A process for the synthesis of (E)- (N'- (4-cyanophenyl) -N-cyclooctylcarbamoyl) -2-aminoethanoic acid

Abstract

The application belongs to the technical field of synthesis of (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid, and particularly relates to a synthesis method of (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid, which comprises the following steps: 1) preparation of N-cyclooctyl-N'-(4-cyanophenyl) thiourea; 2) preparation of N-cyclooctyl-N'-(4-cyanophenyl)-S-methyl isothiourea; 3) (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid; the yield of (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid prepared by the method can be effectively improved.

Description

Technical Field

[0001] This invention belongs to the field of synthetic technology of ((E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid, specifically relating to a method for synthesizing (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid. Background Technology

[0002] French patent FR2597096 discloses a method for preparing (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid, in which urea formation is achieved using a 95% ethanol solution and methylation is achieved using acetone. However, this method has a low yield and a long reaction time.

[0003] Example 7 of French patent FR2606404 discloses a method for preparing (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid, obtained from glycine and N-cyclooctyl-N'-(4-cyanophenyl)-S-methylthiourea. Its sweetness is 170,000 times that of a 2% sucrose solution, 130,000 times that of a 5% sucrose solution, and 100,000 times that of a 10% sucrose solution, exhibiting a very high sweetness ratio. Furthermore, its sweetness is similar to sucrose, and it does not produce any bitterness even when used in large quantities. However, the yield of (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid prepared by this method is relatively low. The reaction equation is shown below:

[0004]

[0005] GW Muller, DE Walters, and GE DuBois N, N'-disubstituted guanidine high-potency sweeteners (J. Med. Chem. 1992, 36, 740-743) provided an alternative condensation synthesis route. The oxidation of thiourea to thiourea trioxide yielded 75%, but the subsequent condensation with glycine yielded only 30%, resulting in a combined yield of 22.5%. This is significantly lower than the thiourea methylation route.

[0006] US Patent 9907766, page 12, mentions the preparation of N-cyclooctyl-N'-(4-cyanophenyl)thiourea. The reaction in dioxane lasts up to 15 hours. After complex purification and extraction, the yield is good, but the reaction time is too long, too much solvent is used (1:20), and the melting point of dioxane is 12°C, which is too high and not conducive to industrial production. Summary of the Invention

[0007] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid. The preparation of (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid by this method can effectively improve the product yield and shorten the reaction time.

[0008] The object of this invention is achieved as follows: a method for synthesizing (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid, comprising the following steps: 1) Preparation of N-cyclooctyl-N'-(4-cyanophenyl)thiourea Take a certain amount of 4-cyanophenyl isothiocyanate and add an appropriate amount of toluene to the reaction vessel. Then, dissolve the 4-cyanophenyl isothiocyanate in the toluene. Then, under room temperature conditions, add an appropriate amount of cyclooctylamine dropwise while stirring. Then, heat the reaction vessel to 60~70℃ for reaction. After the reaction is completed, cool it to 20~25℃. Then, separate the filtrate and filter cake in the reaction vessel. Wash the separated filter cake with toluene. Then, combine the washed toluene and filtrate. The combined filtrate can be used to dissolve 4-cyanophenyl isothiocyanate. After drying the filter cake, N-cyclooctyl-N'-(4-cyanophenyl)thiourea can be obtained. 2) Preparation of N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea Weigh a certain amount of N-cyclooctyl-N'-(4-cyanophenyl)thiourea obtained in step 1), and add an appropriate amount of dimethyl carbonate to another reaction vessel. Then, dissolve the weighed N-cyclooctyl-N'-(4-cyanophenyl)thiourea in dimethyl carbonate. Then, add an appropriate amount of dimethyl sulfate to the reaction vessel and heat the reaction vessel to 85~92℃ for reaction. After the reaction is completed, cool it down to 10~15℃, then add sodium hydroxide aqueous solution and stir. Then, let it stand to separate the organic layer. Then, add an appropriate amount of saturated salt to the organic layer, stir for 10 minutes, and then separate the organic layer again. Remove dimethyl carbonate under reduced pressure to obtain N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea. 3) Preparation of (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid Add an appropriate amount of ethanol to the N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea obtained in step 2), stir, and then add an appropriate amount of potassium glycine. The reaction vessel is then heated to 60°C, and a catalyst is added. The reaction vessel is then heated further to 68-78°C. After the reaction is complete, the catalyst is filtered off while hot. The solution is then concentrated to dryness, and the residue is dissolved in a 1% potassium hydroxide aqueous solution. The resulting solution is then extracted three times with dichloromethane (397.5 g each time). After the dichloromethane is separated, the solution is neutralized with a 5% hydrochloric acid solution. When the pH reaches 7, a large amount of precipitate will appear in the reaction vessel. This precipitate is separated by filtration. The filter cake is washed twice with water and then transferred to a new reaction vessel. An appropriate amount of ethanol is added to the new vessel, and the reaction vessel containing the filter cake is heated to 75-78°C and stirred for 1 hour. Then, the temperature is lowered to 20-25°C, and the mixture is centrifuged. The filter cake is washed twice with ethanol and then vacuum dried to obtain 53.2 g of (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid with a purity of 99.1%. The total yield of steps 2) and 3) is 81%.

