Preparation method of 3, 3-dimethyl-2-oxobutyric acid

Abstract

The invention discloses a preparation method of 3, 3-dimethyl-2-oxobutyric acid (3, 3-dimethyl-2-oxobutyric acid). The method comprises the following steps: under an acidic condition, carrying out oximation reaction on 3, 3-dimethyl-2-butanone and a sodium nitrite solution under the catalysis of cation exchange resin to obtain 3, 3-dimethyl-2-oxobutanal oxime; the preparation method comprises the following steps: under the catalytic action of protonic acid, carrying out Beckmann rearrangement on 3, 3-dimethyl-2-oxobutanal oxime to obtain 3, 3-dimethyl-2-ketobutyramide; in the presence of an inorganic acid sodium nitrite solution, 3, 3-dimethyl-2-ketobutyramide is hydrolyzed to obtain the final oxidation product 3, 3-dimethyl-2-oxobutyric acid. The cation exchange resin with smaller steric hindrance is used as a catalyst for enol conversion in the oximation reaction process, and the problem that an original catalytic system only adapts to a single acetyl aromatic system is solved. The universality of a reaction substrate is improved, and possibility is provided for synthesizing drug intermediates, natural products and the like containing polyfunctional groups.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for preparing 3,3-dimethyl-2-oxobutyric acid. Background Technology

[0002] 3,3-Dimethyl-2-oxobutyric acid is an important pharmaceutical intermediate, mainly used in the preparation of triazine herbicides. Triazine herbicides, due to their good solubility, low residue, and high selectivity, have been widely used on crops such as soybeans, corn, rice, and wheat. Currently, researchers both domestically and internationally are continuously dedicated to improving the production processes and formulations of existing triazine herbicides and developing new varieties. Triazine herbicides still have significant potential for future development.

[0003] Patent CN113004141A discloses a method using dichloropinazone as a raw material, which involves alkaline hydrolysis to obtain sodium 3,3-dimethyl-2-hydroxybutyrate, followed by oxidation with oxygen or oxygen-containing gas in an alkaline medium and in the presence of a ruthenium catalyst and a compound of platinum or palladium to obtain sodium 3,3-dimethylbutyrate, which is further acidified to obtain 3,3-dimethyl-2-oxobutyric acid. This method is costly due to the use of the precious metal ruthenium as a catalyst. Furthermore, the high temperature and pressure conditions required for the reaction place high demands on equipment and pose significant safety risks, making it difficult to scale up production in actual industrial applications. US Patent US3905801A discloses the oxidation of 3,3-dimethyl-2-hydroxybutyrate with potassium permanganate to prepare 3,3-dimethyl-2-oxobutyric acid. However, the manganese dioxide byproduct generated in this reaction is currently difficult to recover and reuse, resulting in high costs and additional environmental damage, making large-scale industrial production difficult. Patent CN110627754A discloses a method for preparing 2-oxo-2-furanylacetic acid using a continuous flow microchannel reactor. It utilizes 2-acetylfuran as a raw material in the presence of nitric acid solution and sodium nitrite, with toluenesulfonic acid as a catalyst. The sodium nitrite and nitric acid system achieves mild oxidation via NO2 / NO radicals, but this method has low substrate universality; current literature reports only its applicability to acetyl aromatic systems. Patent CN103923040A discloses a method for preparing furanooxime acid. It involves mixing 2-acetylfuran with sodium nitrite and hydrochloric acid to undergo an oximation reaction to generate a ketoxime. The ketoxime then undergoes a Beckmann rearrangement reaction catalyzed by a Brønsted acid ionic liquid catalyst to produce an amide. The amide is then hydrolyzed under acidic conditions to yield 2-oxo-2-furanylacetic acid. The substrate used in this patent, 2-acetylfuran, has an aromatic ring of furan attached to its carbonyl end. Furan and the carbonyl group readily form a conjugation, facilitating oxime reaction to generate an oxime intermediate. In contrast, the substrate for 3,3-dimethyl-2-oxobutyric acid is 3,3-dimethyl-2-butanone, whose carbonyl end is attached to a tert-butyl group. The tert-butyl group is an electron-donating group, making it difficult for the carbonyl end to interconvert to the enol form, thus hindering the formation of the oxime intermediate. Therefore, overcoming the difficulty of converting 3,3-dimethyl-2-butanone from a ketone to its corresponding enol tautomer is crucial for exploring and developing an economically feasible and safe industrial production route for 3,3-dimethyl-2-oxobutyric acid. Summary of the Invention

[0004] In view of the above-mentioned prior art, the purpose of this invention is to provide a method for preparing 3,3-dimethyl-2-oxobutyric acid. The method of this invention features mild reaction conditions, simple operation, high reaction yield, and broad substrate applicability.

