A method for preparing and analyzing trans-4-amino-cyclohexylacetic acid

Abstract

This invention discloses a method for preparing and analyzing trans-4-aminocyclohexylacetic acid. The preparation method is as follows: 4-nitrophenylacetic acid undergoes catalytic hydrogenation in a solvent, followed by filtration. The filtrate is then treated with acid to obtain a 4-aminophenylacetic acid salt solution. The collected catalyst is activated. The 4-aminophenylacetic acid salt solution is mixed with isopropanol, barium hydroxide, tetrabutylammonium bromide, 18-crown ether-6, and dibutyl phthalate. The activated catalyst is then added to initiate a catalytic hydrogenation reaction. After the reaction, the reaction solution is cooled and filtered. The resulting solid is mixed with a preheated dilute sulfuric acid solution and stirred to form a slurry. The mixture is then filtered, and the filtrate is neutralized and filtered again. The collected filtrate is concentrated and crystallized. The crystallized precipitate is washed and dried to obtain trans-4-aminocyclohexylacetic acid. The method provided by this invention has high reaction efficiency, mild conditions, and is suitable for industrial production. It yields high product purity and reliability. Furthermore, the analytical method provided by this invention is accurate and reliable.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for preparing and analyzing trans-4-amino-cyclohexylacetic acid. Background Technology

[0002] Trans-4-amino-cyclohexylacetic acid is one of the synthetic intermediates for the psychotropic drug caliprazine hydrochloride. The trans-4-substituted cyclohexane fragment in its molecular structure forms the core framework of caliprazine's three-dimensional configuration. The amino functional group in this compound exhibits high reactivity, participating in the construction of the crucial pharmacophore—the piperazine-amide structural unit—through key reactions such as the formation of amide bonds in subsequent multi-step synthesis. This unit plays a decisive role in the selective binding of the drug to receptors such as dopamine D2 and 5-HT1A in the central nervous system. Therefore, the stereochemical purity and structure of this intermediate directly affect the pharmacological activity and safety of the final drug substance. During process scale-up and production, the synthesis of this intermediate requires strict control of the cyclohexane stereoconfiguration to ensure a high proportion of the trans isomer.

[0003] Patent WO2009019174A1 discloses a preparation method comprising the following steps: adding 4-nitrophenylacetic acid to a sodium hydroxide solution to form a clear yellow solution; transferring the solution to a high-pressure reactor; and catalyzing hydrogenation with a 2-molar amount of sponge nickel catalyst at 115 bar hydrogen pressure and 125°C for 48 hours. After the reaction, the system is cooled and depressurized, and a 2-molar amount of sponge nickel catalyst is added back in. The pressure is then restored to 115 bar, and the reaction is continued at 130°C with stirring for 5 days. After the reaction is complete, the system is cooled to room temperature, residual gas is discharged, and the reaction mixture is purged with nitrogen. The reaction mixture is filtered through a filter aid to separate the catalyst. After concentrating the filtrate and removing the solvent, 74 g of crude product is obtained. This method suffers from problems such as a long reaction cycle, high temperature and pressure requirements, and a large amount of catalyst used, thus limiting its applicability to large-scale production.

[0004] Patent WO2019016828A1 discloses a method for preparing trans-4-amino-cyclohexylacetic acid. The method includes: mixing sodium hydroxide and trans-2-(4-acetamidocyclohexyl)acetic acid in n-butanol at 25-30°C with stirring, followed by reaction at 115-120°C for 16 hours; removing the solvent by vacuum distillation, adding dimethylcarbamoyl chloride in dichloromethane in two portions, reacting at 25-30°C for 8 hours and 6 hours respectively; then, after acid precipitation, washing with water, and drying, the resulting solid is reacted in 2-methoxyethanol at elevated temperature, cooled to crystallize, filtered, and dried to obtain the target product, with a yield of approximately 70%. This process suffers from high raw material costs, long reaction cycles, stringent condition control, and a narrow temperature range, making it unsuitable for large-scale production applications.

