An improved process for the preparation and purification of isopropyl 2-hydroxy-4-methylthio-butanoate

Abstract

The application discloses an improved preparation and refining method of 2-hydroxy-4-methylthio-butanoic acid isopropyl ester, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: raw material pretreatment, esterification reaction and post-treatment. In the esterification reaction, a raw material mixture and dichloromethane are added into a four-necked flask with a condensing device, the temperature of the four-necked flask is controlled to 85-90 DEG C, stirring is carried out, then a solid acid catalyst and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride are added, stirring is carried out for 6-7 h, and a reaction solution is obtained. The preparation method of the solid acid catalyst comprises the following steps: preparing a carrier, primary impregnation modification and secondary impregnation modification. The application can improve the purity of the prepared 2-hydroxy-4-methylthio-butanoic acid isopropyl ester, does not cause corrosion of production equipment, and uses a catalyst with high catalytic activity and high thermal stability, which is not prone to blockage in use and can be used repeatedly.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to an improved method for the preparation and purification of isopropyl 2-hydroxy-4-methylthio-butyrate. Background Technology

[0002] Methionine is one of the main limiting amino acids in ruminant diets based on corn. In the animal body, it can be used to synthesize body protein and can be quickly converted into cystine to meet the animal's needs. It can also provide the body with active methyl groups to synthesize some methyl compounds such as choline, keratin and nucleic acids. Therefore, it has a wide range of applications in the feed industry. However, methionine has poor stability and is easily destroyed when used in feeding, which affects the shelf life of feed and its application effect in feed.

[0003] Isopropyl 2-hydroxy-4-methylthio-butyrate can replace methionine, which can increase milk production in dairy cows and provide better nutritional benefits. Moreover, it is highly stable and not easily damaged. Therefore, the application of isopropyl 2-hydroxy-4-methylthio-butyrate in feed is becoming more and more widespread.

[0004] The existing method for preparing isopropyl 2-hydroxy-4-methylthio-butyrate mainly uses 2-hydroxy-4-(methylthio)butyric acid and isopropanol as reactants, and carries out an esterification reaction under the action of a strong acid catalyst to obtain isopropyl 2-hydroxy-4-methylthio-butyrate. However, this method produces many byproducts, resulting in low purity of the prepared isopropyl 2-hydroxy-4-methylthio-butyrate. In addition, the strong acid catalyst can also corrode the production equipment, leading to a shortened lifespan of the production equipment.

[0005] To address these issues, the most common approach is to replace strong acid catalysts with solid acid catalysts. However, solid acid catalysts have poor thermal stability, limiting reactions to low temperatures; they are prone to clogging and cannot be reused multiple times; and their catalytic activity is lower than that of strong acid catalysts, resulting in longer reaction times. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides an improved method for the preparation and purification of isopropyl 2-hydroxy-4-methylthiobutyrate, which can improve the purity of the prepared isopropyl 2-hydroxy-4-methylthiobutyrate, avoid corrosion of production equipment, and use a catalyst with high catalytic activity and thermal stability, which is not easily clogged during use and can be reused multiple times.

[0007] To solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0008] An improved method for preparing isopropyl 2-hydroxy-4-methylthio-butyrate includes: raw material pretreatment, esterification reaction, and post-treatment.

[0009] The raw material pretreatment involves treating the hydroxymethionine analogue with water using n-heptane, then mixing the water-treated hydroxymethionine analogue with isopropanol and subjecting it to ultrasonic vibration under a nitrogen atmosphere. After ultrasonic vibration, a raw material mixture is obtained.

[0010] In the raw material pretreatment, the mass ratio of the hydroxymethionine analogue after water treatment to isopropanol is 290-300:160-170.

[0011] The ultrasonic oscillation frequency is 20-30kHz, the duration is 2-2.5h, and the temperature is 15-25℃;

[0012] The composition of the hydroxymethionine analogue, by weight, includes: 82-85 parts of 2-hydroxy-4-methylthio-butyric acid, 5-7 parts of 2-hydroxy-4-methylthio-butyric acid dimer, and 10-12 parts of water.

