Synthetic method of oxaloacetic acid

Abstract

The invention discloses a synthesis method of oxaloacetic acid, which comprises the following steps: S1, under the protection of inert gas, oxalyl chloride and alcohol react in an organic solvent, the reaction temperature is 0-70 DEG C, the reaction time is 1-12 hours, oxalic acid diester is obtained, and an alkaline substance is dispersed in the organic solvent; s2, under the protection of inert gas, oxalic acid diester and acetic ester are subjected to a Claisen ester condensation reaction in an organic solvent, the reaction temperature is 0-70 DEG C, the reaction time is 1-12 h, a condensation product is obtained, and an alkaline substance is dispersed in the organic solvent; and S3, adding an aqueous solution of an alkaline substance into the condensation product, reacting at 0-70 DEG C for 1-24 hours, adding acid to adjust the pH value to 1-6, and purifying to obtain oxaloacetic acid. According to the synthesis method of oxaloacetic acid, the total yield reaches up to 80.03%, the yield is stable, the reaction process is easy to control, and industrial production is easy.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for synthesizing oxaloacetic acid. Background Art

[0002] Oxalacetic acid (OAA), also known as oxaloacetic acid, 2-carbonylsuccinic acid, and 2-oxosuccinic acid, is a four-carbon small molecule that participates in metabolic processes such as gluconeogenesis, the tricarboxylic acid cycle, the urea cycle, and amino acids. It is also an essential component for producing ATP, maintaining the tricarboxylic acid cycle, and the electron transport chain. It is an important intermediate metabolite that plays a great role in human health.

[0003] Oxaloacetate has a wide range of pharmacological effects. It can promote neurogenesis and mitochondrial generation; clear blood glutamate and promote the transport of glutamate from the brain to the peripheral blood; it can also promote glycolysis of nerve cells; it has anti-inflammatory and antioxidant effects; and it has certain therapeutic effects on cerebral ischemia, amyotrophic lateral sclerosis, epilepsy, glioma, Alzheimer's disease and other diseases.

[0004] Oxaloacetate is synthesized biochemically by oxidation of L-malate by malate dehydrogenase. Although the biochemical route is highly selective, it is greatly affected by the space-time yield.

[0005]

[0006] There are few reports on the chemical synthesis of oxaloacetic acid. Summary of the invention

[0007] In view of the above-mentioned defects of the prior art, the present invention provides a method for synthesizing oxaloacetic acid, which produces oxaloacetic acid by chemical synthesis to overcome the limitations of output and yield brought about by biochemical pathways.

[0008] In order to solve the above technical problems, the present invention provides a method for synthesizing oxaloacetic acid, comprising the following steps:

[0009] S1. Under the protection of inert gas, oxalyl chloride reacts with alcohol in an organic solvent at a reaction temperature of 0-70° C. for a reaction time of 1-12 h to obtain oxalic acid diester, wherein an alkaline substance is dispersed in the organic solvent;

[0010] S2, under the protection of inert gas, oxalic acid diester and acetate are subjected to Claisen ester condensation reaction in an organic solvent, the reaction temperature is 0-70° C., the reaction time is 1-12 h, and a condensation product is obtained, wherein the organic solvent is dispersed with an alkaline substance;

[0011] S3. Add an aqueous solution of an alkaline substance to the condensation product, react at 0-70° C. for 1-24 hours, add acid to adjust the pH value to 1-6, and purify to obtain oxaloacetic acid.

[0012] As a preferred embodiment, in step S1, the alcohol is selected from any one or more combinations of methanol, ethanol, isopropanol, n-butanol, and tert-butanol.

[0013] As a preferred embodiment, the organic solvent in step S1 is selected from any one or more combinations of methanol, ethanol, propanol, isopropanol, tert-butanol, acetonitrile, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, ether, isopropyl ether, and methyl tert-butyl ether.

[0014] As a more preferred embodiment, the organic solvent in step S1 is selected from methanol or ethanol.

