A kind of synthetic method of alpha-ketoglutaric acid

Abstract

The present invention relates to the technical field of organic synthesis, and a method for synthesizing α-ketoglutaric acid is proposed, comprising the following steps: S1, methyl dichloroacetate and methyl acrylate react in the presence of sodium methoxide to obtain 2,2-dichloroglutaric acid dimethyl ester; S2, 2,2-dichloroglutaric acid dimethyl ester is reacted with 10-20% alkaline solution and 25-35% alkaline solution in sequence to obtain a crude α-ketoglutaric acid aqueous solution; S3, the mixture is refined to obtain α-ketoglutaric acid. Through the above technical scheme, the problems of low yield and low purity of α-ketoglutaric acid in the α-ketoglutaric acid synthesis method in the prior art are solved.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing alpha-ketoglutaric acid. Background Art

[0002] α-Ketoglutaric acid is one of the two keto-derivatives of glutaric acid, and is a white fine crystalline powder. The anion of α-ketoglutaric acid, α-ketoglutarate, is an important biological compound. It is the ketoacid product of glutamate deamination, and is an important metabolic intermediate in the tricarboxylic acid cycle of microorganisms. It is a key node connecting carbon-nitrogen metabolism in cells. α-Ketoglutaric acid can bind to nitrogen formed in cells and prevent excessive accumulation of nitrogen in cells. α-Ketoglutaric acid can also be used as a dietary supplement to reduce the many problems caused by ammonia poisoning. It has been used for patients undergoing hemodialysis, so its application is very good. However, the current synthesis method of α-ketoglutaric acid has low yield and low purity, which affects the widespread application of α-ketoglutaric acid. Summary of the invention

[0003] The invention provides a method for synthesizing α-ketoglutaric acid, which solves the problems of low yield and low purity of α-ketoglutaric acid in the method for synthesizing α-ketoglutaric acid in the related art.

[0004] The technical solution of the present invention is as follows:

[0005] A method for synthesizing α-ketoglutaric acid comprises the following steps:

[0006] S1, methyl dichloroacetate and methyl acrylate react in the presence of sodium methoxide to obtain dimethyl 2,2-dichloroglutarate;

[0007] S2, reacting dimethyl 2,2-dichloroglutarate with 10-20% alkali solution and 25-35% alkali solution in sequence to obtain a crude α-ketoglutaric acid aqueous solution;

[0008] S3. Refining the crude α-ketoglutaric acid aqueous solution to obtain α-ketoglutaric acid.

[0009] As a further technical solution, the dimethyl 2,2-dichloroglutarate in S2 is reacted with 15% alkali solution and 30% alkali solution in sequence to obtain a crude α-ketoglutaric acid aqueous solution.

[0010] As a further technical solution, S2 comprises the following steps:

[0011] A1. Add water and dimethyl 2,2-dichloroglutarate into reactor A and control the temperature to 8-10°C;

[0012] A2, add 15% sodium hydroxide to reactor A until the pH is 6.5-7.0;

[0013] A3, add 30% sodium hydroxide to continue the reaction until the pH is 8-8.5;

[0014] A4, add inorganic salt, control the temperature to 70-80℃, and stir for 2-3h;

[0015] A5. After stirring, cool to 20-25°C and centrifuge to obtain a mixture;

[0016] A6, add water and mixture into reactor B, and control the temperature to ≤10°C;

[0017] A7, add acid solution to reactor B, adjust pH to 1.3-1.4, control temperature to 22-27°C, and react for 1.5-2.5h;

[0018] A8, filter, wash and collect the filtrate to obtain a crude α-ketoglutaric acid aqueous solution.

[0019] As a further technical solution, when 15% sodium hydroxide is added dropwise to A2, the temperature is controlled to be ≤25°C and the adding time is 1.5-2.5h.

[0020] As a further technical solution, 30% sodium hydroxide is added to A3, the temperature is controlled at 95-100° C., and refluxed for 3-4 hours.

[0021] As a further technical solution, the mass ratio of dimethyl 2,2-dichloroglutarate to water in A1 is 1:2; the mass ratio of the mixture to water in A6 is 1:2-3.