[0013] The esterification reaction involves adding the raw material mixture and dichloromethane into a four-necked flask equipped with a condenser, controlling the temperature of the four-necked flask to 85-90°C, stirring, and then adding a solid acid catalyst and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, stirring for 6-7 hours to obtain the reaction solution.

[0014] In the esterification reaction, the mass ratio of the raw material mixture, dichloromethane, solid acid catalyst, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 400-420:800-900:4-4.5:240-260.

[0015] The method for preparing the solid acid catalyst includes: preparing a support, primary impregnation modification, and secondary impregnation modification;

[0016] The preparation of the carrier involves adding ferric chloride and deionized water to a four-necked flask, controlling the temperature of the flask at 15-35°C, and stirring to obtain a ferric chloride solution; adding graphene oxide and deionized water to the four-necked flask, controlling the temperature of the flask at 15-35°C, stirring, and then ultrasonically vibrating to obtain a graphene oxide sol; adding tetraethyl orthosilicate, anhydrous ethanol, deionized water, and ammonia to the four-necked flask, controlling the temperature of the flask at 40-50°C, stirring, and then ultrasonically vibrating to obtain a silica sol; and then adding graphene oxide... The olefin sol was added to a four-necked flask equipped with a reflux condenser. The temperature of the four-necked flask was controlled at 40-50℃, and the mixture was stirred. Then, ferric chloride solution was added dropwise to the four-necked flask. After the addition was completed, the temperature of the four-necked flask was controlled at 115-125℃ for reflux reaction. After 6-7 hours, silica sol was added dropwise to the four-necked flask. After the addition was completed, the reflux reaction was continued for 5-6 hours. Then, heating and stirring were stopped, and the mixture was allowed to cool naturally to room temperature. The mixture was filtered, the filter residue was washed and dried, and then calcined at 500-550℃ under a nitrogen atmosphere to obtain the support.

[0017] In the ferric chloride solution, the mass ratio of ferric chloride to deionized water is 2.5-3:1000-1050;

[0018] In the graphene oxide sol, the mass ratio of graphene oxide to deionized water is 20-25:1000-1050;

[0019] In the silica sol, the mass ratio of tetraethyl orthosilicate, anhydrous ethanol, deionized water, and ammonia is 40-42:360-370:40-45:2.5-3.

[0020] The mass fraction of the ammonia solution is 22-25%.

[0021] The ferric chloride solution contains ferric chloride, the graphene oxide sol contains graphene oxide, and the tetraethyl orthosilicate in the silica sol is in a ratio of 2.5-3:20-25:40-42.

[0022] In the preparation of the carrier, the ferric chloride solution is added at a rate of 10-12 g / min;

[0023] The dropping rate of silica sol is 6-8 g / min;

[0024] The first impregnation modification involves adding tungstic acid, citric acid, and deionized water to a four-necked flask, controlling the temperature of the flask to 60-70°C, stirring, adding ammonia water to adjust the pH to 9-9.5, and continuing stirring to obtain a first impregnation solution; adding the carrier to the first impregnation solution and impregnating it at 40-50°C, then calcining the carrier at 700-750°C to obtain a carrier modified by the first impregnation.

[0025] In the primary impregnation modification, the mass ratio of tungstic acid, citric acid, deionized water, and carrier is 2-2.2:6.5-6.8:90-92:20-22;

[0026] The mass fraction of the ammonia solution is 22-25%.

[0027] The secondary impregnation modification involves adding perfluorosulfonic acid resin, dimethyl sulfoxide, and isopropanol to a four-necked flask, controlling the temperature of the four-necked flask to 15-35°C, and stirring to obtain a secondary impregnation solution; adding the primary impregnation modified carrier to the secondary impregnation solution, impregnating at 40-50°C, and then freeze-drying the carrier to obtain a solid acid catalyst.

[0028] In the secondary impregnation modification, the mass ratio of perfluorosulfonic acid resin, dimethyl sulfoxide, isopropanol, and the carrier of the primary impregnation modification is 9-10:10-15:85-90:20-22.

