Methionine and preparation method thereof

Abstract

The invention relates to the technical field of synthesis of organic chemicals, in particular to methionine and a preparation method thereof. The preparation method of methionine provided by the invention comprises the following steps: (1) dissolving isonitrile acetate in an aprotic solvent to form a first solution, adding a non-nucleophilic strong base into the first solution for reaction, and then adding 2-halogenated ethyl methyl sulfide for reaction to obtain a reaction solution containing 2-isocyan-4-(methylthio) butyrate; (2) adding an ammonium salt of an acid and an alcohol solvent into the reaction solution of the 2-isocyanato-4-(methylthio) butyrate obtained in the step (1), and reacting to obtain a 2-amino-4-(methylthio) butyrate solution; and (3) adding alkali into the 2-amino-4-(methylthio) butyrate solution obtained in the step (2) to carry out saponification reaction, and then adjusting the pH value to 5-7 to obtain methionine. The preparation method provided by the invention avoids the use of high-toxicity reagents, and the reaction is safer.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, specifically to a methionine and its preparation method. Background Technology

[0002] Methionine is an essential sulfur-containing amino acid that plays a vital role in the diets of humans and animals. Currently, the industrial production of DL-methionine mainly employs chemical synthesis methods, with the hydantoin process being the most widely used technology.

[0003] For example, in CN103764240B, this process typically uses acrolein, methanethiol, and highly toxic hydrogen cyanide (HCN) as starting materials. Methanethiol-cyanohydrin (MMP-CN) is synthesized from 3-methylthiopropionaldehyde and hydrogen cyanide. Methanethiol-cyanohydrin reacts with ammonia and CO2 to synthesize 5-(2-methylthioethyl)-hydantoin (hydantoin). Hydantoin is then hydrolyzed, acidified, and crystallized to obtain methionine.

[0004] This traditional method also has many significant limitations, and its reliance on highly toxic chemicals such as hydrogen cyanide, acrolein, and methanethiol poses serious safety hazards and environmental risks.

[0005] There is an urgent need in the existing technology for a green, safe, and high-yield method for preparing methionine. Summary of the Invention

[0006] This invention provides a methionine and its preparation method to solve the problem of the urgent need for a green, safe, and high-yield method for preparing methionine in the prior art.

[0007] In a first aspect, the present invention provides a method for preparing methionine, comprising the following steps: (1) Under the action of a non-nucleophilic strong base, isonitrile acetate and 2-haloethyl methyl sulfide were subjected to C-alkylation reaction in an aprotic solvent to obtain a reaction solution containing 2-isocyano-4-(methyl thio)butyrate. (2) Add an ammonium salt of acid and an alcohol solvent to the reaction solution of 2-isocyano-4-(methylthio)butyrate obtained in step (1) to react, wherein the isocyanate undergoes ammonolysis reaction, and thus a 2-amino-4-(methylthio)butyrate solution is obtained. (3) After adding alkali to the 2-amino-4-(methylthio)butyrate solution obtained in step (2) to carry out saponification reaction, the pH is adjusted to 5-7 to obtain methionine.

[0008] The exemplary main reaction pathway in steps (1)-(3) of the methionine preparation method provided by this invention is as follows: Step (1)

[0009] Step (2)

[0010] Step (3)

[0012] In one alternative embodiment, the nonnucleophilic strong base is added to the first solution in the form of a nonnucleophilic strong base solution; In one optional embodiment, the concentration of the nonnucleophilic strong base in the nonnucleophilic strong base solution is 1-3 mol / L; In one optional embodiment, the process of adding the non-nucleophilic strong base solution to the first solution is dropwise addition; In one optional embodiment, the system temperature is -10 to 10°C during the addition of the non-nucleophilic strong base solution to the first solution; In one optional embodiment, the molar ratio of the non-nucleophilic strong base to isonitrile acetate is (1-1.5):1; In one optional embodiment, the molar ratio of the non-nucleophilic strong base to isonitrile acetate is (1-1.1):1; In one optional embodiment, the solvent in the non-nucleophilic strong base solution is selected from aprotic solvents; In one optional embodiment, the solvent in the non-nucleophilic strong base solution is selected from tetrahydrofuran; In one alternative embodiment, the reaction time for adding a non-nucleophilic strong base to the first solution is 20-40 min; In one alternative embodiment, the temperature at which a non-nucleophilic strong base is added to the first solution for reaction is -20 to 10°C.