[0022] As a further technical solution, the mass ratio of dimethyl 2,2-dichloroglutarate to inorganic salt in A2 is 1:0.5-1.

[0023] As a further technical solution, S3 comprises the following steps:

[0024] B1, adding crude α-ketoglutaric acid aqueous solution and activated carbon into a reactor for reaction, and then performing decompression dehydration;

[0025] B2, add acetone to the reactor and stir, then cool to 23-27°C, filter, wash and evaporate to remove acetone;

[0026] B3. Add ethyl acetate to the reactor, control the temperature to -5°C-10°C, and stir for 1.2-2.5h;

[0027] B4, after centrifugation and drying, α-ketoglutaric acid is obtained.

[0028] As a further technical solution, the reaction temperature in B1 is 55-65°C, and the reaction time is 35-45min.

[0029] As a further technical solution, after adding acetone to B2, the temperature is controlled at ≤45°C and stirred for 25-35 minutes.

[0030] The working principle and beneficial effects of the present invention are:

[0031] 1. In the synthesis process of the present invention, 15% sodium hydroxide is first used to complete dechlorination without causing olefin polymerization, and 30% sodium hydroxide is then used to improve the yield and purity of α-ketoglutaric acid.

[0032] 2. The present invention uses activated carbon, acetone and ethyl acetate to purify the crude α-ketoglutaric acid aqueous solution in sequence, thereby improving the purity of the product. DETAILED DESCRIPTION

[0033] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] In the following examples and comparative examples, dimethyl 2,2-dichloroglutarate was synthesized by the following steps:

[0035] (1) Add 144.18 kg of methyl acrylate and 220 kg of methyl dichloroacetate into an enameled kettle A and stir. After the reaction, cool to 10°C.

[0036] (2) Control the temperature to 15-20°C and add 24.28 kg of 30% sodium methoxide solution to the enameled kettle A for 2.5 hours;

[0037] (3) After the addition is complete, the temperature is controlled at 24-26°C and stirred for 2.5 hours to generate a reaction product;

[0038] (4) After the reaction is qualified, add 100L of water, stir for 30min, let stand, separate into layers, and collect the organic phase; perform liquid separation twice;

[0039] (5) The organic phase was transferred to a distillation kettle, 30 L of pure water was added twice, and the mixture was distilled at 55° C. and -0.09 MPa under reduced pressure until the gas phase detected the product with 2,2-dichloroglutarate of ≥93%, thereby obtaining dimethyl 2,2-dichloroglutarate.

[0040] Example 1

[0041] A method for synthesizing α-ketoglutaric acid comprises the following steps:

[0042] (1) Add 200 kg of water and 100 kg of dimethyl 2,2-dichloroglutarate into an enameled kettle B and control the temperature to 8-10°C;

[0043] (2) Add 15% sodium hydroxide to the enameled kettle B until the pH reaches 6.5, control the temperature at 20-25°C, and add for 2 hours;

[0044] (3) Add 30% sodium hydroxide to the enameled kettle B, control the temperature to 95-100°C, reflux for 3 hours, and react until the pH reaches 8;

[0045] (4) Add 75 kg of anhydrous calcium chloride to the enameled kettle B, control the temperature to 70-75°C, and stir for 2 hours;

[0046] (5) After the stirring is completed, the temperature is lowered to 20° C. and the mixture is obtained by centrifugation;

[0047] (6) Add 240 kg of water and 80 kg of the mixture into the reactor and stir, and control the temperature to 0-5°C;

[0048] (7) Add 30% aqueous sulfuric acid solution to the reaction kettle, adjust the pH to 1.3, control the temperature to 22-25° C., and react for 2 h; during the reaction, maintain the pH at 1.3-1.4;

[0049] (8) After drying with a plastic-lined centrifuge, the filtrate is rinsed with pure water, and the filtrate is dried again and collected to obtain a crude α-ketoglutaric acid aqueous solution;

[0050] (9) The crude α-ketoglutaric acid aqueous solution and 8 kg of activated carbon were mixed in an enamel kettle C and heated to 60° C. The reaction time was 40 min, and then dehydrated under reduced pressure;

