Method for synthesizing 2,2-dimethylpentanedioic acid

Abstract

The present invention relates to the technical field of drug synthesis, and in particular to a method for synthesizing 2,2-dimethylpentanedioic acid. The method comprises the following steps: (1) uniformly mixing isobutyraldehyde, acrylonitrile, and tetrahydrofuran, cooling the mixture to 0-5°C, dropwise adding a sodium hydroxide aqueous solution, then carrying out a reaction while maintaining the temperature, heating to 50-55°C for a reaction, and separating a cyanoaldehyde intermediate; (2) uniformly mixing the cyanoaldehyde intermediate, water, and potassium dihydrogen phosphate, cooling the mixture to 0-5°C, and adding hydrogen peroxide; and dropwise adding a sodium chlorite aqueous solution, then heating to 23-28°C, carrying out a reaction while maintaining the temperature, dropwise adding a sodium bisulfite aqueous solution to quench the reaction, and separating a cyanic acid intermediate; and (3) uniformly mixing the cyanic acid intermediate with sulfuric acid, heating the mixture to 95-100°C while stirring, carrying out a reaction while maintaining the temperature, cooling to room temperature, and separating a crude 2,2-dimethylpentanedioic acid product; and adding cyclohexane for crystallization to obtain a product. The synthesis route of the present invention is simple and novel, the raw materials used have low prices, the synthesis method is simple and convenient to operate, and the product yield is relatively high.

Description

A synthesis method of 2,2-dimethyl pentanedioic acid TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a synthesis method of 2,2-dimethyl pentanedioic acid. BACKGROUND

[0002] 2,2-dimethyl pentanedioic acid is a white to light yellow powder crystal, which is an important intermediate in organic synthesis and can be used to prepare various organic compounds such as esters and amides. In drug synthesis, 2,2-dimethyl pentanedioic acid can be used as a raw material or intermediate to synthesize compounds with specific biological activity. In drug synthesis, 2,2-dimethyl pentanedioic acid also has potential application value and can be used to synthesize new pesticides or improve the performance of existing pesticides.

[0003] At present, the synthesis methods of 2,2-dimethyl pentanedioic acid mainly include esterification reaction method, oxidation method and microbial fermentation method, but most of the above methods have defects such as high reaction condition requirement, complex operation and low product purity. The defects of high reaction condition requirement and complex operation will make the production cost of 2,2-dimethyl pentanedioic acid higher, and the defect of low product purity will directly affect the specific use of 2,2-dimethyl pentanedioic acid. Therefore, it is necessary to develop a synthesis method of 2,2-dimethyl pentanedioic acid with mild reaction condition, simple operation and high product purity. SUMMARY

[0004] The technical problem to be solved by the present application is to provide a synthesis method of 2,2-dimethyl pentanedioic acid. The synthesis route of the present application is simple and novel, the raw materials used are low in price, the synthesis method is simple to operate, the product yield is high and the product has high purity.

[0005] To solve the above technical problems, the technical solution provided by the present application is:

[0006] A synthesis method of 2,2-dimethyl pentanedioic acid, comprising the following steps:

[0007] (1) uniformly mix isobutyraldehyde, acrylonitrile and tetrahydrofuran, and cool to 0-5℃, then add sodium hydroxide aqueous solution dropwise, after the dropwise addition is completed, keep the reaction, then warm to 50-55℃ for reaction; then separate to obtain a cyanal intermediate, the structure of the cyanal intermediate is shown as formula I;

[0008] (2) uniformly mix the cyanal intermediate, water and potassium dihydrogen phosphate, and cool to 0-5℃, then add hydrogen peroxide; then add sodium chlorite aqueous solution dropwise, after the dropwise addition is completed, warm to 23-28℃ for reaction, then add sodium bisulfite aqueous solution dropwise to quench the reaction, then separate to obtain a cyanic acid intermediate, the structure of the cyanic acid intermediate is shown as formula II:

[0009] (3) mixing cyanic acid intermediate and sulfuric acid uniformly, stirring and heating to 95~100℃, keeping reaction, then cooling to room temperature, and separating to obtain 2,2-dimethyl pentandioic acid crude product; adding cyclohexane to 2,2-dimethyl pentandioic acid crude product to crystallize 2,2-dimethyl pentandioic acid product.

