CN109438217B

CN109438217B - Preparation method of 2, 2-dimethylbutyric acid

Info

Publication number: CN109438217B
Application number: CN201811483197.3A
Authority: CN
Inventors: 孙发明; 姜殿宝; 张洪学
Original assignee: DALIAN QIKAI MEDICAL TECHNOLOGY CO LTD
Current assignee: DALIAN QIKAI MEDICAL TECHNOLOGY CO LTD
Priority date: 2018-12-05
Filing date: 2018-12-05
Publication date: 2021-07-16
Anticipated expiration: 2038-12-05
Also published as: CN109438217A

Abstract

The invention discloses a preparation method of 2, 2-dimethylbutyric acid, and belongs to the field of pharmaceutical and chemical intermediate preparation processes. Isoamyl formate is obtained as intermediate under the action of catalytic amount of sulfuric acid with isoamyl alcohol and formic acid as material, and then reacted with sulfuric acid to produce 2, 2-dimethyl butyric acid. The preparation method has simple process and less sulfuric acid consumption, further reduces corresponding waste sulfuric acid solution, and is easy for industrial production.

Description

Preparation method of 2, 2-dimethylbutyric acid

Technical Field

The invention relates to a preparation method of alkyl carboxylic acid, in particular to a carboxylation process of 2, 2-dimethyl butyric acid, belonging to the field of preparation processes of pharmaceutical and chemical intermediates.

Background

2, 2-dimethylbutyric acid is an important basic chemical raw material, and 2, 2-dimethylbutyric acid chloride is generated after chlorination and is a key intermediate of spirodiclofen serving as an agricultural insecticide and simvastatin serving as a blood fat reducing drug.

Spirodiclofen is the spirocyclic tetronic acid insecticide and acaricide developed by Bayer company at first, and is currently used for controlling pests such as whitefly and spider mite on crops such as cotton, vegetable vegetables, orange, grapes and the like. As an acaricide with a brand-new action mechanism developed by Bayer crop science company for more than ten years, the acaricide mechanism is completely different from the existing acaricides. The spirodiclofen finally kills mites by inhibiting fat synthesis in mite bodies and destroying energy metabolism activities of the mites, is a brand-new and high-efficiency non-systemic foliar treatment acaricide, does not have the problem of cross resistance with other existing acaricides, has good control effect and excellent persistence on different mites of various crops, kills eggs and young mites, and is particularly suitable for preventing and controlling harmful mites which generate resistance to the existing acaricides.

Simvastatin is a statin-type hypolipidemic drug developed by merck corporation of the united states, which is named in the basic drug list of the world health organization and belongs to one of the essential drugs of the basic medical system. The product is first marketed in 1988, approved by FDA in US 12 months in 1991, and listed as the second name in the global sales list of Merck (Zocor) in 2000, and has great market demand.

Currently, the main production processes of 2, 2-dimethylbutyric acid include the following:

first, oxo synthesis method

The catalyst is prepared by taking isoamylene and carbon monoxide as raw materials and carrying out high-pressure reaction in the presence of catalysts such as boron trifluoride and hydrofluoric acid, and the process needs high-pressure equipment and uses carbon monoxide gas, so that certain risks exist.

Second, Grignard reagent synthesis method

Methyl magnesium bromide is prepared in tetrahydrofuran, butanone is added into the prepared Grignard reagent to obtain 2-methyl-2-butanol, then carbon monoxide is introduced, and carbonylation reaction is carried out by taking cuprous oxide as a catalyst to obtain 2, 2-dimethylbutyric acid.

Method III, catalytic synthesis of isoamyl alcohol and formic acid

The isoamyl alcohol and the formic acid react under the catalysis of sulfuric acid, and the molar ratio of the three raw materials is 1.0:1.2: 7.0. The process has the disadvantages of large amount of waste sulfuric acid, low production efficiency and high cost. The large amount of dilute sulfuric acid produced by the reaction contains a small amount of products and impurities, and cannot be recycled, so that the adverse effects of increased production cost, environmental pollution and the like are caused.