[0051] (10) Add 130 kg of acetone to the enamel kettle C, control the temperature to 35-40° C., stir for 30 min, cool to 25° C., filter with a plastic filter, wash with acetone, and evaporate to remove the acetone;

[0052] (11) Cool down to 10°C, add 16 kg of ethyl acetate to the enameled kettle C, control the temperature to -2-2°C, and stir for 2 h;

[0053] (12) After centrifugation, the filter cake was placed in a double cone dryer for drying to obtain 192.1 kg of α-ketoglutaric acid with a yield of 85.44% and a purity of 99.22%.

[0054] Example 2

[0055] A method for synthesizing α-ketoglutaric acid comprises the following steps:

[0056] (1) Add 200 kg of water and 100 kg of dimethyl 2,2-dichloroglutarate into an enameled kettle B and control the temperature to 8-10°C;

[0057] (2) Add 15% sodium hydroxide to the enameled kettle B until the pH is 7.0, control the temperature at 15-20°C, and add for 1.5 hours;

[0058] (3) Add 30% sodium hydroxide to the enameled kettle B, control the temperature to 95-100°C, reflux for 3.5 hours, and maintain the pH at 8.3;

[0059] (4) Add 50 kg of anhydrous calcium chloride to the enameled kettle B, control the temperature to 75-80°C, and stir for 2.5 hours;

[0060] (5) After the stirring is completed, the mixture is cooled to 23° C. and centrifuged to obtain a mixture;

[0061] (6) Add 160 kg of water and 80 kg of the mixture into the reactor and stir, and control the temperature to 6-10°C;

[0062] (7) Add 30% aqueous sulfuric acid solution to the reaction kettle, adjust the pH to 1.4, control the temperature to 25-27° C., and react for 1.5 hours; during the reaction, maintain the pH at 1.3-1.4;

[0063] (8) After drying with a plastic-lined centrifuge, the filtrate is rinsed with pure water, and the filtrate is dried again and collected to obtain a crude α-ketoglutaric acid aqueous solution;

[0064] (9) The crude α-ketoglutaric acid aqueous solution and 8 kg of activated carbon were mixed in an enamel kettle C and heated to 55° C. The reaction time was 35 min, and then dehydrated under reduced pressure;

[0065] (10) Add 124 kg of acetone to the enamel kettle C, control the temperature to 30-35° C., stir for 25 min, cool to 23° C., filter with a plastic filter, wash with acetone, and evaporate to remove the acetone;

[0066] (11) Cool down to 10°C, add 12 kg of ethyl acetate to the enameled kettle C, control the temperature to 3-7°C, and stir for 2 h;

[0067] (12) After centrifugation, the filter cake was placed in a double cone dryer for drying to obtain 191.4 kg of α-ketoglutaric acid with a yield of 85.13% and a purity of 98.95%.

[0068] Example 3

[0069] A method for synthesizing α-ketoglutaric acid comprises the following steps:

[0070] (1) Add 200 kg of water and 100 kg of dimethyl 2,2-dichloroglutarate into an enameled kettle B and control the temperature to 8-10°C;

[0071] (2) Add 15% sodium hydroxide to the enameled kettle B until the pH is 7.0, control the temperature at 10-15°C, and add for 2.5 hours;

[0072] (3) Add 30% sodium hydroxide to the enameled kettle B, control the temperature to 95-100°C, reflux for 4 hours, and maintain the pH at 8.5;

[0073] (4) Add 100 kg of anhydrous calcium chloride to the enameled kettle B, control the temperature to 70-75°C, and stir for 3 hours;

[0074] (5) After the stirring is completed, the mixture is cooled to 25° C. and centrifuged to obtain a mixture;

[0075] (6) Add 200 kg of water and 80 kg of the mixture into the reactor and stir, and control the temperature to 2-6 ° C;

[0076] (7) Add 30% aqueous sulfuric acid solution to the reaction kettle, adjust the pH to 1.3, control the temperature to 25-27° C., and react for 2.5 hours; during the reaction, maintain the pH at 1.3-1.4;