[0010] The synthesis method of 2,2-dimethyl pentandioic acid is as follows:

[0011] Preferably, in step (1), the molar ratio of isobutyraldehyde and acrylonitrile is 1:1.2~2, and the mass ratio of the total amount of isobutyraldehyde and tetrahydrofuran to acrylonitrile is 3~5:1.

[0012] The reaction time of the heat preservation is 2~3h, and the reaction time of heating to 50~55℃ is 5~6h.

[0013] Preferably, in step (1), the molar ratio of isobutyraldehyde and sodium hydroxide is 1:0.05~0.1; the temperature of the aqueous sodium hydroxide solution is between 0~10℃, and the mass concentration is 5~20%.

[0014] Preferably, in step (1), the separation of the cyanal intermediate specifically includes the following steps: adding water and dichloromethane to the reaction system after 5~6h of reaction at 50~55℃, and the mass ratio of water, dichloromethane and isobutyraldehyde is 1~1.5:3~5:1; then stirring, standing, separating the organic phase and washing with water, and then distilling under reduced pressure to obtain the cyanal intermediate and recovering the organic solvent.

[0015] Preferably, in step (2), the mass ratio of the cyanal intermediate, water and potassium dihydrogen phosphate is 1:4.5~5.5:2.0~2.2; the heat preservation time of heating to 23~28℃ is 2~3h.

[0016] Preferably, in step (2), the molar ratio of the cyanal intermediate and hydrogen peroxide is 1:1.02~1.1; the temperature of the added hydrogen peroxide is between 0~5℃;

[0017] The molar ratio of the cyanal intermediate and sodium chlorite is 1:2.02~2.2, the temperature of the aqueous sodium chlorite solution is between 0~10℃, and the mass concentration is 30~33%.

[0018] Preferably, in step (2), the mass concentration of the aqueous sodium bisulfite solution is 8~10%, and the mass ratio of the cyanal intermediate and the aqueous sodium bisulfite solution is 1:1.0~1.5.

[0019] Preferably, in step (2), the separation of the cyanic acid intermediate specifically comprises the following steps: adding dichloromethane to the reaction system after quenching the reaction with sodium bisulfite aqueous solution, extracting, separating the organic phase, then washing with water, and then removing the organic solvent by reduced pressure distillation to obtain the cyanic acid intermediate; the mass ratio of the cyanic aldehyde intermediate to dichloromethane is 1:5.0-5.5.

[0020] Preferably, in step (3), the mass ratio of the cyanic acid intermediate to sulfuric acid is 1:2.5-3.0; the reaction time is 19-22h.

[0021] The mass concentration of the sulfuric acid is 55-70%; the mass ratio of the cyclohexane to the cyanic acid intermediate is 1.5-2.0:1.

[0022] Preferably, in step (3), the separation of the 2,2-dimethyl pentandioic acid crude product specifically comprises the following steps: adding dichloromethane to the reaction system after cooling to room temperature, extracting twice, the total amount of dichloromethane to the mass ratio of the cyanic acid intermediate is 3-5:1; washing with water after combining the organic phase, and then removing the organic solvent by reduced pressure distillation to obtain the 2,2-dimethyl pentandioic acid crude product.

[0023] The beneficial effects of the present application are:

[0024] The raw materials involved in the synthesis method of the present application are isobutyraldehyde, acrylonitrile, potassium dihydrogen phosphate, tetrahydrofuran, etc., which are easy to obtain and have low cost. At the same time, the reaction conditions are mild, and the preparation can be carried out using conventional reactor equipment, and the overall operation is simple. And by the synthesis method of the present application, 2,2-dimethyl pentandioic acid products with high purity can be prepared, and the overall product yield is high.

[0025] The synthesis method of the present application has low production cost, high yield and high purity, and is very suitable for industrial production, and the obtained product has wide application. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme in the embodiments of the present application will be described clearly and completely. Obviously, the described embodiments are part of the embodiments of the present application, not all. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor belong to the scope of protection of the present application.

