A process for the preparation of 2-ethyl-2-methylpentanoic acid

Abstract

The application discloses a preparation method of 2-ethyl-2-methyl pentanoic acid, wherein in the process of preparing a key intermediate 2-cyanopentanoate (compound B), compound A is removed by using an alkali extraction method, high-purity compound B is separated by using rectification (a yield of 20% and a purity of 98%), and the operation process is simple. In the preparation method, reagents used are sodium methoxide, sodium hydroxide, sulfuric acid, sodium hydride and sodium nitrite, the reagents are simple, the danger is relatively small, and the experimental operation is relatively safe. In the preparation method, the post-treatment processes of alkylation, hydrolysis, deacidification and cyano hydrolysis do not use a chromatographic column purification process, and a conventional extraction distillation operation is adopted, so that the output of unit volume of instrument equipment is high.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of 2-ethyl-2-methylvaleric acid preparation, and particularly relates to a preparation method of 2-ethyl-2-methylvaleric acid. BACKGROUND

[0002] 2-ethyl-2-methylvaleric acid is an impurity easily produced in the preparation process of sodium valproate raw medicine, plays a key role in the detection and control of related substances in the production of sodium valproate raw medicine, and has the following structural formula:

[0003]

[0004] In the prior art, patent CN112174799A provides a preparation method of sodium valproate impurity K, mainly through the alkylation of ethyl acetoacetate (I) and bromopropane (II) to obtain compound III, the alkylation of compound III and iodomethane to obtain compound IV, the reduction of compound IV by sodium borohydride to obtain compound V, and the hydrolysis of compound V by alkali to obtain 2-ethyl-2-methylvaleric acid (J):

[0005]

[0006] The above process has the following defects: (1) when preparing the key intermediate propyl acetoacetate ethyl ester (compound III), a dialkyl by-product compound VI is inevitably produced, no purification method is proposed, and the next step reaction is directly performed, so that more by-products are produced in the next step reaction, and the purification difficulty is increased; (2) the strong reducing agent sodium borohydride is used in the preparation of 2-ethyl-2-methylvalerate (compound V), and the experimental operation is relatively dangerous; (3) the chromatographic column method is used in the preparation of 2-ethyl-2-methylvaleric acid, the solvent consumption is relatively large, the equipment processing capacity is low, and the unit volume instrument equipment capacity is low. SUMMARY

[0007] The present application aims at the deficiencies in the prior art, and provides a preparation method of 2-ethyl-2-methylvaleric acid.

[0008] To achieve the above object, the technical scheme adopted by the present application is as follows:

[0009] A preparation method of 2-ethyl-2-methylvaleric acid is provided, which comprises the following steps:

[0010] Step one, preparing 2-cyanovalerate: adding cyanoacetate, methanol and bromopropane into a reaction container, adding a methanol solution of an alkaline compound dropwise under stirring, controlling the reaction temperature to be 50-60 DEG C, refluxing, distilling off the methanol, filtering off the salt, extracting with a 5-10 wt.% sodium hydroxide aqueous solution, washing with water, and rectifying to obtain 2-cyanovalerate;

[0011] Step two, preparation of 2-cyano-2-methyl pentanoate: in a reaction vessel, 2-cyano pentanoate, methanol, methyl iodide, control temperature 50-60℃, dropwise add methanol solution of basic compound, reflux to reaction end, the reaction liquid is concentrated under reduced pressure, extraction, water washing, oil phase concentration, distillation to obtain 2-cyano-2-methyl pentanoate;

[0012] Step three, preparation of 2-cyano-2-methyl pentanoic acid: in a reaction vessel, 2-cyano-2-methyl pentanoate, then add 10-15% sodium hydroxide solution, heat to 60-70℃, reaction to end, add concentrated hydrochloric acid to pH = 1-1.5, post-processing, to obtain 2-cyano-2-methyl pentanoic acid;

[0013] Step four, preparation of 2-methyl pentanenitrile: 2-cyano-2-methyl pentanoic acid is placed in a normal pressure reaction and distillation reaction device, slowly heated to 140-190℃, the fraction is collected, to obtain 2-methyl pentanenitrile;

[0014] Step five, preparation of 2-methyl-2-ethyl pentanenitrile: in a reaction vessel, add base reagent solid powder, THF, iodoethane, then slowly add 2-methyl pentanenitrile, control temperature 60-70℃, reaction 10-12 hours, post-processing, to obtain 2-methyl-2-ethyl pentanenitrile;

[0015] Step six, preparation of 2-ethyl-2-methyl pentanoic acid: in a reaction vessel, add 2-methyl-2-ethyl pentanenitrile, 75-80% concentrated sulfuric acid, after reaction end and cooling, dropwise add 30-38% sodium nitrite aqueous solution, after cooling, add 10-15% sodium hydroxide aqueous solution, to obtain aqueous phase, post-processing, to obtain 2-ethyl-2-methyl pentanoic acid.

