CN108503531B - Preparation method of 3, 3-dimethyl-2-oxobutyric acid - Google Patents
Preparation method of 3, 3-dimethyl-2-oxobutyric acid Download PDFInfo
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Abstract
The invention relates to a preparation method of 3, 3-dimethyl-2-oxobutyric acid, belonging to the technical field of synthesis of drug intermediates. In order to solve the problems of serious pollution and low yield of the existing synthetic route, the method for preparing the 3, 3-dimethyl-2-oxobutyric acid comprises the steps of carrying out halogenation reaction on the 3, 3-dimethylbutyric acid and a halogenating reagent in an organic solvent to obtain an intermediate product; then carrying out hydrolysis reaction to obtain a corresponding hydrolyzed product; and in the presence of a TEMPO catalyst, carrying out oxidation reaction on the hydrolyzed product under the action of an oxidant, and then acidifying to obtain the product 3, 3-dimethyl-2-oxobutyric acid. The invention avoids the adoption of a mixed catalyst of noble metal and transition metal catalyst, has the advantages of reducing the pollution to the environment and lowering the cost, and can still ensure the effects of high yield and high purity.
Description
Technical Field
The invention relates to a preparation method of 3, 3-dimethyl-2-oxobutyric acid, belonging to the technical field of synthesis of drug intermediates.
Background
3, 3-dimethyl-2-oxobutanoic acid, also known as trimethylpyruvic acid, is mainly used for pharmaceutical intermediates, gene engineering reagents, nutritional additives, coating raw materials and the like. At present, the demand of the anti-AIDS atazanavir intermediate in the international market is large, so that the intermediate 3, 3-dimethyl-2-oxobutyric acid has wide market prospect.
At present, 3-dimethyl-2-oxobutanoic acid is synthesized by using dichloropinacolone as a raw material at home and abroad to synthesize a corresponding intermediate product.
For example, Chinese patent application (publication No. CN1483715A) discloses a method for preparing 3, 3-dimethyl-2-hydroxy-butyric acid sodium salt by hydrolyzing dichloropinacolone as raw material with alkaline water, oxidizing with oxygen or oxygen-containing gas in alkaline water medium and in the presence of palladium catalyst and bismuth or bismuth compound to obtain 3, 3-dimethyl-2-oxo-butyric acid sodium salt, further acidifying to obtain 3, 3-dimethyl-2-oxo-butyric acid
The method adopts the noble metal palladium as the catalyst, so that the cost is higher, and the reaction under the conditions of high temperature and pressure has higher requirements on equipment and high safety risk.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of 3, 3-dimethyl-2-oxobutyric acid, and solves the problem of how to provide a new synthesis process which does not need to adopt a noble metal catalyst, has less environmental pollution and high yield.
The invention aims to realize the following technical scheme, and the preparation method of the 3, 3-dimethyl-2-oxobutyric acid is characterized by comprising the following steps:
A. carrying out a halogenation reaction on 3, 3-dimethylbutyric acid and a halogenating agent in an organic solvent to obtain an intermediate compound shown in a formula I, wherein X in the compound shown in the formula I is halogen;
B. carrying out hydrolysis reaction on the compound of the formula I to obtain a compound of a formula II;
C. in the presence of a TEMPO catalyst, carrying out oxidation reaction on a compound shown in a formula II under the action of an oxidant, and then carrying out acidification treatment to obtain a product, namely a compound shown in a formula III;
3, 3-dimethylbutyric acid is used as a starting material, halogen atoms on the halogen are hydrolyzed to form hydroxyl groups after halogenation, so that a corresponding intermediate is obtained, wherein halogen substitution is preferably chlorine, bromine, iodine or the like; therefore, in the subsequent oxidation reaction process, hydroxyl can be oxidized into corresponding ketone only under the action of the catalytic amount of the TEMPO catalyst, and the effect of high-efficiency conversion can be achieved, so that a mixed catalytic system of noble metal palladium, heavy metal bismuth and the like is effectively avoided, the pollution of heavy metals and the like to the environment is reduced, and the advantage of reducing the production cost by adopting expensive noble metal catalysis is also avoided; and the TEMPO catalyst adopted can realize the repeated application after simple treatment, and is also favorable for further reducing the production cost, wherein the TEMPO catalyst is an abbreviation of tetramethyl piperidine nitrogen oxide catalyst. In addition, after the new starting material 3, 3-dimethylbutyric acid is adopted, in order to avoid the hydrolysis phenomenon of a halogenating reagent and the existence of a large amount of water in a reaction system, the halogenating reaction is carried out in an organic solvent, so that the hydrolysis of the halogenating reagent is reduced, the conversion rate of the reaction can be better improved, the yield is improved, other possible byproducts are reduced, the purity and quality requirements of intermediate products are ensured, and the purity and quality requirements of final products are also favorably improved; meanwhile, 3-dimethylbutyric acid is adopted as a starting raw material, so that the raw materials in each step have the advantage of low cost, and the improved process can ensure that the overall reaction in each step has the effect of high yield. Of course, the amount of the raw materials used in the present invention can be adjusted according to the basic reaction ratio in the reaction process, for example, 3-dimethylbutyric acid is used as the starting material in an amount corresponding to the molar equivalent ratio of the raw materials or intermediate products in each step.
