A method for recycling and reuse of the solvent for separating pregabalin intermediates

Abstract

The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a method for recycling and reusing the resolution solvent of pregabalin intermediates. More specifically, it relates to a method for recycling and reusing the resolution solvent chloroform / ethanol / R-(+)-α-phenylethylamine of pregabalin intermediates, including the preparation of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid phenethylamine salt, the preparation of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid, the obtaining of the recycled resolution solvent, the detection of the recycled resolution solvent, and the application of the recycled resolution solvent. The recycling and reusing method of the present invention has low requirements for production equipment, a simple operation process, low production costs, does not require distillation, the obtained recycled resolution solvent can be recycled for a long time, greatly reduces the emission of toxic waste gas of trichloromethane, and there is no distillation residue, reducing the waste liquid emission, being highly efficient and environmentally friendly.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for recycling and reuse of the resolution solvent for pregabalin intermediates, and more particularly to a method for recycling and reuse of the resolution solvent chloroform / ethanol / R-(+)-α-phenylethylamine for pregabalin intermediates. Background Art

[0002] Pregabalin, chemically named (3S)-3-aminomethyl-5-methylhexanoic acid, was developed by Warner-Lambert Company of the United States. After years of research and development, it has been clinically found that pregabalin has analgesic, anticonvulsant and anti-anxiety effects so far.

[0003] The current typical process route of pregabalin is obtained by resolving, liberating 3-carbamoylmethyl-5-methylhexanoic acid and then performing Hoffmann degradation. The synthetic route is as follows:

[0004]

[0005] There is currently no relevant patent reporting on the recovery method of the resolution solvent chloroform / ethanol / R-(+)-α-phenylethylamine. After the resolution solvent chloroform / ethanol / R-(+)-α-phenylethylamine is recovered, it can not only be recycled, but also greatly reduce the emission of three wastes. Therefore, it is necessary to develop a convenient, environmentally friendly and low-cost method for recycling and reuse of the resolution solvent for pregabalin intermediates. Summary of the Invention

[0006] Aiming at the above defects or improvement requirements of the prior art, the present invention provides a method for recycling and reuse of the resolution solvent chloroform / ethanol / R-(+)-α-phenylethylamine for pregabalin intermediates. This method has simplicity, is easy to implement industrially, has low requirements for equipment, can greatly improve the resolution efficiency of pregabalin intermediates, and can obtain the recycled resolution solvent system (chloroform / ethanol / R-(+)-α-phenylethylamine) only through stratification and extraction. After using the verified test method to determine the proportion of each component, and then adding an appropriate amount of components, the recycling can be achieved.

[0007] To achieve the above object, the present invention provides a method for recycling and reuse of the resolution solvent for pregabalin intermediates, comprising the following steps:

[0008] (1) Preparation of phenyl ethylamine salt of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid: 3-carbamoylmethyl-5-methylhexanoic acid was dissolved in a certain amount of chloroform / ethanol / R-(+)-α-phenylethylamine or the recycled solvent system by heating to 50-60 °C until clear, and then cooled to 32 ± 1 °C for crystallization. After solid-liquid separation, the solid was phenyl ethylamine salt of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid, and the filtrate was the chloroform solution of the S isomer; among them, the chloroform solution of the S isomer was the chloroform solution containing excessive S-(+)-3-carbamoylmethyl-5-methylhexanoic acid phenyl ethylamine salt;

[0009] (2) Preparation of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid: The phenyl ethylamine salt of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid obtained in step (1) was added with a certain amount of water and heated to 40-50 °C for dissolution. After standing and separating layers, the lower organic phase was combined into the chloroform solution of the S isomer described in step (1). The upper aqueous layer was acidified with a certain amount of inorganic acid to a system pH of 1-2, and then crystallized and centrifuged to obtain the crude product of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid and the mother liquor water. The crude product of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid was refined and dried with ethyl acetate to obtain the finished product of pregabalin intermediate, and the mother liquor water was recycled to the chloroform solution of the S isomer and the R-(+)-α-phenylethylamine was recovered by alkali dissociation;