[0013] In one optional embodiment, the 2-haloethyl methyl sulfide is added dropwise; In one optional embodiment, the temperature for adding 2-haloethyl methyl sulfide is -20 to 5°C, preferably -10 to 0°C. In one optional embodiment, the C-alkylation reaction is carried out at a temperature of 0-50°C for 2-12 hours. In one optional embodiment, the C-alkylation reaction is carried out at a temperature of 15-25°C; In one optional embodiment, the C-alkylation reaction time is 4-8 hours; In one optional embodiment, the molar ratio of the 2-haloethyl methyl sulfide to the isonitrile acetate is (1-1.5):1; In one optional embodiment, the molar ratio of the 2-haloethyl methyl sulfide to the isonitrile acetate is (1-1.1):1; In one alternative embodiment, the concentration of the isonitrile acetate in the first solution is 0.3-2 mol / L.

[0014] In one alternative embodiment, the 2-haloethyl methyl sulfide is selected from at least one of 2-bromoethyl methyl sulfide and 2-chloroethyl methyl sulfide. In one optional embodiment, the isonitrile acetate is selected from at least one of isonitrile methyl acetate or isonitrile ethyl acetate; In one optional embodiment, the nonnucleophilic strong base is selected from at least one of sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, and potassium tert-butoxide. In one alternative embodiment, the aprotic polar solvent is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0015] In one optional embodiment, the reaction temperature in step (2) is 40-120°C and the reaction time is 3-8 hours; In one optional embodiment, the reaction temperature in step (2) is 60-100°C and the reaction time is 3-5 hours.

[0016] In one optional embodiment, the molar ratio of the amount of ammonium salt of acid added to that of isonitrile acetate in step (1) is (2-10):1; In one optional embodiment, the ratio of alcohol solvent to isonitrile acetate is (0.3-1) L: 1 mol.

[0017] In one optional embodiment, the ammonium salt of the acid is selected from at least one of ammonium formate and ammonium acetate; In one alternative embodiment, the alcohol solvent is selected from at least one of methanol and ethanol.

[0018] In one optional embodiment, in step (3), the molar ratio of the amount of alkali added to the molar ratio of the amount of isonitrile acetate in step (1) is (2-4):1; In one optional embodiment, the molar ratio of the added base to the molar ratio of the isonitrile acetate in step (1) is (2-2.5):1; In one optional embodiment, the alkali is selected from alkali metal hydroxides, preferably at least one of sodium hydroxide and potassium hydroxide; In one optional embodiment, the alkali is added in the form of an aqueous alkali solution; In one optional embodiment, the concentration of alkali in the alkaline aqueous solution is 5-7 mol / L; In one alternative implementation, the pH is adjusted by at least one of carbon dioxide, hydrochloric acid, sulfuric acid, and carbonic acid.

[0019] In one optional embodiment, the temperature of step (3) is 20-100°C and the reaction time is 1-8h; In one optional embodiment, the reaction temperature in step (3) is 20-80°C and the reaction time is 2-4 hours.

[0020] In one alternative embodiment, the saponification reaction is followed by extraction, crystallization, washing, and recrystallization steps.

[0021] Secondly, the present invention also provides methionine, prepared by the preparation method described above. The technical solution of the present invention has the following advantages: The present invention provides a method for preparing methionine, comprising the following steps: (1) dissolving isonitrile acetate in an aprotic solvent to form a first solution, adding a non-nucleophilic strong base to the first solution to generate a carbanion, and then adding 2-haloethyl methyl sulfide to carry out a C-alkylation reaction to obtain a reaction solution containing 2-isocyano-4-(methyl thio)butyrate; (2) adding an ammonium salt of an acid and an alcohol solvent to the reaction solution of 2-isocyano-4-(methyl thio)butyrate obtained in step (1) to carry out a reaction, wherein the isocyanate undergoes an ammonolysis reaction to obtain an ethyl 2-amino-4-(methyl thio)butyrate solution; (3) adding an alkali to the ethyl 2-amino-4-(methyl thio)butyrate solution obtained in step (2) to carry out a saponification reaction and then adjusting the pH to 5-7 to obtain methionine.

[0022] The method for preparing methionine provided by this invention avoids the use of highly toxic reagents, making the reaction safer.