[0016] Further, in step one, the cyanoacetate is one of cyanoacetic acid methyl ester, cyanoacetic acid ethyl ester, cyanoacetic acid propyl ester, cyanoacetic acid butyl ester; the basic compound is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate; the molar ratio of the basic compound to the cyanoacetate is (0.4-1.5):1.

[0017] Further, in step one, the molar ratio of the bromopropane to the cyanoacetate is (0.5-1.5):1.

[0018] Further, in step one, the water washing is specifically: using 1-3% sulfuric acid aqueous solution to wash once, then using deionized water to wash once to neutral PH.

[0019] Further, in step two, the basic compound is one of sodium methoxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, the molar ratio of the basic compound to the 2-cyanopentanoic acid ester is (1-2):1, and the molar ratio of the iodomethane to the 2-cyanopentanoic acid ester is (1.05-1.5):1.

[0020] Further, in step three, the molar ratio of sodium hydroxide to the 2-cyanopentanoic acid ester is (1-4):1.

[0021] Further, in step five, the basic reagent is one of sodium hydride, lithium aluminum hydride, butyl lithium, sodium amide, and calcium hydride, the molar ratio of the basic reagent to the 2-methylpentanenitrile is (2-3):1, and the molar ratio of the iodoethane to the 2-methylpentanenitrile is (1-2):1.

[0022] Further, in step five, the post-treatment specifically includes: adding water to terminate the reaction, concentrating THF under reduced pressure in a water bath at 50 DEG C, adding toluene to extract the remaining aqueous phase, discarding the aqueous phase, and distilling the oil phase using a 10 cm packing column.

[0023] Further, in step six, after adding concentrated sulfuric acid, the reaction temperature is 80-85 DEG C, and the reaction time is 2-5 hours; after adding sodium nitrite aqueous solution, the temperature is 50-70 DEG C, and the stirring time is 0.5-5 hours; the temperature is lowered to 25 DEG C, water is added to dilute the reaction liquid, toluene is added, stirring is performed for 0.5 hours, the phases are separated, the aqueous phase is back-extracted with toluene, the phases are separated, the toluene phases are combined, the toluene phase is slowly added to 15% sodium hydroxide aqueous solution, the temperature is maintained at 50 DEG C for 0.5 hours, the temperature is lowered to room temperature, the aqueous phase is extracted with toluene, the oil phase is discarded, the aqueous phase is extracted with dichloromethane, the oil phase is discarded, the aqueous phase is neutralized to pH=1 with hydrochloric acid, isopropyl acetate is added to extract, the phases are separated, the oil phase is extracted with water, the phases are separated, the oil phase is concentrated to dryness under reduced pressure at 60 DEG C, and the oil phase is further concentrated to dryness under reduced pressure at 70 DEG C.

[0024] The present application adopts the above technical solution, and has the following technical effects compared with the prior art:

[0025] The preparation method of the present application uses alkali extraction to remove compound A in the preparation of the key intermediate 2-cyanopentanoic acid ester (compound B), and uses rectification to successfully separate high-purity compound B (yield 20%,

[0026] 98%, and the operation process is simple.

[0027] The reagents used in the preparation method of the present application are sodium methoxide, sodium hydroxide, sulfuric acid, 60% sodium hydride, and sodium nitrite, the reagents are simple, the danger is relatively small, and the experimental operation is relatively safe.

[0028] The post-treatment process of alkylation, hydrolysis, deacidification and cyano hydrolysis in the preparation method of the application does not use chromatographic column purification process, and adopts conventional extraction distillation operation, so that the output of unit volume of instrument equipment is high. BRIEF DESCRIPTION OF DRAWINGS

[0029] Figure 1 The mass spectrum of the compound J prepared in the application. DETAILED DESCRIPTION

[0030] The application will be further described below in conjunction with the drawings and specific examples, but not as a limitation of the application. It should be noted that the examples in the application and the features in the examples can be combined with each other without conflict.

