A highly efficient and green method for synthesizing 2,3-dimethylbutyramide

Abstract

The invention discloses a kind of efficient and green synthetic method of 2,3-dimethylbutanamide, adds MTBE solvent into reactor, adds quantitative propionitrile and 2-bromopropane, slowly puts into quantitative sodium amide;After the reaction is finished, heat up and take off MTBE, add water and stir to keep alkali concentration after being cooled to room temperature;After the hydrolysis reaction is finished, suction filtration is carried out to the reaction solution, and the obtained filtrate is layered and processed;The filter cake obtained is 2,3-dimethylbutanamide crude product, refluxes with water through MTBE solvent, and 2,3-dimethylbutanamide finished product is obtained by drying after crystallization. The present invention adopts a kind of efficient and green synthetic method of 2,3-dimethylbutanamide of the above-mentioned steps, and the first two steps are in the same reaction system, and the alkali concentration of the whole system is adjusted using unreacted sodium amide, and the sodium bromide saturated solution in the aqueous phase is used to force out 2,3-dimethylbutanamide solid after the hydrolysis reaction, and it is simple to operate and efficient.

Description

Technical Field

[0001] The invention relates to the technical field of chemical production, and in particular to a highly efficient and green method for synthesizing 2,3-dimethylbutyramide. Background Art

[0002] 2,3-Dimethylbutanamide, CAS No.: 66309-91-9, can be used for drug synthesis. It is a general organic synthesis intermediate and has a wide range of applications in industrial production, such as dyes, pesticides, polymer materials and preservatives.

[0003] Hu Yuanyuan et al. prepared dipeptidyl peptidase-4 inhibitor with 2,3-dimethylbutyramide and studied its protective effect and mechanism on kidney. Liu Qingsong et al. prepared a new type of PI3K kinase inhibitor as a targeted inhibitor using 2,3-dimethylbutyramide as raw material. It has unique advantages in inhibiting tumor cell proliferation, inducing tumor cell apoptosis and reversing tumor cell resistance. It can be used alone or in combination with other targeted drugs.

[0004] Nitriles can be hydrolyzed into primary amides by adding water. Since primary amides will continue to hydrolyze into carboxylic acids, the conditions of hydrolysis are generally controlled. There are many methods reported, and sometimes it is necessary to select acidic, alkaline or neutral hydrolysis conditions according to the characteristics of the substrate. As neutral conditions, there are also methods reported in the literature using nickel or palladium catalysts. Under acidic conditions, cyano groups connected to saturated carbon can be easily hydrolyzed and converted into amides in acid, and when the conditions are more intense, they are easily further hydrolyzed into acids. However, the hydrolysis conditions of vinyl or aromatic nitrile require much more intense conditions, generally requiring strong acid conditions, and generally will not be further hydrolyzed.

[0005] Under alkaline conditions, the method of hydrogen peroxide oxidation can hydrolyze cyano groups to primary amides in a short time at room temperature, which is a relatively reliable method. Using the NaOH (aq.) -CH2Cl2 phase transfer catalytic system, the DMSO-K2CO3 system can be used to hydrolyze various nitriles to primary amides. However, these acid- and base-catalyzed reactions have certain limitations for the preparation of amides. The main limitation is that whether it is an acid- or base-catalyzed reaction, the final neutralization process will lead to the generation of a large amount of cyanide salts, which will cause pollution problems. Summary of the invention

[0006] The purpose of the present invention is to provide an efficient and green synthesis method of 2,3-dimethylbutyramide. Steps S1 and S2 are in the same reaction system, unreacted sodium amide is used to adjust the alkali concentration of the whole system, and after the hydrolysis reaction, a saturated sodium bromide solution in the aqueous phase is used to force out the 2,3-dimethylbutyramide solid. The operation is simple and efficient.