In the above method for preparing 3, 3-dimethyl-2-oxobutanoic acid, as a preferable scheme, in step a, the halogenating agent is selected from phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, chlorine, bromine, iodine, triphosgene or carbon tetrachloride, and X corresponds to halogen in the halogenating agent. Halogen substitution can be effectively introduced to methylene, and the yield and purity effect of single-step reaction can be further improved. In a further preferred embodiment, the halogenating agent is preferably selected from thionyl chloride. The raw materials have the advantages of low cost and relatively more favorable operation.
In the above preparation method of 3, 3-dimethyl-2-oxobutanoic acid, as a preferred embodiment, the oxidation reaction in step C further comprises performing in the presence of a catalyst promoter, wherein the catalyst promoter is one or more selected from potassium bromide, ferric chloride, sodium nitrite, and crown ether. The catalytic assistant is an auxiliary catalyst for promoting TEMPO catalytic activation, so that the performance of activating catalysis can be better achieved, the raw materials are converted more efficiently, and the yield of single-step reaction is improved. As a further preferable mode, the catalytic assistant is a mixture of ferric trichloride, sodium nitrite and crown ether, and the ratio of ferric trichloride: sodium nitrite: the mass ratio of the crown ether is 1: 0.8-1.2: 0.2 to 0.5. The crown ether herein may be 18-crown-6 ether or 15-crown-5 ether, etc. It is preferred to use the promoter iron dichloride: sodium nitrite: the mass ratio of crown ether is 1.0: 1.0: 0.5.
in the above preparation method of 3, 3-dimethyl-2-oxobutanoic acid, as a preferable scheme, the oxidizing agent in step C is selected from one or more of hydrogen peroxide, sodium periodate, sodium hypochlorite, sodium hypobromite, oxygen and air. The method has the advantages of good oxidation effect, no generation of a large amount of solid wastes in the reaction process, avoidance of influence of the generation of the solid wastes on the quality of an intermediate product, mild reaction conditions and contribution to better improvement of the purity and quality of the intermediate product. More preferably, air is used as the oxidizing agent. After the catalytic system is adopted, air can be effectively adopted as an oxidant, cost and pressure are basically avoided, the production cost is reduced, other impurities cannot be introduced into water generated in the oxidation process, and the quality and the yield of the product are effectively improved.
In the above method for preparing 3, 3-dimethyl-2-oxobutanoic acid, as a preferred embodiment, the organic solvent in step a is selected from one or more of dichloromethane, ethyl acetate, dichloroethane, tetrahydrofuran and cyclohexane, and the temperature of the halogenation reaction is carried out at 25 ℃ or lower. The method has the advantages of easily obtained raw materials and low cost, and the solvents are easy to dehydrate, so that the reaction system can be better ensured to be carried out under the anhydrous or basically anhydrous condition, the decomposition of the halogenating reagent is better avoided, the yield and the quality effect of the single intermediate product are ensured, and as a preferred scheme, the temperature of the halogenating reaction is controlled to be carried out under the condition of 0-5 ℃.