[0005] During process development and quality control, the inventors also discovered that the benzene ring of the target compound was saturated during the hydrogenation reduction process, leading to the destruction of its conjugated structure and a significant change in its UV absorption characteristics. Compared to the starting material, its UV absorption intensity at the same concentration was significantly reduced. This resulted in decreased sensitivity when using a UV detector for purity monitoring in conventional liquid chromatography, and increased differences in the UV response between trace impurities and the main component, thus interfering with the accurate determination of purity results. To ensure the reliability and accuracy of the analytical method, the detection strategy under these conditions needs to be optimized, or alternative analytical methods need to be developed. Summary of the Invention

[0006] In view of this, the present invention provides a method for preparing and analyzing trans-4-amino-cyclohexylacetic acid. The method provided by the present invention has high reaction efficiency, mild conditions, is suitable for industrial production, and yields products with high yield and purity. The analytical method provided by the present invention is reliable and accurate.

[0007] To better solve the above-mentioned technical problems, the present invention provides the following technical solution: In a first aspect, a method for preparing trans-4-amino-cyclohexylacetic acid includes the following steps: (1) 4-Nitrophenylacetic acid is subjected to catalytic hydrogenation in a certain solvent, filtered, and the filtrate is added with acid solution to obtain 4-aminophenylacetic acid salt solution. The catalyst collected by filtration is activated. (2) Add the above 4-aminophenylacetic acid salt solution to the reaction vessel, then add isopropanol, barium hydroxide, tetrabutylammonium bromide, 18-crown ether-6 and dibutyl phthalate, stir and mix, then add the catalyst activated in step (1) to carry out catalytic hydrogenation reaction; (3) After the reaction is completed, the reaction solution is cooled and filtered. The obtained solid is mixed with preheated dilute sulfuric acid solution, stirred and slurried, filtered, the filtrate is neutralized, filtered again, the filtrate is collected, concentrated and crystallized, the crystal precipitate is washed and dried to obtain trans-4-aminocyclohexylacetic acid.

[0008] Preferably, in step (1), the solvent is selected from at least one of water, methanol, ethanol, and isopropanol; the catalyst used in the catalytic hydrogenation reaction is one or more of Raney nickel, 5% Pd / C, 10% Pd / C, 5% Ru / C, and PtO2; the hydrogen pressure in the catalytic hydrogenation reaction is 0.5-5 MPa, and the system temperature is 30-90°C; the amount of catalyst added is 8-12% of the mass of 4-nitrophenylacetic acid.

[0009] Preferably, in step (1), the activation process is as follows: the catalyst collected by filtration is washed multiple times with deionized water, then washed with dilute hydrochloric acid solution, then washed with deionized water until neutral and dried, and finally activated by hydrogen reduction to obtain the activated catalyst.

[0010] Preferably, the concentration of the dilute hydrochloric acid solution is 4-7 wt%; the hydrogen reduction activation temperature is 200℃, the time is 1-2 h, and the hydrogen flow rate is 100 ml / min.

[0011] Preferably, in step (1), the acid solution is one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and acetic acid; the mass ratio of the acid to the 4-nitrophenylacetic acid is (2-3):10.

[0012] Preferably, in step (2), the amount of barium hydroxide added is 80-85% of the molar amount of 4-aminophenylacetate, the amount of tetrabutylammonium bromide added is 4-5% of the mass of 4-aminophenylacetate, the amount of isopropanol added is 70-80% of the volume of the 4-aminophenylacetate solution, the amount of 18-crown ether-6 added is 2-3% of the mass of 4-aminophenylacetate, the amount of dibutyl phthalate added is 0.5-0.7% of the mass of 4-aminophenylacetate, and the amount of activated catalyst used is 6-7% of the mass of 4-aminophenylacetate.