[0027] Example 1:

[0028] A synthesis method of 2,2-dimethyl pentandioic acid, comprising the following steps:

[0029] (1) 3000ml three-port bottle into isobutyraldehyde (300g, 4.17mol), acrylonitrile (270g, 5.09mol), tetrahydrofuran (900g), stirring mixed uniformly and cooling to 0~2℃, dropwise addition of temperature between 0~10℃, mass concentration of 5% sodium hydroxide solution (170g, 0.21mol), dropwise addition of 2h after the reaction, then heated to 50~55℃ reaction 5h, detection reaction complete, add water (300g), dichloromethane (900g), stirring 30min, 30min, separate out the organic phase, washed with water (300g) once, then reduced pressure distillation to obtain cyanal intermediate 427g (yield: 82%, purity: 98.5%), 1 H NMR (400 MHz, CDCl3) δ: 9.31 (s, 1H), 2.22~2.18 (t, 2H), 1.78~1.76 (t, 2H), 0.99 (s, 6H); recovery of organic solvent.

[0030] The structural formula of cyanal intermediate is shown as formula I;

[0031] (2) 10000ml three-port bottle into water (1800g), open stirring, sequentially adding potassium dihydrogen phosphate (800g, 5.88mol), cyanal intermediate (400g, 3.2mol), cooling to 0~2℃, adding mass concentration of 30% hydrogen peroxide (370g, 3.26mol), 5min after stirring; Then dropwise addition of temperature between 0~10℃, mass concentration of 31% sodium chlorite aqueous solution (1900g, 6.51mol), about 2.5h drop, remove the cold bath, heated to 25℃ reaction 2h, detection reaction complete, dropwise addition of mass concentration of 8% sodium bisulfite solution (400g) quenching, then add dichloromethane (2000g) stirring 30min, 30min, separate out the lower organic phase, organic phase added water (800g) washing once, then reduced pressure distillation to remove organic solvent to obtain cyanic acid intermediate (directly into the next step).

[0032] The structural formula of cyanic acid intermediate is shown as formula II:

[0033] (3) 3000ml three-necked flask was added cyanic acid intermediate (500 g, 2.72 mol), 60% mass concentration sulfuric acid (1250 g, 8.29 mol) and mixed uniformly, while stirring, the temperature was increased to 95-100°C, and the reaction was kept for 20h. After the reaction was completed, the temperature was decreased to room temperature, dichloromethane (1500g) was added and stirred for 30 minutes, and then separated after standing for 30 minutes. The organic phase was separated, the water phase was extracted with dichloromethane (1000g) again, the organic phase was combined, washed with water (1000g) once, and then the organic solvent was removed by distillation under reduced pressure to obtain 2,2-dimethyl pentanedioic acid crude product, and the organic solvent was recovered; 2,2-dimethyl pentanedioic acid crude product was added to cyclohexane (750g) to crystallize to obtain product 2,2-dimethyl pentanedioic acid 482g (yield: 85%, purity: 99.3%). 1 H NMR (400 MHz, CDCl3) δ: 2.47~2.44 (t, 2H), 1.96~1.92 (t, 2H), 1.24 (s, 6H).

Claims

1. A method for the synthesis of 2,2-dimethyl pentandioic acid, characterized in that, Comprising the following steps: (1) uniformly mix isobutyraldehyde, acrylonitrile, tetrahydrofuran and cool to 0-5℃, then drop in sodium hydroxide aqueous solution, after drop completion, keep reaction, then raise temperature to 50-55℃ and react; then separate to obtain cyanoaldehyde intermediate, the structural formula of the intermediate cyanoaldehyde is shown as formula I; (2) cyanal intermediate, water, potassium dihydrogen phosphate are mixed uniformly and cooled to 0-5 °C, hydrogen peroxide is added; then sodium chlorite aqueous solution is added dropwise, after dropwise addition is completed, temperature is increased to 23-28 °C, reaction is preserved, then sodium bisulfite aqueous solution is added dropwise to quench the reaction, then cyan acid intermediate is separated, the structure of the intermediate cyan acid is shown as formula II: (3) The cyanic acid intermediate, sulfuric acid is mixed uniformly, stirring while heating to 95~100℃, and then separated to obtain 2,2-dimethyl pentandioic acid crude product; cyclohexane is added to the 2,2-dimethyl pentandioic acid crude product to crystallize 2,2-dimethyl pentandioic acid product.