[0010] (3) Obtaining of the recycled resolution solvent: The mother liquor water obtained in step (2) was added to the chloroform solution of the S isomer obtained in step (1), and then a certain amount of 30% liquid alkali was added to adjust the pH of the aqueous layer ≥ 10. After separation of layers, the aqueous layer was extracted once with a certain amount of chloroform, and the lower organic phases were combined. Then, a certain amount of water was added for washing once, and after standing for 2 hours, separation of layers was carried out. The lower layer was the recycled resolution solvent; the upper aqueous layer was acidified to recover the S isomer; among them, the S isomer was S-(+)-3-carbamoylmethyl-5-methylhexanoic acid;

[0011] (4) Detection of the recycled resolution solvent: The recycled resolution solvent obtained in step (3) was stirred or pumped to be mixed evenly, and then sampled for inspection. The contents of ethanol and R-(+)-α-phenylethylamine were determined by the GC external standard method, and the content results were reported;

[0012] (5) Recycling of the recycled resolution solvent: According to the requirements of the recycled solvent standard, based on the GC content results of the recycled resolution solvent in step (4), a certain amount of fresh ethanol and fresh R-(+)-α-phenylethylamine were added to obtain the recycled resolution solvent system, and then this recycled resolution solvent system was recycled to the preparation of the next batch of phenyl ethylamine salt of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid.

[0013] Further, in the above technical solution, in step (1), when using chloroform / ethanol / R-(+)-α-phenylethylamine, in the system, the volume ratio of chloroform to 3-carbamoylmethyl-5-methylhexanoic acid is 15:1; the weight ratio of ethanol to 3-carbamoylmethyl-5-methylhexanoic acid is 0.67:1; the weight ratio of R-(+)-α-phenylethylamine to 3-carbamoylmethyl-5-methylhexanoic acid is 0.65:1; when using recycled resolution solvent, the recycled resolution solvent used is recycled chloroform / ethanol / R-(+)-α-phenylethylamine, and then 0 to 0.5 parts by weight of ethanol and 0 to 0.03 parts by weight of R-(+)-α-phenylethylamine based on 3-carbamoylmethyl-5-methylhexanoic acid are added. In this technical solution, by strictly controlling the material ratios of chloroform, ethanol, and R-(+)-α-phenylethylamine, the product resolution yield can be maximized and the material utilization rate can be optimized. Among them, the molar ratio of the amount of R-(+)-α-phenylethylamine material to the substrate 3-carbamoylmethyl-5-methylhexanoic acid is almost 1:1, without waste.

[0014] Further, in step (2) of the above technical solution, the amount of water added is 1.5 to 3 times the volume of 3-carbamoylmethyl-5-methylhexanoic acid; preferably 2 times.

[0015] Further, in step (2) of the above technical solution, the inorganic acid is concentrated hydrochloric acid or dilute sulfuric acid.

[0016] Further, in step (3) of the above technical solution, the liquid alkali is any one of sodium hydroxide solution, potassium hydroxide solution, potassium carbonate solution, and sodium carbonate solution; preferably sodium hydroxide solution.

[0017] Further, in step (3) of the above technical solution, the volume ratio of chloroform to 3-carbamoylmethyl-5-methylhexanoic acid is 1 to 3:1, preferably 1.5:1. In this technical solution, by controlling the amount of chloroform used for extraction, the proportion of each component in the recycled resolution solvent system can be effectively controlled to ensure the stability of the system and achieve reuse.

[0018] Further, in step (3) of the above technical solution, the amount of washing water used is 0.5 to 2 times the volume of 3-carbamoylmethyl-5-methylhexanoic acid; preferably 0.5 to 1 times. In this technical solution, by controlling the amount of washing water used, the ethanol proportion in the recycled resolution solvent system can be effectively controlled to ensure the stability of the system and achieve reuse.

[0019] Further, in step (5) of the above technical solution, the amount of fresh ethanol used is 0 to 0.5 times the weight of 3-carbamoylmethyl-5-methylhexanoic acid; preferably 0.25 times.

[0020] Further, in step (5) of the above technical solution, the dosage of fresh R-(+)-α-phenethylamine is 0 to 0.03 times the weight of 3-carbamoylmethyl-5-methylhexanoic acid.