[0013] Preferably, in step (2), the conditions for the catalytic hydrogenation reaction are: hydrogen pressure of 0.3-0.5 MPa and temperature of 120°C.

[0014] Preferably, in step (3), the mass concentration of the dilute sulfuric acid solution is 4-5%; the temperature of the sulfuric acid solution is 75-80℃; and the mass ratio of the dilute sulfuric acid solution to the solid is (1.0-1.2):1.

[0015] Preferably, in step (3), at least one of carbonate, bicarbonate and sulfate is used for neutralization, and the pH of the system after neutralization is 6.5-7.0.

[0016] Preferably, in step (3), the temperature of the stirring and slurrying is 60-70℃ and the time is 20-30min.

[0017] Preferably, in step (3), the concentration conditions are: temperature of 55-60℃, vacuum degree of 0.08-0.09MPa, and concentration until 1 / 3 of the original volume.

[0018] Preferably, in step (3), the crystallization conditions are: temperature of 0-5℃ and time of 1-2h.

[0019] Secondly, an analytical method for trans-4-amino-cyclohexylacetic acid includes the following steps: S1. Prepare a sample solution of a certain concentration using the trans-4-amino-cyclohexylacetic acid. S2. Mix the sample solution to be tested, the derivatizing reagent solution, and the sodium bicarbonate aqueous solution evenly, then heat the mixture to react. After the reaction is complete, add hydrochloric acid solution and dilute evenly. Finally, perform chromatographic analysis. Mix evenly, dilute the reaction solution to a suitable concentration using liquid mobile phase, and perform chromatographic injection analysis.

[0020] Preferably, in step S1, the solvent of the sample solution to be tested is methanol, and the concentration of the sample solution to be tested is 4-5 mg / ml.

[0021] Preferably, in step S2, the solute of the derivatizing reagent solution is N-α-(2,4-dinitro-5-fluorophenyl)-L-propanamide (FDAA), the solvent is methanol, and the concentration of the derivatizing reagent solution is 4-5 mg / ml.

[0022] Preferably, in step S2, the concentration of the sodium bicarbonate aqueous solution is 1 mol / L, and the volume ratio of the sample solution to be tested, the derivatizing reagent solution, and the sodium bicarbonate aqueous solution is (2-3):5:(2-3).

[0023] Preferably, in step S2, the heating reaction conditions are: heating in a water bath at 45-55℃ for 1-1.5 hours.

[0024] Preferably, in step S2, the concentration of the hydrochloric acid solution is 1 mol / L, and the volume ratio of the hydrochloric acid solution to the sample solution to be tested is 1:1.

[0025] Preferably, in step S2, the reaction solution is diluted to 100 μg / mL using a 50 wt% methanol solution.

[0026] Preferably, in step S2, the conditions for chromatographic analysis are as follows: Chromatographic column: C18 column or other column with equivalent column efficiency; Mobile phase: phosphate buffer and alcohol solvent; the volume ratio of the phosphate buffer to the alcohol solvent is 90:10 to 0:100; Flow rate of mobile phase: 1.0 mL / min; Detection wavelength: 254nm; Elution method: isocratic elution; Injection volume: 10 μL.

[0027] Preferably, the alcohol solvent is one or more of methanol, ethanol, and isopropanol; the phosphate buffer solution is one or more of phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate aqueous solution.

[0028] Preferably, the concentration of the phosphate buffer solution is 0.01~0.1mol / L, and the pH is 1.0-4.0.

[0029] Compared with the prior art, the present invention has at least the following advantages: This invention provides a method for preparing trans-4-amino-cyclohexylacetic acid. By optimizing the catalytic hydrogenation system and reaction conditions, the two-step hydrogenation reaction can be carried out efficiently under relatively mild pressure and temperature, significantly reducing equipment requirements and energy consumption, improving process safety and operability, and facilitating large-scale production.