[0007] To achieve the above object, the present invention provides an efficient and green method for synthesizing 2,3-dimethylbutyramide, comprising the steps of: adding MTBE solvent to a reaction kettle, adding a certain amount of propionitrile and 2-bromopropane, heating the reaction kettle to a reflux temperature, and slowly adding a certain amount of sodium amide to the reaction kettle at the reflux temperature;

[0008] S2, after sodium amide is added, keep warm, take samples to detect whether the content of 2-bromopropane is less than 0.5%, if so, the reaction reaches the end point, after the reaction is completed, heat up to remove MTBE, cool to room temperature, add water and stir to maintain the alkali concentration;

[0009] S3, taking the upper oil phase in S2 for gas chromatography detection, when the content of 2-isopropylpropionitrile is ≤1.0%, the hydrolysis reaction reaches the end point, after the hydrolysis reaction is completed, the reaction solution is filtered, and the obtained filtrate is layered;

[0010] S4. The filter cake obtained from S3 is a crude 2,3-dimethylbutyramide, which is refluxed with MTBE solvent to carry water, and then dried to obtain a finished 2,3-dimethylbutyramide.

[0011] Preferably, in S1, n(sodium amide):n(propionitrile):n(2-bromopropane)=1.2-2.5:1-1.5:1.

[0012] Preferably, in S1, the mass ratio of sodium amide to MTBE is 1:3-10, the reflux temperature is 54-60° C., and the addition time of sodium amide is 4-12 h.

[0013] Preferably, in S2, the insulation time is 2-8h, the removal temperature of MTBE solvent is 60-130°C, the amount of water added is 5-12 times the mass of sodium amide, and the alkali concentration is 1.0-30%.

[0014] Preferably, in S4, the MTBE solvent is 5-12 times the mass of the crude 2,3-dimethylbutyramide, and the drying temperature is 40-120°C.

[0015] Therefore, the present invention adopts an efficient and green synthesis method of 2,3-dimethylbutyramide using the above steps, and its beneficial effects are:

[0016] 1. In the present invention, propionitrile is used as a starting material in a NaNH2 / MTBE system, and a unilateral condensation reaction is carried out with isopropyl bromide at a reflux temperature to generate a 2-isopropylpropionitrile intermediate product, and then water is added to hydrolyze in the same system to prepare 2,3-dimethylbutanamide in a one-pot method. The method is simple and efficient;

[0017] 2. Steps S1 and S2 are in the same reaction system, and the unreacted sodium amide is used to adjust the alkali concentration of the entire system. After the hydrolysis reaction, the saturated sodium bromide solution in the aqueous phase is used to force out the 2,3-dimethylbutyramide solid. The operation is simple and efficient.

[0018] 3. The 2,3-dimethylbutanamide synthesis method provided by the present invention is low-pollution, green and efficient, and convenient for industrial production.

[0019] The technical solution of the present invention is further described in detail below through the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It is the nuclear magnetic hydrogen spectrum of 2-isopropylpropionitrile in the highly efficient and green synthesis method of 2,3-dimethylbutanamide of the present invention. DETAILED DESCRIPTION

[0021] The technical solution of the present invention is further described below through the accompanying drawings and embodiments.

[0022] The present invention can be explained in more detail by the following examples. The purpose of disclosing the present invention is to protect all changes and improvements within the scope of the present invention. The present invention is not limited to the following examples.

[0023] Example 1

[0024] The reaction equation is as follows:

[0025]

[0026] S1. Add 850g MTBE solvent to a 2000ml reactor, then add 150g propionitrile and 330g 2-bromopropane, and heat to a reflux temperature (ice water condensation) of about 55° C. Feed 128g sodium amide to the reactor through a solid feeder, and control the feeding time to 8-10h.

[0027] S2. After the feeding is completed, the temperature is kept at the reflux temperature for 4 hours, and a sample is taken to detect the 2-bromopropane content of 0.18% (excluding the solvent). The temperature is raised to remove most of the MTBE solvent, and the temperature is evaporated to 130° C., 755 g of MTBE solvent is evaporated, and the temperature is cooled to room temperature.