[0015] As a preferred embodiment, the alkaline substance in step S1 is selected from any one or more combinations of potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, sodium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, pyridine, triethylamine, sodium acetate, sodium formate, potassium tert-butoxide, sodium tert-butoxide, and diisopropylethylamine.

[0016] As a more preferred embodiment, the alkaline substance in step S1 is selected from triethylamine or diisopropylethylamine.

[0017] As a preferred embodiment, step S1 further includes a step of adding a quenching agent for quenching after the reaction.

[0018] As a more preferred embodiment, the quenching agent is selected from any one or more combinations of sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, citric acid, and ammonium chloride.

[0019] As a more preferred embodiment, the quenching agent is selected from sulfuric acid or hydrochloric acid.

[0020] As a preferred embodiment, the oxalic acid diester in step S2 is selected from any one of dimethyl oxalate, diethyl oxalate, isopropyl oxalate, n-butyl oxalate, and tert-butyl oxalate.

[0021] As a more preferred embodiment, the oxalic acid diester in step S2 is dimethyl oxalate or diethyl oxalate.

[0022] As a preferred embodiment, the acetate in step S2 is selected from any one of methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, and tert-butyl acetate.

[0023] As a more preferred embodiment, the acetate in step S2 is methyl acetate or ethyl acetate.

[0024] As a preferred embodiment, the organic solvent in step S2 is selected from any one or more combinations of methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetonitrile, water, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, ether, isopropyl ether, and methyl tert-butyl ether.

[0025] As a preferred embodiment, the alkaline substance in step S2 is selected from any one of n-butyl lithium, sec-butyl lithium, tert-butyl lithium, sodium hydride, trityl sodium, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, and sodium tert-butoxide.

[0026] As a preferred embodiment, the alkaline substance in step S3 is selected from any one of lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium methoxide, sodium ethoxide, and ammonia water.

[0027] As a preferred embodiment, the acid in step S3 is selected from a mixture of any one or more of sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, citric acid, and ammonium chloride.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] (1) The method for synthesizing oxaloacetic acid of the present invention has high total yield, stable yield, easy control of the reaction process, and is easy for industrial production.

[0030] (2) The oxaloacetic acid synthesized by the present invention can be left at room temperature, is not easy to deteriorate, and the product is stable.

[0031] (3) The method for synthesizing oxaloacetic acid of the present invention has mild reaction conditions, simple operation steps, and is convenient for expanding production.

[0032] The concept, specific structure and technical effects of the present invention will be further described below in conjunction with the accompanying drawings to fully understand the purpose, characteristics and effects of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is the H-NMR spectrum of oxaloacetic acid obtained in Example 1 of the present invention.

[0034] Figure 2 It is the liquid chromatography-mass spectrometry (LCMS) spectrum of oxaloacetic acid prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0035] In order to make the technical means, creative features, objectives and effects of the invention easier to understand, the invention is further described below with reference to specific illustrations. However, the invention is not limited to the following implementation cases.

[0036] It should be noted that the structures, proportions, sizes, etc. illustrated in the drawings of this specification are only used to match the contents disclosed in the specification so as to facilitate understanding and reading by persons familiar with this technology. They are not used to limit the conditions under which the present invention can be implemented, and therefore have no substantive technical significance. Any structural modification, change in proportion or adjustment of size, without affecting the effects and purposes that can be achieved by the present invention, should still fall within the scope of the technical contents disclosed by the present invention.

[0037] Oxaloacetic acid is widely used and has a large demand for its use. However, currently oxaloacetic acid is mostly synthesized biochemically by oxidizing L-malic acid with malate dehydrogenase, but the yield and production rate are relatively low and cannot meet the current demand for use.

[0038] In order to solve this technical problem, the applicant of the present invention explored a chemical synthesis method, using oxalyl chloride as a raw material, reacting with alcohol to form oxalic acid diester, and the oxalic acid diester and acetate undergo Claisen ester condensation reaction, the condensation product is hydrolyzed under alkaline conditions, and further acid is added to adjust the pH value to obtain oxaloacetic acid.