[0029] The post-processing involves filtering the reaction solution, using the filter residue as a catalyst, reusing the catalyst, concentrating the filtrate under reduced pressure, washing it with deionized water, concentrating the washed organic phase under reduced pressure to obtain a concentrated solution, and distilling the concentrated solution to obtain a crude product.

[0030] An improved method for purifying isopropyl 2-hydroxy-4-methylthio-butyrate involves completely dissolving the crude product in n-heptane, adjusting the pH to 8-8.5 with saturated sodium carbonate solution, and then distilling the organic phase to obtain isopropyl 2-hydroxy-4-methylthio-butyrate.

[0031] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0032] (1) The present invention can improve the purity and yield of the prepared isopropyl 2-hydroxy-4-methylthio-butyrate, increasing the purity of the isopropyl 2-hydroxy-4-methylthio-butyrate to 98.4-99.3% and the yield to 92.0-95.6%;

[0033] (2) The solid acid catalyst used in this invention will not cause corrosion of production equipment, thereby improving the lifespan of the production equipment;

[0034] (3) The solid acid catalyst of the present invention has high catalytic activity and can shorten the esterification reaction time to 6-7h;

[0035] (4) The solid acid catalyst used in this invention has high thermal stability. After the solid acid catalyst of this invention is placed at 150°C and allowed to stand for 100 h, it is used to prepare and purify isopropyl 2-hydroxy-4-methylthio-butyrate. The molar yield of isopropyl 2-hydroxy-4-methylthio-butyrate is 90.7-94.8%.

[0036] (5) The solid acid catalyst used in this invention is not easily clogged during use and can be reused multiple times. After the solid acid catalyst of this invention is reused 50 times, the molar yield is 84.8-88.3%. Detailed Implementation

[0037] To provide a clearer understanding of the technical features, objectives, and effects of the present invention, specific embodiments of the present invention are now described.

[0038] Example 1

[0039] An improved method for the preparation and purification of isopropyl 2-hydroxy-4-methylthio-butyrate, specifically as follows:

[0040] 1. Raw material pretreatment: After treating the hydroxymethionine analogue with n-heptane to remove water, 290g of the water-treated hydroxymethionine analogue and 160g of isopropanol were mixed and ultrasonically vibrated under a nitrogen atmosphere. The ultrasonic vibration frequency was controlled at 20kHz, the time was 2h, and the temperature was 15℃. After ultrasonic vibration was completed, the raw material mixture was obtained.

[0041] The composition of the hydroxymethionine analogue, by weight, includes: 82 parts of 2-hydroxy-4-methylthio-butyric acid, 5 parts of 2-hydroxy-4-methylthio-butyric acid dimer, and 10 parts of water;

[0042] 2. Esterification reaction: 400g of raw material mixture and 800g of dichloromethane were added to a four-necked flask equipped with a condenser. The temperature of the four-necked flask was controlled at 85℃ and the stirring speed was controlled at 200rpm. Then, 4g of solid acid catalyst and 240g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added and stirred for 6h to obtain the reaction solution.

[0043] The preparation method of the solid acid catalyst is as follows:

[0044] (1) Preparation of carrier: 2.5g of ferric chloride and 1000g of deionized water were added to a four-necked flask. The temperature of the four-necked flask was controlled at 15℃ and the stirring speed was controlled at 100rpm. After stirring for 20min, a ferric chloride solution was obtained. 20g of graphene oxide and 1000g of deionized water were added to a four-necked flask. The temperature of the four-necked flask was controlled at 15℃ and the stirring speed was controlled at 100rpm. After stirring for 30min, ultrasonic vibration was performed. The frequency of ultrasonic vibration was controlled at 20kHz and the time was 30min. After ultrasonic vibration, graphene oxide sol was obtained. 40g of tetraethyl orthosilicate, 360g of anhydrous ethanol, 40g of deionized water and 2.5g of ammonia water with a mass fraction of 22% were added to a four-necked flask. The temperature of the four-necked flask was controlled at 40℃ and the stirring speed was controlled at 100rpm. After stirring for 2h, ultrasonic vibration was performed. The ultrasonic oscillation was controlled at a frequency of 20 kHz for 50 min, and silica sol was obtained after ultrasonic oscillation. The graphene oxide sol was added to a four-necked flask equipped with a reflux condenser. The temperature of the four-necked flask was controlled at 40 °C and the stirring speed was controlled at 100 rpm. Then, ferric chloride solution was added dropwise to the four-necked flask at a rate of 10 g / min. After the addition was completed, the temperature of the four-necked flask was controlled at 115 °C for reflux reaction. After 6 h, silica sol was added dropwise to the four-necked flask at a rate of 6 g / min. After the addition was completed, the reflux reaction was continued for 5 h. Then, heating and stirring were stopped, and the mixture was allowed to cool naturally to room temperature. The mixture was filtered, and the filter residue was washed four times with five times the mass of the filter residue using deionized water. After drying at 120 °C, the mixture was calcined at 500 °C for 2 h under a nitrogen atmosphere to obtain the carrier.