[0005] To achieve the above objectives, the present invention adopts the following technical solution: This invention provides a method for preparing 3,3-dimethyl-2-oxobutyric acid, comprising the following steps: (1) Under acidic conditions, 3,3-dimethyl-2-butanone and sodium nitrite solution were subjected to oxime reaction catalyzed by cation exchange resin to obtain 3,3-dimethyl-2-oxobutanal oxime; under the catalysis of protic acid, 3,3-dimethyl-2-oxobutanal oxime was subjected to Beckmann rearrangement to obtain 3,3-dimethyl-2-ketobutanamide; Alternatively, under acidic conditions, 3,3-dimethyl-2-butanone and sodium nitrite solution undergo oxime reaction and Beckmann rearrangement sequentially under the catalysis of cation exchange resin and protic acid to obtain 3,3-dimethyl-2-ketobutyramide; (2) In the presence of inorganic acid and sodium nitrite solution, 3,3-dimethyl-2-ketobutyramide undergoes hydrolysis to obtain the final oxidation product 3,3-dimethyl-2-oxobutyric acid.

[0006] The synthetic route for 3,3-dimethyl-2-oxobutyric acid is as follows: .

[0007] Preferably, in step (1), the acid used in the acidic conditions is an inorganic acid; the inorganic acid is selected from hydrochloric acid solution or sulfuric acid solution; the concentration of the hydrochloric acid solution is 30 wt%; and the concentration of the sulfuric acid solution is 60 wt%.

[0008] Preferably, in step (1), the concentration of the sodium nitrite solution is 40 wt%; the molar ratio of the inorganic acid, 3,3-dimethyl-2-butanone and sodium nitrite is (2-2.5):1:(1-1.5).

[0009] Preferably, in step (1), the cation exchange resin is 732 cation exchange resin; the mass ratio of 3,3-dimethyl-2-butanone to 732 cation exchange resin is 1:0.05~0.15.

[0010] Preferably, in step (1), the temperature of the oxime reaction is 0~10℃.

[0011] Preferably, in step (1), the protic acid is a mixture of phosphoric acid solution and polyphosphoric acid solution; the molar ratio of the protic acid to 3,3-dimethyl-2-oxobutyraldehyde oxime is 0.1:1; and the molar ratio of phosphoric acid to polyphosphoric acid is 0.06:0.04.

[0012] Preferably, in step (1), the Beckmann rearrangement temperature is 25°C.

[0013] Preferably, in step (2), the inorganic acid is selected from at least one of hydrochloric acid solution, sulfuric acid solution, phosphoric acid solution and polyphosphoric acid solution; the concentration of the hydrochloric acid solution is 30 wt%.

[0014] Preferably, in step (2), the molar ratio of the inorganic acid, 3,3-dimethyl-2-ketobutyramide and sodium nitrite is (2-2.5):1:(1-1.5).

[0015] Preferably, in step (2), the temperature of the hydrolysis reaction is 60-70℃.

[0016] The beneficial effects of this invention are: (1) This invention utilizes a cation exchange resin with less steric hindrance as a catalyst for the enol conversion during the oxime reaction, solving the problem that the original catalytic system is only suitable for a single acetyl aromatic system. This improves the universality of the reaction substrate, making it possible to synthesize drug intermediates and natural products containing multiple functional groups, and also makes it easier to realize efficient processes such as one-pot synthesis and continuous flow reaction, thus promoting molecular design innovation in the fields of medicine and materials.