In the actual reaction process, formic acid is dripped into concentrated sulfuric acid to generate carbon monoxide and water, the concentration of the sulfuric acid is lower and lower along with the reaction, the reaction cannot be carried out when the concentration of the sulfuric acid is lower than 91 percent, so a large amount of sulfuric acid is needed to be used as a solvent, the sulfuric acid needs to be diluted to 50-60 percent after the reaction is finished, and a large amount of dilute sulfuric acid cannot be recycled.

Disclosure of Invention

The invention aims to solve the problem of large amount of waste sulfuric acid in the production process aiming at the defects of the prior art of the third process. In order to reduce the using amount of sulfuric acid, the invention adopts the scheme that: isoamyl formate is obtained as intermediate under the action of catalytic amount of sulfuric acid with isoamyl alcohol and formic acid as material, and then reacted with sulfuric acid to produce 2, 2-dimethyl butyric acid. The preparation method has the advantages of simple process, less sulfuric acid consumption, less waste sulfuric acid solution and easy industrial production.

A preparation method of 2, 2-dimethylbutyric acid, characterized by comprising the following steps:

1) mixing isoamyl alcohol and formic acid, and heating and reacting under the catalysis of sulfuric acid to obtain isoamyl formate;

2) dripping isoamyl formate into concentrated sulfuric acid, and heating to react to obtain 2, 2-dimethyl butyric acid.

Further, in the above technical scheme, in the step 1), the sulfuric acid is added dropwise or added at one time, and then the temperature is slowly increased for reaction. The reaction at elevated temperature is preferably carried out under reflux.

Further, in the technical scheme, in the step 1), the molar weight ratio of the isoamyl alcohol, the formic acid and the sulfuric acid is 1.0:1.0-1.8: 0.01-0.1. Preferably, the molar weight ratio of the isoamyl alcohol to the formic acid to the sulfuric acid is 1.0:1.2-1.5: 0.03-0.05.

Further, in the above technical scheme, in the step 2), the reaction temperature is 40-80 ℃. The reaction temperature is preferably 55 to 60 ℃.

Further, in the technical scheme, in the step 2, the molar ratio of concentrated sulfuric acid to isoamyl formate is 0.8-1.5: 1.

Further, in the above technical solution, in the step 2, the stirring speed has a large influence on the reaction, and is preferably 200-.

Advantageous effects of the invention

The invention adopts isoamyl alcohol and formic acid to react under the action of catalytic amount of sulfuric acid by heating to obtain intermediate isoamyl formate, and then the intermediate isoamyl formate reacts with sulfuric acid to generate 2, 2-dimethyl butyric acid. The preparation method has simple process, can be continuously carried out, and effectively reduces the using amount of sulfuric acid, so that the generated waste sulfuric acid solution is obviously reduced, and the industrial production is easy.

Detailed Description

Example 1

440.8g of isoamyl alcohol, 368.2g of formic acid and 22g of concentrated sulfuric acid are added into a 1L four-neck flask provided with a condenser, a mechanical stirrer and a thermometer sleeve, the temperature is increased and the reflux is carried out for 5 to 6 hours, the temperature is reduced, the layers are separated, the upper layer is 560g of an oil layer, and the oil layer is separated for standby application.

Adding 500g of sulfuric acid into another 1L four-neck flask, stirring at the rotating speed of 200r/min, heating to 55-60 ℃, slowly dripping the separated oil layer, stirring for 0.5-1 hour after dripping is finished, cooling to room temperature, dripping the obtained reaction liquid into 200g of ice-water mixture, keeping the temperature at 0-5 ℃, layering after dripping is finished, adding 150g of dichloromethane into a waste sulfuric acid layer, extracting twice, combining organic layers, adding 150g of water, washing once, separating an organic layer concentrated solvent, and distilling under reduced pressure at the temperature of 110 +/-0.095 MPa to obtain 460g of 2, 2-dimethylbutyric acid with the yield of 79.3%.

Example 2

352.5g of isoamyl alcohol and 324.0g of formic acid are added into a 1L four-neck flask provided with a condenser, a mechanical stirrer and a thermometer sleeve, 15g of concentrated sulfuric acid is dripped at room temperature, after 20 minutes of dripping, the mixture is heated and refluxed for 5 to 6 hours, cooled and layered, the upper layer is 445g of an oil layer, and the oil layer is separated for later use.