[0039] The reaction equation is as follows:

[0040]

[0041] The above reaction involves three steps:

[0042] Step S1, under the protection of inert gas, oxalyl chloride and alcohol react in an organic solvent, the reaction temperature is 0-70° C., the reaction time is 1-12 hours, and oxalic acid diester is obtained, wherein alkaline substances are dispersed in the organic solvent.

[0043] The reaction conditions involved in step S1 are as follows:

[0044] The molar equivalent ratio of oxalyl chloride to alcohol is 1:2-1:100, preferably 1:2-1:5, more preferably 1:3;

[0045] The alcohol is selected from any one or more combinations of methanol, ethanol, isopropanol, n-butanol, and tert-butanol. Preferably, the alcohol is selected from methanol or ethanol.

[0046] The mass volume ratio of oxalyl chloride to the organic solvent is 1:1-1:100, preferably 1:7-1:10;

[0047] It should be noted that the mass-to-volume ratio refers to the stoichiometric relationship between the reaction raw materials and the solvent in a chemical reaction. The proportional relationship is the ratio of the reaction raw materials (grams) to the solvent (milliliters). It reflects the proportional relationship between the reactions of different chemical substances. For example, the mass-to-volume ratio of oxalyl chloride to organic solvent is 1:1-1:100, which corresponds to 1g:1mL-1g:100mL.

[0048] The organic solvent is selected from any one or more combinations of methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetonitrile, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, ether, isopropyl ether, and methyl tert-butyl ether. Preferably, it is methanol or ethanol.

[0049] The molar equivalent ratio of oxalyl chloride to the alkaline substance is 1:2-1:10, preferably 1:2-1:5, and more preferably 1:2.2;

[0050] It should be noted that molar equivalent refers to the stoichiometric relationship between chemical substances in a chemical reaction, and its unit is mole (mol). Equivalent is the amount of chemical substance required or produced in a chemical reaction, which reflects the proportional relationship between the reactions of different chemical substances.

[0051] The alkaline substance is selected from any one or more combinations of potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, sodium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, pyridine, triethylamine, sodium acetate, sodium formate, potassium tert-butoxide, sodium tert-butoxide, and diisopropylethylamine. Preferably, the alkaline substance is selected from triethylamine or diisopropylethylamine.

[0052] After the reaction in step S1, a quencher is added, and the quencher is selected from any one or more combinations of sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, citric acid, and ammonium chloride. Preferably, the quencher is selected from sulfuric acid or hydrochloric acid.

[0053] S2. Under the protection of inert gas, oxalic acid diester and acetate are subjected to Claisen ester condensation reaction in an organic solvent at a reaction temperature of 0-70° C. for a reaction time of 1-12 h to obtain a condensation product, wherein an alkaline substance is dispersed in the organic solvent.

[0054] The reaction conditions involved in step S2 are as follows:

[0055] The molar equivalent ratio of oxalic acid diester to acetate is 1:1-1:5, preferably 1:1-1:2, and more preferably 1:1.5.

[0056] The oxalic acid diester is selected from any one of dimethyl oxalate, diethyl oxalate, isopropyl oxalate, n-butyl oxalate, and tert-butyl oxalate. Preferably, the oxalic acid diester is dimethyl oxalate or diethyl oxalate.

[0057] The acetate is selected from any one of methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and tert-butyl acetate. Preferably, the acetate is methyl acetate or ethyl acetate.

[0058] The organic solvent is selected from any one or more combinations of methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetonitrile, water, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, ether, isopropyl ether, and methyl tert-butyl ether. Preferably, the organic solvent is acetonitrile or tetrahydrofuran.

[0059] The mass volume ratio of oxalic acid diester to organic solvent is 1:1-1:100, preferably 1:7-1:10.

[0060] The alkaline substance is selected from any one of n-butyllithium, sec-butyllithium, tert-butyllithium, sodium hydride, trityl sodium, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and sodium tert-butoxide.

[0061] The molar equivalent ratio of the oxalic acid diester to the alkaline substance is 1:1-1:5, preferably 1:1-1:2.

