three-step reaction is 88.9%.

[0096] Comparative Example 1

[0097] Step 1: Dissolve 65 kg of sodium hydroxide solid in 240 L of water, cool to 5°C, slowly add 100 kg of 70% cyanoacetic acid dropwise, control the temperature at 5°C, add 52 kg of isovaleraldehyde dropwise, and keep the reaction warm for 1.5 hours.

[0098] Step 2: Add 390 kg of concentrated hydrochloric acid to the reaction system, raise the temperature to 115 ° C, and keep the reaction for 16 hours. Extract the reaction solution with 1100 L of xylene, let it stand for stratification, remove the aqueous phase, retain the organic phase, and distill off about 550 L of xylene to obtain a xylene solution of compound IV. The content of compound IV therein is measured by HPLC.

[0099] Step 3: Add 38 kg of urea to the above xylene solution, raise the temperature to 130 ° C, reflux for 13 hours, and after the reaction is completed, cool to 8 ° C to precipitate the solid, filter, then add 100 L of acetone and 1300 L of pure water, slurry at 25 ° C, cool to room temperature, filter and dry to obtain 79.9 kg of compound V with a purity of 95.8%. The yield relative to compound IV is 86.1%, and the total yield of the three-step reaction is 78.2%.

[0100] Comparative Example 2

[0101] Step 1: Dissolve 110 kg of sodium hydroxide solid in 500 L of water, cool to 5°C, slowly add 250 kg of 70% cyanoacetic acid dropwise, maintain the temperature at 5°C, add 73 kg of isovaleraldehyde dropwise, and keep the temperature for 1 hour.

[0102] Step 2: Add 460 kg of concentrated sulfuric acid to the reaction system, raise the temperature to 110°C, and keep the reaction warm for 20 hours. Extract the reaction solution with 1000 L of xylene, let it stand for stratification, remove the aqueous phase, retain the organic phase, and distill off about 500 L of xylene to obtain a xylene solution of compound IV. The content of compound IV therein is measured by HPLC.

[0103] Step 3: 160 kg of urea was added to the above xylene solution, the temperature was raised to 130 ° C, and the reaction was refluxed for 20 hours. After the reaction was completed, the temperature was cooled to 10 ° C to precipitate the solid, which was filtered. Then 90 L of acetone and 750 L of pure water were added, and the mixture was slurried at 25 ° C. The mixture was cooled to room temperature, filtered and dried to obtain 113.4 kg of compound V with a purity of 94.9%. The yield relative to compound IV was 87.4%, and the total yield of the three-step reaction was 79.5%.

[0104] Comparative Example 3

[0105] Step 1: Dilute 170 kg of morpholine with 200 L of water, cool to 5°C, slowly add 100 kg of cyanoacetic acid dropwise, maintain the temperature at 5°C, add 60 kg of isovaleraldehyde dropwise, and keep the reaction warm for 5 hours.

[0106] Step 2: Add 320 kg of trifluoroacetic acid to the reaction system, raise the temperature to 110 ° C, and keep the reaction for 15 hours. Take the reaction solution with 1200 L of toluene, let it stand for stratification, remove the aqueous phase, retain the organic phase, and distill off about 600 L of toluene to obtain a toluene solution of compound IV. The content of compound IV therein is measured by HPLC.

[0107] Step 3: Add 85 kg of urea to the above toluene solution, heat to 130 ° C, reflux for 10 hours, and after the reaction is completed, cool to 0 ° C to precipitate the solid, filter, then add 200 L of acetone and 1900 L of pure water, slurry at 20 ° C, cool to room temperature, filter and dry to obtain 90.9 kg of compound V with a purity of 95.7%. The yield relative to compound IV is 85.5%, and the total yield of the three-step reaction is 77.1%.

[0108] Comparative Example 4

[0109] Compound V was prepared according to the method described in CN100410242C: 200.0 g (1.06 mol) of 3-isobutylglutaric acid and 63.8 g (1.06 mol) of urea were added to a 1000 ml three-necked flask. The mixture was heated to 160°C in an oil bath and reacted at 160-180°C for 2 hours. The mixture was then cooled to 90°C and directly added with stirring to 400 ml of water and 400 ml of ethanol. 15 g of activated carbon was optionally added. The mixture was then heated under reflux for 30 minutes and filtered while hot. The filtrate was cooled, the solution was filtered off, and the crystals were dried in vacuo at 50°C to obtain 152.3 g of Compound V with a yield of 78.3% and a purity of 92.4%.

[0110] The specific impurity contents in the final products of the examples and comparative examples are shown in the following table:

Claims

1. A method for preparing compound V, characterized in that: The following steps are involved: Step 3: Compound IV reacts with a nitrogen-containing reagent in the presence of acid a to generate compound V.

2. The method according to claim 1, characterized in that The nitrogen-containing reagent in step 3 is any one or more combinations of urea, ammonium bicarbonate, and ammonium chloride; The acid a in step 3 is any one or more combinations of organic acids or inorganic acids, preferably any one or more combinations of phosphoric acid, hydrochloric acid, sulfuric acid, nitric acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, more preferably any one or more combinations of phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, acetic acid, trifluoroacetic acid; The amount of the nitrogen-containing reagent used in step 3 is 0.5 to 1.5 molar equivalents of compound IV; The amount of acid a used in step 3 is 0.02 to 0.5 molar equivalent of compound IV.

3. The method according to claim 1, characterized in that The reaction in step 3 is carried out in organic solvent A.

4. The method according to claim 3, characterized in that In step 3, the organic solvent A is any one or more of toluene, xylene, ethylene glycol dimethyl ether, and ethyl benzoate; preferably, the organic solvent A is toluene or xylene; more preferably, the organic solvent A is toluene; In step 3, the concentration of compound IV in organic solvent A is 1.2-4 mol / L; The reaction temperature in step 3 is 105-145°C, preferably 110-130°C; The reaction time in step 3 is 10 to 20 hours, preferably 13 to 18 hours.

5. The method according to claim 1, characterized in that The preparation method of the compound V further comprises the following step 4: Step 4: After the reaction is completed, cool down to crystallize, filter, add solvent to slurry, and filter to obtain compound V.

6. The method according to claim 5, characterized in that The solvent in step 4 is an organic solvent B or a mixed solvent thereof with water, preferably acetone; The beating temperature in step 4 is -5 to 50°C, preferably 20 to 50°C.

7. The method according to any one of claims 1 to 6, characterized in that The preparation method of the compound V further comprises the following steps: Step 2: Compound III reacts in the presence of acid b to generate compound IV.

8. The method according to claim 7, characterized in that: The acid b in step 2 is any one or more of hydrochloric acid, sulfuric acid and trifluoroacetic acid; The reaction temperature in step 2 is 90-130°C; The reaction time in step 2 is 8 to 30 hours, preferably 15 to 25 hours; The solvent for the reaction in step 2 is water.

9. The method according to claim 7, characterized in that: The preparation method of the compound V further comprises the following steps: Step 1: Compound I reacts with compound II in an alkali solution to generate compound III.

10. The method according to claim 9, characterized in that: The base in step 1 is an organic base or an inorganic base, or a combination of two thereof, preferably a combination of any one or more of triethylamine, diethylamine, n-propylamine, diisopropylethylamine, isopropylamine, morpholine, N-methylmorpholine, piperidine, pyridine, and piperazine; further preferably an alkali metal hydroxide; The reaction temperature in step 1 is 0-10°C.

11. A method for preparing pregabalin, comprising the following steps: Step 3: Compound IV reacts with a nitrogen-containing reagent in the presence of acid a to generate compound V. Compound V was further prepared into pregabalin.