Adding 400g of sulfuric acid into another 1L four-neck flask, stirring at the rotating speed of 200r/min, heating to 45-50 ℃, slowly dripping the separated oil layer, stirring for 0.5-1 hour after dripping is finished, cooling to room temperature, dripping the obtained reaction liquid into 160g of ice-water mixture, keeping the temperature at 0-5 ℃, layering after dripping is finished, adding dichloromethane into a waste sulfuric acid layer for extraction twice, combining organic layers, adding 120g of water for washing once, concentrating a solvent of the separated organic layer, and distilling under reduced pressure at 110 +/-0.095 MPa to obtain 353g of 2, 2-dimethylbutyric acid with the yield of 76.2%.

Example 3

396.0g of isoamyl alcohol, 331.2g of formic acid and 20g of concentrated sulfuric acid are added into a 1L four-neck flask provided with a condenser, a mechanical stirrer and a thermometer sleeve, the temperature is increased and the reflux is carried out for 5 to 6 hours, the temperature is reduced, the layers are separated, the upper layer is 498g of an oil layer, and the oil layer is separated for standby application.

Adding 450g of sulfuric acid into another 1L four-neck flask, stirring at the rotating speed of 250r/min, heating to 65-70 ℃, slowly dripping the separated oil layer, stirring for 0.5-1 hour after dripping, cooling to room temperature, dripping the obtained reaction liquid into an ice-water mixture, keeping the temperature at 0-5 ℃, layering after dripping, adding dichloromethane into a waste sulfuric acid layer to extract twice, combining organic layers, adding 130g of water to wash once, concentrating a solvent of the separated organic layer, and distilling under reduced pressure at the temperature of 110 ℃ to 0.095Mpa to obtain 392.0g of 2, 2-dimethylbutyric acid, wherein the yield is 75.0%.

Example 4

Adding 400 kg of isoamyl alcohol, 335 kg of formic acid and 20 kg of concentrated sulfuric acid into a 1000L reaction kettle, slowly heating to 90-100 ℃, refluxing for 5-6 hours, cooling, and layering, wherein the upper layer is 500 kg of an oil layer.

And slowly adding the separated oil layer into a 2000L reaction kettle filled with 450 kg of concentrated sulfuric acid, wherein the reaction temperature is 65-70 ℃, stirring for 0.5-1 hour after the dropwise addition is finished, cooling to room temperature, dropwise adding the obtained reaction liquid into 180 kg of water, keeping the temperature at 0-5 ℃, layering after the dropwise addition is finished, adding dichloromethane into the waste sulfuric acid layer to extract twice, combining the organic layers, adding 100 kg of water to wash once, concentrating the separated organic layer to obtain a solvent, and distilling under reduced pressure at 110 ℃ to 0.095Mpa to obtain 407 kg of 2, 2-dimethylbutyric acid, and the yield is 78.0%.

The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.

Claims

1. A preparation method of 2, 2-dimethylbutyric acid, characterized by comprising the following steps: 1) mixing isoamyl alcohol and formic acid, and heating and reacting under the catalysis of sulfuric acid to obtain isoamyl formate; in the step, the molar weight ratio of isoamyl alcohol, formic acid and sulfuric acid is 1.0:1.0-1.8: 0.01-0.1; 2) dripping isoamyl formate into concentrated sulfuric acid, and heating for reaction to obtain 2, 2-dimethylbutyric acid; in the step, the reaction temperature is 40-80 ℃; the molar ratio of concentrated sulfuric acid to isoamyl formate is 0.8-1.5: 1; the stirring speed is 200-300 rpm.

2. The method of producing 2, 2-dimethylbutyric acid according to claim 1, wherein: in the step 1), after dropwise adding or adding the sulfuric acid at one time, slowly heating and refluxing for reaction.

3. The method of producing 2, 2-dimethylbutyric acid according to claim 1, wherein: in the step 1), the molar weight ratio of isoamyl alcohol, formic acid and sulfuric acid is 1.0:1.2-1.5: 0.03-0.05.

4. The method of producing 2, 2-dimethylbutyric acid according to claim 1, wherein: in the step 2), the reaction temperature is 55-60 ℃.