[0030] This invention recycles and activates the catalyst in the first step of the catalytic hydrogenation process, effectively removing impurities adsorbed on the catalyst surface and restoring its activity, realizing the reuse of the catalyst, reducing the consumption of precious metal catalysts, and significantly reducing production costs.

[0031] During the transformation process, this invention employs a composite additive system composed of barium hydroxide, tetrabutylammonium bromide, 18-crown ether-6, and dibutyl phthalate. The different components synergistically promote the hydrogenation process and significantly improve the selectivity of the trans isomer. Subsequently, through dilute sulfuric acid slurrying, neutralization, concentration, and low-temperature crystallization, reaction byproducts and cis isomers are effectively removed, ultimately yielding trans-4-aminocyclohexylacetic acid with high yield and high chemical purity.

[0032] In analyzing products, this invention uses N-α-(2,4-dinitro-5-fluorophenyl)-L-propanamide (FDAA) as a derivatizing reagent. Under mild conditions, it reacts specifically with the amino group in the target product to generate a derivative with strong ultraviolet absorption, overcoming the difficulty of weak ultraviolet absorption of the raw material itself and significantly improving the detection sensitivity and accuracy. Attached Figure Description

[0033] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0034] Figure 1 The HPLC chromatogram of the product derivatized in Example 1 is shown below. Figure 2The HPLC chromatogram of the product derivatization in Example 2 is shown below. Figure 3 The HPLC chromatogram of the product derivatization in Example 3 is shown. Detailed Implementation

[0035] To further illustrate the technical means and effects of the present invention in achieving its intended purpose, the following detailed description of the specific implementation methods, structures, features, and effects of the present invention, in conjunction with the accompanying drawings and preferred embodiments, is provided below.

[0036] The catalyst in the following examples is 10% Pd / C with a Pd loading of 10wt%; purchased from Shaanxi Ruike New Material Co., Ltd., with a moisture content of 57.95%, a carrier specific surface area ≥700m2 / g, and a carrier particle size of 200 mesh.

[0037] Example 1 A method for preparing trans-4-amino-cyclohexylacetic acid includes the following steps: (1) Add 100g of 4-nitrophenylacetic acid, 500mL of methanol and 10g of 10% Pd / C to a 1000mL high-pressure reactor, stir and mix evenly, replace with nitrogen three times, then purge with hydrogen to 2.0 MPa, heat to 40℃, and react until the pressure does not change significantly within 30min. Stop stirring, and discharge the material after nitrogen replacement is safe. Add 135g of 20wt% sulfuric acid aqueous solution to the reaction solution, filter, and obtain 4-aminophenylacetic acid sulfate solution; wash the catalyst collected by filtration with deionized water (100ml×3 times), then wash with 5wt% dilute hydrochloric acid solution (100ml×1 time), and finally wash with deionized water until the filtrate is neutral. Dry at 120℃ for 4h, and the obtained solid is hydrogenated and reduced at 200℃ and hydrogen flow rate of 100ml / min for 1.5h to obtain activated catalyst for later use. (2) Add the 4-aminophenylacetic acid sulfate solution obtained in step (1) to a 1000 mL high-pressure reactor, then add isopropanol (80% of the volume of the 4-aminophenylacetic acid sulfate solution), barium hydroxide (82% of the molar amount of 4-aminophenylacetic acid sulfate), tetrabutylammonium bromide (4.5% of the mass of 4-aminophenylacetic acid sulfate), 18-crown ether-6 (2.5% of the mass of 4-aminophenylacetic acid sulfate), and dibutyl phthalate (0.6% of the mass of 4-aminophenylacetic acid sulfate). Stir and mix for 10 min, add the activation catalyst from step (1) (7% of the mass of 4-aminophenylacetic acid sulfate), seal the reactor, replace the air with nitrogen three times, fill the reactor with hydrogen to a pressure of 0.4 MPa, raise the temperature to 120 °C, and react at a stirring rate of 350 r / min until the pressure inside the reactor does not change within 30 min. (3) After the reaction was completed, the reaction solution was cooled to 55°C, filtered, and the obtained solid was added to a 4.5 wt% dilute sulfuric acid solution preheated to 78°C (the mass ratio of dilute sulfuric acid solution to solid was 1.07:1). The solution was stirred and slurried at 65°C for 25 min, filtered, and an acidic filtrate was obtained. Calcium carbonate powder was added to the acidic filtrate to adjust the pH of the system to 6.8, filtered, and the filtrate was collected. The filtrate was concentrated to 1 / 3 of its original volume at 58°C and a vacuum of 0.085 MPa, then cooled to 3°C and crystallized for 1.5 h. The crystallized liquid was filtered, and the precipitate was washed twice with ice water. The washed solid was placed in a vacuum oven at 50°C and dried to constant weight to obtain 81.2 g of the target product trans-4-aminocyclohexylacetic acid, with a yield of 93.5%.

