A process for the preparation of 2-hydroxy-3-oxopentanedioic acid

Abstract

The application discloses a preparation method of 2-hydroxy-3-oxopentane diacid, which comprises the following steps: S1), an oxidation reaction: acetyl acetate is added into a solvent, an oxidant is added, and a first product is prepared through reaction; S2), a condensation reaction: the first product and carbonic ester are added into a solvent, an alkali is added, and a second product is prepared through reaction; and S3), a hydrolysis reaction: the second product is added into water containing a catalyst, and 2-hydroxy-3-oxopentane diacid is prepared through reflux reaction. The preparation method is simple in process, easy to operate, environment-friendly, pollution-free, low in cost, safe in operation, easy for industrial scale production, high in conversion rate and good in product quality.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to a preparation method of 2-hydroxy-3-oxopentanedioic acid. BACKGROUND

[0002] 2-hydroxy-3-oxopentanedioic acid is a highly reactive substance, and a large number of downstream compounds can be synthesized by using 2-hydroxy-3-oxopentanedioic acid as a raw material, wherein the most important class of downstream compounds is furanone compounds. Furanone compounds widely exist in nature, and have a wide range of uses due to their small molecules and high biological activity, such as: 4-hydroxy-2,5-dimethyl-3(2H)-furanone is used in the perfume, food industry, and research in the field of medicine; (E)-1(3H)-isobenzofuranone-3-acetamide compounds have anti-convulsive activity; 4-(4-methylsulfonyl)phenyl-3-phenyl-2(5H)-furanone has in-vitro anticancer activity; 3-substituted-1(3H)-isobenzofuranone optical isomers have anti-platelet activity; bromo 2-(5H)-furanone has an inhibitory effect on the formation of green pyocyanin biofilm; and 2-hydroxy-3-oxopentanedioic acid is an intermediate of the mother nucleus structure of the antitumor drug gemcitabine.

[0003] 2-hydroxy-3-oxopentanedioic acid is an important basic raw material, but its preparation method has not been disclosed, and therefore the present application provides a preparation method of 2-hydroxy-3-oxopentanedioic acid with a simple process. SUMMARY

[0004] The present application aims to provide a preparation method of 2-hydroxy-3-oxopentanedioic acid, which has the advantages of simple process, easy operation, short process, environmental protection, easy industrial scale production, and high conversion rate.

[0005] To achieve the above-mentioned purpose, the technical solution adopted by the present application is as follows: a preparation method of 2-hydroxy-3-oxopentanedioic acid, comprising the following steps:

[0006] S1) oxidation reaction: acetoacetic ester is added to a first solvent, and an oxidizing agent is slowly added while maintaining a temperature of-10-20℃, to obtain a first product, and the structural formula of the first product is:

[0007]

[0008] S2) condensation reaction: the first product and carbonic ester are added to a second solvent, and a base is slowly added at a temperature of 0-30℃, and after the reaction is completed, the second product is obtained by acidification, and the structural formula of the second product is:

[0009]

[0010] S3) Hydrolysis reaction: The second product is added to a third solvent with a catalyst, refluxed for 3-6 hours, adjusted to weakly acidic, to produce 2-hydroxy-3-oxopentanedioic acid.

[0011] As a further optimization, R1 in S1 is methyl, ethyl, isopropyl, tert-butyl, or benzyl, preferably methyl or ethyl.

[0012] As a further optimization, the first solvent in S1 is one or more of dichloromethane, trichloromethane, 1,2-dichloroethane, ethyl acetate, benzene, and diethyl ether, preferably dichloromethane, and / or 1,2-dichloroethane, in a weight ratio of (1-10): 1, preferably a mass ratio of 8: 1, to acetoacetate.

[0013] As a further optimization, the oxidizing agent in S1 is one or more of meta-chloroperoxybenzoic acid, iodobenzene acid, cobalt dodecatungstate, sodium percarbonate, preferably meta-chloroperoxybenzoic acid, in a molar ratio of (1-2): 1, preferably a molar ratio of 1.2: 1, to acetoacetate.