[0023] The preparation method provided by this invention achieves highly selective synthesis of the key intermediate 2-isocyano-4-(methylthio)butyrate by employing a non-nucleophilic strong base-aprotic solvent system; and in step (b), the ammonium acetate / alcohol system provides a buffer system that catalyzes the ammonolysis reaction and inhibits the hydrolysis of ester bonds and the thioether side reaction, achieving a mild and efficient conversion of isocyanate to amino group, and obtaining ethyl 2-amino-4-(methylthio)butyrate, the precursor of methionine, in high yield, and finally obtaining methionine in high yield. Detailed Implementation

[0024] The following embodiments are provided to better understand the present invention, but the following embodiments do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the scope of protection of the present invention.

[0025] Main raw material sources Unless otherwise specified, all reagents used in this invention are purchased from Inokai AR grade reagents.

[0026] Analytical methods The analytical instrument used was an Agilent 1260 high-performance liquid chromatograph (HPLC) with a C18 column. The mobile phase consisted of acetonitrile and an aqueous solution of phosphoric acid, with a volume ratio of acetonitrile to water of 95:5. The mass fraction of phosphoric acid in the aqueous solution was 1.0%. Example 1 This embodiment provides a method for preparing methionine, including the following steps: (1) Synthesis of ethyl 2-isocyano-4-(methylthio)butyrate (C-alkylation) Under argon protection, ethyl isonitrile (11.3 g, 0.1 mol) and N,N-dimethylformamide (DMF) (100 mL) were added to a 500 mL three-necked round-bottom flask equipped with a magnetic stirrer, thermometer, and constant-pressure dropping funnel. The reaction system was cooled to -20°C in an ice-salt bath. With vigorous stirring, a THF solution of sodium bis(trimethylsilyl)amino(NaHMDS) (2 M, 50 mL, 0.1 mol) was slowly added dropwise through the constant-pressure dropping funnel, controlling the dropping rate to maintain the temperature at -10°C. After the addition was complete, stirring was continued at this temperature for 30 minutes. The solution gradually turned orange-red, indicating that carbanions had been generated.

[0027] Subsequently, 17.1 g of 2-bromoethyl methyl sulfide (0.11 mol) was slowly added dropwise at -10°C. After the addition was complete, the ice bath was removed, and the reaction solution was allowed to warm naturally and maintained at 15°C, with stirring continued for 5 hours. Thin-layer chromatography (TLC, developing solvent: petroleum ether / ethyl acetate = 3 / 1) showed that the isonitrile ethyl acetate starting material had essentially disappeared, yielding the reaction solution of ethyl 2-isocyano-4-(methylthio)butyrate.

[0028] (2) Synthesis of ethyl 2-amino-4-(methylthio)butyrate (ammonolysis) Ammonium acetate (38.5 g, 0.5 mol) and anhydrous ethanol (50 mL) were directly added to the reaction solution containing ethyl 2-isocyano-4-(methylthio)butyrate obtained in step (1) above. The reaction system was heated to about 80°C and stirred for 5 hours. TLC (developing solvent: dichloromethane / methanol = 10 / 1) showed that the isocyanate compound disappeared, indicating that the reaction was complete. Heating was stopped, and the reaction solution was cooled to room temperature to obtain the ethyl 2-amino-4-(methylthio)butyrate reaction solution.

[0029] (3) Synthesis of methionine (saponification and acidification) The solution of ethyl 2-amino-4-(methylthio)butyrate obtained in step (2) above was cooled in an ice-water bath. While stirring, 35 mL of a 6 M sodium hydroxide aqueous solution was slowly added dropwise, controlling the dropping rate to prevent excessive temperature. After the addition was complete, the ice bath was removed, and the reaction solution was heated to 80°C and stirred for 3 hours to carry out saponification. After saponification was completed, the reaction solution was cooled back to room temperature.

[0030] The saponification liquid was subjected to liquid chromatography analysis, and the total yield of methionine was determined to be 92.4% (molar yield) by external standard method.

[0031] While stirring, CO2 gas is slowly introduced, and the pH is monitored using precision pH paper or a pH meter until the pH of the aqueous phase reaches 5-6 (near the isoelectric point of methionine). At this point, a large amount of white solid precipitates. The mixture is then further cooled and aged in an ice-water bath for 1 hour. The mixture is then filtered, and the filter cake is washed several times with a small amount of ice water to remove residual inorganic salts. The resulting white solid is placed in a vacuum drying oven and dried at 50°C for 6 hours to obtain a white to light yellow crystalline solid, which is the target product, methionine.

[0032] The product was identified as methionine by ¹H NMR: 400 MHz, D₂O: δ 2.10 (s, 3H), 2.15–2.32 (m, 2H), 2.52–2.73 (m, 2H), 3.65–3.92 (m, 1H).

