One-pot method for preparing DL-serine

Abstract

The present invention discloses a one-pot method for preparing DL-serine, which belongs to the field of chemical synthesis technology. The present invention adds a monochloroacetic acid aqueous solution, a sodium carbonate aqueous solution, and copper (II) sulfate to a saturated ammonium bicarbonate aqueous solution, controls the reaction temperature, reaction time, and pH value of the reaction solution, and then separates and concentrates the product with a cation exchange resin to obtain DL-serine. Compared with the prior art, the present invention completes chemical synthesis in an aqueous phase and is environmentally friendly; utilizes ammonium bicarbonate, an inorganic salt, to achieve amino substitution on an organic carbon chain and add a carbon atom to extend the carbon chain; the reaction raw materials are widely available, the reaction conditions are mild, the product yield is high, the reproducibility is good, and the product is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a method for preparing DL-serine through a one-pot process. Background Art

[0002] DL-serine is widely used in the food, feed, pharmaceutical, agricultural, and cosmetic industries. Its primary applications include: as a food additive, added to animal feed to improve plant protein absorption and utilization, promoting animal growth and development; as a raw material for protein synthesis, providing a carbon backbone for the synthesis of important substances such as purines, thymine, methionine, and choline; and, due to its exceptional wettability, as a cosmetic additive in creams (moisturizers) to maintain stratum corneum moisture. Furthermore, serine is an essential and irreplaceable substrate for the enzymatic production of tryptophan by microorganisms, directly impacting the price of this "second essential amino acid." Consequently, the development of DL-serine production processes has attracted considerable industry attention.

[0003] Currently, representative production processes for DL-serine include:

[0004] 1. Improved Strecker amino acid synthesis reaction

[0005]

[0006] For example, Chinese invention patent publication number CN01127227, Japanese invention patent publication number JPH03240760A, and European invention patent publication number EP0376184A2 each disclose methods for preparing DL-serine using a modified Strecker reaction. Although the chemical structures of the starting materials used in these patents differ slightly, cyanide is used in all reactions. As is well known, cyanide is a highly toxic compound. The purchase and use process is cumbersome and potentially dangerous, making it unsuitable for industrial production.

[0007] 2. Preparation using 2-substituted aziridine as intermediate

[0008]

[0009] For example, Japanese invention patents with publication numbers JPS61186356A and JPS61140551A, international invention patents with publication numbers WO8204044A1, and European invention patents with publication numbers EP0030474A1 and EP0030475A1 disclose methods for preparing DL-serine using 2-substituted aziridines as intermediates. This route simply requires hydrolysis of the 2-substituted aziridine under acidic conditions to produce serine. 2-Substituted aziridines are often prepared using acrylonitrile or monochloroacetaldehyde as raw materials, and the process route is as follows:

[0010]

[0011] As can be seen from the above process flow, the synthesis route of 2-substituted aziridine as a raw material is long, and sodium cyanide, chlorine, etc. are used. The reaction conditions are relatively harsh, which is also not conducive to industrial production.

[0012] 3. Copper glycine method

[0013]

[0014] The copper glycinate method for preparing DL-serine requires only one step, reducing the losses caused by multiple steps. The raw materials used in the copper glycinate method are glycine and formaldehyde solution, and the reaction mechanism is as follows:

[0015]

[0016] The purpose of adding formaldehyde in the method is to utilize the carbon atoms of formaldehyde to extend the carbon chain.

[0017] Japanese patent publication number JPS59163352A discloses the preparation of DL-serine by reacting glycine copper salt or glycine cuprous salt with aqueous formaldehyde solution under strong base catalysis. However, because the reaction must be carried out under pressure, the conditions are relatively harsh, making scale-up difficult.

[0018] 4. Preparation using monochloroacetic acid as raw material

[0019] Japanese invention patent publication number JPS60218361A discloses a method for preparing serine using monochloroacetic acid and formaldehyde as raw materials through a "one-pot cooking" method. Monochloroacetic acid, ammonia water, ammonium carbonate, formaldehyde aqueous solution, sodium hydroxide and a catalytic amount of cadmium formate are added to the reactor at 20kg / cm 2 Under pressure, the reaction was carried out at 120°C for 1 hour, resulting in a 23.3% yield of DL-serine. This reaction also uses ammonia to replace the chlorine atoms in monochloroacetic acid and the carbon atoms in formaldehyde to extend the carbon chain. This reaction, conducted under high pressure, is highly hazardous and results in a very low serine yield.