In the above method for preparing 3, 3-dimethyl-2-oxobutanoic acid, as a preferred embodiment, the oxidation reaction in step C is carried out in one or more solvents of benzene, toluene, dichloroethane, dichloromethane and trifluorotoluene, and the temperature of the oxidation reaction is 30 ℃ to reflux temperature. Has the advantages of easily obtained raw materials, low toxicity and mild reaction conditions.
In the above method for producing 3, 3-dimethyl-2-oxobutanoic acid, as a preferable mode, the hydrolysis reaction in step B is carried out in the presence of an inorganic acid or an inorganic base, and the temperature of the hydrolysis reaction is 30 to 80 ℃. Mainly for hydrolyzing the halogen introduced in the previous step in the presence of acid or alkali to convert the halogen into hydroxyl, the hydrolysis of the halogen can be generally carried out by acidic hydrolysis or alkaline hydrolysis, and the halogen halide in the halogen can be effectively converted into the compound of the formula II with high yield. As a further preferable scheme, the inorganic acid can be one or more selected from hydrochloric acid, sulfuric acid, phosphoric acid and polyphosphoric acid; the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and potassium carbonate.
In the above preparation method of 3, 3-dimethyl-2-oxobutanoic acid, the TEMPO catalyst is generally used in a catalytic amount, that is, the added catalyst is enough to enable the reaction to proceed, but in order to improve the reaction efficiency and the reaction effect, the TEMPO catalyst is preferably used in an amount of 3 to 5 wt% of the amount of 3, 3-dimethyl-butanoic acid; the mass ratio of the TEMPO catalyst to the catalytic auxiliary agent is 1: 0.5-1: 2.0.
the method for preparing 3, 3-dimethyl-2-oxobutanoic acid according to the present invention can be represented by the following reaction equation:
in summary, compared with the prior art, the invention has the following advantages:
1. by adopting 3, 3-dimethylbutyric acid as a raw material and halogenating, the formed intermediate product can realize efficient conversion only under the action of TEMPO or TEMPO and a catalytic auxiliary agent, thereby avoiding the adoption of a mixed catalyst of a noble metal catalyst and a transition metal catalyst, reducing the pollution to the environment and lowering the cost, and still ensuring the effects of high yield and high purity.
2. The intermediate formed by halogenating the 3, 3-dimethylbutyric acid used as the raw material adopts TEMPO or catalysis containing TEMPO and a catalytic auxiliary agent, so that air can be adopted as the oxidant, and the method has the advantages of mild reaction conditions and low production safety risk, and the byproduct water has little pollution to the environment and avoids the problem of impurity residue of the oxidant, so that the method has the advantages of better yield improvement and product purity improvement.
Detailed Description
The technical solution of the present invention is further specifically described below by way of specific examples, but the present invention is not limited to these examples.
Example 1
Adding 50g of 3, 3-dimethylbutyric acid into a dry and clean reactor, adding 100mL of dichloromethane, then starting stirring, slowly cooling to below 5 ℃, and starting dropwise adding a dichloromethane solution of solid phosgene, wherein the dosage of the solid phosgene added in the example is according to a molar equivalent ratio, and the dosage added in the example is that 3, 3-dimethylbutyric acid: the molar ratio of the solid phosgene is 1: 1.05, keeping the temperature below 10 ℃ in the dripping process, keeping the temperature at 5-10 ℃ after finishing dripping, continuing to perform heat preservation at the temperature of 5-10 ℃ for halogenation reaction until the raw materials are basically reacted completely, and after finishing the reaction, controlling the temperature below 50 ℃ for concentration to remove the solvent to obtain a residue containing the compound 2-chloro-3, 3-dimethylbutyric acid of the formula I;
adding 120g of sodium hydroxide solution with the mass percent of 30% into the residue, then heating to 65-70 ℃ for heat preservation to perform hydrolysis reaction, adding 50mL of dichloromethane after the reaction is finished, extracting, layering, collecting a water layer, and directly using the water layer for the next reaction; the dichloromethane is added for extraction so as to better remove impurities and be beneficial to better improving the purity and quality of the intermediate product; directly adding 1.75g of TEMPO catalyst and 1g of 18-crown-6-ether into a water layer, adding 100mL of toluene to ensure that a reaction solvent is a mixed solvent system of water and toluene, stirring to slowly raise the temperature and control the temperature to be in a range of 70-80 ℃, introducing air into the reaction system to perform oxidation reaction until the intermediate product in the last step is completely reacted, filtering and recovering the catalyst after the reaction is finished, standing the filtrate, layering, removing an organic layer, adjusting the pH value of a collected water layer to be less than 1 by using a dilute hydrochloric acid aqueous solution with the mass percent of 5% to perform acidification treatment, adding dichloromethane to extract a product after the acidification treatment is finished, performing reduced pressure concentration treatment on the collected organic layer to remove the solvent, drying to obtain 45g of a final product of 3, 3-dimethyl-2-oxobutyric acid with the yield of 80%, the gas phase purity content was 98.5%.
