A process for the preparation of d,l-methionine

Abstract

The application discloses a preparation method of D,L-methionine, which comprises the following steps: mixing glycine ethyl ester hydrochloride, benzaldehyde and a solvent, heating to 40-50 DEG C, opening a negative pressure and a reflux water separation device, keeping the system outside steam by adjusting the negative pressure, and dropping triethylamine; solid-liquid separation is performed on the reaction solution, the liquid is heated to reflux, 2-chloroethyl methyl sulfide is dropped, and reflux reaction is continuously performed; the temperature of the reaction solution is reduced to less than or equal to 60 DEG C, the reflux is stopped, and hydrogen chloride gas is introduced; solid-liquid separation is performed on the reaction solution, the liquid is heated to reflux, hydrochloric acid is dropped, and reflux hydrolysis reaction is performed; the reaction solution is subjected to rotary evaporation, the remaining material is washed and dried to obtain D,L-methionine. The application adopts the mode of amino protection and removal, avoids the use of cyanide and high-temperature and high-pressure reaction, is safe and environment-friendly in the whole process, has high reaction selectivity, has few side reactions, and the by-products and the solvent are easy to separate, so that the cost is further reduced, and the industrialization popularization is facilitated.

Description

Technical Field

[0001] This invention belongs to the field of amino acid synthesis technology, specifically relating to a method for preparing D,L-methionine. Background Technology

[0002] Methionine, also known as methionine, is one of the eight essential amino acids in the human body. As the only sulfur-containing essential amino acid, methionine can effectively enhance immunity, provide antioxidant benefits, and promote animal growth, and is widely used in medicine, food, feed, cosmetics, and other fields.

[0003] Methionine is optically active and exists in both L and D configurations. However, unlike most amino acids where only the L configuration is biologically active, D-configured methionine can be automatically converted into the biologically active L configuration within the animal body. This means that both D- and L-configured methionine molecules can be absorbed and utilized by animals without the need for further L- and D-configuration separation. Methionine is an important feed additive with huge demand in both domestic and international markets. Based on these two points, chemical methods have a greater industrial advantage compared to protein hydrolysis, microbial methods, and other production methods.

[0004] Currently used chemical methods mainly include the cyanohydrin method, the hydantoin method, and the glycine ethyl ester hydrochloride method. Researchers have also made technical improvements to these methods. Patent CN112679397B discloses a method for preparing D,L-methionine, using hydrogen cyanide and 3-methylthiopropional to prepare 4-methylthio-2-hydroxybutyronitrile, which is then reacted with ammonia and CO2 to generate 5-(2-methylthioethyl)hydantoin, followed by hydrolysis, acidification, and separation to obtain methionine. Patent CN103641758B discloses another method for preparing D,L-methionine, first using hydrogen cyanide and 3-methylthiopropional to prepare 4-methylthio-2-hydroxybutyronitrile, then reacting it with ammonia under heat and pressure to generate 4-methylthio-2-aminobutyronitrile, which is then acidified with an inorganic acid to obtain methionine. Patent CN103420882B discloses a method for preparing L-methionine. Specifically, the saponified liquid after hydrolysis of 5-(2-methylthioethyl)hydantoin is acetylated, and then methionine is obtained by dissolving and separating it with an organic solvent. L-methionine is then further separated by aminotransferase and other means. In "Synthesis of Methionine by Solid-Liquid Phase Transfer Catalysis", Shi Cheng et al. introduced the preparation of methionine by reacting glycine ethyl ester hydrochloride and 2-chloroethyl methyl sulfide. The intermediate does not need to be separated. Methionine is obtained by direct mild hydrolysis with hydrochloric acid. This method first generates an aromatic imine to protect the amino group, and then introduces a β-methylthioethyl group by taking advantage of the reactivity of the α-hydrogen atom of the imine. Finally, methionine is obtained by hydrolysis with a yield of 73.8% (Chemical Engineer, 1999, (2): 5~6).

[0005] These research findings indicate that current research focuses on routes using hydrogen cyanide or cyanide as raw materials, employing the cyanohydrin or hydantoin process to first add sulfhydryl groups followed by amino substitution. This route boasts a relatively mature production process and high capacity, but the high-temperature and high-pressure reaction conditions during production reduce its inherent safety, especially when using highly toxic cyanide. In the event of leaks or explosions, severe secondary disasters could occur, posing a serious threat and damage to both safety and the environment. Summary of the Invention

[0006] To address the issues of low safety and low yield in the preparation of methionine using existing technologies, this invention provides a method for preparing D,L-methionine that exhibits high reaction selectivity, fewer side reactions, and easy separation of byproducts and solvents, thereby further reducing production costs and facilitating industrial-scale application.