[0009] In step 1), the mass ratio of 4-cyanophenyl isothiocyanate to cyclooctylamine is 1:0.5~1.

[0010] In step 1), the mass ratio of 4-cyanophenyl isothiocyanate to toluene used to dissolve 4-cyanophenyl isothiocyanate is 1:6~9, and the mass ratio of 4-cyanophenyl isothiocyanate to toluene used to wash the filter cake is 1:1.5~2.

[0011] In step 1), the addition of cyclooctylamine and the separation of the filter cake and filtrate are all carried out under nitrogen protection, and the filter cake is dried by blowing nitrogen.

[0012] In step 2), the mass ratio of N-cyclooctyl-N'-(4-cyanophenyl)thiourea to dimethyl sulfate is 1:0.2~0.7, and the mass ratio of N-cyclooctyl-N'-(4-cyanophenyl)thiourea to dimethyl carbonate is 1:4~7.

[0013] In step 2), the sodium hydroxide aqueous solution is a 5% sodium hydroxide aqueous solution, and the mass ratio of N-cyclooctyl-N'-(4-cyanophenyl)thiourea to the sodium hydroxide aqueous solution is 1:4~7.

[0014] In step 3), the mass ratio of ethanol to N-cyclooctyl-N'-(4-cyanophenyl)thiourea is 6~10:1, and the mass ratio of potassium glycine to N-cyclooctyl-N'-(4-cyanophenyl)thiourea is 0.4~0.7:1.

[0015] The catalyst added in step 3) is Raney nickel, and the mass ratio of Raney nickel to N-cyclooctyl-N'-(4-cyanophenyl)thiourea is 0.02~0.03:1.

[0016] In step 3), the mass ratio of 1% potassium hydroxide aqueous solution to N-cyclooctyl-N'-(4-cyanophenyl)thiourea is 7~9:1.

[0017] Compared with the prior art, the beneficial effects of the present invention are: 1. In this invention, the urea-forming solvent is replaced with toluene instead of 95% ethanol, which not only effectively improves the product yield, but also allows the replaced solvent to be used continuously without further treatment; 2. The solvent for methylation is improved by using environmentally friendly dimethyl carbonate. The improved methylation method has a shorter production time and is easier to neutralize to obtain S-methylisothiourea. 3. Using Raney nickel as a catalyst in the condensation reaction makes it easier for the methanethiol in S-methylisothiourea to be converted and removed, thereby shortening the reaction time and effectively improving the overall yield of the two steps. Attached Figure Description

[0018] Figure 1 The liquid phase diagram is shown for ((E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid obtained in Example 1 of the present invention.

[0019] Figure 2 The liquid phase diagram is shown for ((E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid obtained in Example 2 of the present invention.

[0020] Figure 3 This is a liquid phase diagram of ((E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid obtained in Example 3 of the present invention. Detailed Implementation Example 1

[0021] A method for synthesizing ((E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid, comprising the following steps: 1) Preparation of N-cyclooctyl-N'-(4-cyanophenyl)thiourea Take 48g (0.3mol) of 4-cyanophenyl isothiocyanate and add 400ml of toluene to the reaction vessel. Then dissolve the 4-cyanophenyl isothiocyanate in the toluene. Under nitrogen protection and at room temperature, add 38.1g (0.3mol) of cyclooctylamine dropwise while stirring for 40 minutes. After the addition is complete, heat the reaction vessel to 60-70℃ to react. After reacting for 2 hours, cool it to 20-25℃. Then filter the filtrate and filter cake in the reaction vessel under nitrogen protection. Wash the separated filter cake with 100ml of toluene. Then combine the washed toluene and filtrate. The combined filtrate can be used to dissolve 4-cyanophenyl isothiocyanate for reuse. Dry the filter cake with nitrogen and weigh it to obtain 82.6g of N-cyclooctyl-N'-(4-cyanophenyl)thiourea, with a yield of 96%.