[0017] (2) This invention avoids the problems of high cost and difficulty in recycling of precious metal and transition metal catalysts used in traditional synthesis processes. It also avoids high-salt wastewater and solid waste, reducing environmental pollution and lowering raw material costs and waste treatment costs. Furthermore, it is simple to operate, has low equipment requirements, improves production safety and environmental protection, and is suitable for industrial production. Attached Figure Description

[0018] Figure 1 Example 1: Liquid phase spectrum of the reaction solution; Figure 2 : Liquid phase spectrum of the reaction solution in Comparative Example 1; Figure 3 NMR spectrum of 3,3-dimethyl-2-oxobutyric acid prepared in Example 1. Detailed Implementation

[0019] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of this application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0020] As described in the background section, the reaction substrate of 3,3-dimethyl-2-oxobutyric acid is 3,3-dimethyl-2-butanone, in which a carbon-1 end is connected to a tert-butyl group. The tert-butyl group is an electron-donating group, which makes it difficult for the carbon-1 end to interconvert to the enol form, and thus difficult to generate the oxime intermediate.

[0021] Based on this, the purpose of this invention is to provide a method for preparing 3,3-dimethyl-2-oxobutyric acid. This invention first involves an oxime reaction in an acidic environment using 3,3-dimethyl-2-butanone and sodium nitrite as raw materials, catalyzed by a cation exchange resin, to obtain 3,3-dimethyl-2-oxobutyraldehyde oxime. The cation exchange resin acts as a catalyst to promote the conversion of the ketone to its corresponding enol tautomer, thereby attacking the nitroso ion and generating an unstable nitroso compound. The hydrogen atom of the unstable nitroso compound transfers from the carbon atom to the oxygen atom of the nitroso group, thus yielding the stable oxime, i.e., intermediate I compound (3,3-dimethyl-2-oxobutyraldehyde oxime). This method overcomes the limitation of existing catalytic systems that are only suitable for a single acetyl aromatic system. It improves the universality of the reaction substrate, providing possibilities for the synthesis of pharmaceutical intermediates and natural products containing multiple functional groups. Then, under the catalysis of a protic acid, 3,3-dimethyl-2-oxobutyraldehyde oxime underwent a Beckmann rearrangement to obtain intermediate II, 3,3-dimethyl-2-ketobutyramide. Verification experiments revealed that the oximation and Beckmann rearrangement of the starting material 3,3-dimethyl-2-butanone are continuous reactions. Adding the protic acid required for the rearrangement directly to the substrate (rather than intermediate I) also completes the Beckmann rearrangement, generating the corresponding 3,3-dimethyl-2-ketobutyramide. Furthermore, 3,3-dimethyl-2-ketobutyramide exists in the aqueous phase of the reaction, and the collected aqueous phase can be used for hydrolysis. Finally, in the presence of an inorganic acid, intermediate II, 3,3-dimethyl-2-ketobutyramide, undergoes amide hydrolysis to yield the final oxidation product, 3,3-dimethyl-2-oxobutyric acid. Adding sodium nitrite to the hydrolysis reaction can hydrolyze the amide. Under sodium nitrite conditions, the amide undergoes a diazotization-denitrification reaction. The core of this reaction is that the -NH2 group of the amide is diazotized before HNO2 to form an unstable diazonium salt, which then releases nitrogen gas. After further hydrolysis, it finally produces a carboxylic acid.

[0022] To enable those skilled in the art to better understand the technical solution of this application, the technical solution of this application will be described in detail below with reference to specific embodiments.

[0023] The test materials used in the embodiments of this invention are all conventional test materials in the art and can be purchased through commercial channels.

[0024] Example 1: (1) 50.03 g of 3,3-dimethyl-2-butanone was added to a dry and clean reactor, followed by 50 g of water and 5 g of 732 cation exchange resin (732 hydrogen-type strong acid cation exchange resin, brand: Maclean), and 121.5 g of 30 wt% hydrochloric acid solution. Then, stirring was started, and the reactor was placed in an ice bath to slowly cool down to below 10°C. 86.3 g of 40 wt% sodium nitrite solution was slowly added dropwise over 90 minutes. The temperature was kept below 10°C during the dropwise addition. After the dropwise addition was completed, the oxime reaction was continued at 0-10°C until the raw materials reacted completely. The resulting reaction solution was extracted with 0.1 kg of dichloromethane to separate the organic phase. Anhydrous sodium sulfate was added to the organic phase to remove residual water. The solution was filtered, and the solvent was removed by vacuum distillation of the filtrate to obtain 62.12 g of intermediate I compound 3,3-dimethyl-2-oxobutanal oxime, with a yield of 96.31%.