[0014] As a further optimization, R2 in S2 is methyl, ethyl, isopropyl, tert-butyl, or benzyl, preferably methyl or ethyl.

[0015] As a further optimization, the molar ratio of the carbonate to the first product in S2 is (1-1.5): 1, preferably a molar ratio of 1: 1.

[0016] As a further optimization, the second solvent in S2 is one or more of methanol, ethanol, tert-butanol, preferably methanol, and / or ethanol, in a mass ratio of (1-10): 1, preferably a mass ratio of 10: 1, to the first product.

[0017] As a further optimization, the base in S2 is one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, potassium hydride, sodium hydride, sodium triphenylmethide, lithium diisopropylamide, a Grignard reagent, preferably sodium methoxide, and / or sodium ethoxide, in a molar ratio of (1-2): 1, preferably a molar ratio of 1.5: 1, to the first product.

[0018] As a further optimization, the third solvent in S3 is water, in a mass ratio of (5-20): 1, preferably a mass ratio of 10: 1, to the second product.

[0019] As a further optimization, the catalyst in S3 is one or more of hydrochloric acid, sulfuric acid, potassium hydroxide, sodium hydroxide, preferably hydrochloric acid or sulfuric acid, in a molar ratio of (5-10): 1, preferably a molar ratio of 10: 1, to the second product.

[0020] The preparation process of the present application is:

[0021]

[0022] Compared with the prior art, the present application has the following advantages:

[0023] 1. The preparation method is simple, easy to operate and short in process flow;

[0024] 2. The raw materials are environmentally friendly and pollution-free, and the cost is low;

[0025] 3. The process is safe, easy to produce on an industrial scale, has high conversion rate and good product quality. DETAILED DESCRIPTION

[0026] The following are specific embodiments of the present application, which further describe the technical solutions of the present application, but the present application is not limited to these embodiments.

[0027] Example 1

[0028] A preparation method of 2-hydroxy-3-oxopentane diacid, comprising:

[0029] S1) Oxidation reaction: 116.1 g of methyl acetoacetate and 930 g of dichloromethane are added to a 2L three-necked flask, cooled to 0°C, and 207 g of m-chloroperbenzoic acid is slowly added while controlling the temperature, and after completion of the addition, the reaction is maintained for 6 h, water is added to the reaction system, filtered, and the organic layer is washed once with 5% sodium bisulfite aqueous solution and twice with water, dried, and evaporated to obtain 122.7 g of a first product (R1 is methyl);

[0030] S2) Condensation reaction: 122.7 g of the first product, 83.66 g of dimethyl carbonate and 1200 g of methanol are added to a 2L three-necked flask, and the temperature is controlled at 20°C in a water bath, and a solution of 75.3 g of sodium methoxide and 100 g of methanol is slowly added dropwise, and the system slowly precipitates solids until the addition is complete and the system no longer increases, and the reaction is detected to be complete, the reaction liquid is filtered, the filter cake is washed twice with methanol, the filter cake is a sodium salt of the second product, the filter cake is added to methanol, and the pH is adjusted to 5 with hydrochloric acid methanol, and the methanol is evaporated under reduced pressure to obtain 141.4 g of the second product (R2 is methyl);

[0031] S3) Hydrolysis reaction: 141.4 g of the second product, 750 g of concentrated hydrochloric acid and 1.4 L of water are added to a 3L three-necked flask, heated to reflux for 6 h, the reaction is detected to be complete, the temperature is lowered to 5°C, the pH is adjusted to 5-6 with sodium hydroxide aqueous solution, the reaction liquid is extracted with DCM, washed twice with water, once with saturated sodium chloride aqueous solution, dried, and all low-boiling-point components are removed under reduced pressure to obtain 114 g of 2-hydroxy-3-oxopentane diacid.

[0032] The content is 98.9% as determined by HPLC.