[0031] Example 1

[0032] Preparation of 2-cyanovaleric acid methyl ester (compound B):

[0033]

[0034] In a 5L reaction bottle, 720g of methyl cyanoacetate (compound A), 1140g of methanol, 714g (molar ratio of methyl cyanoacetate is 0.8) of bromopropane, and 784g of 30% sodium methoxide (molar ratio of methyl cyanoacetate is 0.6) in methanol were added, and the temperature was raised to 50 degrees. Under mechanical stirring, a 30% sodium methoxide solution in methanol was added dropwise, and the reaction temperature was controlled at 50-60°C. After refluxing for 1 hour, the methanol was distilled off, 800ml of isopropyl acetate was added, and the salt was removed by beating and filtering to obtain a mixture (compound A is 8%, compound B is 45%, and compound K is 47%). Then, the isopropyl acetate phase was washed with 500ml*6 of 5% sodium hydroxide aqueous solution. Compound A is converted to compound L and has certain water solubility, while compounds B and K remain in the oil phase, and compound A can be removed by phase separation. The oil phase was washed once with 500ml of 1% sulfuric acid aqueous solution and once with 500ml of deionized water to neutralize the PH. The oil phase was concentrated to dryness to obtain 360g of crude product (compound B is 79% and compound K is 21%), and 2-cyano-2-pentanoic acid methyl ester (compound B, 205g, purity is 98.5%, yield is 20%) was obtained by distillation using a rectifying column.

[0035] Example 2

[0036] Preparation of 2-cyano-2-methylvaleric acid methyl ester (compound C)

[0037]

[0038] In a reaction flask, 2-cyanopentanoic acid methyl ester (compound B) 70 g, methanol 110 g, methyl iodide 74 g (molar ratio of 2-cyanopentanoic acid methyl ester 1.05), temperature control to 50-60°C, drop 93.7 g of 30% sodium methoxide (molar ratio of 2-cyanopentanoic acid methyl ester 1.1) in methanol, drop to reflux for 3 hours after the end of the reaction. The reaction was completed, the reaction liquid was concentrated to dryness under reduced pressure, 150 ml of isopropyl acetate and 100 ml of water were added to extract the salt, the phases were separated, the oil phase was extracted with 100 ml of water once, the oil phase was concentrated to dryness to obtain 74 g of crude product, and distillation was carried out to obtain 2-cyanopentanoic acid methyl ester (compound C, 59 g, purity 98%, yield 76%).

[0039] Example 3

[0040] Preparation of 2-cyanopentanoic acid methyl ester (compound B)

[0041]

[0042] In a reaction flask, 2-cyanopentanoic acid methyl ester (compound B) 70 g, methanol 110 g, methyl iodide 74 g (molar ratio of 2-cyanopentanoic acid methyl ester 1.05), temperature control to 50-60°C, drop 93.7 g of 30% sodium methoxide (molar ratio of 2-cyanopentanoic acid methyl ester 1.1) in methanol, drop to reflux for 3 hours after the end of the reaction. The reaction was completed, the reaction liquid was concentrated to dryness under reduced pressure, 150 ml of isopropyl acetate and 100 ml of water were added to extract the salt, the phases were separated, the oil phase was extracted with 100 ml of water once, the oil phase was concentrated to dryness to obtain 74 g of crude product, and distillation was carried out to obtain 2-cyanopentanoic acid methyl ester (compound C, 59 g, purity 98%, yield 76%).

[0043] Example 4

[0044] Preparation of 2-cyanopentanoic acid methyl ester (compound B)

[0045]

[0046] In a reaction flask, 2-cyanopentanoic acid methyl ester (compound B) 70 g, methanol 110 g, methyl iodide 74 g (molar ratio of 2-cyanopentanoic acid methyl ester 1.05), temperature control to 50-60°C, drop 93.7 g of 30% sodium methoxide (molar ratio of 2-cyanopentanoic acid methyl ester 1.1) in methanol, drop to reflux for 3 hours after the end of the reaction. The reaction was completed, the reaction liquid was concentrated to dryness under reduced pressure, 150 ml of isopropyl acetate and 100 ml of water were added to extract the salt, the phases were separated, the oil phase was extracted with 100 ml of water once, the oil phase was concentrated to dryness to obtain 74 g of crude product, and distillation was carried out to obtain 2-cyanopentanoic acid methyl ester (compound C, 59 g, purity 98%, yield 76%).