[0007] This invention is achieved through the following technical solution:

[0008] A method for preparing D,L-methionine includes the following steps:

[0009] (1) Mix glycine ethyl ester hydrochloride, benzaldehyde and solvent, heat to 40~50℃, turn on the negative pressure and reflux water separation device, and keep the system externally evaporated by adjusting the negative pressure. Add triethylamine dropwise. After the addition is completed, the externally evaporated liquid is separated into water and the organic phase is added to the system. Continue the external evaporation reaction under negative pressure.

[0010] (2) After the reaction in step (1) is completed, the reaction solution is separated into solid and liquid. The liquid is heated and refluxed, and 2-chloroethyl methyl sulfide is added dropwise. After the addition is completed, the reflux reaction continues.

[0011] (3) After the reaction in step (2) is completed, the temperature of the reaction solution drops to ≤60℃, reflux is stopped, the gas circulation device is turned on, and hydrogen chloride gas is introduced.

[0012] (4) After the gas is introduced in step (3), the reaction liquid is separated into solid and liquid. The liquid is heated to reflux and hydrochloric acid is added dropwise. After the addition is completed, the reflux hydrolysis reaction is carried out.

[0013] (5) After the reflux hydrolysis reaction in step (4) is completed, the reaction solution is rotary evaporated and the temperature is gradually increased to remove ethanol, solvent, water and 2-chloroethyl methyl sulfide in sequence. The remaining material is washed and dried to obtain D,L-methionine.

[0014] Further, the solvent mentioned in step (1) is n-hexane or cyclohexane, and the amount of solvent used is 2 to 3 times the mass of glycine ethyl ester hydrochloride.

[0015] Furthermore, in steps (1) and (2), the molar ratio of glycine ethyl ester hydrochloride, benzaldehyde, triethylamine and 2-chloroethyl methyl sulfide is 1:1~1.05:1.1~1.2:1.1~1.2.

[0016] Furthermore, in step (1), the triethylamine is added over a period of 0.5 to 3 hours, and the external evaporation reaction under negative pressure is carried out over a period of 2 to 3 hours; in step (2), the 2-chloroethyl methyl sulfide is added over a period of 0.5 to 3 hours, and the reflux reaction is carried out over a period of 2 to 3 hours.

[0017] Furthermore, in step (3), the flow rate of hydrogen chloride gas is 1~3%C / min, where C is the volume of the reaction vessel, and the hydrogen chloride gas is introduced for 30 min.

[0018] Further, in step (4), the mass fraction of hydrochloric acid is 10-15%, the amount added is 0.3 times the mass of glycine ethyl ester hydrochloride, the adding time is 0.5-1.5h, and the reflux hydrolysis reaction time is 2-3h.

[0019] Furthermore, the vacuum degree of rotary evaporation in step (5) is -70~-50Kpa.

[0020] Furthermore, in step (5), anhydrous diethyl ether is used for washing, and the amount of anhydrous diethyl ether is 0.3 to 0.5 times the mass of glycine ethyl ester hydrochloride.

[0021] The relevant chemical formula for the preparation of D,L-methionine in this invention is as follows:

[0022]

[0023] The beneficial effects of this invention are as follows:

[0024] This invention uses n-hexane / cyclohexane as a solvent and dehydrating agent, triethylamine as a catalyst and hydrochloride extractant, and employs an amino-protected and then dehydrated method, followed by heating and reflux, separation, and hydrolysis to prepare methionine. This method avoids the use of cyanide and high-temperature and high-pressure reactions, making the entire production process safer and more environmentally friendly. It also features high reaction selectivity, fewer side reactions, and easy separation of byproducts and solvents, further reducing production costs and facilitating industrial-scale promotion. Detailed Implementation

[0025] The following examples further illustrate the above-mentioned content of the present invention in detail, but it should not be construed as limiting the scope of the subject matter of the present invention to the following examples. All technologies implemented based on the above-mentioned content of the present invention fall within the protection scope of the present invention.

[0026] In the following examples, the reactor is a 2L vessel and the rotary evaporator is a 1L vessel.

[0027] Example 1

[0028] (1) Add 200g glycine ethyl ester hydrochloride, 152g benzaldehyde and 247g n-hexane to reactor No. 1, start stirring, heat to 45±2℃, turn on vacuum device and reflux water separation device, and maintain external evaporation reflux of system by adjusting negative pressure, add 160g triethylamine into reactor, the addition of triethylamine is completed in 2h, after the addition is completed, the water-containing external evaporation liquid of n-hexane is separated and n-hexane is returned to reactor No. 1, and the external evaporation reaction continues under negative pressure for 2h;

[0029] (2) After the reaction in step (1) is completed, stop heating and negative pressure, filter the reaction solution directly, transfer the filtrate into reactor No. 2, turn on the stirring and reflux device, heat the filtrate to reflux, and start to add 190g of 2-chloroethyl methyl sulfide at a uniform rate. The addition is completed in 2h, and the reflux reaction continues for 2h.