[0021] Further, in step (5) of the above technical solution, after adding fresh ethanol and fresh R-(+)-α-phenethylamine, the ethanol content is controlled at 1-3%, and the R-(+)-α-phenethylamine content is controlled at 2-3%.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0023] 1. Compared with the known technology of distillation and then recycling, the time cost required for distillation recovery is high, the production efficiency is low, the production cost is higher, the difficulty of industrial implementation is great, and it will increase the distillation residue liquid and organic waste gas, bringing a great deal of treatment costs to EHS (environment, health, safety). By strictly controlling the raw material ratio, reaction temperature, pH and other conditions in each step, the present invention can greatly improve the resolution efficiency of pregabalin intermediates. The recycled resolution solvent system can be obtained only through layering and extraction, without the need for distillation steps, greatly improving the production efficiency, with low cost and easy industrialization. At the same time, it has been found through research that repeated distillation will significantly degrade the resolution reagent R-(+)-α-phenethylamine, while the method of the present invention does not require distillation, and the stability of R-(+)-α-phenethylamine is high, further reducing the production cost;

[0024] 2. The present invention verifies the recycled resolution solvent, measures the proportion of each component, and then adds an appropriate amount of components, so as to achieve infinite recycling, without waste and with low cost;

[0025] 3. The present invention has low requirements for production equipment, a simple operation process, low production cost, and the recycled resolution solvent can be recycled for a long time, greatly reducing the emission of toxic waste gases such as chloroform, and there is no distillation residue, reducing the waste liquid discharge, being efficient and environmentally friendly. Specific embodiments

[0026] The experimental methods in the following examples are all conventional methods unless otherwise specified. The raw materials involved in the following examples are all ordinary commercially available products unless otherwise specified, and can all be obtained through market purchase.

[0027] All the above technical features of the present invention and the technical features specifically described below (such as in the implementation cases) can be combined with each other to form new or preferred technical solutions.

[0028] Example 1

[0029] A method for recycling a resolution solvent of pregabalin intermediate, comprising the following steps:

[0030] (1) Preparation of phenyl ethylamine salt of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid

[0031] Into a 4000L reactor, 225 kg of 3-carbamoylmethyl-5-methylhexanoic acid was charged, and 3375 L of chloroform, 150 kg of ethanol and 145 kg of R-(+)-α-phenylethylamine were pumped in. The mixture was stirred and heated to 50 - 60 °C until clear, held at this temperature for 30 minutes, then cooled to 32 °C for crystallization. The crystals were filtered through a two-in-one filter, and the material was rinsed with an appropriate amount of chloroform. The filtrate was received in a 5000L reactor; the solid material in the pressure filter was the phenyl ethylamine salt of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid, and the liquid in the 5000L reactor was a batch of mother liquor for resolution.

[0032] (2) Preparation of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid

[0033] 450 kg of water was added to the above-mentioned phenyl ethylamine salt of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid, and the mixture was heated to 40 - 50 °C for dissolution. After standing for phase separation, the lower organic phase was combined with the chloroform solution of the S isomer. The upper aqueous layer was acidified with 50 L of concentrated hydrochloric acid to a system pH of 1 - 2, and then crystallized and centrifuged to obtain the crude product of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid and mother liquor water. Among them, the crude product was refined and dried with ethyl acetate to obtain 81 kg of dry product of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid (resolution yield 36%, purity 99.8%, chiral ee value 100%). The mother liquor water was recycled to the chloroform solution of the S isomer, and R-(+)-α-phenylethylamine was recovered by alkali dissociation.

[0034] (3) Recovery of the resolution solvent: chloroform / ethanol / R-(+)-α-phenylethylamine solution system

[0035] The mother liquor water from step (2) was added to a 5000L reactor. While stirring, 265 kg of 30% liquid alkali was added to adjust the pH of the aqueous layer ≥10. After standing for phase separation, the aqueous layer was extracted once with 230 L of chloroform. The chloroform layers were combined, washed once with 155 kg of water, and after standing for 2 hours, phase separation was carried out. The lower aqueous layer was combined and acidified to recover the S isomer, and the lower organic phase was the recovered resolution solvent. After detection, the GC external standard results showed that the ethanol content was 2.24% and the R-(+)-α-phenylethylamine content was 2.76%, which could be directly recycled to the preparation section of the phenyl ethylamine salt of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid for the next batch.

[0036] Example 2

[0037] A method for recycling and reuse of the resolution solvent for pregabalin intermediate, comprising the following steps:

[0038] (1) Preparation of phenyl ethylamine salt of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid

[0039] Into a 4000L reactor, 225 kg of 3-carbamoylmethyl-5-methylhexanoic acid was charged, and 3375 L of the recovered resolution solvent obtained in Example 1, 56 kg of ethanol, and 3 kg of R-(+)-α-phenylethylamine were pumped in. The mixture was stirred and heated to 50 - 60 °C until clear, held at this temperature for 30 minutes, then cooled to 32 °C for crystallization. The mixture was filtered through a two-in-one filter, and the material was rinsed with an appropriate amount of chloroform. The filtrate was received in a 5000L reactor; the solid material in the pressure filter was the R-(-)-3-carbamoylmethyl-5-methylhexanoic acid phenethylamine salt, and the liquid in the 5000L reactor was a batch of mother liquor for resolution.