[0045] (2) One-time impregnation modification: 2g tungstic acid, 6.5g citric acid and 90g deionized water were added to a four-necked flask. The temperature of the four-necked flask was controlled at 60℃ and the stirring speed was controlled at 200rpm. After stirring for 40min, 22% ammonia water was added to adjust the pH to 9. After stirring for 18h, the first impregnation solution was obtained. 20g of the carrier was added to the first impregnation solution and impregnated at 40℃ for 3h. Then the carrier was calcined at 700℃ for 5h to obtain the carrier modified by one-time impregnation.

[0046] (3) Secondary impregnation modification: 9g of perfluorosulfonic acid resin, 10g of dimethyl sulfoxide and 85g of isopropanol were added to a four-necked flask. The temperature of the four-necked flask was controlled at 15℃ and the stirring speed was controlled at 100rpm. After stirring for 20min, a secondary impregnation solution was obtained. 20g of the primary impregnation modified carrier was added to the secondary impregnation solution and impregnated at 40℃ for 20min. Then the carrier was placed at -40℃ for freeze drying for 7h to obtain a solid acid catalyst.

[0047] 3. Post-processing: The reaction solution is filtered, and the filter residue is used as catalyst. The catalyst is reused. The filtrate is concentrated under reduced pressure and washed with deionized water. The washed organic phase is then concentrated under reduced pressure to obtain a concentrated solution. The concentrated solution is then distilled to obtain the crude product.

[0048] 4. Purification: The crude product was completely dissolved in 1200g of n-heptane, and the pH was adjusted to 8 by adding saturated sodium carbonate solution. The organic phase was then distilled at a pressure of -0.09MPa and a temperature of 120℃ to obtain isopropyl 2-hydroxy-4-methylthio-butyrate. The mass of isopropyl 2-hydroxy-4-methylthio-butyrate was 335.4g, the purity was 99.2%, and the molar yield was 95.6%.

[0049] Example 2

[0050] An improved method for the preparation and purification of isopropyl 2-hydroxy-4-methylthio-butyrate, specifically as follows:

[0051] 1. Raw material pretreatment: After dehydrating the hydroxymethionine analogue with n-heptane, 295g of the dehydrated hydroxymethionine analogue and 165g of isopropanol were mixed and ultrasonically vibrated under a nitrogen atmosphere. The ultrasonic vibration frequency was controlled at 25kHz, the time was 2.2h, and the temperature was 20℃. After ultrasonic vibration, the raw material mixture was obtained.

[0052] The composition of the hydroxymethionine analogue, by weight, includes: 84 parts of 2-hydroxy-4-methylthio-butyric acid, 6 parts of 2-hydroxy-4-methylthio-butyric acid dimer, and 11 parts of water;

[0053] 2. Esterification reaction: 410g of raw material mixture and 850g of dichloromethane were added to a four-necked flask equipped with a condenser. The temperature of the four-necked flask was controlled at 88℃ and the stirring speed was controlled at 250rpm. Then, 4.2g of solid acid catalyst and 250g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added and stirred for 6.5h to obtain the reaction solution.