[0038] Example 2 A method for preparing trans-4-amino-cyclohexylacetic acid includes the following steps: (1) Add 100g of 4-nitrophenylacetic acid, 500mL of methanol and 10g of 10% Pd / C to a 1000mL high-pressure reactor, stir and mix evenly, replace with nitrogen three times, then purge with hydrogen to 2.0 MPa, heat to 45℃, and react until the pressure does not change significantly within 30min. Stop stirring, and discharge the material after nitrogen replacement is safe. Add 135g of 20% sulfuric acid aqueous solution to the hydrogenated liquid, filter, and obtain 4-aminophenylacetic acid sulfate solution. Wash the catalyst collected by filtration with deionized water (100ml×4 times), then wash with 4wt% dilute hydrochloric acid solution (100ml×1 time), and finally wash with deionized water until the filtrate is neutral. Dry at 110℃ for 5h, and the obtained solid is hydrogenated and reduced at 200℃ and hydrogen flow rate of 100ml / min for 1h to obtain activated catalyst for use. (2) Add the 4-aminophenylacetic acid sulfate solution prepared in step (1) to a 1000 mL high-pressure reactor, then add isopropanol (70% of the volume of 4-aminophenylacetic acid sulfate), barium hydroxide (80% of the molar amount of 4-aminophenylacetic acid sulfate), tetrabutylammonium bromide (4% of the mass of 4-aminophenylacetic acid sulfate), 18-crown ether-6 (2% of the mass of 4-aminophenylacetic acid sulfate), and dibutyl phthalate (0.5% of the mass of 4-aminophenylacetic acid sulfate). Stir and mix for 8 min, add the activation catalyst from step (1) (6% of the mass of 4-aminophenylacetic acid sulfate), seal the reactor, replace the air with nitrogen three times, fill the reactor with hydrogen to a pressure of 0.3 MPa, raise the temperature to 120 °C, and react at a stirring rate of 320 r / min until the pressure inside the reactor does not change within 30 min. (3) After the reaction was completed, the reaction solution was cooled to 50°C, filtered, and the obtained solid was added to a 4wt% dilute sulfuric acid solution preheated to 75°C (the mass ratio of dilute sulfuric acid solution to solid was 1:1). The solution was stirred and slurried at 60°C for 20 min, filtered, and an acidic filtrate was obtained. Sodium bicarbonate was added to the acidic filtrate to adjust the pH of the system to 6.5, filtered, and the filtrate was collected. The filtrate was concentrated to 1 / 3 of its original volume at 55°C and a vacuum of 0.08 MPa, then cooled to 0°C and crystallized for 2 h. The crystallized solution was filtered, and the precipitate was washed twice with ice water. The washed solid was placed in a vacuum oven at 50°C and dried to constant weight to obtain 80.6 g of the target product trans-4-aminocyclohexylacetic acid, with a yield of 92.8%.

