A method for preparing diethyl 2,3-diisopropylsuccinate

Abstract

The present application relates to the technical field of organic compound preparation, in particular to a method for preparing 2,3-diisopropyl succinic acid diethyl ester, comprising the following steps: (1) taking 3-methyl-2-cyanobutyric acid ethyl ester as raw material, and reacting with a potassium alcohol mixture composed of potassium ethoxide and potassium butoxide in ethanol, and then concentrating and filtering to obtain product I; (2) in an aprotic solvent, product I is heated and refluxed with 2-bromoisovaleric acid ethyl ester to obtain product II; (3) product II is hydrolyzed and decarboxylated under the action of acid to generate 2,3-diisopropyl succinic acid; (4) under acidic conditions, 2,3-diisopropyl succinic acid is esterified with ethanol to obtain 2,3-diisopropyl succinic acid diethyl ester. By using the potassium alcohol mixture composed of potassium ethoxide and potassium butoxide as reactants and optimizing the molar ratio of the reactants, the yield of the final product is not less than 85%, the purity is not less than 98%, and the racemate content is more than 70%.

Description

Technical Field

[0001] This invention relates to the field of organic compound preparation technology, and specifically to a method for preparing diethyl 2,3-diisopropylsuccinate. Background Technology

[0002] Diethyl 2,3-diisopropylsuccinate (DISE) is an important chemical intermediate, primarily used as an internal electron donor in Ziegler-Natta polypropylene catalysts. Compared to traditional phthalate-based internal electron donors, propylene polymerization catalysts using DISE as the internal electron donor exhibit high activity, high stereoregulation, and better hydrogen-modulated sensitivity, resulting in polypropylene with a wider relative molecular mass distribution. Therefore, developing efficient, economical, and industrially suitable methods for DISE preparation is of great significance.

[0003] In the prior art, there are relevant reports on the synthesis methods of diethyl 2,3-diisopropylsuccinate. Chinese invention patent CN101811983A discloses a method for preparing 2,3-diisopropyl-2-cyanosuccinate diesters. The technical route of this patent is as follows: using a 3-methyl-2-cyanobutyrate ester as a raw material, it first reacts with a potassium alkoxide compound in an alcoholic solution to generate a potassium salt, then undergoes a coupling reaction with 2-bromoisovalerate in an aprotic solvent to generate a 2,3-diisopropyl-2-cyanosuccinate diester. Subsequently, 2,3-diisopropylsuccinic acid is prepared through hydrolysis and decarboxylation, and further esterified to prepare 2,3-diisopropylsuccinate compounds. The beneficial effect of this patent is that it provides a preparation method conducive to commercial production; however, the potassium alkoxide compound used is a single component, such as potassium methoxide or potassium ethoxide, and does not involve the use of mixed potassium alkoxide systems.

[0004] Furthermore, research institutions such as the Beijing Research Institute of Chemical Industry have conducted in-depth studies on the effective configurations of DISE as an internal electron donor. Studies have shown that among the two isomers of diethyl 2,3-diisopropylsuccinate, the racemic version (rac-2,3-DISE) is the effective internal electron donor. Compared to the meso-2,3-DISE, rac-2,3-DISE imparts higher polymerization activity to the catalyst (up to 58.1 kg / (g·h)), resulting in a wider relative molecular mass distribution (11.8) and higher isotacticity (96.93%) in the obtained polypropylene. Other studies have indicated that although the enantiomers of DISE with different optical rotations differ in molecular configuration, their performance as internal electron donors is not significantly different.

[0005] Although existing technologies have provided methods for synthesizing DISE, the following shortcomings still exist: (1) The product yield and purity need to be further improved. In Chinese invention patent application CN101811983A, a single potassium alkoxide (such as potassium methoxide or potassium ethoxide) is used as the condensation reagent. The conversion rate and selectivity of the coupling reaction still have room for improvement. The process control of subsequent hydrolysis and esterification steps also needs to be refined, which affects the total yield and purity of the final product. (2) There is a lack of directional control over the proportion of effective isomers (racemic mixtures). Existing synthesis methods do not involve how to improve the proportion of rac-2,3-DISE in the product through optimization of process conditions. Since rac-2,3-DISE is the effective component of DISE as an internal electron donor, increasing its proportion in the product is of direct significance for improving the application performance of DISE. (3) The selection of potassium alkoxide condensation reagents is limited. The types of potassium alkoxides disclosed in the prior art include potassium methoxide, potassium ethanol, potassium propoxide, potassium isopropoxide, and potassium butoxide, but they are all used as single components and do not involve the impact of mixing different potassium alkoxides on reaction efficiency and product quality.