[0077] (8) After drying with a plastic-lined centrifuge, the filtrate is rinsed with pure water, and the filtrate is dried again and collected to obtain a crude α-ketoglutaric acid aqueous solution;

[0078] (9) Add the crude α-ketoglutaric acid aqueous solution and 8 kg of activated carbon into the enamel kettle C, mix, heat to 65° C., react for 45 min, and then dehydrate under reduced pressure;

[0079] (10) Add 132 kg of acetone to the enameled kettle C, control the temperature to 25-30° C., stir for 35 min, cool to 27° C., filter with a plastic filter, wash with acetone, and evaporate to remove the acetone;

[0080] (11) Cool down to 10°C, add 18 kg of ethyl acetate to the enameled kettle C, control the temperature to -5-0°C, and stir for 2 h;

[0081] (12) After centrifugation, the filter cake was placed in a double cone dryer for drying to obtain 191.8 kg of α-ketoglutaric acid with a yield of 85.35% and a purity of 99.15%.

[0082] Example 4

[0083] A method for synthesizing α-ketoglutaric acid comprises the following steps:

[0084] (1) Add 200 kg of water and 100 kg of dimethyl 2,2-dichloroglutarate into an enameled kettle B and control the temperature to 8°C;

[0085] (2) Add 15% sodium hydroxide to the enameled kettle B until the pH is 7, control the temperature at 20-25°C, and add for 2 hours;

[0086] (3) Add 30% sodium hydroxide to the enameled kettle B, control the temperature to 95-100°C, reflux for 3 hours, and maintain the pH at 8.2;

[0087] (4) Add 75 kg of anhydrous calcium chloride to the enameled kettle B, control the temperature to 72-76°C, and stir for 2 hours;

[0088] (5) After the stirring is completed, the temperature is lowered to 25° C. and the mixture is obtained by centrifugation;

[0089] (6) Add 200 kg of water and 80 kg of the mixture into the reactor and stir, controlling the temperature to 5-10°C;

[0090] (7) Add 30% aqueous sulfuric acid solution to the reaction kettle, adjust the pH to 1.3, control the temperature to 24-26° C., and react for 2 h; during the reaction, maintain the pH at 1.3-1.4;

[0091] (8) After drying with a plastic-lined centrifuge, the filtrate is rinsed with pure water, and the filtrate is dried again and collected to obtain a crude α-ketoglutaric acid aqueous solution;

[0092] (9) The crude α-ketoglutaric acid aqueous solution and 8 kg of activated carbon were mixed in an enamel kettle C and heated to 60° C. The reaction time was 40 min, and then dehydrated under reduced pressure;

[0093] (10) Add 130 kg of acetone to the enamel kettle C, control the temperature to 35-40° C., stir for 30 min, cool to 25° C., filter with a plastic filter, wash with acetone, and evaporate to remove the acetone;

[0094] (11) Cool down to 10°C, add 16 kg of ethyl acetate to the enameled kettle C, control the temperature to -2-2°C, and stir for 2 h;

[0095] (12) After centrifugation, the filter cake was placed in a double cone dryer for drying to obtain 191.1 kg of α-ketoglutaric acid with a yield of 84.99% and a purity of 98.92%.

[0096] Comparative Example 1

[0097] Compared with Example 1, Comparative Example 1 replaced 15% sodium hydroxide with 30% sodium hydroxide, and the rest was the same as Example 1. 182.9 kg of α-ketoglutaric acid was obtained, with a yield of 81.35% and a purity of 98.97%.

[0098] Comparative Example 2

[0099] Compared with Example 1, in Comparative Example 2, 30% sodium hydroxide was replaced by 15% sodium hydroxide, and the rest was the same as Example 1. 183.8 kg of α-ketoglutaric acid was obtained, with a yield of 81.75% and a purity of 99.03%.

[0100] Comparative Example 3

[0101] Compared with Example 1, Comparative Example 3 added 30% sodium hydroxide, controlled the temperature to 70-75°C, and the rest was the same as Example 1. 185.4 kg of α-ketoglutaric acid was obtained, with a yield of 82.46% and a purity of 99.13%.