[0047] Example 5

[0048] Preparation of 2-cyanopentanoic acid methyl ester (compound B)

[0049]

[0050] In a reaction bottle, 15.5 g of sodium hydride solid powder (mass content 60%), 60 ml of THF, 40 g of iodoethane, 2-methylpentanenitrile (compound E, 16 g) were slowly added, and the reaction was carried out at 60-70°C for 10-12 hours, and then the temperature was lowered to room temperature, 50 g of purified water was added to terminate the reaction, and the THF was concentrated under reduced pressure in a water bath at 50°C, the remaining aqueous phase was extracted with 100 ml of toluene, the aqueous phase was discarded, and the oil phase was concentrated to dryness to obtain 20 g, and then a 10 cm packed column was used for distillation to obtain 2-methyl-2-ethylpentanenitrile (compound F, 4.1 g, yield 20%, purity 70%).

[0051] Example 6

[0052] Preparation of 2-ethyl-2-methylpentanoic acid (compound J)

[0053]

[0054] In a reaction bottle, 2-ethyl-2-methylpentanenitrile (compound F, 3.5 g) was added, 17.5 g of concentrated sulfuric acid with a mass concentration of 80% was added, and the reaction was carried out at 81°C for 2 hours. After the reaction was completed, the reaction liquid was cooled to 50°C, 7.6 g of sodium nitrite aqueous solution with a mass concentration of 38% was slowly added dropwise, and the mixture was stirred at 50°C for 0.5 hours, then the temperature was slowly lowered to 25°C, 13 g of water was added to dilute the reaction liquid, 10 ml of toluene was added, and the mixture was stirred for 0.5 hours, then the phases were separated, 6 ml of toluene was added to the aqueous phase for back extraction, the phases were separated, and the toluene phases were combined. The toluene phase was slowly added to 12 g of sodium hydroxide aqueous solution with a mass concentration of 15% at 50°C for 0.5 hours, the temperature was lowered to room temperature, 10 ml of toluene was added to the aqueous phase for extraction, the phases were separated, and the oil phase was discarded. The aqueous phase was extracted with 10 ml of dichloromethane, the phases were separated, and the oil phase was discarded. The aqueous phase was neutralized to pH = 1 with 4 g of hydrochloric acid, 18 ml of isopropyl acetate was added to the system, the phases were extracted and separated, the oil phase was extracted with 10 ml of toluene, the phases were separated, and the oil phase was concentrated to dryness under reduced pressure at 60 degrees. The oil pump was continued to be used to concentrate to dryness under reduced pressure at 70 degrees to obtain 2-ethyl-2-methylpentanoic acid (compound J, 1.8 g, yield 66%, purity 96%). The compound was confirmed by hydrogen proton and mass spectrum (Figure 1) to have a correct structure. Figure 1

[0055] 2-ethyl-2-methylpentanoic acid hydrogen proton statistics are shown in Table 1 below:

[0056] Table 1

[0057]

[0058]

[0059] According to the statistics in the table, the chemical shift of hydrogen proton and the number of hydrogen atoms correspond to the structure of the compound, so the structure of the prepared compound is correct.

[0060] ​The above merely describes preferred embodiments of the present application, and is not intended to limit the embodiments and protection scope of the present application. It should be noted by those skilled in the art that any equivalent substitutions and obvious changes made according to the content of the present application and drawings should be included in the protection scope of the present application.

Claims

1. A method for preparing 2-ethyl-2-methylpentanoic acid, characterized in that, Includes the following steps: Step 1, Preparation of 2-cyanopentyl ester: Add cyanoacetate, methanol, and bromopropane to a reaction vessel. Add a methanol solution of an alkaline compound dropwise while stirring. Control the reaction temperature at 50-60℃. Reflux, distill off methanol, filter to remove salt, extract with a 5-10% sodium hydroxide aqueous solution, wash with water, and distill to obtain 2-cyanopentyl ester. Step 2, Preparation of 2-cyano-2-methylvalerate: Add 2-cyanovalerate, methanol, and iodomethane to a reaction vessel, control the temperature at 50-60℃, add a methanol solution of an alkaline compound dropwise, reflux and keep warm until the reaction is complete, concentrate the reaction solution under reduced pressure, extract and desalt, wash with water, concentrate the oil phase and distill to obtain 2-cyano-2-methylvalerate; Step 3, preparation of 2-cyano-2-methylvaleric acid: 2-cyano-2-methylvaleric acid ester is added to the reaction vessel, followed by 10-15% sodium hydroxide aqueous solution. The reaction is kept at 60-70℃ until completion. Concentrated hydrochloric acid is added to adjust the pH to 1-1.