[0020] In summary, providing a method for preparing DL-serine with a wide range of reaction raw materials, mild reaction conditions, high product yield, good reproducibility, and suitable for industrial production has important practical value and significance. Summary of the Invention

[0021] In view of the above-mentioned deficiencies in the prior art, in a first aspect of the present invention, a method for preparing DL-serine is provided, which has a wide range of raw material sources, mild reaction conditions, high product yield, good reproducibility, and is suitable for industrial production. The method is based on a one-pot synthesis process and comprises the following steps:

[0022] (1) adding a monochloroacetic acid aqueous solution to a saturated ammonium bicarbonate aqueous solution to carry out a reaction, exhausting gas to suppress ammonia during the reaction, and controlling the reaction solution to be non-alkaline to obtain solution A;

[0023] (2) adding a sodium carbonate aqueous solution to the solution A to carry out a reaction, and also exhausting gas and suppressing ammonia during the reaction process to control the reaction solution to be non-alkaline, thereby obtaining a solution B;

[0024] (3) adding copper (II) sulfate to the solution B to react and obtain solution C;

[0025] (4) The solution C is separated and purified to obtain DL-serine.

[0026] Preferably, in step (1), the mass ratio of ammonium bicarbonate to monochloroacetic acid is 5 to 9:1.

[0027] Preferably, in step (1), the reaction temperature is 40-80° C., the reaction time is 1-10 h, and the pH of the reaction solution is controlled to 4-7.

[0028] Preferably, in step (2), the mass ratio of sodium carbonate to monochloroacetic acid is 0.2 to 0.8:1.

[0029] Preferably, in step (2), the reaction temperature is 40-80° C., the reaction time is 10-300 min, and the pH of the reaction solution is controlled to 4-7.

[0030] Copper (II) sulfate includes copper sulfate or copper sulfate pentahydrate commonly used in the art. For the purpose of wider raw material sources and convenient storage, copper sulfate pentahydrate is a particularly suitable type of copper (II) sulfate selected in the present invention.

[0031] Preferably, in step (3), copper (II) sulfate is copper sulfate pentahydrate, and the mass ratio of copper sulfate pentahydrate to monochloroacetic acid is 0.005-0.03:1.

[0032] Preferably, in step (3), the reaction temperature is 80-100° C., and the reaction time is 10-300 min.

[0033] Various methods are available for isolating the DL-serine product in the art, and the appropriate purification method can be selected based on actual application requirements. For the purposes of cost reduction and ease of operation, commercially available cation exchange resins are particularly suitable purification materials for this process. After separation and concentration, the purified DL-serine product can be obtained.

[0034] Preferably, in step (4), separation and purification are performed using a cation exchange resin, and DL-serine is obtained after concentration.

[0035] The difficulty in optimizing the preparation of DL-serine lies in simplifying the synthesis process while reducing the temperature and pressure conditions required for the reaction. Based on the above technical solutions, the design concept and uniqueness of the present invention lies in selecting a new synthesis path and adjusting the feeding steps. Although the synthesis process involves multiple feeding steps, the reaction still occurs in a single step, achieving the goal of a gentle one-pot synthesis of DL-serine, avoiding the pollution and increased costs caused by multiple separations.

[0036] The synthetic route of the present invention is as follows:

[0037]

[0038] The present invention utilizes ammonium bicarbonate, an inorganic salt, to achieve two objectives: the amino group in the ammonium bicarbonate replaces the chlorine atom in monochloroacetic acid, introducing an amino group; and the inorganic carbon in the ammonium bicarbonate inserts into the monochloroacetic acid carbon chain, adding a carbon atom to the organic carbon chain and extending the carbon chain. Furthermore, sodium carbonate and copper sulfate react to form basic copper carbonate, catalyzing the reaction and avoiding the use of strong bases such as sodium hydroxide. In the synthesis process of the present invention, all raw materials except monochloroacetic acid are inorganic salts, and the chemical synthesis is carried out in an aqueous phase, resulting in minimal production of "three wastes" and environmentally friendly products. Furthermore, the production process is simple, the reaction conditions are mild, and the reaction can be completed by appropriate heating at normal pressure, without the need for pressurization or high temperature.