[0033] Example 2 This embodiment provides a method for preparing methionine, including the following steps: (1) Synthesis of methyl 2-isocyano-4-(methylthio)butyrate (C-alkylation) Under argon protection, methyl isonitrile acetate (9.9 g, 0.1 mol) and dimethyl sulfoxide (DMSO) (50 mL) were added to a 500 mL three-necked round-bottom flask equipped with a magnetic stirrer, thermometer, and constant-pressure dropping funnel. The reaction system was cooled to -20°C in an ice-salt bath. With vigorous stirring, a THF solution of potassium bis(trimethylsilyl)amino(KHMDS) (1 M, 105 mL, 0.105 mol) was slowly added dropwise through the constant-pressure dropping funnel, controlling the dropping rate to maintain the temperature at -5°C. After the addition was complete, stirring was continued at this temperature for 30 minutes, until the solution gradually turned orange-red, indicating the formation of carbanions. Subsequently, 2-bromoethylmethyl sulfide (16.3 g, 0.105 mol) was slowly added dropwise at -5°C. After the addition was complete, the ice bath was removed, and the reaction solution was allowed to warm naturally and maintained at 20°C, with stirring continued for 7 hours. Thin-layer chromatography (TLC, developing solvent: petroleum ether / ethyl acetate = 3 / 1) showed that the isonitrile acetate raw material was basically lost, yielding the methyl 2-isocyano-4-(methylthio)butyrate reaction solution. (2) Synthesis of methyl 2-amino-4-(methylthio)butyrate (ammonolysis) Ammonium formate (63.1 g, 1 mol) and anhydrous methanol (100 mL) were directly added to the reaction solution containing methyl 2-isocyano-4-(methylthio)butyrate obtained in step (1) above. The reaction mixture was heated to approximately 70 °C and stirred for 8 hours. TLC (evolving solvent: dichloromethane / methanol = 10 / 1) showed that the isocyanate compound disappeared, indicating that the reaction was complete. Heating was stopped, and the reaction solution was cooled to room temperature to obtain the methyl 2-amino-4-(methylthio)butyrate reaction solution.

[0034] (3) Synthesis of methionine (saponification and acidification) The solution of methyl 2-amino-4-(methylthio)butyrate obtained in step (2) above was cooled in an ice-water bath. While stirring, 40 mL of potassium hydroxide aqueous solution (6 M) was slowly added dropwise, controlling the dropping rate to prevent the temperature from becoming too high. After the addition was complete, the ice bath was removed, and the reaction solution was heated to 80°C and stirred for 3 hours to carry out saponification. After saponification was completed, the reaction solution was cooled back to room temperature.

[0035] The saponification solution was analyzed by liquid chromatography, and the total yield of methionine was determined to be 91.2% (molar yield) by external standard method.

[0036] While stirring, slowly add dilute hydrochloric acid (1M), monitoring with precision pH paper or a pH meter, until the pH of the aqueous phase is 5-6 (near the isoelectric point of methionine). At this point, a large amount of white solid precipitates. Continue cooling and aging the mixture in an ice-water bath for 1 hour. Filter, and wash the filter cake several times with a small amount of ice water to remove residual inorganic salts. Place the resulting white solid in a vacuum drying oven and dry at 50°C for 6 hours to obtain a white to light yellow crystalline solid, which is the target product, methionine.

[0037] The product was identified as methionine by ¹H NMR: 400 MHz, D₂O: δ 2.10 (s, 3H), 2.15–2.32 (m, 2H), 2.52–2.73 (m, 2H), 3.65–3.92 (m, 1H).

[0038] Example 3 This embodiment provides a method for preparing methionine, including the following steps: (1) Synthesis of ethyl 2-isocyano-4-(methylthio)butyrate (C-alkylation) Under argon protection, ethyl isonitrile (11.3 g, 0.1 mol) and N-methylpyrrolidone (NMP) (200 mL) were added to a 500 mL three-necked round-bottom flask equipped with a magnetic stirrer, thermometer, and constant-pressure dropping funnel. The reaction system was cooled to -20°C in an ice-salt bath. Potassium tert-butoxide (t-BuOK) (11.2 g, 0.1 mol) was slowly added with vigorous stirring, maintaining the addition rate at 0°C. After the addition was complete, stirring was continued at this temperature for 30 minutes, during which the solution gradually turned orange-red, indicating the formation of carbanions. Subsequently, 2-chloroethyl methyl sulfide (11.1 g, 0.1 mol) was slowly added dropwise at 0°C. After the addition was complete, the ice bath was removed, and the reaction solution was allowed to warm naturally and maintained at 25°C, with stirring continued for 8 hours. Thin-layer chromatography (TLC, developing solvent: petroleum ether / ethyl acetate = 3 / 1) showed that the isonitrile ethyl acetate raw material had basically disappeared, yielding the ethyl 2-isocyano-4-(methylthio)butyrate reaction solution.