[0062] S3. Add an aqueous solution of an alkaline substance to the condensation product, react at 0-70° C. for 1-24 hours, add acid to adjust the pH value to 1-6, and purify to obtain oxaloacetic acid.

[0063] The reaction conditions involved in step S3 are as follows:

[0064] The alkaline substance is selected from any one of lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium methoxide, sodium ethoxide, and ammonia water. Preferably, the alkaline substance is selected from sodium hydroxide or potassium hydroxide.

[0065] The molar equivalent ratio of the oxalic acid diester to the alkaline substance is 1:2-1:10, preferably 1:2-1:5.

[0066] The acid is selected from any one or more of sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, citric acid, and ammonium chloride. Preferably, the acid is citric acid or sulfuric acid.

[0067] Example 1

[0068]

[0069] Under nitrogen protection, triethylamine (175.40 g, 2.2 eq) and DMAP (4-dimethylaminopyridine, 4.81 g, 0.05 eq, acting as a catalyst) were added to anhydrous ethanol (1000 mL), and oxalyl chloride (100.00 g, 1.0 eq) was added dropwise under stirring, and the temperature was controlled at 30-40° C. The addition time was about 2 hours. After the addition was completed, the mixture was stirred at room temperature for 12 hours. The reaction was detected by LC-MS. After the reaction was complete, the mixture was filtered; 3 mol / L hydrochloric acid was added dropwise to the filtrate to adjust the pH to 5-6, and dichloromethane was added to extract the separated liquids. The organic phase was concentrated to obtain a white solid I, i.e., diethyl oxalate (104.35 g, 90.63% yield);

[0070] Under nitrogen protection, acetonitrile (500 mL) was added to diethyl oxalate (50.00 g, 1.0 eq) and ethyl acetate (45.22 g, 1.5 eq), and the mixture was stirred evenly. The temperature was lowered to 0°C, sodium ethoxide (41.91 g, 1.8 eq) was added in batches, the temperature was controlled at 0-10°C, and the mixture was stirred at a constant temperature for 2 hours after the addition was completed. After the reaction was detected by LC-MS, a 3 mol / L sodium hydroxide aqueous solution (342.1 mL, 3.0 eq) was added to the reaction system, and the mixture was slowly warmed to room temperature and stirred at room temperature for 5 hours. After the reaction was detected by LC-MS, the reaction solution was poured into an icy citric acid aqueous solution, the pH was adjusted to 4-5, and the mixture was stirred for 20-30 min. After concentration, the mixture was slurried with ethyl acetate (150 mL), filtered, and the filtrate was concentrated to obtain an oxaloacetic acid solid, which was dried at 50°C in vacuum for 16 hours to obtain a white target product, oxaloacetic acid (39.90 g, yield: 88.30%, purity: 101%, melting point: 161-163°C). The purity was identified by titration and melting point measurement. The nuclear magnetic hydrogen spectrum (H-NMR) is shown in Figure 1 , and its LCMS spectra are shown in Figure 2 .

[0071] The synthesis method of oxaloacetic acid involves three reaction steps. In step 1, oxalic acid diester is generated. The preparation of oxalic acid diester uses oxalyl chloride as a raw material, which is low in price. When alcohol is used as a reaction solvent and triethylamine is used as a base, the reaction yield can be improved, and the yield can reach up to 90%; Steps 2 and 3 adopt a continuous feeding method, that is, after the condensation product is generated in step 2, it is directly hydrolyzed without treatment to obtain the final product, thereby simplifying the post-processing operation; in step 2, acetonitrile is used as a solvent, so that no more impurities are generated in the reaction, the post-reaction processing is simple, and the total yield is higher.