Example 2
Adding 50g of 3, 3-dimethylbutyric acid into a dry and clean reactor, adding 100mL of dichloromethane, then starting stirring, slowly cooling to below 5 ℃, and starting dropwise adding a phosphorus oxychloride dichloromethane solution, wherein the phosphorus oxychloride is added according to a molar equivalent ratio, and the amount added in the embodiment is that the 3, 3-dimethylbutyric acid: the molar ratio of phosphorus oxychloride is 1: 1.12, keeping the temperature below 10 ℃ in the dripping process, keeping the temperature at 5-8 ℃ after finishing dripping, keeping the temperature to perform a halogenation reaction until the raw materials are basically reacted completely, and after finishing the reaction, controlling the temperature below 50 ℃ to perform concentration to remove the solvent to obtain a residue containing the compound 2-chloro-3, 3-dimethylbutyric acid of the formula I;
adding 100g of 20% hydrochloric acid solution into the residue, heating to 60-65 ℃ for carrying out hydrolysis reaction, after the reaction is finished, adding 50mL of dichloromethane for extraction, layering, collecting an organic layer, adding water for washing and extraction, washing twice, using 40mL of water each time, concentrating to remove the organic solvent to obtain an intermediate residue, directly using the intermediate residue in the next reaction, adding 1.5g of TEMPO catalyst and 0.75g of 15-crown-5-ether into the direct residue, adding 100mL of toluene and 80mL of water to obtain a mixed solvent system of water and toluene, stirring to slowly raise the temperature, controlling the temperature to be in the range of 70-80 ℃, introducing air into the reaction system for carrying out oxidation reaction until the intermediate product in the previous step is completely reacted, filtering and recovering the catalyst after the reaction is finished, standing the filtrate, and (3) layering, removing an organic layer, adjusting the pH value of a collected water layer to be below 1 by using 8 mass percent polyphosphoric acid aqueous solution for acidification treatment, adding dichloromethane for extraction and product extraction after the acidification treatment is finished, performing reduced pressure concentration treatment on the collected organic layer to remove a solvent, and drying to obtain a final product of 45g of 3, 3-dimethyl-2-oxobutyric acid, wherein the yield is 76 percent, and the gas phase purity content is 98.4 percent.
Example 3
Putting 50g of 3, 3-dimethylbutyric acid into a dry and clean reactor, adding 200mL of dichloromethane, then starting stirring, slowly cooling to below 5 ℃, starting dropwise adding 80g of bromine, keeping the temperature below 5 ℃ in the dropwise adding process, after the dropwise adding is finished, continuing to perform heat preservation at the temperature of 3-7 ℃ for halogenation reaction until the raw materials are basically reacted completely, and after the reaction is finished, controlling the temperature below 50 ℃ for concentration to remove the solvent to obtain a residue containing the compound 2-bromo-3, 3-dimethylbutyric acid of the formula I;
adding 120g of sodium hydroxide solution with the mass percent of 30% into the residue, heating to 30-35 ℃, preserving the heat, completely performing hydrolysis reaction, adding 50mL of dichloromethane after the reaction is finished, extracting, layering, collecting a water layer, and directly using the water layer for the next reaction; the dichloromethane is added for extraction so as to better remove impurities and be beneficial to better improving the purity and quality of the intermediate product; directly adding 1.75g of TEMPO catalyst, 1.75g of ferric trichloride and 1.75g of sodium nitrite into a water layer, adding 100mL of toluene, enabling a solvent for reaction to be a mixed solvent system of water and toluene, stirring, dropwise adding a sodium hypochlorite solution at room temperature, carrying out oxidation reaction until the intermediate product in the previous step is completely reacted, filtering and recovering the catalyst after the reaction is finished, standing the filtrate, layering, removing an organic layer, adjusting the pH value of the collected water layer to be less than 1 by using a dilute hydrochloric acid aqueous solution with the mass percent of 5% to carry out acidification treatment, adding 100mL of toluene after the acidification treatment is finished, extracting and extracting a product, carrying out reduced pressure concentration treatment on the collected organic layer to remove the solvent, and drying to obtain a final product of 42g of 3, 3-dimethyl-2-oxobutyric acid, wherein the yield is 75%, and the gas phase purity is 98.5%.