[0039] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0040] The present invention provides a one-pot method for preparing DL-serine. The method adopts a new synthesis route and optimizes the steps. The reaction raw materials required for the synthesis are widely available, the reaction conditions are mild, the product yield is high, the reproducibility is good, and the method is suitable for industrial production. DETAILED DESCRIPTION

[0041] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0042] Example 1

[0043] The one-pot method for preparing DL-serine comprises the following steps:

[0044] (1) Add 70 L of saturated ammonium bicarbonate aqueous solution to a 100 L reactor, then dropwise add 875 mL of monochloroacetic acid aqueous solution (2.345 kg of monochloroacetic acid dissolved in 875 mL of water), control the reaction liquid temperature to 65 ° C. After the dropwise addition is completed, react at 65 ° C. for 5 h, pumping out ammonia during the process to reduce the pH of the reaction liquid to 5.0, and obtain Solution A after the reaction is completed;

[0045] (2) Solution A was pumped into a 500 L reactor, and a sodium carbonate aqueous solution (1.330 kg of sodium carbonate dissolved in 210 L of water) was placed in a dropping tank. The sodium carbonate solution was slowly added dropwise to Solution A, and the temperature of the reaction solution was controlled to be 65 ° C. After the addition was completed, the reaction was carried out at 65 ° C for 40 minutes, and the ammonia was removed by evacuation to reduce the pH of the reaction solution to 6.0 to obtain Solution B;

[0046] (3) Add 42 g of copper sulfate pentahydrate to solution B, raise the temperature to 93°C and react for 40 min to obtain solution C;

[0047] (4) After solution C was cooled to room temperature, the product was separated using a cation exchange resin and concentrated to obtain 1.599 kg of a white solid, namely DL-serine, with a yield of 61.3% and a melting point of 240.8°C.

[0048] Example 2

[0049] The one-pot method for preparing DL-serine comprises the following steps:

[0050] (1) Add 53 L of saturated ammonium bicarbonate aqueous solution to a 100 L reactor, then dropwise add 875 mL of monochloroacetic acid aqueous solution (2.345 kg of monochloroacetic acid dissolved in 875 mL of water), control the reaction liquid temperature to 65 ° C. After the dropwise addition is completed, react at 65 ° C. for 5 h, during which ammonia is pumped out to reduce the pH of the reaction liquid to 5.0, and after the reaction is completed, obtain Solution A;

[0051] (2) Solution A was pumped into a 500 L reactor, and a sodium carbonate aqueous solution (1.330 kg of sodium carbonate dissolved in 210 L of water) was placed in a dropping tank. The sodium carbonate solution was slowly added dropwise to Solution A, and the temperature of the reaction solution was controlled to be 65 ° C. After the addition was completed, the reaction was carried out at 65 ° C for 40 minutes, and the ammonia was removed by evacuation to reduce the pH of the reaction solution to 6.0 to obtain Solution B;

[0052] (3) Add 42 g of copper sulfate pentahydrate to solution B, raise the temperature to 93°C and react for 40 min to obtain solution C;

[0053] (4) After solution C was cooled to room temperature, the product was separated using a cation exchange resin and concentrated to obtain 1.398 kg of a white solid, namely DL-serine, with a yield of 53.6% and a melting point of 241.2°C.

[0054] Example 3

[0055] The one-pot method for preparing DL-serine comprises the following steps:

[0056] (1) Add 47 L of saturated ammonium bicarbonate aqueous solution to a 100 L reactor, then dropwise add 875 mL of monochloroacetic acid aqueous solution (2.345 kg of monochloroacetic acid dissolved in 875 mL of water), control the reaction liquid temperature to 45 ° C. After the dropwise addition is completed, react at 45 ° C. for 2 h, pumping out ammonia during the process to reduce the pH of the reaction liquid to 5.0, and obtain solution A after the reaction is completed;

[0057] (2) Solution A was pumped into a 500 L reactor, and a sodium carbonate aqueous solution (0.470 kg of sodium carbonate dissolved in 210 L of water) was placed in a dropping tank. The sodium carbonate solution was slowly added dropwise to Solution A, and the temperature of the reaction solution was controlled to be 45 ° C. After the addition was completed, the reaction was carried out at 45 ° C for 30 min, and the ammonia was removed by evacuation to reduce the pH of the reaction solution to 6.0 to obtain Solution B;

[0058] (3) Add 24 g of copper sulfate pentahydrate to solution B, heat to 85°C and react for 30 min to obtain solution C;

[0059] (4) After solution C was cooled to room temperature, the product was separated using a cation exchange resin and concentrated to obtain 0.837 kg of a white solid, namely DL-serine, with a yield of 32.1% and a melting point of 241.1°C.