[0033] Example 2

[0034] A method for preparing 2-hydroxy-3-oxopentanedioic acid, comprising:

[0035] S1) Oxidation reaction: 116.1 g of methyl acetoacetate and 930 g of dichloromethane were added into a 2 L three-necked flask, and the temperature was lowered to 0 °C. Then 207 g of meta-chloroperoxybenzoic acid was slowly added under temperature control. After completion of the addition, the reaction was maintained for 6 h. When the reaction was completed, water was added to the reaction system, and the mixture was filtered, separated, and washed with 5% sodium bisulfite aqueous solution once and water twice. The organic layer was dried and evaporated to obtain 120 g of a first product (R1 is methyl);

[0036] S2) Condensation reaction: 120 g of the first product, 107.3 g of diethyl carbonate, and 1200 g of ethanol were added into a 2 L three-necked flask, and the temperature was controlled at 20 °C in a water bath. Then a solution of 92.7 g of sodium ethoxide and 100 g of ethanol was slowly added dropwise. Solid was slowly precipitated from the reaction system until the addition was completed and the amount of the solid no longer increased. When the reaction was completed, the reaction liquid was filtered, and the filter cake was washed with ethanol twice. The filter cake was a sodium salt of a second product. The filter cake was added into methanol, and the pH was adjusted to 5 with hydrochloric acid in methanol. The methanol was evaporated under reduced pressure to obtain 133.6 g of the second product (R2 is ethyl);

[0037] S3) Hydrolysis reaction: 133.6 g of the second product, 720 g of concentrated hydrochloric acid, and 1.4 L of water were added into a 3 L three-necked flask, and the temperature was raised to reflux for 6 h. When the reaction was completed, the temperature was lowered to 5 °C, and the pH was adjusted to 5-6 with a potassium hydroxide aqueous solution. The reaction liquid was extracted with DCM, washed with water twice, and saturated sodium chloride aqueous solution once, and dried. All low-boiling-point components were removed under reduced pressure to obtain 106.8 g of 2-hydroxy-3-oxopentanedioic acid.

[0038] The content determined by HPLC was 99.0%.

[0039] Example 3

[0040] A method for preparing 2-hydroxy-3-oxopentanedioic acid, comprising:

[0041] S1) Oxidation reaction: 116.1 g of methyl acetoacetate and 930 g of dichloromethane were added into a 2 L three-necked flask, and the temperature was lowered to 0 °C. Then 207 g of meta-chloroperoxybenzoic acid was slowly added under temperature control. After completion of the addition, the reaction was maintained for 6 h. When the reaction was completed, water was added to the reaction system, and the mixture was filtered, separated, and washed with 5% sodium bisulfite aqueous solution once and water twice. The organic layer was dried and evaporated to obtain 120 g of a first product (R1 is methyl);

[0042] S2) Condensation reaction: in a 2L three-necked flask, add 141.7g of the first product, 87.2g of dimethyl carbonate and 1400g of methanol, control the temperature of water bath at 20°C, slowly add a solution of 78.5g of sodium methoxide and 100g of methanol, solid is slowly separated out in the reaction system until the addition is completed, the solid in the system no longer increases, detect the end of the reaction, filter the reaction liquid, wash the filter cake with methanol twice, the filter cake is the sodium salt of the second product, add methanol to the filter cake, adjust the pH to 5 with hydrochloric acid methanol, evaporate the methanol under reduced pressure to obtain 158.4g of the second product (R2 is methyl);

[0043] S3) Hydrolysis reaction: in a 3L three-necked flask, add 158.4g of the second product, 380g of concentrated sulfuric acid and 1.6L of water, heat to reflux for 6h after addition, detect the completion of the reaction, cool to 5°C, adjust the pH to 5-6 with sodium hydroxide aqueous solution, add DCM to extract the reaction liquid, wash with water twice, wash with saturated sodium chloride aqueous solution once, dry, and remove all low boiling point components under reduced pressure to obtain 112.9g of 2-hydroxy-3-oxopentane diacid.

[0044] The content is 98.3% by HPLC.