[0006] In conclusion, developing a preparation method that can further improve the yield, purity, and proportion of effective isomers (racemic derivatives) of diethyl 2,3-diisopropylsuccinate has significant industrial application value. Summary of the Invention

[0007] To address the problems existing in the prior art, this invention provides a method for preparing diethyl 2,3-diisopropylsuccinate. By using a potassium alkoxide mixture composed of potassium ethoxide and potassium butoxide as reactants and optimizing the molar ratio of the reactants, the yield of the final product is not less than 85%, the purity is not less than 98%, and the content of racemic mixture is above 70%.

[0008] This invention is achieved through the following technical solution: A method for preparing diethyl 2,3-diisopropylsuccinate, characterized in that the method comprises the following steps: (1) Using ethyl 3-methyl-2-cyanobutyrate as raw material, react with a mixture of potassium ethoxide and potassium butoxide in ethanol, and after concentration and filtration, product I is obtained; (2) In an aprotic solvent, product I is reacted with ethyl 2-bromoisovalerate under reflux to obtain product II; (3) Product II undergoes hydrolysis and decarboxylation under the action of acid to generate 2,3-diisopropylsuccinic acid; (4) Under acidic conditions, the 2,3-diisopropylsuccinic acid undergoes an esterification reaction with ethanol to obtain diethyl 2,3-diisopropylsuccinate.

[0009] Preferably, the molar ratio of potassium ethoxide to potassium butoxide in step (1) is 1:4-4:1.

[0010] More preferably, the molar ratio of potassium ethoxide to potassium butoxide is 2:3-3:2; more preferably, it is 1:1.

[0011] Preferably, the molar ratio of the potassium alkoxide mixture to ethyl 3-methyl-2-cyanobutyrate in step (1) is 1-1.5:1.

[0012] Preferably, the mass-to-volume ratio of ethyl 3-methyl-2-cyanobutyrate to ethanol in step (1) is 1g:15-30mL.

[0013] Preferably, the temperature of the reaction in step (1) is -10 to 45°C.

[0014] More preferably, the temperature of the reaction in step (1) is 10-30℃.

[0015] Preferably, the aprotic solvent in step (2) is selected from at least one of dimethyl sulfoxide, tetrahydrofuran, acetonitrile, and toluene.

[0016] Preferably, the molar ratio of product I to ethyl 2-bromoisovalerate in step (2) is 1:1.0-1.5.

[0017] Preferably, the reflux reaction time in step (2) is 1-6 hours.

[0018] Preferably, the acid in step (3) is sulfuric acid, with a mass fraction of 60%-90%, and the reaction temperature is 80℃-150℃.

[0019] Preferably, the catalyst for the esterification reaction in step (4) is sulfuric acid or p-toluenesulfonic acid, the reaction temperature is the reflux temperature, and the reaction time is 4-12 h.

[0020] Preferably, the yield of the diethyl 2,3-diisopropylsuccinate is not less than 85%, the purity is not less than 98%, and the racemic content is above 70%.

[0021] The beneficial effects of this invention are as follows: by using a mixture of potassium ethoxide and potassium butoxide as reactants and optimizing the molar ratio of reactants, the yield of the final product is not less than 85%, the purity is not less than 98%, and the content of racemic mixture is more than 70%. Detailed Implementation

[0022] To clarify the purpose, technical solution, and advantages of this invention, the following detailed description is provided in conjunction with specific embodiments. To facilitate understanding of the technical means, creative features, and achieved objectives and effects of this invention, the following detailed description further clarifies the invention in conjunction with specific embodiments. However, these embodiments are merely preferred embodiments and not exhaustive. Other embodiments obtained by those skilled in the art based on the embodiments described herein without creative effort are all within the scope of protection of this invention. In the following embodiments, unless otherwise specified, the operating methods used are conventional operating methods, the equipment used is conventional equipment, and the equipment materials used in each embodiment are the same. This invention does not limit the source of the raw materials used. Unless otherwise specified, the raw materials used in this invention are all commercially available products in this technical field, with a purity of 98% or higher.