2. The method of synthesizing 2,2-dimethyl glutaric acid according to claim 1, characterized in that: In step (1), the molar ratio of isobutyraldehyde and acrylonitrile is 1:1.2~2, and the mass ratio of the total amount of isobutyraldehyde and tetrahydrofuran to acrylonitrile is 3~5:1; The time of the heat preservation reaction is 2~3h, and the reaction time of heating to 50~55℃ is 5~6h.

3. The method of synthesizing 2,2-dimethyl glutaric acid according to claim 1, wherein: In step (1), the molar ratio of isobutyraldehyde and added sodium hydroxide is 1:0.05~0.1; the temperature of the aqueous sodium hydroxide solution is between 0~10℃, and the mass concentration is 5~20%.

4. The method of synthesizing 2,2-dimethyl glutaric acid according to claim 1, wherein, In step (1), the separation of the cyanal intermediate specifically includes the following steps: water and dichloromethane are added to the reaction system after 5~6h of reaction at 50~55℃, and the mass ratio of water, dichloromethane and isobutyraldehyde is 1~1.5:3~5:1; then stirring, standing, separating the organic phase and washing with water, and then distilling under reduced pressure to obtain the cyanal intermediate and recovering the organic solvent.

5. The method of synthesizing 2,2-dimethyl glutaric acid according to claim 1, wherein: In step (2), the mass ratio of the cyanal intermediate, water and potassium dihydrogen phosphate is 1:4.5~5.5:2.0~2.2; the heat preservation reaction time of heating to 23~28℃ is 2~3h.

6. The method of synthesizing 2,2-dimethyl glutaric acid according to claim 1, wherein: In step (2), the molar ratio of the cyanal intermediate and hydrogen peroxide is 1:1.02~1.1; the temperature of the added hydrogen peroxide is between 0~5℃; The molar ratio of the cyanal intermediate and sodium chlorite is 1:2.02~2.2, and the mass concentration of the aqueous sodium chlorite solution is 30~33% at a temperature of 0~10℃.

7. The method of synthesizing 2,2-dimethyl glutaric acid according to claim 1, wherein: In step (2), the mass concentration of the aqueous sodium bisulfite solution is 8~10%, and the mass ratio of the cyanal intermediate and the aqueous sodium bisulfite solution is 1:1.0~1.

5.

8. The method of synthesizing 2,2-dimethyl glutaric acid according to claim 1, wherein, In step (2), the separation of the cyanic acid intermediate specifically includes the following steps: dichloromethane is added to the reaction system after quenching the reaction of the aqueous sodium bisulfite solution, and the organic phase is separated and then washed with water, and then the organic solvent is removed by distillation under reduced pressure to obtain the cyanic acid intermediate; the mass ratio of the cyanal intermediate and dichloromethane is 1:5.0~5.

5.

9. The method of synthesizing 2,2-dimethyl glutaric acid according to claim 1, wherein: In step (3), the mass ratio of the cyanic acid intermediate and sulfuric acid is 1:2.5~3.0; the heat preservation reaction time is 19~22h; The mass concentration of the sulfuric acid is 55~70%, and the mass ratio of cyclohexane and cyanic acid intermediate is 1.5~2.0:

1.

10. The method of synthesizing 2,2-dimethyl glutaric acid according to claim 1, wherein, In step (3), the separation of 2,2-dimethyl pentandioic acid crude product specifically includes the following steps: dichloromethane is added to the reaction system after cooling to room temperature and extracted twice, and the total amount of dichloromethane and the mass ratio of cyanic acid intermediate is 3~5:1; the organic phase is combined and washed with water, and then the organic solvent is removed by distillation under reduced pressure to obtain 2,2-dimethyl pentandioic acid crude product.

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