[0072] Example 2

[0073]

[0074] Under nitrogen protection, triethylamine (17.54 g, 2.2 eq) was added to anhydrous methanol (100 mL), and oxalyl chloride (10.00 g, 1.0 eq) was added dropwise under stirring, and the temperature was controlled at 30-40° C. The dropping time was about 2 hours. After the dropping was completed, the mixture was stirred at room temperature for 36 hours. The reaction was detected by LC-MS. After the reaction was complete, the mixture was filtered by suction; 3 mol / L hydrochloric acid was added dropwise to the filtrate to adjust the pH to 5-6, and dichloromethane was added to extract the separated liquids. The organic phase was concentrated to obtain a white solid I, i.e., dimethyl oxalate (8.03 g, 86.27% yield);

[0075] Under nitrogen protection, acetonitrile (50 mL) was added to dimethyl oxalate (5.00 g, 1.0 eq) and methyl acetate (4.70 g, 1.5 eq) and stirred evenly. The temperature was lowered to 0 ° C, sodium methoxide (4.12 g, 1.8 eq) was added in batches, and the temperature was controlled at 0-10 ° C. After the addition, the mixture was stirred at a constant temperature for 1 hour. After the reaction was complete by LC-MS, 3 mol / L sodium hydroxide aqueous solution (42.3 mL, 3.0 eq) was added to the reaction system, and the mixture was slowly heated to room temperature and stirred at room temperature for 3 hours. After the reaction was complete by LC-MS, the reaction solution was poured into an icy citric acid aqueous solution, the pH was adjusted to 4-5, and the mixture was stirred for 20-30 min. The mixture was concentrated, slurried with ethyl acetate (15 mL), filtered, and the filtrate was concentrated to obtain oxaloacetic acid solid, which was dried at 50 ° C in vacuum for 16 hours to obtain off-white solid oxaloacetic acid (4.67 g, yield 83.46%).

[0076] Example 3

[0077]

[0078] Under nitrogen protection, potassium carbonate (27.22g, 5eq) was added to anhydrous ethanol (50mL) and stirred evenly. The temperature was raised to 50°C, and oxalyl chloride (5.00g, 1.0eq) was slowly added dropwise, and the temperature was controlled at 50-60°C. The addition time was about 1 hour. After the addition was completed, the mixture was stirred at a constant temperature for 8 hours. The reaction was detected by LC-MS. After the reaction was complete, the mixture was filtered by suction; 3mol / L hydrochloric acid was added dropwise to adjust the pH to 5-6, and the liquid was extracted with dichloromethane. The organic phase was concentrated to obtain a white solid I, i.e. diethyl oxalate (3.59g, 62.41% yield). In this step, the choice of alkaline substances is crucial. Replacing triethylamine with potassium carbonate reduces the yield by more than 20%.

[0079] Under nitrogen protection, tetrahydrofuran (30 mL) was added to diethyl oxalate (3.00 g, 1.0 eq) and methyl acetate (3.04 g, 2.0 eq) and stirred evenly. The temperature was lowered to 5 ° C, potassium ethoxide [15% w / v ethanol solution] (28.8 mL, 2.5 eq) was slowly added dropwise, and the temperature was controlled at 5-15 ° C. After the addition, the temperature was kept constant for 1 hour. After LC-MS detection, the reaction system was added with 3 mol / L potassium hydroxide aqueous solution (20.5 mL, 3.0 eq), and the temperature was slowly raised to room temperature. Stirred at room temperature for 2 hours. After LC-MS detection, the reaction solution was poured into icy citric acid aqueous solution, pH = 4-5, stirred for 20-30 min, concentrated, slurried with ethyl acetate (10 mL), filtered, and concentrated the filtrate to obtain oxaloacetic acid solid, which was dried at 50 ° C in vacuum for 16 hours to obtain off-white oxaloacetic acid (1.95 g, yield 71.84%). Therefore, potassium ethanolate is used as a reaction reagent in the step, and impurities are relatively more, and the yield obtained is low.