[0023] Note: In the following examples and comparative examples, the purity of the finished product was determined by gas chromatography (GC); the content of the racemic rac-DISE was determined by chiral high performance liquid chromatography; the total yield was calculated based on the mass of the initial ethyl 3-methyl-2-cyanobutyrate; and nitrogen anhydrous protection was used throughout the process.

[0024] Example 1: A method for preparing diethyl 2,3-diisopropylsuccinate, comprising the following steps: (1) The 2L anhydrous reactor was purged with nitrogen three times, and 2000mL of anhydrous ethanol was added. Stirring was started. 29.49g of potassium ethoxide and 39.33g of potassium n-butoxide were added in sequence and stirred at room temperature until the solid was completely dissolved. 100g of ethyl 3-methyl-2-cyanobutyrate was slowly added dropwise at 20℃. After the addition was completed, the mixture was kept warm and stirred for 3h. 85% of the ethanol in the system was removed by vacuum concentration. A large amount of white solid precipitated in the reactor. The mixture was cooled to 0℃, filtered under pressure, and the solid was dried under vacuum for 4h to obtain product I for later use.

[0025] (2) Add all of the product I obtained in step (1) to a 5L reactor, add 800mL of DMSO, stir and dissolve under nitrogen; add 134.5g of ethyl 2-bromoisovalerate, heat to the reflux temperature of DMSO, and keep refluxed for 3h; cool the reaction solution to room temperature, slowly add 2 times the volume of deionized water, and extract with ethyl acetate 3 times; combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate; remove ethyl acetate and DMSO from the organic phase under reduced pressure to obtain the oily crude product II.

[0026] (3) All product II obtained in step (2) was put into an enamel reactor and 400g of 80wt.% concentrated sulfuric acid was added. The temperature was raised to 120℃ and kept warm for 4h. The heating was stopped and ice water was slowly added dropwise to dilute the system. After the system cooled down, a large amount of white solid precipitated out. The solid was filtered, washed with water until neutral, and dried under vacuum to obtain 2,3-diisopropylsuccinic acid solid.

[0027] (4) Add all the 2,3-diisopropylsuccinic acid solid obtained in step (3), 1200 mL of anhydrous ethanol, and 5 g of p-toluenesulfonic acid to the esterification reactor; install a water separation reflux device; heat to the ethanol reflux temperature and continue the water separation reaction for 8 h; cool the reaction solution, neutralize it with saturated sodium carbonate solution to pH=7.8, and let it stand to separate the layers; wash the organic phase twice with water; distill the organic phase under reduced pressure, collect the corresponding fractions, and obtain colorless and transparent diethyl 2,3-diisopropylsuccinate product.

[0028] Test results: The total yield was 87.1%, the purity was 98.7%, and the content of racemic compounds was 74.3%.

[0029] Example 2: A method for preparing diethyl 2,3-diisopropylsuccinate, comprising the following steps: (1) Under nitrogen protection, 1500 mL of anhydrous ethanol was added to a 2 L anhydrous reactor, followed by 23.59 g of potassium ethoxide and 47.19 g of potassium n-butoxide, and stirred to dissolve. 100 g of ethyl 3-methyl-2-cyanobutyrate was slowly added dropwise, and the temperature was controlled at 10 °C. After the addition was completed, the mixture was kept warm and stirred for 4 h. 85% of the ethanol in the system was removed by vacuum concentration. The mixture was cooled to 0 °C, filtered, and dried under vacuum for 4 h to obtain product I for later use.

[0030] (2) Add all of the product I obtained in step (1) to a 5L reactor, add 750mL of acetonitrile, stir and dissolve under nitrogen; add 146.7g of ethyl 2-bromoisovalerate, heat to reflux with acetonitrile, and keep refluxed for 4h; cool the reaction solution to room temperature, slowly add 2 times the volume of deionized water, and extract with ethyl acetate 3 times; combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate; remove ethyl acetate and acetonitrile from the organic phase under reduced pressure to obtain the oily crude product II.