[0039] Example 3 A method for preparing trans-4-amino-cyclohexylacetic acid includes the following steps: 100g of 4-nitrophenylacetic acid, 500mL of methanol, and 10g of 10% Pd / C were added to a 1000mL high-pressure reactor and stirred until homogeneous. After three gas purgings with nitrogen, hydrogen was introduced to 2.0 MPa, the temperature was raised to 45℃, and maintained at 40~50℃. The reaction was carried out at 2.0 MPa until no significant change in pressure was observed within 30 minutes. Stirring was stopped, and after safe nitrogen purging, the product was discharged. 135g of 20% phosphoric acid aqueous solution was added to the hydrogenated liquid, and the mixture was filtered to obtain a 4-aminophenylacetic acid phosphate solution. The catalyst collected by filtration was washed with deionized water (100ml × 4 times), then washed with a 7wt% dilute hydrochloric acid solution (100ml × 1 time), and finally washed with deionized water until the filtrate was neutral. The solution was dried at 130℃ for 3h, and the obtained solid was hydrogenated and reduced at 200℃ and a hydrogen flow rate of 100ml / min for 2h to obtain an activated catalyst for later use. (2) Add the 4-aminophenylacetic acid phosphate solution prepared in step (1) to a 1000 mL high-pressure reactor, then add isopropanol (78% of the volume of the 4-aminophenylacetic acid phosphate solution), barium hydroxide (85% of the molar amount of 4-aminophenylacetic acid phosphate), tetrabutylammonium bromide (5% of the mass of 4-aminophenylacetic acid phosphate), 18-crown ether-6 (3% of the mass of 4-aminophenylacetic acid phosphate), and dibutyl phthalate (0.7% of the mass of 4-aminophenylacetic acid phosphate). Stir and mix for 12 min, add the activation catalyst from step (1) (7% of the mass of 4-aminophenylacetic acid phosphate), seal the reactor, replace the air with nitrogen three times, fill the reactor with hydrogen to a pressure of 0.5 MPa, raise the temperature to 120 °C, and react at a stirring rate of 380 r / min until the pressure inside the reactor does not change within 30 min. (3) After the reaction was completed, the reaction solution was cooled to 60°C, filtered, and the obtained solid was added to a 5wt% dilute sulfuric acid solution preheated to 80°C (the mass ratio of dilute sulfuric acid solution to solid was 1.2:1). The solution was stirred and slurried at 70°C for 30 min, filtered, and an acidic filtrate was obtained. Potassium carbonate was added to the acidic filtrate to adjust the pH of the system to 7.0, filtered, and the filtrate was collected. The filtrate was concentrated to 1 / 3 of its original volume at 60°C and a vacuum of 0.09 MPa, then cooled to 5°C and crystallized for 1 h. The crystallized liquid was filtered, and the precipitate was washed twice with ice water. The washed solid was placed in a vacuum oven at 55°C and dried to constant weight to obtain 81.3 g of the target product, trans-4-aminocyclohexylacetic acid, with a yield of 93.7%.

[0040] The target product obtained in the above embodiments was analyzed by high performance liquid chromatography. The analysis process and results are as follows: Analysis process: (1) Preparation of derivatization reagent solution: Dissolve FDAA in methanol to prepare a solution with a concentration of 5 mg / mL; (2) Preparation of test sample solutions: Dissolve the test sample in a 50wt% methanol solution to prepare test sample solutions with a concentration of 2mg / mL; denoted as A1, A2, and A3 respectively; (3) Derivatization: Accurately transfer 2.5 mL of the sample solution to be tested, 5 mL of the derivatizing reagent solution and 2.5 mL of sodium bicarbonate aqueous solution (concentration of 1 mol / L) into a sealed reaction flask, mix well, and then place the reaction flask in a 50℃ water bath and heat for 1 h. After the reaction is completed, add 2.5 mL of hydrochloric acid solution (concentration of 1 mol / L) and continue to mix well; finally, dilute the reaction solution to 100 μg / mL with 50 wt% methanol solution and perform chromatographic analysis. The chromatographic conditions are as follows: Column: C18 column (250×4.6 mm, 5 μm); Mobile phase: aqueous phase and organic phase are mixed at a volume ratio of 45:55. The aqueous phase is 0.05 mol / L potassium dihydrogen phosphate solution, and the pH is adjusted to 2.5 with phosphoric acid; the organic phase is methanol; Elution method: isocratic elution; Detection wavelength: 254 nm; Flow rate: 1.0 mL / min; Injection volume: 10 μL.