Example 4
Putting 50g of 3, 3-dimethylbutyric acid into a dry and clean reactor, adding 150mL of ethyl acetate, then starting stirring, slowly cooling to below 5 ℃, starting to dropwise add 25g of thionyl chloride, keeping the temperature below 5 ℃ in the dropwise adding process, after the dropwise adding is finished, continuing to perform heat preservation at the temperature of 5-10 ℃ for halogenation reaction until the raw materials are basically reacted completely, and after the reaction is finished, controlling the temperature below 50 ℃ for concentration to remove the solvent to obtain a residue containing the compound 2-chloro-3, 3-dimethylbutyric acid of the formula I;
adding 150g of saturated sodium carbonate aqueous solution into the residue by mass percent, heating to 50-55 ℃, preserving heat, completely performing hydrolysis reaction, adding 50mL of ethyl acetate after the reaction is finished, extracting, layering, collecting a water layer, and directly using the water layer for the next reaction; the ethyl acetate is added for extraction so as to better remove impurities and be beneficial to better improving the purity and quality of the intermediate product; directly adding 1.75g of TEMPO catalyst and 0.8g of ferric trichloride and 0.8g of sodium nitrite and 0.5g of 18-crown-6-ether into a water layer, adding 120mL of trifluorotoluene, leading the solvent of the reaction to be a mixed solvent system of water and trifluorotoluene, introducing air at room temperature under a stirring state to carry out oxidation reaction for 4 hours till the intermediate product in the previous step is completely reacted, filtering and recovering the catalyst after the reaction is finished, standing the filtrate, layering, removing an organic layer, adjusting the pH value of the collected water layer to be less than 1 by using 5 mass percent of dilute hydrochloric acid aqueous solution to carry out acidification treatment, adding 100mL of dichloromethane to extract and extract the product after the acidification treatment is finished, carrying out reduced pressure concentration treatment on the collected organic layer to remove the solvent, drying to obtain 52g of the final product 3, 3-dimethyl-2-oxobutyric acid, the yield was 92.8%, and the gas phase purity content was 99.1%.
Example 5
Putting 50g of 3, 3-dimethylbutyric acid into a dry and clean reactor, adding 120mL of cyclohexane, then starting stirring, slowly cooling to below 5 ℃, introducing chlorine gas under the condition of controlling the temperature to be 20-25 ℃ to perform halogenation reaction until the raw materials are basically reacted completely, and after the reaction is finished, controlling the temperature to be below 50 ℃ to perform concentration to remove the solvent to obtain a 2-chloro-3, 3-dimethylbutyric acid residue containing the compound of the formula I;
adding 130g of potassium hydroxide aqueous solution with the mass percent of 25% into the residue, heating to 75-80 ℃, preserving the temperature, completely performing hydrolysis reaction, adding 50mL of dichloromethane after the reaction is finished, extracting, layering, collecting a water layer, and directly using the water layer for the next reaction; directly adding 2.5g of TEMPO catalyst and 1.0g of ferric trichloride into a water layer, adding 150mL of dichloroethane, enabling a reaction solvent to be a mixed solvent system of water and dichloroethane, introducing air at room temperature under a stirring state to perform oxidation reaction for 3 hours till the intermediate product in the previous step is completely reacted, filtering and recovering the catalyst after the reaction is finished, standing the filtrate, layering, removing an organic layer, adjusting the pH value of the collected water layer to be below 1 by using a dilute sulfuric acid aqueous solution with the mass percent of 5% to perform acidification treatment, adding 100mL of dichloromethane to extract and extract a product after the acidification treatment is finished, performing reduced pressure concentration treatment on the collected organic layer to remove the solvent, drying to obtain 51g of a final product of 3, 3-dimethyl-2-oxobutyric acid, the yield was 91% and the gas phase purity was 99%.