[0102] Comparative Example 4

[0103] A method for synthesizing α-ketoglutaric acid comprises the following steps:

[0104] (1) Add 200 kg of water and 100 kg of dimethyl 2,2-dichloroglutarate into an enameled kettle B and control the temperature to 8-10°C;

[0105] (2) Add 30% sodium hydroxide to the enameled kettle B until the pH reaches 6.5, control the temperature at 20-25°C, and add for 2 hours;

[0106] (3) Add 15% sodium hydroxide to the enameled kettle B, control the temperature to 95-100°C, reflux for 3 hours, and maintain the pH at 8;

[0107] (4) Add 75 kg of anhydrous calcium chloride to the enameled kettle B, control the temperature to 70-75°C, and stir for 2 hours;

[0108] (5) After the stirring is completed, the temperature is lowered to 20° C. and the mixture is obtained by centrifugation;

[0109] (6) Add 240 kg of water and 80 kg of the mixture into the reactor and stir, and control the temperature to 0-5°C;

[0110] (7) Add 30% aqueous sulfuric acid solution to the reaction kettle, adjust the pH to 1.3, control the temperature to 22-25° C., and react for 2 h; during the reaction, maintain the pH at 1.3-1.4;

[0111] (8) After drying with a plastic-lined centrifuge, the filtrate is rinsed with pure water, and the filtrate is dried again and collected to obtain a crude α-ketoglutaric acid aqueous solution;

[0112] (9) The crude α-ketoglutaric acid aqueous solution and 8 kg of activated carbon were mixed in an enamel kettle C and heated to 60° C. The reaction time was 40 min, and then dehydrated under reduced pressure;

[0113] (10) Add 130 kg of acetone to the enamel kettle C, control the temperature to 35-40° C., stir for 30 min, cool to 25° C., filter with a plastic filter, wash with acetone, and evaporate to remove the acetone;

[0114] (11) Cool down to 10°C, add 16 kg of ethyl acetate to the enameled kettle C, control the temperature to -2-2°C, and stir for 2 h;

[0115] (12) After centrifugation, the filter cake was placed in a double cone dryer for drying to obtain 182.2 kg of α-ketoglutaric acid with a yield of 81.04% and a purity of 99.01%.

[0116] Comparative Example 5

[0117] A method for synthesizing α-ketoglutaric acid comprises the following steps:

[0118] (1) Add 200 kg of water and 100 kg of dimethyl 2,2-dichloroglutarate into an enameled kettle B and control the temperature to 8-10°C;

[0119] (2) Add 15% sodium hydroxide to the enameled kettle B until the pH reaches 6.5, control the temperature at 20-25°C, and add for 2 hours;

[0120] (3) Add 30% sodium hydroxide to the enameled kettle B, control the temperature to 95-100°C, reflux for 3 hours, and maintain the pH at 8;

[0121] (4) Add 75 kg of anhydrous calcium chloride to the enameled kettle B, control the temperature to 70-75°C, and stir for 2 hours;

[0122] (5) After the stirring is completed, the temperature is lowered to 20° C. and the mixture is obtained by centrifugation;

[0123] (6) Add 240 kg of water and 80 kg of the mixture into the reactor and stir, and control the temperature to 0-5°C;

[0124] (7) Add 30% aqueous sulfuric acid solution to the reaction kettle, adjust the pH to 1.3, control the temperature to 22-25° C., and react for 2 h; during the reaction, maintain the pH at 1.3-1.4;

[0125] (8) After drying with a plastic-lined centrifuge, the filtrate is rinsed with pure water, and the filtrate is dried again and collected to obtain a crude α-ketoglutaric acid aqueous solution;

[0126] (10) The crude α-ketoglutaric acid aqueous solution and 30 kg of acetone were mixed in an enamel kettle C and heated to 35-40° C., stirred for 30 min, cooled to 25° C., filtered using a plastic filter, washed with acetone, and then evaporated to remove the acetone;

[0127] (11) Cool down to 10°C, add 16 kg of ethyl acetate to the enameled kettle C, control the temperature to -2-2°C, and stir for 2 h;

[0128] (12) After centrifugation, the filter cake was placed in a double cone dryer for drying to obtain 191.5 kg of α-ketoglutaric acid with a yield of 85.17% and a purity of 99.01%.