[0041] The above analytical methods were used to analyze the derivatization of FDAA blank, trans-4-amino-cyclohexylacetic acid, and cis-4-amino-cyclohexylacetic acid. Figure 1 , Figure 2 , Figure 3 As shown.

[0042] from Figure 1 , Figure 2 , Figure 3It can be seen that the method provided by the present invention can stably prepare high-purity trans target products and can accurately analyze trans target products and cis isomers.

[0043] The test results are shown in Table 1.

[0044] Table 1 As can be seen from the results in Table 1, the purity of the target product obtained in the embodiments of the present invention is as high as 99.77%.

[0045] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for preparing trans-4-amino-cyclohexylacetic acid, characterized in that, Includes the following steps: (1) 4-Nitrophenylacetic acid is subjected to catalytic hydrogenation in a certain solvent, filtered, and the filtrate is added with acid solution to obtain 4-aminophenylacetic acid salt solution. The catalyst collected by filtration is activated. (2) Add the above 4-aminophenylacetic acid salt solution to the reaction vessel, then add isopropanol, barium hydroxide, tetrabutylammonium bromide, 18-crown ether-6 and dibutyl phthalate, stir and mix, then add the catalyst activated in step (1) to carry out catalytic hydrogenation reaction; (3) After the reaction is completed, the reaction solution is cooled and filtered. The obtained solid is mixed with preheated dilute sulfuric acid solution, stirred and slurried, filtered, the filtrate is neutralized, filtered again, the filtrate is collected, concentrated and crystallized, the crystal precipitate is washed and dried to obtain trans-4-aminocyclohexylacetic acid.

2. The method for preparing trans-4-amino-cyclohexylacetic acid according to claim 1, characterized in that, In step (1), the preparation of the 4-aminophenylacetic acid salt solution includes at least one of the following characteristics: The solvent is selected from at least one of water, methanol, ethanol, and isopropanol; The catalyst used in the catalytic hydrogenation reaction is one or more of Raney nickel, 5% Pd / C, 10% Pd / C, 5% Ru / C, and PtO2; During the catalytic hydrogenation reaction, the hydrogen pressure is 0.5-5 MPa and the system temperature is 30-90℃. The catalyst is added at an amount of 8-12% of the mass of 4-nitrophenylacetic acid; The acid solution is one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and acetic acid; the mass ratio of the acid to the 4-nitrophenylacetic acid is (2-3):

10.

3. The method for preparing trans-4-amino-cyclohexylacetic acid according to claim 1, characterized in that, In step (1), the activation process is as follows: the catalyst collected by filtration is washed multiple times with deionized water, then washed with a dilute hydrochloric acid solution with a concentration of 4-7wt%, then washed with deionized water until neutral and dried, and finally activated by hydrogen reduction. The temperature of hydrogen reduction activation is 200℃, the time is 1-2h, and the hydrogen flow rate is 100ml / min to obtain the activated catalyst.