5. After post-treatment, 2-cyano-2-methylvaleric acid is obtained. Step 4, Preparation of 2-methylpentanilonitrile: 2-cyano-2-methylpentanoic acid is placed in a reaction apparatus that combines atmospheric pressure reaction and distillation, and the temperature is slowly raised to an internal temperature of 140-190℃. The distillate is collected to obtain 2-methylpentanilonitrile. Step 5, Preparation of 2-methyl-2-ethylpentanilonitrile: Add alkali reagent solid powder, THF, and iodoethane to the reaction vessel, then slowly add 2-methylpentanilonitrile, control the temperature at 60-70℃, react for 10-12 hours, and then perform post-treatment to obtain 2-methyl-2-ethylpentanilonitrile; the post-treatment specifically involves: adding water to terminate the reaction, concentrating THF under reduced pressure in a water bath at 50℃, extracting the remaining aqueous phase with toluene, discarding the phase-separated aqueous phase, and distilling the concentrated oil phase using a 10 cm packed column. In step five, the alkaline reagent is one of sodium hydride, lithium aluminum hydride, butyllithium, sodium amino, and calcium hydride, and the molar ratio of the alkaline reagent to the 2-methylpentanonitrile is (2-3):1; the molar ratio of iodoethane to the 2-methylpentanonitrile is (1-2):

1. Step 6, Preparation of 2-ethyl-2-methylpentanoic acid: Add 2-methyl-2-ethylpentanilide and concentrated sulfuric acid with a mass concentration of 75-80% to the reaction vessel. After the reaction is completed and the temperature is lowered, add sodium nitrite aqueous solution dropwise. After cooling, add sodium hydroxide aqueous solution to obtain an aqueous phase. After post-treatment, 2-ethyl-2-methylpentanoic acid is obtained.

2. The method for preparing 2-ethyl-2-methylpentanoic acid according to claim 1, characterized in that, In step one, the cyanoacetate is one of methyl cyanoacetate, ethyl cyanoacetate, propyl cyanoacetate, and butyl cyanoacetate; the alkaline compound is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, and potassium carbonate; and the molar ratio of the alkaline compound to the cyanoacetate is (0.4-1.5):

1.

3. The method for preparing 2-ethyl-2-methylpentanoic acid according to claim 1, characterized in that, In step one, the molar ratio of bromopropane to cyanoacetate is (0.5-1.5):

1.

4. The method for preparing 2-ethyl-2-methylpentanoic acid according to claim 1, characterized in that, In step one, the water washing specifically involves washing once with a sulfuric acid aqueous solution with a mass concentration of 1-3%, and then washing once with deionized water until the pH is neutral.

5. The method for preparing 2-ethyl-2-methylpentanoic acid according to claim 1, characterized in that, In step two, the alkaline compound is one of sodium methoxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, and sodium tert-butoxide, and the molar ratio of the alkaline compound to the 2-cyanopentate is (1-2):1; the molar ratio of iodomethane to the 2-cyanopentate is (1.05-1.5):

1.

6. The method for preparing 2-ethyl-2-methylpentanoic acid according to claim 1, characterized in that, In step three, the molar ratio of sodium hydroxide to the 2-cyano-2-methylpentanoate is (1-4):

1.

7. The method for preparing 2-ethyl-2-methylpentanoic acid according to claim 1, characterized in that, In step six, after adding concentrated sulfuric acid, the reaction temperature is 80-85℃ and the reaction time is 2-5 hours; after adding sodium nitrite aqueous solution, the temperature is 50-70℃ and the mixture is stirred for 0.5-5 hours; the temperature is lowered to 25℃, water is added to dilute the reaction solution, toluene is added, and the mixture is stirred for 0.5 hours. The aqueous phase is back-extracted with toluene, and the phases are separated. The toluene phases are combined, and the toluene phase is slowly added to a 15% sodium hydroxide aqueous solution and kept at 50℃ for 0.5 hours. The temperature is lowered to room temperature, and the aqueous phase is extracted with toluene. The oil phase is separated and discarded. The aqueous phase is extracted with dichloromethane, and the oil phase is separated and discarded. The aqueous phase is neutralized to pH=1 with hydrochloric acid, and isopropyl acetate is added for extraction and phase separation. The oil phase is extracted with water and phase separated. The oil phase is concentrated to dryness under reduced pressure at 60℃, and then concentrated to dryness under reduced pressure at 70℃ using an oil pump.

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