[0028] The MTBE solvent content was 31.6% and the 2-isopropylpropionitrile content was 61.5%. 640 g of water was added to the reactor, and the alkali concentration was 2.68% after sampling. The mixture was stirred at room temperature for 12 hours.

[0029] S3. A large amount of scaly solids are precipitated in the reactor and float on the upper layer. The upper oil phase is taken and the content of the intermediate product 2-isopropylpropionitrile is 0.85% in the gas chromatograph, and the hydrolysis reaction is completed. The solid is placed in a suction filtration tank for suction filtration, and the filtrate is separated from the upper oil phase for the next batch of hydrolysis reactions.

[0030] S4. The filter cake obtained from S3 is 308 g, which is then put into a 5000 ml reaction bottle, and then 3000 ml of MTBE solvent is added. It is first refluxed with water, cooled and crystallized, and then dried at 85°C for 5 hours to obtain 256 g of 2,3-dimethylbutanamide product, with a yield of 83.1% based on 2-bromopropane.

[0031] Example 2

[0032] S1. Add 850g of MTBE solvent to a 2000ml reactor, then add 150g of propionitrile and 330g of 2-bromopropane, and heat to a reflux temperature (ice water condensation) of about 55° C. Feed 168g of sodium amide to the reactor through a solid feeder, and control the feeding time to 8-10h.

[0033] S2. After the feeding is completed, the temperature is kept at the reflux temperature for 4 hours, and a sample is taken to detect the 2-bromopropane content of 0.05% (excluding the solvent). The temperature is raised to remove most of the MTBE solvent, and the mixture is evaporated to 130° C., 748 g of MTBE solvent is evaporated, and the mixture is cooled to room temperature.

[0034] The MTBE solvent content was 30.6% and the 2-isopropylpropionitrile content was 58.8%. 640 g of water was added to the reactor, and the alkali concentration was 6.05% after sampling. The mixture was stirred at room temperature for 12 hours.

[0035] S3. A large amount of scaly solids are precipitated in the reactor and float on the upper layer. The upper oil phase is taken and the content of the intermediate product 2-isopropylpropionitrile is 0.45% in the gas chromatograph, and the hydrolysis reaction is completed. The solid is placed in a suction filtration tank for suction filtration, and the filtrate is separated from the upper oil phase for the next batch of hydrolysis reactions.

[0036] S4. The filter cake obtained from S3 is 319 g, which is then put into a 5000 ml reaction bottle, and then 3000 ml of MTBE solvent is added. It is first refluxed with water, cooled and crystallized, and then dried at 85°C for 5 hours to obtain 270 g of 2,3-dimethylbutanamide product, with a yield of 87.3% based on 2-bromopropane.

[0037] Example 3

[0038] S1. Add 850g of MTBE solvent to a 2000ml reactor, then add 150g of propionitrile and 330g of 2-bromopropane, and heat to a reflux temperature (ice water condensation) of about 55° C. Feed 209g of sodium amide to the reactor through a solid feeder, and control the feeding time to 8-10h.

[0039] S2. After the feeding is completed, the temperature is kept at the reflux temperature for 4 hours, and a sample is taken to detect the 2-bromopropane content of 0.25% (excluding the solvent). The temperature is raised to remove most of the MTBE solvent, and the mixture is evaporated to 130° C., 750 g of MTBE solvent is evaporated, and the mixture is cooled to room temperature.

[0040] The MTBE solvent content was 28.4% and the 2-isopropylpropionitrile content was 66%. 640 g of water was added to the reactor, and the alkali concentration was 11.7% after sampling. The mixture was stirred at room temperature for 12 hours.

[0041] S3. A large amount of scaly solids are precipitated in the reactor and float on the upper layer. The upper oil phase is taken and the content of the intermediate product 2-isopropylpropionitrile is 1.65% in the gas chromatograph, and the hydrolysis reaction is completed. The solid is placed in a suction filtration tank for suction filtration, and the filtrate is separated into the upper oil phase for the next batch of hydrolysis reactions.