[0040] (2) Preparation of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid

[0041] 450 kg of water was added to the above-mentioned R-(-)-3-carbamoylmethyl-5-methylhexanoic acid phenethylamine salt and heated to 40 - 50 °C for dissolution. After standing for liquid separation, the lower organic phase was combined into the chloroform solution of the S isomer. The upper aqueous layer was acidified with 49 L of concentrated hydrochloric acid to a system pH of 1 - 2, and then through crystallization and centrifugation, crude R-(-)-3-carbamoylmethyl-5-methylhexanoic acid and mother liquor water were obtained. Among them, the crude product was refined and dried with ethyl acetate to obtain 80 kg of dry R-(-)-3-carbamoylmethyl-5-methylhexanoic acid (resolution yield 35.6%, purity 99.9%, chiral ee value 100%). The mother liquor water was recycled to the chloroform solution of the S isomer and the R-(+)-α-phenylethylamine was recovered by alkali dissociation;

[0042] (3) Recovery of the resolution solvent: chloroform / ethanol / R-(+)-α-phenylethylamine solution system

[0043] The mother liquor water from step (2) was added to a 5000L reactor. While stirring, 265 kg of 30% liquid alkali was added to adjust the pH of the aqueous layer ≥ 10. After standing for liquid separation, the aqueous layer was extracted once with 230 L of chloroform. The chloroform layers were combined, washed once with 155 kg of water, and after standing for 2 hours, liquid separation was carried out. The upper aqueous layer was combined and sent for acidification to recover the S isomer, and the lower organic phase was the recovered resolution solvent. After detection, the GC external standard result showed that the ethanol content was 2.25% and the R-(+)-α-phenylethylamine content was 2.74%, which could be continuously recycled to the preparation section of the R-(-)-3-carbamoylmethyl-5-methylhexanoic acid phenethylamine salt for the next batch.

[0044] Example 3

[0045] A method for recycling and reuse of a resolution solvent for pregabalin intermediate, comprising the following steps:

[0046] (1) Preparation of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid phenethylamine salt

[0047] Into a 4000L reactor, 225 kg of 3-carbamoylmethyl-5-methylhexanoic acid was charged, and 3375 L of the recovered and resolved solvent obtained in Example 2, 56 kg of ethanol, and 2 kg of R-(+)-α-phenylethylamine were pumped in. The mixture was stirred and heated to 50 - 60 °C until clear, held at this temperature for 30 minutes, then cooled to 31 °C for crystallization. The crystals were filtered through a two-in-one filter, and the material was rinsed with an appropriate amount of chloroform. The filtrate was collected in a 5000L reactor; the solid material in the pressure filter was R-(-)-3-carbamoylmethyl-5-methylhexanoic acid phenethylamine salt, and the liquid in the 5000L reactor was a batch of mother liquor for resolution.

[0048] (2) Preparation of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid

[0049] 450 kg of water was added to the above-mentioned R-(-)-3-carbamoylmethyl-5-methylhexanoic acid phenethylamine salt and heated to 40 - 50 °C for dissolution. After standing for liquid separation, the lower organic phase was combined into the chloroform solution of the S isomer. The upper aqueous layer was acidified with 51 L of concentrated hydrochloric acid to a system pH of 1 - 2, and then through crystallization and centrifugation, crude R-(-)-3-carbamoylmethyl-5-methylhexanoic acid and mother liquor water were obtained. Among them, the crude product was refined with ethyl acetate and dried to obtain 82 kg of dry R-(-)-3-carbamoylmethyl-5-methylhexanoic acid (resolution yield 36.4%, purity 99.8%, chiral ee value 100%). The mother liquor water was recycled to the chloroform solution of the S isomer, and R-(+)-α-phenylethylamine was recovered by alkali dissociation.