Example 6
Adding 50g of 3, 3-dimethylbutyric acid into a dry and clean reactor, adding 100mL of dichloromethane, then starting stirring, slowly cooling to below 5 ℃, and starting dropwise adding a phosphorus oxychloride dichloromethane solution, wherein the amount of phosphorus oxychloride added in the example is in a molar equivalent ratio, and the amount added in the example is that the 3, 3-dimethylbutyric acid: the mol ratio of phosphorus oxychloride is 1: 1.2, keeping the temperature below 5 ℃ in the dripping process, keeping the temperature at 5-8 ℃ after finishing dripping, continuing to perform heat preservation at the temperature of 5-8 ℃ for halogenation reaction until the raw materials are basically reacted completely, and after finishing the reaction, controlling the temperature below 50 ℃ for concentration to remove the solvent to obtain a residue containing the compound 2-chloro-3, 3-dimethylbutyric acid of the formula I;
adding 100g of 30 mass percent sodium hydroxide solution into the residue, heating to 70-75 ℃ for carrying out hydrolysis reaction, adding 50mL of ethyl acetate for extraction after the reaction is finished, layering, collecting a water layer, and directly using the water layer for the next reaction; the ethyl acetate is added for extraction so as to better remove impurities and be beneficial to better improving the purity and quality of the intermediate product; directly adding 1.5g of TEMPO catalyst and 1.0g of ferric trichloride, 1.2g of sodium nitrite and 0.5g of 18-crown-6-ether into a water layer, adding 100mL of dichloromethane, enabling a reaction solvent to be a mixed solvent system of water and dichloromethane, stirring to slowly raise the temperature, controlling the temperature under a reflux condition, dropwise adding 30g of 20% hydrogen peroxide solution into the reaction system to perform oxidation reaction until the intermediate product in the previous step is completely reacted, filtering and recovering the catalyst after the reaction is finished, standing filtrate, layering, removing an organic layer, adjusting the pH value of the collected water layer to be below 1 by using 5% dilute phosphoric acid aqueous solution by mass percent to perform acidification treatment, adding ethyl acetate to extract an extraction product after the acidification treatment is finished, performing reduced pressure concentration treatment on the collected organic layer to remove the solvent, drying to obtain a final product 3, 50g of 3-dimethyl-2-oxobutyric acid, the yield is 89.2%, and the gas phase purity content is 99.2%.
Example 7
The preparation method of 3, 3-dimethyl-2-oxobutanoic acid in this example is substantially the same as example 5, except that the amounts of TEMPO and co-catalyst used are different, specifically, the amount of TEMPO added in this example is 2.0g, the co-catalyst is a mixture of ferric chloride, sodium nitrite and crown ether, and the amounts of ferric chloride, sodium nitrite and 18-crown-6-ether are 0.4g, 0.4g and 0.2g, respectively. The final product, 3-dimethyl-2-oxobutanoic acid, 50.2g, was obtained in 89.6% yield with a gas phase purity content of 99.2%.
Example 8
The process for the preparation of 3, 3-dimethyl-2-oxobutanoic acid of this example is essentially identical to that of example 3, except that only TEMPO is used as the catalyst during the oxidation reaction, no co-catalyst is added, and the amount of TEMPO added in this example is 2.5 g. 45g of the finally obtained product, 3-dimethyl-2-oxobutanoic acid, was found to have a yield of 80.3% and a gas-phase purity of 98.8%.