[0080] Example 4

[0081]

[0082] Under nitrogen protection, add diisopropylethylamine (12.73g, 2.5eq) to anhydrous methanol (50mL) and stir evenly. Cool to 5°C, slowly add oxalyl chloride (5.00g, 1.0eq), control the temperature at 5-10°C, and add for about 1 hour. After the addition is complete, naturally return to room temperature and stir for 12 hours. LC-MS is used to detect the reaction. After the reaction is complete, filter with suction; add 3mol / L hydrochloric acid to the filtrate to adjust the pH to 5-6, extract the separated liquid with dichloromethane, and concentrate the organic phase to obtain white solid I, i.e. dimethyl oxalate (3.87g, 83.26% yield);

[0083] Under nitrogen protection, tetrahydrofuran (30 mL) was added to dimethyl oxalate (3.00 g, 1.0 eq) and ethyl acetate (3.76 g, 2.0 eq) and stirred evenly. The temperature was lowered to 10 ° C, potassium methoxide (4.45 g, 2.5 eq) was added in batches, and the temperature was controlled at 10-20 ° C. After the addition, the mixture was stirred at a constant temperature for 1 hour. After the reaction was complete by LC-MS, 3 mol / L potassium hydroxide aqueous solution (25.4 mL, 3.0 eq) was added to the reaction system, and the mixture was slowly heated to room temperature and stirred at room temperature for 2 hours. After the reaction was complete by LC-MS, the reaction solution was poured into an icy citric acid aqueous solution, the pH was adjusted to 4-5, and the mixture was stirred for 20-30 min. The mixture was concentrated, slurried with ethyl acetate (10 mL), filtered, and the filtrate was concentrated to obtain oxaloacetic acid solid, which was dried at 50 ° C in vacuum for 16 hours to obtain off-white oxaloacetic acid (2.46 g, yield 73.33%). In this step, since potassium methoxide is used as a reaction reagent, there are many impurities, the reaction effect is poor, and the yield of the target product is low.

[0084] Example 5

[0085]

[0086] Under nitrogen protection, methyl tert-butyl ether (30 mL) was added to dimethyl oxalate (3.00 g, 1.0 eq) and ethyl acetate (2.82 g, 1.5 eq) prepared in Example 2, and stirred evenly. The mixture was cooled to 10 ° C, and sodium tert-butyl alcohol (4.39 g, 1.8 eq) was added in batches, and the temperature was controlled at 10-20 ° C. After the addition, the mixture was stirred at a constant temperature for 1 hour. After the reaction was complete by LC-MS detection, 15 mL of 1 mol / L dilute hydrochloric acid was added to quench the mixture, and the liquid was extracted with methyl tert-butyl ether, and the organic phase was concentrated to obtain a yellow oil. Under nitrogen protection, tetrahydrofuran (30 mL) was added to the yellow oil and stirred evenly. The temperature was lowered to 10-20°C, 3 mol / L potassium hydroxide aqueous solution (25.4 mL, 3.0 eq) was added dropwise, the temperature was slowly raised to room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into glacial citric acid aqueous solution, the pH was adjusted to 4-5, and the mixture was stirred for 20-30 min. The mixture was concentrated, slurried with ethyl acetate (10 mL), filtered, and the filtrate was concentrated to obtain oxaloacetic acid solid, which was dried in vacuo at 50°C for 16 hours to obtain off-white oxaloacetic acid (2.07 g, yield 61.84%).

[0087] By comparing Example 2 with Example 5, it can be seen that the total yield of steps S2 and S3 can be improved by nearly 20% by directly performing subsequent steps on the condensation product generated in step S2 without post-treatment.

[0088] Example 6

[0089]

[0090] Under nitrogen protection, acetonitrile (10 mL) was added to dimethyl oxalate (1.00 g, 1.0 eq) and methyl acetate (0.94 g, 1.5 eq) prepared in Example 2, and stirred evenly. The mixture was cooled to 0 ° C, and sodium methoxide (0.82 g, 1.8 eq) was added in batches, and the temperature was controlled at 30-40 ° C. After the addition, the mixture was heated to 50 ° C and stirred for 1 hour. After LC-MS detected that the raw material reacted completely, 3 mol / L potassium hydroxide aqueous solution (8.5 mL, 3.0 eq) was added to the reaction system, and the mixture was slowly heated to room temperature and stirred at room temperature for 3 hours. After LC-MS detected that the reaction was complete, the reaction solution was poured into an icy citric acid aqueous solution, the pH was adjusted to 4-5, and the mixture was stirred for 20-30 min, concentrated, and slurried with ethyl acetate (3.5 mL), filtered, and the filtrate was concentrated to obtain oxaloacetic acid solid, which was dried at 50 ° C in vacuum for 16 hours to obtain off-white solid oxaloacetic acid (0.60 g, yield 53.76%).