[0022] 2) Preparation of N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea Weigh 57.4 g (0.2 mol) of N-cyclooctyl-N'-(4-cyanophenyl)thiourea obtained in step 1), and add 300 ml of dimethyl carbonate to another reaction vessel. Then dissolve the weighed N-cyclooctyl-N'-(4-cyanophenyl)thiourea in the dimethyl carbonate. Next, add 25.2 g (0.2 mol) of dimethyl sulfate to the reaction vessel and heat the reaction vessel to 85-92°C for 2 hours to complete the reaction. Then cool the vessel to 10-15°C, add 320 ml of 5% sodium hydroxide aqueous solution and stir for 10 minutes. Let it stand to separate the organic layer. Then add 300 ml of saturated brine to the organic layer, stir for 10 minutes, and separate the organic layer again. Remove the dimethyl carbonate under reduced pressure to obtain N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea for the next step.

[0023] 3) Preparation of (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid Add 600 ml of ethanol to the N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea obtained in step 2), stir, and then add 30 g (0.27 mol) of potassium glycine. Then heat the reaction vessel to 60 °C and add 1.5 g of Raney nickel catalyst. Continue heating the reaction vessel to 68-78 °C and react for 5 hours. Filter off the catalyst while hot, then concentrate the solution to dryness and dissolve the residue in 500 ml of ethanol. The solution was extracted three times with 397.5 g of dichloromethane from a 1% potassium hydroxide aqueous solution. After extraction, the dichloromethane was separated (the solution was allowed to stand for 20-60 minutes, during which time the layers separated, with the heavier components at the bottom). The solution was then neutralized to pH 7 with 5% hydrochloric acid solution. A large amount of precipitate appeared in the reaction vessel, which was separated by filtration. The filter cake was washed twice with 100 ml of water each time. The filter cake was then transferred to a new reaction vessel, and 300 ml of ethanol was added. The reaction vessel containing the filter cake was heated to 75-78°C and stirred for 1 hour. The temperature was then lowered to 20-25°C, and the mixture was centrifuged. The filter cake was washed twice with 50 ml of ethanol each time and then vacuum dried to obtain 53.2 g of (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid with a purity of 99.1%. The total yield of steps 2) and 3) was 81%.

[0024] In this invention, the urea-forming solvent was changed from 95% ethanol to toluene, increasing the yield from 77% to 96%, and the solvent can be used continuously without further treatment. The methylation solvent was improved to use environmentally friendly dimethyl carbonate, which is easily neutralized after methylation, facilitating industrial processing. The improved methylation method has a shorter production time and is easier to neutralize to obtain S-methylisothiourea. Raney nickel was used as a catalyst in the condensation reaction, making it easier to convert and remove the methanethiol in S-methylisothiourea, thereby accelerating the reaction rate. The reaction time was reduced from 10 hours to 5 hours, and the overall yield of the two steps increased from 68.8% to 81%. Example 2

[0025] A method for synthesizing ((E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid, comprising the following steps: 1) Preparation of N-cyclooctyl-N'-(4-cyanophenyl)thiourea Take 48g (0.3mol) of 4-cyanophenyl isothiocyanate and add 400ml of toluene to the reaction vessel. Then dissolve the 4-cyanophenyl isothiocyanate in the toluene. Under nitrogen protection and at room temperature, add 44.45g (0.35mol) of cyclooctylamine dropwise while stirring for 40 minutes. After the addition is complete, heat the reaction vessel to 60-70℃ to react. After reacting for 2 hours, cool it to 20-25℃. Then filter the filtrate and filter cake in the reaction vessel under nitrogen protection. Wash the separated filter cake with 100ml of toluene. Then combine the washed toluene and filtrate. The combined filtrate can be used to dissolve 4-cyanophenyl isothiocyanate for reuse. Dry the filter cake with nitrogen and weigh it to obtain 83.4g of N-cyclooctyl-N'-(4-cyanophenyl)thiourea, with a yield of 97%.