The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Claims (9)
1. A method for preparing 3, 3-dimethyl-2-oxobutanoic acid, comprising the steps of:
A. carrying out a halogenation reaction on 3, 3-dimethylbutyric acid and a halogenating agent in an organic solvent to obtain an intermediate compound shown in a formula I, wherein X in the compound shown in the formula I is halogen;
B. carrying out hydrolysis reaction on the compound of the formula I to obtain a compound of a formula II;
C. in the presence of a catalytic assistant and a TEMPO catalyst, carrying out oxidation reaction on a compound shown in a formula II under the action of an oxidant, and then carrying out acidification treatment to obtain a product, namely a compound shown in a formula III; the catalytic auxiliary agent is a mixture of ferric trichloride, sodium nitrite and crown ether, and the weight ratio of ferric trichloride: sodium nitrite: the mass ratio of the crown ether is 1: 0.8-1.2: 0.2 to 0.5;
2. the method of preparing 3, 3-dimethyl-2-oxobutanoic acid according to claim 1, wherein in step a the halogenating agent is selected from phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, chlorine gas, bromine, iodine, triphosgene or carbon tetrachloride, and X corresponds to a halogen in the halogenating agent.
3. A process for the preparation of 3, 3-dimethyl-2-oxobutanoic acid according to claim 1, wherein in step C the crown ether is selected from 18-crown-6-ether or 15-crown-5-ether.
4. A method for preparing 3, 3-dimethyl-2-oxobutanoic acid as claimed in claim 1, wherein said oxidizing agent in step C is selected from one or more of hydrogen peroxide, sodium periodate, sodium hypochlorite, sodium hypobromite, oxygen and air.
5. A process for preparing 3, 3-dimethyl-2-oxobutanoic acid according to any one of claims 1 to 4, wherein in step A the organic solvent is selected from one or more of dichloromethane, ethyl acetate, dichloroethane and cyclohexane, and the temperature of the halogenation reaction is carried out at 25 ℃ or lower.
6. A process for the preparation of 3, 3-dimethyl-2-oxobutanoic acid according to any one of claims 1 to 4, wherein the oxidation reaction in step C is carried out in one or more solvents selected from the group consisting of benzene, toluene, dichloroethane, dichloromethane, and trifluorotoluene, and the temperature of the oxidation reaction is from 30 ℃ to reflux temperature.
7. The process for producing 3, 3-dimethyl-2-oxobutanoic acid according to any one of claims 1 to 4, wherein the hydrolysis reaction in step B is carried out in the presence of an inorganic acid or an inorganic base, and the temperature of the hydrolysis reaction is from 30 ℃ to 80 ℃.
8. The method of producing 3, 3-dimethyl-2-oxobutanoic acid according to claim 7, wherein the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and polyphosphoric acid; the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and potassium carbonate.
9. A process for the preparation of 3, 3-dimethyl-2-oxobutanoic acid according to claim 1 or 3, wherein the TEMPO catalyst is used in an amount of 3 to 5 wt% based on the amount of 3, 3-dimethylbutyric acid; the mass ratio of the TEMPO catalyst to the catalytic auxiliary agent is 1: 0.5-1: 2.0.
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| CN111170846B (en) * | 2019-02-20 | 2023-03-10 | 武汉珈汇精化科技有限公司 | Method for preparing 3,3-dimethyl-2-oxo-butyric acid |
| CN113004141A (en) * | 2019-12-19 | 2021-06-22 | 北京颖泰嘉和生物科技股份有限公司 | Process for the preparation of 3, 3-dimethyl-2-oxobutanoic acid and triazinones |
| CN111393272A (en) * | 2020-04-21 | 2020-07-10 | 惠泽化学科技(濮阳)有限公司 | Synthetic method of 3' -methyl propiophenone |
| CN112225666B (en) * | 2020-11-10 | 2022-04-19 | 江苏八巨药业有限公司 | Preparation method of (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate |
| CN112592265B (en) * | 2020-12-21 | 2023-09-01 | 安达兰泽科技有限公司 | Preparation method of 3, 3-dimethyl-2-oxo-butyric acid and sodium salt thereof |
| CN116354805A (en) * | 2021-12-28 | 2023-06-30 | 上海飞凯材料科技股份有限公司 | Synthesis method of camphorquinone |
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