[0030] (3) After the reaction in step (2) is completed, stop heating. When the temperature of reactor No. 2 drops to 60°C, turn off the reflux device and turn on the gas circulation device. Introduce hydrogen chloride gas from the bottom of reactor No. 2 at a flow rate of 20 ml / min. After 30 min, stop the gas circulation.

[0031] (4) After the gas is introduced in step (3), the reaction liquid in reactor No. 2 is filtered and the filtrate is transferred to reactor No. 3. The stirring and reflux device is turned on, the mixture is heated to reflux, and 60g of 10wt% hydrochloric acid is added dropwise at a uniform rate. The addition is completed in 1 hour, and then the reflux hydrolysis reaction is carried out for 2 hours.

[0032] (5) After the reflux hydrolysis reaction in step (4) is completed, stop heating and transfer the reaction liquid in reactor No. 3 to rotary evaporator. Under vacuum of -70KPa, rotary evaporation is carried out to raise the temperature in the reactor to 100±2℃ in stages. Ethanol, solvent, water and 2-chloroethyl methyl sulfide are removed in sequence. The remaining material in the rotary evaporator is washed with 60g of anhydrous diethyl ether. After washing, the solid is separated and dried to obtain 184.5g of D,L-methionine.

[0033] The purity of D,L-methionine was 99.0%, and the yield was 86.3%.

[0034] Example 2

[0035] 200g glycine ethyl ester hydrochloride, 160g benzaldehyde and 370g n-hexane were added to reactor No. 1. Stirring was started and the temperature was raised to 45±2℃. The vacuum device and reflux water separator were turned on. By adjusting the negative pressure, the external evaporation of the system was kept under reflux. 174g triethylamine was added dropwise into the reactor. The addition of triethylamine was completed in 2 hours. After the addition was completed, the water-containing external evaporation liquid of n-hexane was separated and the n-hexane was returned to reactor No. 1. The external evaporation reaction under negative pressure continued for 3 hours.

[0036] After the reaction in step (1) is completed, stop heating and negative pressure, filter the reaction solution directly, transfer the filtrate into reactor No. 2, turn on the stirring and reflux device, heat the filtrate to reflux, and start to add 190g of 2-chloroethyl methyl sulfide at a uniform rate. The addition is completed in 2 hours, and the reflux reaction continues for 3 hours.

[0037] After the reaction in step (2) is completed, stop heating. When the temperature of reactor No. 2 drops to 60°C, turn off the reflux device and turn on the gas circulation device. Introduce hydrogen chloride gas from the bottom of reactor No. 2 at a flow rate of 60 ml / min. After 30 minutes, stop the gas circulation.

[0038] After the gas is introduced in step (3), the reaction liquid in reactor No. 2 is filtered and the filtrate is transferred to reactor No. 3. The stirring and reflux device is turned on, the mixture is heated to reflux, and 60g of 15wt% hydrochloric acid is added dropwise at a uniform rate. The addition is completed in 1 hour, and then the reflux hydrolysis reaction is carried out for 3 hours.

[0039] After the reflux hydrolysis reaction in step (4) is completed, heating is stopped, and the reaction liquid in reactor No. 3 is transferred to a rotary evaporator. Under a vacuum of -50 kPa, the temperature inside the reactor is gradually increased to 115 ± 2 °C by rotary evaporation. Ethanol, solvent, water and 2-chloroethyl methyl sulfide are removed in sequence. The remaining material in the rotary evaporator is washed with 60 g of anhydrous diethyl ether. After washing, the solid is separated and dried to obtain 183.2 g of D,L-methionine.

[0040] The purity of D,L-methionine was 99.2%, and the yield was 85.7%.

[0041] Example 3

[0042] (1) Add 200g glycine ethyl ester hydrochloride, 152g benzaldehyde and 241g cyclohexane to reactor No. 1, start stirring, heat to 45±2℃, turn on vacuum device and reflux water separation device, and maintain external evaporation reflux of system by adjusting negative pressure, add 160g triethylamine into reactor, the addition of triethylamine is completed in 2h, after the addition is completed, the external evaporation liquid of cyclohexane with water is separated and cyclohexane is returned to reactor No. 1, and the external evaporation reaction continues under negative pressure for 2h;

[0043] (2) After the reaction in step (1) is completed, stop heating and negative pressure, filter the reaction solution directly, transfer the filtrate into reactor No. 2, turn on the stirring and reflux device, heat the filtrate to reflux, and start to add 174g of 2-chloroethyl methyl sulfide at a uniform rate. The addition is completed in 2h, and the reflux reaction continues for 2h.