[0031] (3) All product II obtained in step (2) was put into an enamel reactor, 420g of 70wt% concentrated sulfuric acid was added, the temperature was raised to 100℃, and the mixture was kept in a sealed environment and stirred for 5h. The heating was stopped, and ice water was slowly added dropwise to dilute the system. After the system cooled down, a large amount of white solid precipitated out. The solid was filtered, washed with water until neutral, and dried under vacuum to obtain 2,3-diisopropylsuccinic acid.

[0032] (4) Add all the 2,3-diisopropylsuccinic acid solid obtained in step (3), 1200 mL of anhydrous ethanol, and 3 g of concentrated sulfuric acid to the esterification reactor and install a water separation reflux device; heat to the ethanol reflux temperature and continue the water separation reaction for 10 h; cool the reaction solution, neutralize it with saturated sodium carbonate solution to pH=7.8, and let it stand to separate the layers; wash the organic phase twice with water; distill the organic phase under reduced pressure, collect the corresponding fractions, and obtain colorless and transparent diethyl 2,3-diisopropylsuccinate product.

[0033] Test results: The total yield was 86.0%, the purity was 98.4%, and the content of racemic compounds was 72.0%.

[0034] Example 3: A method for preparing diethyl 2,3-diisopropylsuccinate, comprising the following steps: (1) Under nitrogen protection, 2900 mL of anhydrous ethanol was added to a 3 L anhydrous reactor, followed by 0.4205 mol (35.38 g) of potassium ethoxide and 0.2804 mol (31.47 g) of potassium n-butoxide. The mixture was stirred and dissolved. 100 g of ethyl 3-methyl-2-cyanobutyrate was slowly added dropwise at 30 °C. After the addition was completed, the mixture was kept warm and stirred for 2.5 h. The system was concentrated under reduced pressure to remove 85% ethanol. The mixture was cooled to 0 °C, filtered, and dried under vacuum for 4 h to obtain product I for later use.

[0035] (2) Add all of the product I obtained in step (1) to a 5L reactor, add 900mL of toluene and stir to dissolve; add 158.8g of ethyl 2-bromoisovalerate, heat to toluene and reflux, and keep refluxed for 5h; cool the reaction solution to room temperature, slowly add 2 times the volume of deionized water, and extract with ethyl acetate 3 times; combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate; remove ethyl acetate and toluene from the organic phase under reduced pressure to obtain the oily crude product II.

[0036] (3) All product II obtained in step (2) was put into an enamel reactor, 380g of 90wt% concentrated sulfuric acid was added, the temperature was raised to 140℃, and the mixture was kept in a sealed environment and stirred for 3h. The heating was stopped, and ice water was slowly added dropwise to dilute the system. After the system cooled down, a large amount of white solid precipitated out. The solid was filtered, washed with water until neutral, and dried under vacuum to obtain 2,3-diisopropylsuccinic acid.

[0037] (4) Add all the 2,3-diisopropylsuccinic acid solid obtained in step (3), 1200 mL of anhydrous ethanol, and 5 g of p-toluenesulfonic acid to the esterification reactor and install a water separation reflux device; heat to the ethanol reflux temperature and continue the water separation reaction for 12 h; cool the reaction solution, neutralize it with saturated sodium carbonate solution to pH=7.8, and let it stand to separate the layers; wash the organic phase twice with water; distill the organic phase under reduced pressure, collect the corresponding fractions, and obtain colorless and transparent diethyl 2,3-diisopropylsuccinate product.

[0038] Test results: The total yield was 85.3%, the purity was 98.2%, and the content of racemic compounds was 71.1%.

[0039] Comparative Example 1: The main difference from Example 1 is that in step (1), only 58.97 g (0.7009 mol) of potassium ethoxide was added, and no potassium n-butoxide was added. All other solvents, temperatures, feeds, reaction times, post-treatment, and esterification processes were the same as in Example 1.

[0040] Test results: The total yield was 76.2%, the purity was 94.1%, and the content of racemic compounds was 56.6%.

[0041] Comparative Example 2: The main difference from Example 1 is that only 78.65 g (0.7009 mol) of potassium n-butoxide was added in step (1), and potassium ethoxide was not added. All other solvents, temperatures, feeds, reaction times, post-treatment, and esterification processes were the same as in Example 1.

[0042] Test results: The total yield was 78.4%, the purity was 95.0%, and the content of racemic compounds was 59.0%.