[0026] 2) Preparation of N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea Weigh 57.4 g (0.2 mol) of N-cyclooctyl-N'-(4-cyanophenyl)thiourea obtained in step 1), and add 300 ml of dimethyl carbonate to another reaction vessel. Then dissolve the weighed N-cyclooctyl-N'-(4-cyanophenyl)thiourea in the dimethyl carbonate. Next, add 37.8 g (0.3 mol) of dimethyl sulfate to the reaction vessel and heat the reaction vessel to 85-92°C for 2 hours to complete the reaction. Then cool the vessel to 10-15°C, add 320 ml of 5% sodium hydroxide aqueous solution and stir for 10 minutes. Let it stand to separate the organic layer. Then add 300 ml of saturated brine to the organic layer, stir for 10 minutes, and separate the organic layer again. Remove the dimethyl carbonate under reduced pressure to obtain N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea for the next step.

[0027] 3) Preparation of (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid Add 600 ml of ethanol to the N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea obtained in step 2), stir, and then add 30 g (0.27 mol) of potassium glycine. Then heat the reaction vessel to 60 °C and add 1.5 g of Raney nickel catalyst. Continue heating the reaction vessel to 68-78 °C and react for 5 hours. Filter off the catalyst while hot, then concentrate the solution to dryness and dissolve the residue in 500 ml of ethanol. The solution was extracted three times with 397.5 g of dichloromethane from a 1% potassium hydroxide aqueous solution. After extraction, the dichloromethane was separated (the solution was allowed to stand for 20-60 minutes, during which time the layers were separated, with the heavier components at the bottom). The solution was then neutralized to pH 7 with 5% hydrochloric acid solution. A large amount of precipitate appeared in the reaction vessel, which was separated by filtration. The filter cake was washed twice with 100 ml of water each time. The filter cake was then transferred to a new reaction vessel, and 300 ml of ethanol was added. The reaction vessel containing the filter cake was heated to 75-78°C and stirred for 1 hour. The temperature was then lowered to 20-25°C and centrifuged. The filter cake was washed twice with 50 ml of ethanol each time and then vacuum dried to obtain 54.7 g of (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamate)-2-aminoacetic acid with a purity of 99.2%. The total yield of steps 2) and 3) was 83%.

[0028] In this invention, the urea-forming solvent was changed from 95% ethanol to toluene, increasing the yield from 77% to 97%, and the solvent can be used continuously without further treatment. The methylation solvent was improved to use environmentally friendly dimethyl carbonate, which is easily neutralized after methylation, facilitating industrial processing. The improved methylation method has a shorter production time and is easier to neutralize to obtain S-methylisothiourea. Raney nickel was used as a catalyst in the condensation reaction, making it easier to convert and remove the methanethiol in S-methylisothiourea, thereby accelerating the reaction rate. The reaction time was reduced from 10 hours to 5 hours, and the overall yield of the two steps increased from 68.8% to 83%. Example 3

[0029] A method for synthesizing ((E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid, comprising the following steps: 1) Preparation of N-cyclooctyl-N'-(4-cyanophenyl)thiourea Take 48g (0.3mol) of 4-cyanophenyl isothiocyanate and add 400ml of toluene to the reaction vessel. Then dissolve the 4-cyanophenyl isothiocyanate in the toluene. Under nitrogen protection and at room temperature, add 38.1g (0.3mol) of cyclooctylamine dropwise while stirring for 40 minutes. After the addition is complete, heat the reaction vessel to 60-70℃ to react. After reacting for 2 hours, cool it to 20-25℃. Then filter the filtrate and filter cake in the reaction vessel under nitrogen protection. Wash the separated filter cake with 100ml of toluene. Then combine the washed toluene and filtrate. The combined filtrate can be used to dissolve 4-cyanophenyl isothiocyanate for reuse. Dry the filter cake with nitrogen and weigh it to obtain 82.6g of N-cyclooctyl-N'-(4-cyanophenyl)thiourea, with a yield of 96%.