[0091] By comparing Example 2 and Example 6, it can be seen that the reaction temperature of step S2 can directly affect the yield of the target product. When the reaction temperature of step S2 is 0-10°C, the total yield of steps S2 and S3 is 83.46%; and when the reaction temperature of step S2 is 30-40°C, the total yield of steps S2 and S3 is only 53.76%, which is reduced by nearly 30%.

[0092] The preferred specific embodiments of the present invention are described in detail above. It should be understood that a person skilled in the art can make many modifications and changes based on the concept of the present invention without creative work. Therefore, any technical solution that can be obtained by a person skilled in the art through logical analysis, reasoning or limited experiments based on the concept of the present invention on the basis of the prior art should be within the scope of protection determined by the claims.

Claims

1. A method for synthesizing oxaloacetic acid, characterized in that: The steps include: S1. Under the protection of inert gas, oxalyl chloride reacts with alcohol in an organic solvent at a reaction temperature of 0-70° C. for a reaction time of 1-12 h to obtain oxalic acid diester, wherein an alkaline substance is dispersed in the organic solvent; S2, under the protection of inert gas, oxalic acid diester and acetate are subjected to Claisen ester condensation reaction in an organic solvent, the reaction temperature is 0-70° C., the reaction time is 1-12 h, and a condensation product is obtained, wherein the organic solvent is dispersed with an alkaline substance; S3. Add an aqueous solution of an alkaline substance to the condensation product, react at 0-70° C. for 1-24 hours, add acid to adjust the pH value to 1-6, and purify to obtain oxaloacetic acid.

2. The method for synthesizing oxaloacetic acid according to claim 1, characterized in that The alcohol in step S1 is selected from any one or more combinations of methanol, ethanol, isopropanol, n-butanol, and tert-butanol, and the organic solvent in step S1 is selected from any one or more combinations of methanol, ethanol, propanol, isopropanol, tert-butanol, acetonitrile, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, ether, isopropyl ether, and methyl tert-butyl ether.

3. The method for synthesizing oxaloacetic acid according to claim 1, characterized in that: The alkaline substance in step S1 is selected from any one or more combinations of potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, pyridine, triethylamine, sodium acetate, sodium formate, potassium tert-butoxide, sodium tert-butoxide, and diisopropylethylamine.

4. The method for synthesizing oxaloacetic acid according to claim 1, characterized in that: After the reaction in step S1, a quenching agent is added for quenching, and the quenching agent is selected from any one or more combinations of sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, citric acid, and ammonium chloride.

5. The method for synthesizing oxaloacetic acid according to claim 1, characterized in that: The oxalic acid diester in step S2 is selected from any one of dimethyl oxalate, diethyl oxalate, isopropyl oxalate, n-butyl oxalate and tert-butyl oxalate.

6. The method for synthesizing oxaloacetic acid according to claim 1, characterized in that: The acetate in step S2 is selected from any one of methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, and tert-butyl acetate.

7. The method for synthesizing oxaloacetic acid according to claim 1, characterized in that: The organic solvent in step S2 is selected from any one or more combinations of methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetonitrile, water, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, ether, isopropyl ether, and methyl tert-butyl ether.

8. The method for synthesizing oxaloacetic acid according to claim 1, characterized in that: The alkaline substance in step S2 is selected from any one of n-butyl lithium, sec-butyl lithium, tert-butyl lithium, sodium hydride, trityl sodium, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, and sodium tert-butoxide.

9. The method for synthesizing oxaloacetic acid according to claim 1, characterized in that: The alkaline substance in step S3 is selected from any one of lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium methoxide, sodium ethoxide, and ammonia water.

10. The method for synthesizing oxaloacetic acid according to claim 1, characterized in that: The acid in step S3 is selected from a mixture of any one or more of sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, citric acid, and ammonium chloride.

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