[0042] S4. The filter cake obtained from S3 is 305 g, which is then put into a 5000 ml reaction bottle, and then 3000 ml of MTBE solvent is added. It is first refluxed with water, cooled and crystallized, and then dried at 85°C for 5 hours to obtain 262 g of finished 2,3-dimethylbutanamide, with a yield of 85.06% based on 2-bromopropane.

[0043] Example 4

[0044] S1. Add 850g of MTBE solvent to a 2000ml reactor, then add 150g of propionitrile and 330g of 2-bromopropane, and heat to a reflux temperature (ice water condensation) of about 55° C. Feed 168g of sodium amide to the reactor through a solid feeder, and control the feeding time to 8-10h.

[0045] S2. After the feeding is completed, the temperature is kept at the reflux temperature for 4 hours, and a sample is taken to detect the 2-bromopropane content of 0.05% (excluding the solvent). The temperature is raised to remove most of the MTBE solvent, and the temperature is evaporated to 130° C., 752 g of MTBE solvent is evaporated, and the temperature is cooled to room temperature.

[0046] The MTBE solvent content was 29.9% and the 2-isopropylpropionitrile content was 59%. 640 g of water was added to the reactor, and the alkali concentration was 6.2% after sampling. The mixture was stirred at room temperature for 24 hours.

[0047] S3. A large amount of scaly solids are precipitated in the reactor and float on the upper layer. The upper oil phase is taken and the content of the intermediate product 2-isopropylpropionitrile is 0.15% in the gas chromatograph, and the hydrolysis reaction is completed. The solid is placed in a suction filtration tank for suction filtration, and the filtrate is separated into the upper oil phase for the next batch of hydrolysis reactions.

[0048] S4. The filter cake obtained from S3 is 318 g, which is then put into a 5000 ml reaction bottle, and then 3000 ml of MTBE solvent is added. It is first refluxed with water, cooled and crystallized, and then dried at 85°C for 5 hours to obtain 273 g of 2,3-dimethylbutanamide product, with a yield of 88.6% based on 2-bromopropane.

[0049] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. An efficient and green method for synthesizing 2,3-dimethylbutanamide, characterized in that: S1, add MTBE solvent into the reactor, then add quantitative propionitrile and 2-bromopropane, heat up to reflux temperature, and slowly add quantitative sodium amide into the reactor at reflux temperature; In S1, n(sodium amide):n(propionitrile):n(2-bromopropane)=1.2-2.5:1-1.5:1; S2, after sodium amide is added, keep warm, take samples to detect whether the content of 2-bromopropane is less than 0.5%, if so, the reaction reaches the end point, after the reaction is completed, heat up to remove MTBE, cool to room temperature, add water and stir to maintain the alkali concentration; S3, taking the upper oil phase in S2 for gas chromatography detection, when the content of 2-isopropylpropionitrile is ≤1.0%, the hydrolysis reaction reaches the end point, after the hydrolysis reaction is completed, the reaction solution is filtered, and the obtained filtrate is layered; S4. The filter cake obtained from S3 is a crude 2,3-dimethylbutyramide, which is refluxed with MTBE solvent to carry water, and then dried to obtain a finished 2,3-dimethylbutyramide.

2. The method for synthesizing an efficient and green 2,3-dimethylbutyramide according to claim 1, characterized in that: In S1, the mass ratio of sodium amide to MTBE is 1:3-10, the reflux temperature is 54-60°C, and the addition time of sodium amide is 4-12h.

3. The method for synthesizing an efficient and green 2,3-dimethylbutyramide according to claim 1, characterized in that: In S2, the heat preservation time is 2-8h, the removal temperature of MTBE solvent is 60-130°C, the amount of water added is 5-12 times the mass of sodium amide, and the alkali concentration is 1.0-30%.

4. The method for synthesizing 2,3-dimethylbutyramide according to claim 1, characterized in that: In S4, the MTBE solvent is 5-12 times the quality of the crude 2,3-dimethylbutanamide, and the drying temperature is 40-120°C.

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