[0060] Example 4

[0061] The one-pot method for preparing DL-serine comprises the following steps:

[0062] (1) Add 47 L of saturated ammonium bicarbonate aqueous solution to a 100 L reactor, then dropwise add 875 mL of monochloroacetic acid aqueous solution (2.345 kg of monochloroacetic acid dissolved in 875 mL of water), control the reaction liquid temperature to 70 ° C. After the dropwise addition is completed, react at 70 ° C. for 8 h, during which ammonia is pumped out to reduce the pH of the reaction liquid to 5.0, and after the reaction is completed, obtain Solution A;

[0063] (2) Solution A was pumped into a 500 L reactor, and a sodium carbonate aqueous solution (0.470 kg of sodium carbonate dissolved in 210 L of water) was placed in a dropping tank. The sodium carbonate solution was slowly added dropwise to Solution A, and the reaction liquid temperature was controlled at 70 ° C. After the addition was completed, the reaction was carried out at 70 ° C for 2 h, and the ammonia was removed by evacuation to reduce the pH of the reaction liquid to 6.0 to obtain Solution B;

[0064] (3) Add 24 g of copper sulfate pentahydrate to solution B, heat to 95°C and react for 2 h to obtain solution C;

[0065] (4) After solution C was cooled to room temperature, the product was separated using a cation exchange resin and concentrated to obtain 0.782 kg of a white solid, namely DL-serine, with a yield of 30.0% and a melting point of 241.0°C.

[0066] Example 5

[0067] The one-pot method for preparing DL-serine comprises the following steps:

[0068] (1) Add 80 L of saturated ammonium bicarbonate aqueous solution to a 100 L reactor, then dropwise add 875 mL of monochloroacetic acid aqueous solution (2.345 kg of monochloroacetic acid dissolved in 875 mL of water), control the reaction liquid temperature to 45 ° C. After the dropwise addition is completed, react at 45 ° C. for 2 h, pumping out ammonia during the process to reduce the pH of the reaction liquid to 5.0, and obtain Solution A after the reaction is completed;

[0069] (2) Solution A was pumped into a 500 L reactor, and a sodium carbonate aqueous solution (1.642 kg of sodium carbonate dissolved in 210 L of water) was placed in a dropping tank. The sodium carbonate solution was slowly added dropwise to Solution A, and the reaction liquid temperature was controlled at 45 ° C. After the addition was completed, the reaction was carried out at 45 ° C for 30 min, and the ammonia was removed by evacuation to reduce the pH of the reaction liquid to 6.0 to obtain Solution B;

[0070] (3) Add 59 g of copper sulfate pentahydrate to solution B, heat to 85°C and react for 30 min to obtain solution C;

[0071] (4) After solution C was cooled to room temperature, the product was separated using a cation exchange resin and concentrated to obtain 0.944 kg of a white solid, namely DL-serine, with a yield of 36.2% and a melting point of 240.8°C.

[0072] Example 6

[0073] The one-pot method for preparing DL-serine comprises the following steps:

[0074] (1) Add 80 L of saturated ammonium bicarbonate aqueous solution to a 100 L reactor, then dropwise add 875 mL of monochloroacetic acid aqueous solution (2.345 kg of monochloroacetic acid dissolved in 875 mL of water), control the reaction liquid temperature to 70 ° C. After the dropwise addition is completed, react at 70 ° C. for 5 h, during which ammonia is pumped out to reduce the pH of the reaction liquid to 5.0, and after the reaction is completed, obtain Solution A;

[0075] (2) Solution A was pumped into a 500 L reactor, and a sodium carbonate aqueous solution (1.642 kg of sodium carbonate dissolved in 210 L of water) was placed in a dropping tank. The sodium carbonate solution was slowly added dropwise to Solution A, and the reaction liquid temperature was controlled at 70°C. After the addition was completed, the reaction was carried out at 70°C for 40 min, and the ammonia was removed by evacuation to reduce the pH of the reaction liquid to 6.0, thereby obtaining Solution B;

[0076] (3) Add 59 g of copper sulfate pentahydrate to solution B, heat to 93°C and react for 40 min to obtain solution C;

[0077] (4) After solution C was cooled to room temperature, the product was separated using a cation exchange resin and concentrated to obtain 1.633 kg of a white solid, namely DL-serine, with a yield of 62.6% and a melting point of 241.1°C.