[0050] (3) Recovery of the resolved solvent: chloroform / ethanol / R-(+)-α-phenylethylamine solution system

[0051] The mother liquor water from step (2) was added to a 5000L reactor. While stirring, 266 kg of 30% liquid alkali was added to adjust the pH of the aqueous layer ≥10. After standing for liquid separation, the aqueous layer was extracted once with 230 L of chloroform. The chloroform layers were combined, washed once with 156 kg of water, and after standing for 2 hours, separated. The upper aqueous layer was combined and sent for acidification to recover the S isomer, and the lower organic phase was the recovered resolved solvent. After detection, the GC external standard results showed that the ethanol content was 2.23% and the R-(+)-α-phenylethylamine content was 2.78%, and it could be continuously recycled to the preparation section of the next batch of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid phenethylamine salt.

[0052] Example 4

[0053] A method for recycling and reuse of a resolved solvent for pregabalin intermediate, comprising the following steps:

[0054] (1) Preparation of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid phenethylamine salt

[0055] Into a 4000L reactor, 225 kg of 3-carbamoylmethyl-5-methylhexanoic acid was charged, and 3375 L of the recovered resolution solvent obtained in Example 3, 56 kg of ethanol and 1 kg of R-(+)-α-phenylethylamine were pumped in. The mixture was stirred and heated to 50 - 60 °C until clear, kept warm for 30 minutes, then cooled to 33 °C for crystallization. After filtration through a two-in-one filter, the material was rinsed with an appropriate amount of chloroform, and the filtrate was received in a 5000L reactor; the solid material in the filter press was the R-(-)-3-carbamoylmethyl-5-methylhexanoic acid phenethylamine salt, and the liquid in the 5000L reactor was a batch of mother liquor for resolution;

[0056] (2) Preparation of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid

[0057] 450 kg of water was added to the above-mentioned R-(-)-3-carbamoylmethyl-5-methylhexanoic acid phenethylamine salt and heated to 40 - 50 °C for dissolution. After standing for liquid separation, the lower organic phase was combined into the chloroform solution of the S isomer. The upper aqueous layer was acidified with 165 L of 49% H2SO4 to a system pH of 1 - 2, and then through crystallization and centrifugation, the crude product of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid and mother liquor water were obtained. Among them, the crude product was refined and dried with ethyl acetate to obtain 81 kg of dry product of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid (resolution yield 36.0%, purity 99.7%, chiral ee value 100%). The mother liquor water was recycled to the chloroform solution of the S isomer and R-(+)-α-phenylethylamine was recovered by alkali dissociation;

[0058] (3) Recovery of the resolution solvent: chloroform / ethanol / R-(+)-α-phenylethylamine solution system

[0059] The mother liquor water from step (2) was added to a 5000L reactor. 265 kg of 30% liquid alkali was added with stirring to adjust the pH of the aqueous layer ≥ 10. After standing for liquid separation, the aqueous layer was extracted once with 230 L of chloroform. The chloroform layers were combined, washed once with 157 kg of water, and after standing for 2 hours, liquid separation was carried out. The upper aqueous layer was combined and sent for acidification to recover the S isomer, and the lower organic phase was the recovered resolution solvent. After detection, the GC external standard result showed that the ethanol content was 2.24% and the R-(+)-α-phenylethylamine content was 2.81%, which could be continuously recycled for the preparation section of the next batch of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid phenethylamine salt.

[0060] In summary, the recovery and recycling method of the present invention has low requirements for production equipment, a simple operation process, low production costs. The recovered resolution solvent obtained can be recycled for a long time (up to hundreds of times), greatly reducing the emission of toxic chloroform waste gas, and there is no distillation residue, reducing the waste liquid discharge, being highly efficient and environmentally friendly.