[0045] Example 4

[0046] A method for preparing 2-hydroxy-3-oxopentane diacid, comprising:

[0047] S1) Oxidation reaction: in a 2L three-necked flask, add 130g of ethyl acetoacetate and 1000g of 1,2-dichloroethane, cool to 0°C, slowly add 207g of m-chloroperbenzoic acid, and react for 6h after addition, detect the end of the reaction, add water to the reaction system, filter, separate the layers, wash the organic layer with 5% sodium bisulfite aqueous solution once, wash with water twice, dry, and evaporate to dryness to obtain 141g of the first product (R1 is ethyl);

[0048] S2) Condensation reaction: in a 2L three-necked flask, add 141g of the first product, 114g of diethyl carbonate and 1400g of ethanol, control the temperature of water bath at 20°C, slowly add a solution of 98.4g of sodium ethoxide and 100g of ethanol, solid is slowly separated out in the reaction system until the addition is completed, the solid in the system no longer increases, detect the end of the reaction, filter the reaction liquid, wash the filter cake with ethanol twice, the filter cake is the sodium salt of the second product, add methanol to the filter cake, adjust the pH to 5 with hydrochloric acid methanol, evaporate the methanol under reduced pressure to obtain 153.6g of the second product (R2 is ethyl);

[0049] S3) hydrolysis reaction: 153.6g of the second product, 380g of concentrated sulfuric acid and 1.6L of water were added into a 3L three-necked flask, and after the addition, the temperature was increased to reflux for 6h, the reaction completion was detected, the temperature was decreased to 5℃, the pH was adjusted to 5-6 by using sodium hydroxide aqueous solution, DCM was added to extract the reaction solution, the reaction solution was washed with water for 2 times, washed with saturated sodium chloride aqueous solution once, dried, and all low boiling point components were removed under reduced pressure to obtain 105.7g of 2-hydroxy-3-oxopentane diacid.

[0050] The content determined by HPLC was 98.5%.

[0051] According to the above experimental data, it can be known that the preparation method is simple in process, easy to operate, environment-friendly, pollution-free, low in cost, safe in operation, easy for industrial scale production, high in conversion rate and good in product quality.

[0052] The specific embodiments described herein are merely illustrative of the spirit of the present application. Those skilled in the art of the present application can make various modifications or supplements to the described specific embodiments or replace them with similar ways, without departing from the spirit of the present application or exceeding the scope defined by the appended claims.

Claims

1. A method for preparing 2-hydroxy-3-oxopentanediol, characterized in that, Includes the following steps: S1) Oxidation reaction: Acetoacetate is added to the first solvent, and an oxidizing agent is added. The reaction yields the first product, the structural formula of which is: ； S2) Condensation reaction: The first product and carbonate are added to a second solvent, and a base is added. The reaction yields a second product, the structural formula of which is: ； S3) Hydrolysis reaction: The second product is added to a third solvent containing the catalyst and refluxed to obtain 2-hydroxy-3-oxopentanediol. In S1, the oxidant is m-chloroperoxybenzoic acid, and its molar ratio with acetoacetate is (1-2):1; the first solvent in S1 is dichloromethane or 1,2-dichloroethane; R1 in S1 is methyl or ethyl; the second solvent in S2 is methanol or ethanol; the base in S2 is sodium methoxide or sodium ethoxide; R2 in S2 is methyl or ethyl; and the catalyst in S3 is concentrated hydrochloric acid or concentrated sulfuric acid.

2. The method for preparing 2-hydroxy-3-oxopentanediol according to claim 1, characterized in that, The weight ratio of the first solvent to acetoacetate in S1 is (1-10):

1.

3. The method for preparing 2-hydroxy-3-oxopentanediol according to claim 1, characterized in that, The molar ratio of carbonate to the first product in S2 is (1-1.5):

1.

4. The method for preparing 2-hydroxy-3-oxopentanediol according to claim 1, characterized in that, The mass ratio of the second solvent to the first product in S2 is (1-10):

1.

5. The method for preparing 2-hydroxy-3-oxopentanediol according to claim 1, characterized in that, The molar ratio of the base to the first product in S2 is (1-2):

1.

6. The method for preparing 2-hydroxy-3-oxopentanediol according to claim 1, characterized in that, The third solvent in S3 is water, and its weight ratio with the second product is (5-20):

1.

7. The method for preparing 2-hydroxy-3-oxopentanediol according to claim 1, characterized in that, The molar ratio of the catalyst to the second product in S3 is (5-10):1.

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