4. The method for preparing trans-4-amino-cyclohexylacetic acid according to claim 1, characterized in that, In step (2), the amount of barium hydroxide added is 80-85% of the molar amount of 4-aminophenylacetate; and / or the amount of tetrabutylammonium bromide added is 4-5% of the mass of 4-aminophenylacetate; and / or the amount of isopropanol added is 70-80% of the volume of the 4-aminophenylacetate solution; and / or the amount of 18-crown ether-6 added is 2-3% of the mass of 4-aminophenylacetate; and / or the amount of dibutyl phthalate added is 0.5-0.7% of the mass of 4-aminophenylacetate; and / or the amount of activated catalyst is 6-7% of the mass of 4-aminophenylacetate; and / or the conditions for catalytic hydrogenation are: hydrogen pressure of 0.3-0.5 MPa and temperature of 120°C.

5. The method for preparing trans-4-amino-cyclohexylacetic acid according to claim 1, characterized in that, In step (3), the mass concentration of the dilute sulfuric acid solution is 4-5%; the temperature of the sulfuric acid solution is 75-80℃; the mass ratio of the dilute sulfuric acid solution to the solid is (1.0-1.2):1; and / or at least one of carbonate, bicarbonate, and sulfate is used for neutralization, and the pH of the system after neutralization is 6.5-7.

0.

6. The method for preparing trans-4-amino-cyclohexylacetic acid according to claim 1, characterized in that, In step (3), the stirring and slurrying temperature is 60-70℃ and the time is 20-30 min; and / or the concentration conditions are: temperature 55-60℃, vacuum degree 0.08-0.09 MPa, and concentration to 1 / 3 of the original volume; and / or the crystallization conditions are: temperature 0-5℃ and time 1-2 h.

7. The analytical method for trans-4-amino-cyclohexylacetic acid prepared according to any one of claims 1 to 6, characterized in that, Includes the following steps: S1. Prepare a sample solution of a certain concentration using the trans-4-amino-cyclohexylacetic acid. S2. Mix the sample solution to be tested, the derivatizing reagent solution, and the sodium bicarbonate aqueous solution evenly, then heat the mixture to react. After the reaction is complete, add hydrochloric acid solution and dilute evenly. Finally, perform chromatographic analysis. Mix evenly, dilute the reaction solution to a suitable concentration using liquid mobile phase, and perform chromatographic injection analysis.

8. The analytical method for trans-4-amino-cyclohexylacetic acid according to claim 7, characterized in that, In step S1, the solvent of the sample solution to be tested is methanol solution, and the concentration of the sample solution to be tested is 4-5 mg / ml.

9. The analytical method for trans-4-amino-cyclohexylacetic acid according to claim 7, characterized in that, In step S2, the solute of the derivatizing reagent solution is N-α-(2,4-dinitro-5-fluorophenyl)-L-propanamide, the solvent is methanol, and the concentration of the derivatizing reagent solution is 4-5 mg / ml; And / or the concentration of the sodium bicarbonate aqueous solution is 1 mol / L, and the volume ratio of the test sample solution, the derivatizing reagent solution, and the sodium bicarbonate aqueous solution is (2-3):5:(2-3); The conditions for the heating reaction are: heating in a water bath at 45-55℃ for 1-1.5 hours; And / or the concentration of the hydrochloric acid solution is 1 mol / L, and the volume ratio of the hydrochloric acid solution to the sample solution to be tested is 1:1; When diluting, the reaction solution is diluted to a concentration of 100 μg / mL with a 50 wt% methanol solution.

10. The analytical method for trans-4-amino-cyclohexylacetic acid according to claim 7, characterized in that, The conditions for chromatographic analysis are as follows: Chromatographic column: C18 column or other column with equivalent column efficiency; Mobile phase: phosphate buffer and alcohol solvent; the volume ratio of phosphate buffer to alcohol solvent is 90:10 to 0:100; the alcohol solvent is one or more of methanol, ethanol, and isopropanol; the phosphate buffer is one or more of phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate aqueous solution; the concentration of the phosphate buffer is 0.01~0.1 mol / L, and the pH is 1.0-4.0; Flow rate of mobile phase: 1.0 mL / min; Detection wavelength: 254nm; Elution method: isocratic elution; Injection volume: 10 μL.

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