[0043] Comparative Example 3: The main difference from Example 1 is that the molar ratio of potassium ethoxide to potassium n-butoxide in step (1) is different. In this comparative example, the amount of potassium ethoxide is 0.1168 mol (9.83 g) and the amount of potassium n-butoxide is 0.5841 mol (65.55 g), that is, the molar ratio of potassium ethoxide to potassium n-butoxide in this comparative example is 1:5; all other parameters and operations are completely consistent with those in Example 1.

[0044] Test results: The total yield was 80.0%, the purity was 95.9%, and the content of racemic compounds was 63.3%.

[0045] Comparative Example 4 The main difference from Example 1 is that the molar ratio of potassium ethoxide to potassium n-butoxide in step (1) is different. In this comparative example, the amount of potassium ethoxide is 0.5841 mol (49.15 g) and the amount of potassium n-butoxide is 0.1168 mol (13.11 g), that is, the molar ratio of potassium ethoxide to potassium n-butoxide in this comparative example is 5:1; all other parameters and operations are completely consistent with those in Example 1.

[0046] Test results: The total yield was 80.5%, the purity was 96.1%, and the content of racemic compounds was 64.0%.

[0047] Based on the above experimental results, it can be seen that: Comparative Examples 1 and 2, which use single potassium ethoxide, have yields of less than 80%, purity of less than 96%, and effective racemic mixtures of less than 60%; In Examples 1-3 of this invention, the molar ratio of potassium ethoxide to potassium n-butoxide is 1:4-4:1. The yield of this compound system is ≥85%, purity ≥98%, and racemic mixture ≥70%, proving that the mixed base of potassium ethoxide and potassium n-butoxide has a synergistic effect. Moreover, the molar ratio of the two must be limited to the range of 1:4 to 4:1. The effect is significantly reduced when the ratio is outside the range. In Comparative Examples 3 (1:5) and 4 (5:1), although they are still mixed potassium ethoxides, the yield, purity, and racemic mixture content decrease significantly after deviating from the protection range, proving that 1:4-4:1 is not an arbitrary range.

[0048] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A process for the preparation of diethyl 2,3-diisopropylsuccinate, characterized in that, The method includes the following steps: (1) Using ethyl 3-methyl-2-cyanobutyrate as raw material, react with a mixture of potassium ethoxide and potassium butoxide in ethanol, and after concentration and filtration, product I is obtained; (2) In an aprotic solvent, product I is reacted with ethyl 2-bromoisovalerate under reflux to obtain product II; (3) Product II undergoes hydrolysis and decarboxylation under the action of acid to generate 2,3-diisopropylsuccinic acid; (4) Under acidic conditions, the 2,3-diisopropylsuccinic acid undergoes an esterification reaction with ethanol to obtain diethyl 2,3-diisopropylsuccinate; wherein The molar ratio of potassium ethoxide to potassium butoxide in step (1) is 1:4-4:

1.

2. The method of claim 1, wherein, The molar ratio of the potassium alkoxide mixture in step (1) to ethyl 3-methyl-2-cyanobutyrate is 1-1.5:

1.

3. The method according to claim 1, characterized in that, In step (1), the mass-to-volume ratio of ethyl 3-methyl-2-cyanobutyrate to ethanol is 1 g: 15-30 mL, and the reaction temperature is -10 to 45 °C.

4. The method according to claim 1, characterized in that, The aprotic solvent mentioned in step (2) is selected from at least one of dimethyl sulfoxide, tetrahydrofuran, acetonitrile, and toluene.

5. The method according to claim 1, characterized in that, The molar ratio of product I to ethyl 2-bromoisovalerate in step (2) is 1:1.0-1.

5.

6. The method according to claim 1, characterized in that, The reflux reaction time in step (2) is 1-6 hours.

7. The method according to claim 1, characterized in that, The acid mentioned in step (3) is sulfuric acid, with a mass fraction of 60%-90%, and the reaction temperature is 80℃-150℃.

8. The method according to claim 1, characterized in that, The catalyst for the esterification reaction in step (4) is sulfuric acid or p-toluenesulfonic acid, the reaction temperature is the reflux temperature, and the reaction time is 4-12 h.

9. The method according to any one of claims 1-8, characterized in that, The yield of the diethyl 2,3-diisopropylsuccinate is not less than 85%, the purity is not less than 98%, and the racemic content is above 70%.