[0044] (3) After the reaction in step (2) is completed, stop heating. When the temperature of reactor No. 2 drops to 60°C, turn off the reflux device and turn on the gas circulation device. Introduce hydrogen chloride gas from the bottom of reactor No. 2 at a flow rate of 20 ml / min. After 30 min, stop the gas circulation.

[0045] (4) After the gas is introduced in step (3), the reaction liquid in reactor No. 2 is filtered and the filtrate is transferred to reactor No. 3. The stirring and reflux device is turned on, the mixture is heated to reflux, and 60g of 10wt% hydrochloric acid is added dropwise at a uniform rate. The addition is completed in 1 hour, and then the reflux hydrolysis reaction is carried out for 2 hours.

[0046] (5) After the reflux hydrolysis reaction in step (4) is completed, stop heating and transfer the reaction liquid in reactor No. 3 to rotary evaporator. Under vacuum of -70KPa, rotary evaporation is carried out to raise the temperature in the reactor to 100±2℃ in stages. Ethanol, solvent, water and 2-chloroethyl methyl sulfide are removed in sequence. The remaining material in the rotary evaporator is washed with 100g of anhydrous diethyl ether. After washing, the solid is separated and dried to obtain 181.9g of D,L-methionine.

[0047] The purity of D,L-methionine was 98.9%, and the yield was 85.1%.

[0048] Example 4

[0049] (1) Add 200g glycine ethyl ester hydrochloride, 160g benzaldehyde and 362g cyclohexane to reactor No. 1, start stirring, heat to 45±2℃, turn on vacuum device and reflux water separation device, and maintain external evaporation reflux of system by adjusting negative pressure, add 174g triethylamine into reactor, the addition of triethylamine is completed in 2h, after the addition is completed, the external evaporation liquid of cyclohexane with water is separated and cyclohexane is returned to reactor No. 1, and the external evaporation reaction continues under negative pressure for 3h;

[0050] (2) After the reaction in step (1) is completed, stop heating and negative pressure, filter the reaction solution directly, transfer the filtrate into reactor No. 2, turn on the stirring and reflux device, heat the filtrate to reflux, and start to add 190g of 2-chloroethyl methyl sulfide at a uniform rate. The addition is completed in 2 hours, and the reflux reaction continues for 3 hours.

[0051] (3) After the reaction in step (2) is completed, stop heating. When the temperature of reactor No. 2 drops to 60°C, turn off the reflux device and turn on the gas circulation device. Introduce hydrogen chloride gas from the bottom of reactor No. 2 at a flow rate of 60 ml / min. After 30 min, stop the gas circulation.

[0052] (4) After the gas is introduced in step (3), the reaction liquid in reactor No. 2 is filtered and the filtrate is transferred to reactor No. 3. The stirring and reflux device is turned on, the mixture is heated to reflux, and 60g of 15wt% hydrochloric acid is added dropwise at a uniform rate. The addition is completed in 1 hour, and then the reflux hydrolysis reaction is carried out for 3 hours.

[0053] (5) After the reflux hydrolysis reaction in step (4) is completed, stop heating and transfer the reaction liquid in reactor No. 3 to rotary evaporator. Under vacuum of -50KPa, rotary evaporation is carried out to raise the temperature in the reactor to 115±2℃ in stages. Ethanol, solvent, water and 2-chloroethyl methyl sulfide are removed in sequence. The remaining material in the rotary evaporator is washed with 100g of anhydrous diethyl ether. After washing, the solid is separated and dried to obtain 180.4g of D,L-methionine.

[0054] The purity of D,L-methionine was 99.0%, and the yield was 84.4%.

[0055] Comparative Example 1 (Synthesis of D,L-methionine by Phase Transfer Method)

[0056] (1) Preparation of ethyl phenylmethylaminoacetate: 2.1 g glycine ethyl ester hydrochloride, 1 g anhydrous magnesium sulfate, 1.6 g benzaldehyde and 23 ml dichloromethane were mixed to form a mixture. 3 ml triethylamine was slowly added dropwise to the mixture under stirring. The mixture was reacted at room temperature for 24 h. After filtration, the dichloromethane was removed by vacuum distillation to obtain 2.3 g of pale yellow oil.