[0030] 2) Preparation of N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea Weigh 57.4 g (0.2 mol) of N-cyclooctyl-N'-(4-cyanophenyl)thiourea obtained in step 1), and add 300 ml of dimethyl carbonate to another reaction vessel. Then dissolve the weighed N-cyclooctyl-N'-(4-cyanophenyl)thiourea in the dimethyl carbonate. Next, add 25.2 g (0.2 mol) of dimethyl sulfate to the reaction vessel and heat the reaction vessel to 85-92°C for 2 hours to complete the reaction. Then cool the vessel to 10-15°C, add 320 ml of 5% sodium hydroxide aqueous solution and stir for 10 minutes. Let it stand to separate the organic layer. Then add 300 ml of saturated brine to the organic layer, stir for 10 minutes, and separate the organic layer again. Remove the dimethyl carbonate under reduced pressure to obtain N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea for the next step.

[0031] 3) Preparation of (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid Add 600 ml of ethanol to the N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea obtained in step 2), stir, and then add 40 g (0.35 mol) of potassium glycine. Then heat the reaction vessel to 60 °C and add 1.5 g of Raney nickel catalyst. Continue heating the reaction vessel to 68-78 °C and react for 5 hours. Filter off the catalyst while hot, then concentrate the solution to dryness and dissolve the residue in 500 ml of ethanol. The solution was extracted three times with 397.5 g of dichloromethane from a 1% potassium hydroxide aqueous solution. After extraction, the dichloromethane was separated (the solution was allowed to stand for 20-60 minutes, during which time the layers were separated, with the heavier components at the bottom). The solution was then neutralized to pH 7 with 5% hydrochloric acid solution. A large amount of precipitate appeared in the reaction vessel, which was separated by filtration. The filter cake was washed twice with 100 ml of water each time. The filter cake was then transferred to a new reaction vessel, and 300 ml of ethanol was added. The reaction vessel containing the filter cake was heated to 75-78°C and stirred for 1 hour. The temperature was then lowered to 20-25°C and centrifuged. The filter cake was washed twice with 50 ml of ethanol each time and then vacuum dried to obtain 54.2 g of (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid with a purity of 98.7%. The total yield of steps 2) and 3) was 83%.

[0032] In this invention, the urea-forming solvent was changed from 95% ethanol to toluene, increasing the yield from 77% to 96%, and the solvent can be used continuously without further treatment. The methylation solvent was improved to use environmentally friendly dimethyl carbonate, which is easily neutralized after methylation, facilitating industrial processing. The improved methylation method has a shorter production time and is easier to neutralize to obtain S-methylisothiourea. Raney nickel was used as a catalyst in the condensation reaction, making it easier to convert and remove the methanethiol in S-methylisothiourea, thereby accelerating the reaction rate. The reaction time was reduced from 10 hours to 5 hours, and the overall yield of the two steps increased from 68.8% to 83%.

[0033] Unless otherwise defined, the technical or scientific terms used herein should be understood in their ordinary sense as would be understood by one of ordinary skill in the art to which this invention pertains. The use of terms such as "a" or "an" in this specification and claims does not necessarily indicate a limitation of quantity. Terms such as "comprising" or "including" mean that the element or object preceding the word encompasses the element or object listed following the word and its equivalents, without excluding other elements or objects. Terms such as "connected" or "linked" are not limited to physical or mechanical connections, but can include electrical connections, whether direct or indirect.

[0034] The exemplary embodiments of the present invention have been described in detail above with reference to preferred embodiments. However, those skilled in the art will understand that various modifications and alterations can be made to the above specific embodiments without departing from the concept of the present invention, and various combinations can be made to the various technical features and structures proposed in the present invention without exceeding the protection scope of the present invention.