[0039] (2) Synthesis of ethyl 2-amino-4-(methylthio)butyrate (ammonolysis) Ammonium acetate (61.7 g, 0.8 mol) and anhydrous ethanol (50 mL) were directly added to the reaction solution containing ethyl 2-isocyano-4-(methylthio)butyrate obtained in step (1) above. The reaction mixture was heated to 100 °C and stirred for 3 hours. TLC (evolving solvent: dichloromethane / methanol = 10 / 1) showed that the isocyanate compound disappeared, indicating that the reaction was complete. Heating was stopped, and the reaction solution was cooled to room temperature to obtain the ethyl 2-amino-4-(methylthio)butyrate reaction solution.

[0040] (3) Synthesis of methionine (saponification and acidification) The solution of ethyl 2-amino-4-(methylthio)butyrate obtained in step (2) above was cooled in an ice-water bath. While stirring, 37 mL of a 6 M sodium hydroxide aqueous solution was slowly added dropwise, controlling the dropping rate to prevent excessive temperature. After the addition was complete, the ice bath was removed, and the reaction solution was heated to 80°C and stirred for 3 hours to carry out saponification. After saponification was completed, the reaction solution was cooled back to room temperature.

[0041] The saponification liquid was subjected to liquid chromatography analysis, and the total yield of methionine was determined to be 90.5% (molar yield) by external standard method.

[0042] While stirring, CO2 gas is slowly introduced, and the pH is monitored using precision pH paper or a pH meter until the pH of the aqueous phase reaches 5-6 (near the isoelectric point of methionine). At this point, a large amount of white solid precipitates. The mixture is then further cooled and aged in an ice-water bath for 1 hour. The mixture is then filtered, and the filter cake is washed several times with a small amount of ice water to remove residual inorganic salts. The resulting white solid is placed in a vacuum drying oven and dried at 50°C for 6 hours to obtain a white to light yellow crystalline solid, which is the target product, methionine.

[0043] The product was identified as methionine by ¹H NMR: 400 MHz, D₂O: δ 2.10 (s, 3H), 2.15–2.32 (m, 2H), 2.52–2.73 (m, 2H), 3.65–3.92 (m, 1H).

[0044] Comparative Example 1 Methionine was prepared from ethyl isonitrile and 2-bromoethyl methyl sulfide according to the method of Example 1, except that sodium bis(trimethylsilyl)amino (NaHMDS) was replaced with an equimolar amount of sodium hydroxide, while other operations and parameters remained unchanged; the yield of methionine was 53.7% (molar yield) as determined by liquid chromatography.

[0045] Comparative Example 2 Methionine was prepared from ethyl isonitrile and 2-bromoethyl methyl sulfide according to the method of Example 1, except that the solvent DMF was replaced with an equal amount of ethanol, while other operations and parameters remained unchanged; the yield of methionine was 61.5% (molar yield) as determined by liquid chromatography.

[0046] Comparative Example 3 Methionine was prepared from ethyl isonitrile and 2-bromoethyl methyl sulfide according to the method of Example 1, except that the ammonium acetate / ethanol solution was replaced with an equimolar amount of concentrated hydrochloric acid / ethanol solution, while other operations and parameters remained unchanged; the yield of methionine was 45.2% (molar yield) as determined by liquid chromatography.

[0047] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for preparing methionine, characterized in that, Includes the following steps: (1) Dissolve isonitrile acetate in an aprotic solvent to form a first solution. Add a non-nucleophilic strong base to the first solution to generate a carbanion. Then add 2-haloethyl methyl sulfide to carry out a C-alkylation reaction to obtain a reaction solution containing 2-isocyano-4-(methyl thio)butyrate. (2) Add an ammonium salt of acid and an alcohol solvent to the reaction solution of 2-isocyano-4-(methylthio)butyrate obtained in step (1) to react, wherein the isocyanate undergoes ammonolysis reaction, and thus a 2-amino-4-(methylthio)butyrate solution is obtained. (3) After adding alkali to the 2-amino-4-(methylthio)butyrate solution obtained in step (2) to carry out saponification reaction, the pH is adjusted to 5-7 to obtain methionine.