[0129] It can be seen from the yields and purities of Examples 1-4 and Comparative Examples 1-5 that Example 1 is the best example of the present invention, with a yield of 85.44% and a purity of 99.22%.

[0130] Compared with Example 1, Comparative Example 1 replaces 15% sodium hydroxide with 30% sodium hydroxide, Comparative Example 2 replaces 30% sodium hydroxide with 15% sodium hydroxide, Comparative Example 3 reduces the reaction temperature of 30% sodium hydroxide, and Comparative Example 4 changes the order of adding 15% sodium hydroxide and 30% sodium hydroxide. As a result, the yields of α-ketoglutaric acid in Comparative Examples 1-4 are all lower than those in Example 1. Comparative Example 5 does not add acetone, and the purity of α-ketoglutaric acid is lower than that in Example 1.

[0131] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing α-ketoglutaric acid, characterized in that: The following steps are involved: S1, methyl dichloroacetate and methyl acrylate react in the presence of sodium methoxide to obtain dimethyl 2,2-dichloroglutarate; S2, reacting dimethyl 2,2-dichloroglutarate with 15% alkali solution and 30% alkali solution in sequence to obtain a crude α-ketoglutaric acid aqueous solution; S3, refining the crude α-ketoglutaric acid aqueous solution to obtain α-ketoglutaric acid; The S2 comprises the following steps: A1. Add water and dimethyl 2,2-dichloroglutarate into reactor A and control the temperature to 8-10°C; A2, add 15% sodium hydroxide to reactor A until the pH is 6.5-7.0; A3, add 30% sodium hydroxide to continue the reaction until the pH is 8-8.5; A4, add inorganic salt, control the temperature to 70-80℃, and stir for 2-3h; A5. After the stirring is completed, the temperature is lowered to 20-25°C and centrifuged to obtain a mixture; A6, add water and mixture into reactor B, and control the temperature to ≤10°C; A7, add acid solution to reactor B, adjust pH to 1.3-1.4, control temperature to 22-27°C, and react for 1.5-2.5h; A8, filtering, washing and collecting the filtrate to obtain a crude α-ketoglutaric acid aqueous solution; When 15% sodium hydroxide is added dropwise to A2, the temperature is controlled to be ≤25°C and the adding time is 1.5-2.5h; When 30% sodium hydroxide is added to A3, the temperature is controlled at 95-100° C. and refluxed for 3-4 hours.

2. The method for synthesizing α-ketoglutaric acid according to claim 1, characterized in that: The mass ratio of dimethyl 2,2-dichloroglutarate to water in A1 is 1:2; the mass ratio of the mixture to water in A6 is 1:2-3.

3. The method for synthesizing α-ketoglutaric acid according to claim 1, characterized in that: The mass ratio of dimethyl 2,2-dichloroglutarate to inorganic salt in A2 is 1:0.5-1.

4. The method for synthesizing α-ketoglutaric acid according to claim 1, characterized in that: The S3 comprises the following steps: B1, adding crude α-ketoglutaric acid aqueous solution and activated carbon into a reactor for reaction, and then performing decompression dehydration; B2. Add acetone to the reactor and stir, then cool to 23-27°C, filter, wash, and evaporate to remove acetone; B3. Add ethyl acetate to the reactor, control the temperature to -5°C-10°C, and stir for 1.2-2.5h; B4, after centrifugation and drying, α-ketoglutaric acid is obtained.

5. The method for synthesizing α-ketoglutaric acid according to claim 4, characterized in that: The reaction temperature in B1 is 55-65° C., and the reaction time is 35-45 min.

6. The method for synthesizing α-ketoglutaric acid according to claim 4, characterized in that: After adding acetone to B2, the temperature was controlled to be ≤45°C and stirred for 25-35 minutes.