Claims

1. A method for synthesizing (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid, characterized in that, Includes the following steps: 1) Preparation of N-cyclooctyl-N'-(4-cyanophenyl)thiourea Take a certain amount of 4-cyanophenyl isothiocyanate and add an appropriate amount of toluene to the reaction vessel. Then, dissolve the 4-cyanophenyl isothiocyanate in the toluene. Then, under room temperature conditions, add an appropriate amount of cyclooctylamine dropwise while stirring. Then, heat the reaction vessel to 60~70℃ for reaction. After the reaction is completed, cool it to 20~25℃. Then, separate the filtrate and filter cake in the reaction vessel. Wash the separated filter cake with toluene. Then, combine the washed toluene and filtrate. The combined filtrate can be used to dissolve 4-cyanophenyl isothiocyanate. After drying the filter cake, N-cyclooctyl-N'-(4-cyanophenyl)thiourea can be obtained. 2) Preparation of N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea Weigh a certain amount of N-cyclooctyl-N'-(4-cyanophenyl)thiourea obtained in step 1), and add an appropriate amount of dimethyl carbonate to another reaction vessel. Then dissolve the weighed N-cyclooctyl-N'-(4-cyanophenyl)thiourea in dimethyl carbonate. Then add an appropriate amount of dimethyl sulfate to the reaction vessel and heat the reaction vessel to 85~92℃ for reaction. After the reaction is completed, cool it down to 10~15℃, then add sodium hydroxide aqueous solution and stir. Then let it stand to separate the organic layer. Then add an appropriate amount of saturated brine to the organic layer, stir for 10 minutes, and then separate the organic layer again. Remove dimethyl carbonate under reduced pressure to obtain N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea. 3) Preparation of (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid Add an appropriate amount of ethanol to the N-cyclooctyl-N'-(4-cyanophenyl)-S-methylisothiourea obtained in step 2), stir, and then add an appropriate amount of potassium glycine. The reaction vessel is then heated to 60°C, and a catalyst is added. The reaction vessel is then heated further to 68-78°C. After the reaction is complete, the catalyst is filtered off while hot. The solution is then concentrated to dryness, and the residue is dissolved in a 1% potassium hydroxide aqueous solution. The resulting solution is then extracted with dichloromethane, 397.5 g each time, for three extractions. The dichloromethane is then separated. The above solution was then neutralized to pH 7 with 5% hydrochloric acid solution. A large amount of precipitate appeared in the reaction vessel. It was separated by filtration. The filter cake was washed twice with water. The filter cake was then transferred to a new reaction vessel and an appropriate amount of ethanol was added. The reaction vessel containing the filter cake was heated to 75-78°C and stirred for 1 hour. Then it was cooled to 20-25°C and centrifuged. The filter cake was washed twice with ethanol and vacuum dried to obtain (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid. The catalyst added in step 3) is Raney nickel, and the mass ratio of Raney nickel to N-cyclooctyl-N'-(4-cyanophenyl)thiourea is 0.02~0.03:

1.

2. The method for synthesizing (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid as described in claim 1, characterized in that: In step 1), the mass ratio of 4-cyanophenyl isothiocyanate to cyclooctylamine is 1:0.5~1.

3. The method for synthesizing (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid as described in claim 1, characterized in that: In step 1), the mass ratio of 4-cyanophenyl isothiocyanate to toluene used to dissolve 4-cyanophenyl isothiocyanate is 1:6~9, and the mass ratio of 4-cyanophenyl isothiocyanate to toluene used to wash the filter cake is 1:1.5~2.

4. The method for synthesizing (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid as described in claim 1, characterized in that: In step 1), the addition of cyclooctylamine and the separation of the filter cake and filtrate are all carried out under nitrogen protection, and the filter cake is dried by blowing with nitrogen.

5. The method for synthesizing (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid as described in claim 1, characterized in that: In step 2), the mass ratio of N-cyclooctyl-N'-(4-cyanophenyl)thiourea to dimethyl sulfate is 1:0.2~0.7, and the mass ratio of N-cyclooctyl-N'-(4-cyanophenyl)thiourea to dimethyl carbonate is 1:4~7.

6. The method for synthesizing (E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid as described in claim 1, characterized in that: In step 2), the sodium hydroxide aqueous solution is a 5% sodium hydroxide aqueous solution, and the mass ratio of N-cyclooctyl-N'-(4-cyanophenyl)thiourea to the sodium hydroxide aqueous solution is 1:4~7.

7. The method for synthesizing (E)-(N'-(4-cyanophenyl)-N-cyclooctylcarbamoyl)-2-aminoacetic acid as described in claim 1, characterized in that: In step 3), the mass ratio of ethanol to N-cyclooctyl-N'-(4-cyanophenyl)thiourea is 6~10:1, and the mass ratio of potassium glycine to N-cyclooctyl-N'-(4-cyanophenyl)thiourea is 0.4~0.7:

1.

8. The method for synthesizing ((E)-(N'-(4-cyanophenyl)-N-cyclooctylaminocarbamoyl)-2-aminoacetic acid as described in claim 1, characterized in that: In step 3), the mass ratio of 1% potassium hydroxide aqueous solution to N-cyclooctyl-N'-(4-cyanophenyl)thiourea is 7~9:1.

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