[0025] (2) Remove the ice bath and set the temperature to 20°C. Add a mixture of phosphoric acid solution (85 wt%) and polyphosphoric acid solution (115 wt%) to the reaction solution from step (1). The molar ratio of intermediate compound I, phosphoric acid, and polyphosphoric acid is 1:0.06:0.04. Monitor the reaction progress using the liquid phase. After the reaction is complete, add 100 mL of dichloromethane for extraction, separate the layers, and collect the aqueous phase for direct use in the next reaction.

[0026] (3) Add 121.5g of 30wt% hydrochloric acid solution to the aqueous phase collected in step (2) to make the reaction under acidic conditions. Stir and slowly raise the temperature to control the temperature in the range of 60-70℃. Slowly add 86.3g of 40wt% sodium nitrite solution to the reaction system. The addition is completed after 90 minutes until the intermediate prepared in step (2) is completely reacted. After the reaction is completed, extract with dichloromethane solution three times. Combine the organic phases obtained from the extraction, add an appropriate amount of anhydrous magnesium sulfate to dry the organic phase, remove the organic solvent by rotary evaporation under negative pressure, and dry to obtain the final product 32.6g of 3,3-dimethyl-2-oxobutyric acid. The reaction yield is 50.1% and the liquid phase purity is 98.6%.

[0027] Example 2 (1) 50.03 g of 3,3-dimethyl-2-butanone was added to a dry and clean reactor, followed by 50 g of water and 5 g of 732 cation exchange resin. 163.3 g of 60 wt% sulfuric acid solution was added dropwise. Then, stirring was started, and the reactor was placed in an ice bath to slowly cool down to below 10 °C. 86.3 g of 40 wt% sodium nitrite solution was then slowly added dropwise over 90 minutes. After the addition was complete, the reaction was continued at 0-10 °C until the reactants were completely reacted. The resulting reaction solution was extracted with 0.1 kg of dichloromethane to separate the organic phase. Anhydrous sodium sulfate was added to the organic phase to remove residual water. The solution was filtered, and the filtrate was distilled under reduced pressure to remove the solvent, yielding 61.12 g of intermediate I compound 3,3-dimethyl-2-oxobutanal oxime, with a yield of 94.75%.

[0028] (2) Remove the ice bath and set the temperature to 20°C. Add a mixture of phosphoric acid solution (85 wt%) and polyphosphoric acid solution (115 wt%) to the reaction solution obtained in step (1). The molar ratio of intermediate compound I, phosphoric acid, and polyphosphoric acid is 1:0.06:0.04. After the reaction is complete, add 100 ml of dichloromethane for extraction, separate the layers, and collect the aqueous phase for direct use in the next step of the reaction.

[0029] (3) Add 121.5g of 30wt% hydrochloric acid to the aqueous phase obtained in step (2) to make the reaction under acidic conditions. Stir and slowly raise the temperature to control the temperature in the range of 60-70℃. Slowly add 86.3g of 40wt% sodium nitrite solution to the reaction system. The addition is completed after 90 minutes until the intermediate prepared in step (2) is completely reacted. After the reaction is completed, extract with dichloromethane solution three times. Combine the organic phases obtained from the extraction, add an appropriate amount of anhydrous magnesium sulfate to dry the organic phase, remove the organic solvent by rotary evaporation under negative pressure, and dry to obtain the final product 28.4g of 3,3-dimethyl-2-oxobutyric acid. The reaction yield is 43.69% and the liquid phase purity is 98.1%.

[0030] Example 3 (1) 50.03 g of 3,3-dimethyl-2-butanone was added to a dry and clean reactor, followed by 50 g of water and 5 g of 732 cation exchange resin, 121.5 g of 30 wt% hydrochloric acid, and a mixture of 2.34 g of phosphoric acid solution (concentration 85 wt%) and 2.25 g of polyphosphoric acid solution (concentration 115 wt%). Stirring was then started, and the reactor was placed in an ice bath to slowly cool down to below 10 °C. 86.3 g of 40 wt% sodium nitrite solution was slowly added dropwise over 90 minutes. During the addition, the temperature was kept below 10 °C. After the addition was completed, the temperature was kept at 0-10 °C until the raw materials reacted completely. The resulting reaction solution was extracted with 0.1 kg of dichloromethane to separate the organic phase and collect the aqueous phase.