2. The preparation method according to claim 1, characterized in that, The non-nucleophilic strong base is added to the first solution in the form of a non-nucleophilic strong base solution; Preferably, the concentration of the nonnucleophilic strong base in the nonnucleophilic strong base solution is 1-3 mol / L; Preferably, the process of adding the non-nucleophilic strong base solution to the first solution is dropwise addition; Preferably, the system temperature is -10 to 10°C during the addition of the non-nucleophilic strong base solution to the first solution; Preferably, the molar ratio of the non-nucleophilic strong base to isonitrile acetate in the non-nucleophilic strong base solution is (1-1.5):1; Preferably, the molar ratio of the non-nucleophilic strong base to isonitrile acetate in the non-nucleophilic strong base solution is (1-1.1):1; Preferably, the solvent in the non-nucleophilic strong base solution is selected from aprotic solvents; Preferably, the solvent in the non-nucleophilic strong base solution is selected from tetrahydrofuran; Preferably, the reaction time for adding a non-nucleophilic strong base to the first solution is 20-40 min; Preferably, the temperature at which a non-nucleophilic strong base is added to the first solution for reaction is -20 to 10°C.

3. The preparation method according to claim 1 or 2, characterized in that, The addition of 2-haloethyl methyl sulfide is by dropwise addition; Preferably, the temperature for adding 2-haloethyl methyl sulfide is -20 to 10°C, more preferably -10 to 0°C; Preferably, the temperature of the C-alkylation reaction is 0-50℃; the reaction time is 2-12h. Preferably, the temperature for the C-alkylation reaction is 15-25°C; Preferably, the C-alkylation reaction time is 4-8 hours; Preferably, the molar ratio of the 2-haloethyl methyl sulfide to the isonitrile acetate is (1-1.5):1; Preferably, the molar ratio of the 2-haloethyl methyl sulfide to the isonitrile acetate is (1-1.1):1; Preferably, the concentration of the isonitrile acetate in the first solution is 0.3-2 mol / L.

4. The preparation method according to any one of claims 1-3, characterized in that, 2-Haloethylmethyl sulfide is selected from at least one of 2-bromoethylmethyl sulfide and 2-chloroethylmethyl sulfide; Preferably, the isonitrile acetate is selected from at least one of isonitrile methyl acetate or isonitrile ethyl acetate; Preferably, the non-nucleophilic strong base is selected from at least one of sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, and potassium tert-butoxide; Preferably, the aprotic polar solvent is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone.

5. The preparation method according to any one of claims 1-4, characterized in that, The reaction temperature in step (2) is 40-120℃, and the reaction time is 3-8h; Preferably, the reaction temperature in step (2) is 60-100℃ and the reaction time is 3-5h.

6. The preparation method according to any one of claims 1-5, characterized in that, The molar ratio of the amount of ammonium salt of acid added to that of isonitrile acetate in step (1) is (2-10):1; Preferably, the ratio of alcohol solvent to isonitrile acetate is (0.3-1) L: 1 mol.

7. The preparation method according to any one of claims 1-6, characterized in that, The ammonium salt of the acid is selected from at least one of ammonium formate and ammonium acetate; Preferably, the alcohol solvent is selected from at least one of methanol and ethanol.

8. The preparation method according to any one of claims 1-7, characterized in that, In step (3), the amount of alkali added is (2-4):1 compared to the amount of isonitrile acetate added in step (1); Preferably, the ratio of the amount of alkali added to the isonitrile acetate in step (1) is (2-2.5):1; Preferably, the alkali is selected from alkali metal hydroxides, and more preferably at least one of sodium hydroxide and potassium hydroxide; Preferably, the alkali is added in the form of an aqueous alkali solution; Preferably, the concentration of alkali in the alkaline aqueous solution is 5-7 mol / L; Preferably, the pH is adjusted by at least one of carbon dioxide, hydrochloric acid, sulfuric acid, and carbonic acid.

9. The preparation method according to any one of claims 1-8, characterized in that, The reaction temperature in step (3) is 20-100℃, and the reaction time is 1-8h; Preferably, the reaction temperature in step (3) is 20-80℃ and the reaction time is 2-4h.

10. A methionine, characterized in that, It is prepared by the preparation method according to any one of claims 1-9.

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