[0061] Finally, it should be emphasized that the above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for recycling and reuse of the solvent for separating pregabalin intermediate, characterized in that, It includes the following steps: (1) Preparation of phenyl ethylamine salt of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid: Dissolve 3-carbamoylmethyl-5-methylhexanoic acid in chloroform / ethanol / R-(+)-α-phenylethylamine or the recycled resolution solvent system by heating to 50-60 °C until clear, then cool to 32 ± 1 °C for crystallization, followed by solid-liquid separation. The solid is phenyl ethylamine salt of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid, and the filtrate is the chloroform solution of the S isomer; when using the chloroform / ethanol / R-(+)-α-phenylethylamine system, the volume ratio of chloroform to 3-carbamoylmethyl-5-methylhexanoic acid is 15:1; the weight ratio of ethanol to 3-carbamoylmethyl-5-methylhexanoic acid is 0.67:1; the weight ratio of R-(+)-α-phenylethylamine to 3-carbamoylmethyl-5-methylhexanoic acid is 0.65:1; the recycled resolution solvent is the recovered chloroform / ethanol / R-(+)-α-phenylethylamine, and then add 0-0.5 times the weight of ethanol and 0-0.03 times the weight of R-(+)-α-phenylethylamine of 3-carbamoylmethyl-5-methylhexanoic acid; (2) Preparation of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid: Add the phenyl ethylamine salt of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid obtained in step (1) to water and heat to 40-50 °C for dissolution, then let it stand for stratification. The lower organic phase is combined with the chloroform solution of the S isomer described in step (1). The upper aqueous layer is acidified with inorganic acid to a system pH of 1-2, and then through crystallization and centrifugation, a crude product of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid and mother liquor water are obtained. The crude product of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid is refined with ethyl acetate and dried to obtain the finished product of pregabalin intermediate; (3) Obtaining the recycled resolution solvent: Add the mother liquor water obtained in step (2) to the chloroform solution of the S isomer after combining the organic phases, then add 30% liquid alkali to adjust the pH of the aqueous layer ≥ 10. After stratification, the aqueous layer is extracted once with chloroform, and the lower organic phases are combined. Then add water for washing once, let it stand for 2 hours and then stratify. The lower layer is the recycled resolution solvent; the upper aqueous layer is acidified to recover the S isomer; (4) Detection of the recycled resolution solvent: After the recycled resolution solvent obtained in step (3) is stirred or pumped to be mixed evenly, take a sample for inspection, and determine the contents of ethanol and R-(+)-α-phenylethylamine by the GC external standard method, and report the content results; (5) Application of the recycled resolution solvent: According to the requirements of the application solvent standard, based on the GC content results of the recycled resolution solvent in step (4), add fresh ethanol and fresh R-(+)-α-phenylethylamine to obtain the applied resolution solvent system, and then apply this applied resolution solvent system to the preparation of the next batch of phenyl ethylamine salt of R-(-)-3-carbamoylmethyl-5-methylhexanoic acid; After adding fresh ethanol and fresh R-(+)-α-phenylethylamine, control the ethanol content at 1-3% and the R-(+)-α-phenylethylamine content at 2-3%.

2. The recycling method of the chiral resolution solvent of pregabalin intermediate according to claim 1, wherein In step (2), the water addition amount is 1.5 to 3 times the volume of the 3-carbamoylmethyl-5-methylhexanoic acid.

3. A method for recycling and reuse of the solvent for resolving pregabalin intermediate according to claim 2, wherein In step (2), the water addition amount is 2 times the volume of the 3-carbamoylmethyl-5-methylhexanoic acid.

4. A method for recycling and reuse of the solvent for resolving pregabalin intermediate according to claim 1, characterized in that, In step (2), the inorganic acid is concentrated hydrochloric acid or dilute sulfuric acid.

5. A method for recycling and reuse of the solvent for separating pregabalin intermediate according to claim 1, characterized in that, In step (3), the liquid alkali is any one of sodium hydroxide solution, potassium hydroxide solution, potassium carbonate solution, and sodium carbonate solution.

6. A method for recycling and reuse of the solvent for separating pregabalin intermediate according to claim 5, characterized in that, In step (3), the liquid alkali is sodium hydroxide solution.

7. A method for recycling and reuse of the solvent for separating pregabalin intermediate according to claim 1, characterized in that, In step (3), the volume ratio of chloroform to the 3-carbamoylmethyl-5-methylhexanoic acid is 1 to 3:

1.

8. A method for recycling and reuse of the solvent for separating pregabalin intermediate according to claim 7, characterized in that, In step (3), the volume ratio of chloroform to the 3-carbamoylmethyl-5-methylhexanoic acid is 1.5:

1.

9. A method for recycling and reuse of the solvent for resolving pregabalin intermediate according to claim 1, characterized in that, In step (3), the water consumption for washing is 0.5 to 2 times the volume of the 3-carbamoylmethyl-5-methylhexanoic acid.

10. A method for recycling and reuse of the solvent for resolving pregabalin intermediate according to claim 9, characterized in that, In step (3), the water consumption for washing is 0.5 to 1 times the volume of the 3-carbamoylmethyl-5-methylhexanoic acid.

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