[0078] Example 7

[0079] The one-pot method for preparing DL-serine comprises the following steps:

[0080] (1) Add 80 L of saturated ammonium bicarbonate aqueous solution to a 100 L reactor, then dropwise add 875 mL of monochloroacetic acid aqueous solution (2.345 kg of monochloroacetic acid dissolved in 875 mL of water), control the reaction liquid temperature to 70 ° C. After the dropwise addition is completed, react at 70 ° C. for 5 h, during which ammonia is pumped out to reduce the pH of the reaction liquid to 4.0, and after the reaction is completed, obtain Solution A;

[0081] (2) Solution A was pumped into a 500 L reactor, and a sodium carbonate aqueous solution (1.642 kg sodium carbonate dissolved in 210 L water) was placed in a dropping tank. The sodium carbonate solution was slowly added dropwise to Solution A, and the reaction liquid temperature was controlled at 70 ° C. After the addition was completed, the reaction was carried out at 70 ° C for 40 min, and the ammonia was pumped out to reduce the pH of the reaction liquid to 7.0 to obtain Solution B;

[0082] (3) Add 59 g of copper sulfate pentahydrate to solution B, heat to 93°C and react for 40 min to obtain solution C;

[0083] (4) After solution C was cooled to room temperature, the product was separated using a cation exchange resin and concentrated to obtain 1.625 kg of a white solid, namely DL-serine, with a yield of 62.3% and a melting point of 241.1°C.

[0084] The examples demonstrate the one-pot production of DL-serine using the present invention and synthetic pathway. The raw materials used are readily available chemicals in the art, resulting in a simple production process. The process steps do not require pressurization, high temperature, or a strong base, and the reaction conditions required are mild. The product in the examples can be purified using a cation exchange resin, achieving a yield of up to 62.6%, making it suitable for large-scale, efficient production and providing a new approach for the industrialized production of DL-serine.

[0085] The above describes in detail the preferred embodiments of the present invention. It should be understood that those skilled in the art can make numerous modifications and variations based on the concepts of the present invention without inventive effort. Therefore, any technical solutions that can be derived by those skilled in the art through logical analysis, reasoning, or limited experimentation based on the concepts of the present invention and the prior art should be within the scope of protection defined by the claims.

Claims

1. A method for preparing DL-serine based on a one-pot synthesis process, characterized in that: The steps include: (1) adding a monochloroacetic acid aqueous solution to a saturated ammonium bicarbonate aqueous solution to carry out a reaction, exhausting gas to suppress ammonia during the reaction, and controlling the reaction solution to be non-alkaline to obtain solution A; (2) adding a sodium carbonate aqueous solution to the solution A to carry out a reaction, and also exhausting gas and suppressing ammonia during the reaction process to control the reaction solution to be non-alkaline, thereby obtaining a solution B; (3) adding copper (II) sulfate to the solution B to react and obtain solution C; (4) The solution C is separated and purified to obtain DL-serine.

2. The method according to claim 1, wherein: In the step (1), the mass ratio of ammonium bicarbonate to monochloroacetic acid is 5 to 9:

1.

3. The method according to claim 1, wherein: In the step (1), the reaction temperature is 40-80° C., the reaction time is 1-10 h, and the pH of the reaction solution is controlled to 4-7.

4. The method according to claim 1, wherein: In the step (2), the mass ratio of sodium carbonate to monochloroacetic acid is 0.2-0.8:

1.

5. The method according to claim 1, wherein: In the step (2), the reaction temperature is 40-80° C., the reaction time is 10-300 min, and the pH of the reaction solution is controlled to 4-7.

6. The method according to claim 1, wherein: In the step (3), copper (II) sulfate is copper sulfate pentahydrate, and the mass ratio of copper sulfate pentahydrate to monochloroacetic acid is 0.005-0.03:

1.

7. The method according to claim 1, wherein: In the step (3), the reaction temperature is 80-100° C., and the reaction time is 10-300 min.

8. The method according to claim 1, wherein: In the step (4), separation and purification are performed using a cation exchange resin, and DL-serine is obtained after concentration.

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