[0031] 121.5 g of 30 wt% hydrochloric acid was added to the aqueous phase to bring the reaction to acidic conditions. The mixture was then stirred and the temperature was slowly increased to 60-70 °C. Sodium nitrite solution was added dropwise to the reaction system until the intermediate product from the previous step was completely reacted. After the reaction was completed, the mixture was extracted three times with dichloromethane solution. The extracted organic phases were combined, and an appropriate amount of anhydrous magnesium sulfate was added to dry the organic phase. The organic solvent was removed by rotary evaporation under negative pressure. After drying, 21.4 g of the final product, 3,3-dimethyl-2-oxobutyric acid, was obtained. The reaction yield was 32.92%, and the liquid phase purity was 98.3%.

[0032] Comparative Example 1 The difference from Example 1 is that 732 cation exchange resin was not added, and 0.89 g of 3,3-dimethyl-2-oxobutyric acid was finally prepared with a reaction yield of 0.14% and a liquid phase purity of 96.8%.

[0033] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A method for preparing 3,3-dimethyl-2-oxobutyric acid, characterized in that, Includes the following steps: (1) Under acidic conditions, 3,3-dimethyl-2-butanone and sodium nitrite solution were subjected to oxime reaction catalyzed by cation exchange resin to obtain 3,3-dimethyl-2-oxobutanal oxime; under the catalysis of protic acid, 3,3-dimethyl-2-oxobutanal oxime was subjected to Beckmann rearrangement to obtain 3,3-dimethyl-2-ketobutanamide; Alternatively, under acidic conditions, 3,3-dimethyl-2-butanone and sodium nitrite solution undergo oxime reaction and Beckmann rearrangement sequentially under the catalysis of cation exchange resin and protic acid to obtain 3,3-dimethyl-2-ketobutyramide; (2) In the presence of inorganic acid and sodium nitrite solution, 3,3-dimethyl-2-ketobutyramide undergoes hydrolysis to obtain the final oxidation product 3,3-dimethyl-2-oxobutyric acid.

2. The preparation method according to claim 1, characterized in that, In step (1), the acid used in the acidic conditions is an inorganic acid; the inorganic acid is selected from hydrochloric acid solution or sulfuric acid solution; the concentration of the hydrochloric acid solution is 30 wt%; the concentration of the sulfuric acid solution is 60 wt%.

3. The preparation method according to claim 1, characterized in that, In step (1), the concentration of the sodium nitrite solution is 40 wt%; the molar ratio of the inorganic acid, 3,3-dimethyl-2-butanone and sodium nitrite is (2-2.5):1:(1-1.5).

4. The preparation method according to claim 1, characterized in that, In step (1), the cation exchange resin is 732 cation exchange resin; the mass ratio of 3,3-dimethyl-2-butanone to 732 cation exchange resin is 1:0.05~0.

15.

5. The preparation method according to claim 1, characterized in that, In step (1), the temperature of the oxime reaction is 0~10℃.

6. The preparation method according to claim 1, characterized in that, In step (1), the protic acid is a mixture of phosphoric acid solution and polyphosphoric acid solution; the molar ratio of the protic acid to 3,3-dimethyl-2-oxobutyraldehyde oxime is 0.1:1; and the molar ratio of phosphoric acid to polyphosphoric acid is 0.06:0.

04.

7. The preparation method according to claim 1, characterized in that, In step (1), the Beckmann rearrangement is performed at a temperature of 25°C.

8. The preparation method according to claim 1, characterized in that, In step (2), the inorganic acid is selected from at least one of hydrochloric acid solution, sulfuric acid solution, phosphoric acid solution and polyphosphoric acid solution; the concentration of the hydrochloric acid solution is 30 wt%.

9. The preparation method according to claim 1, characterized in that, In step (2), the molar ratio of the inorganic acid, 3,3-dimethyl-2-ketobutyramide and sodium nitrite is (2-2.5):1:(1-1.5).

10. The preparation method according to claim 1, characterized in that, In step (2), the temperature of the hydrolysis reaction is 60-70℃.

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