[0057] (2) Synthesis of methionine: 2.3g of a pale yellow oil, 2.08g of potassium hydroxide, 2.54g of anhydrous potassium carbonate and 0.29g of TBAB were added to 60ml of dichloromethane. 1.33g of methyl 2-chloroethyl sulfide was added while stirring. The mixture was reacted at room temperature for 4h. After filtration, the dichloromethane was removed by vacuum distillation to obtain an orange-yellow oil. 18ml of concentrated hydrochloric acid, 3.6ml of water and 2.4ml of ethanol were added to the oil. The mixture was heated under reflux for 3h and hydrolyzed. The mixture was extracted twice with dichloromethane (12ml each time). The solid was then distilled under vacuum to obtain a pale yellow solid. After drying, 50ml of an aqueous ethanol solution (1:3) was added, and the mixture was heated. After cooling, 1.33g of flaky crystals precipitated, which was D,L-methionine.

[0058] The purity of D,L-methionine was 99.1% and the yield was 73.8%.

[0059] This invention uses n-hexane / cyclohexane as a solvent and dehydrating agent, avoiding the use of magnesium sulfate. Furthermore, the physicochemical properties of n-hexane / cyclohexane are more conducive to the separation and purification of subsequent products. Excess triethylamine is used as a catalyst to avoid the introduction of other phase transfer catalysts, which is beneficial for separation and purification. Moreover, the method of this invention results in a higher yield of D,L-methionine and a safer reaction process.

[0060] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing D,L-methionine, characterized in that, Includes the following steps: (1) Mix glycine ethyl ester hydrochloride, benzaldehyde and solvent, heat to 40 ~ 50℃, turn on the negative pressure and reflux water separation device, and keep the system externally evaporated by adjusting the negative pressure. Add triethylamine dropwise. After the addition is completed, the externally evaporated liquid is separated into water and the organic phase is added to the system. Continue the external evaporation reaction under negative pressure. (2) After the reaction in step (1) is completed, the reaction solution is separated into solid and liquid. The liquid is heated and refluxed, and 2-chloroethyl methyl sulfide is added dropwise. After the addition is completed, the reflux reaction continues. (3) After the reaction in step (2) is completed, the temperature of the reaction solution drops to ≤60℃, reflux is stopped, the gas circulation device is turned on, and hydrogen chloride gas is introduced. (4) After the gas is introduced in step (3), the reaction liquid is separated into solid and liquid. The liquid is heated to reflux and hydrochloric acid is added dropwise. After the addition is completed, the reflux hydrolysis reaction is carried out. (5) After the reflux hydrolysis reaction in step (4) is completed, the reaction solution is rotary evaporated and the temperature is gradually increased to remove ethanol, solvent, water and 2-chloroethyl methyl sulfide in sequence. The remaining material is washed and dried to obtain D,L-methionine. The solvent mentioned in step (1) is n-hexane or cyclohexane, and the amount of solvent used is 2 to 3 times the mass of glycine ethyl ester hydrochloride; In steps (1) and (2), the molar ratio of glycine ethyl ester hydrochloride, benzaldehyde, triethylamine and 2-chloroethyl methyl sulfide is 1:1 ~ 1.05:1.1 ~ 1.2:1.1 ~ 1.

2.

2. The method for preparing D,L-methionine according to claim 1, characterized in that, In step (1), the triethylamine is added over a period of 0.5 to 3 hours, and the external evaporation reaction under negative pressure is carried out over a period of 2 to 3 hours. In step (2), the 2-chloroethyl methyl sulfide is added over a period of 0.5 to 3 hours, and the reflux reaction is carried out over a period of 2 to 3 hours.

3. The method for preparing D,L-methionine according to claim 1, characterized in that, In step (3), the flow rate of hydrogen chloride gas is 1 ~ 3%C / min, where C is the volume of the reaction vessel, and the hydrogen chloride gas is introduced for 30 min.

4. The method for preparing D,L-methionine according to claim 1, characterized in that, The hydrochloric acid in step (4) has a mass fraction of 10-15%, the amount added is 0.3 times the mass of glycine ethyl ester hydrochloride, the addition time is 0.5-1.5 h, and the reflux hydrolysis reaction time is 2-3 h.

5. The method for preparing D,L-methionine according to claim 1, characterized in that, The vacuum degree of rotary evaporation in step (5) is -70 ~ -50 kPa.

6. The method for preparing D,L-methionine according to claim 1, characterized in that, In step (5), anhydrous diethyl ether is used for washing, and the amount of anhydrous diethyl ether is 0.3 to 0.5 times the mass of glycine ethyl ester hydrochloride.

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