[0054] The preparation method of the solid acid catalyst is as follows:

[0055] (1) Preparation of carrier: 2.8g of ferric chloride and 1020g of deionized water were added to a four-necked flask. The temperature of the four-necked flask was controlled at 25℃ and the stirring speed was controlled at 150rpm. After stirring for 30min, a ferric chloride solution was obtained. 22g of graphene oxide and 1020g of deionized water were added to a four-necked flask. The temperature of the four-necked flask was controlled at 25℃ and the stirring speed was controlled at 150rpm. After stirring for 40min, ultrasonic vibration was performed. The frequency of ultrasonic vibration was controlled at 25kHz and the time was 35min. After ultrasonic vibration, graphene oxide sol was obtained. 41g of tetraethyl orthosilicate, 365g of anhydrous ethanol, 42g of deionized water and 2.8g of ammonia water with a mass fraction of 24% were added to a four-necked flask. The temperature of the four-necked flask was controlled at 45℃ and the stirring speed was controlled at 150rpm. After stirring for 2.5h, ultrasonic vibration was performed. The ultrasonic oscillation frequency was controlled at 25 kHz for 55 min, and silica sol was obtained after ultrasonic oscillation. The graphene oxide sol was added to a four-necked flask equipped with a reflux condenser. The temperature of the four-necked flask was controlled at 45 °C, and the stirring speed was controlled at 150 rpm. Then, ferric chloride solution was added dropwise to the four-necked flask at a rate of 11 g / min. After the addition was completed, the temperature of the four-necked flask was controlled at 120 °C for reflux reaction. After 6.5 h, silica sol was added dropwise to the four-necked flask at a rate of 7 g / min. After the addition was completed, the reflux reaction was continued for another 5.5 h. Then, heating and stirring were stopped, and the mixture was allowed to cool naturally to room temperature. The mixture was filtered, and the filter residue was washed five times with five times the mass of the filter residue using deionized water. After drying at 125 °C, the mixture was calcined at 520 °C for 2.2 h under a nitrogen atmosphere to obtain the carrier.

[0056] (2) One-time impregnation modification: 2.1g tungstic acid, 6.6g citric acid and 91g deionized water were added to a four-necked flask. The temperature of the four-necked flask was controlled at 65℃ and the stirring speed was controlled at 250rpm. After stirring for 45min, 24% ammonia water was added to adjust the pH to 9.2. After stirring for 19h, a one-time impregnation solution was obtained. 21g of carrier was added to the one-time impregnation solution and impregnated at 45℃ for 3.5h. Then the carrier was calcined at 720℃ for 5.2h to obtain a one-time impregnation modified carrier.

[0057] (3) Secondary impregnation modification: 9.5g of perfluorosulfonic acid resin, 12g of dimethyl sulfoxide and 88g of isopropanol were added to a four-necked flask. The temperature of the four-necked flask was controlled at 25℃ and the stirring speed was controlled at 150rpm. After stirring for 30min, a secondary impregnation solution was obtained. 21g of the primary impregnation modified carrier was added to the secondary impregnation solution and impregnated at 45℃ for 25min. Then the carrier was freeze-dried at -35℃ for 7.5h to obtain a solid acid catalyst.

[0058] 3. Post-processing: The reaction solution is filtered, and the filter residue is used as catalyst. The catalyst is reused. The filtrate is concentrated under reduced pressure and washed with deionized water. The washed organic phase is then concentrated under reduced pressure to obtain a concentrated solution. The concentrated solution is then distilled to obtain the crude product.

[0059] 4. Purification: The crude product was completely dissolved in 1250g of n-heptane, and the pH was adjusted to 8.2 by adding saturated sodium carbonate solution. The organic phase was then distilled at a pressure of -0.09MPa and a temperature of 120℃ to obtain isopropyl 2-hydroxy-4-methylthio-butyrate. The mass of isopropyl 2-hydroxy-4-methylthio-butyrate was 332.1g, the purity was 99.3%, and the molar yield was 93.7%.

[0060] Example 3

[0061] An improved method for the preparation and purification of isopropyl 2-hydroxy-4-methylthio-butyrate, specifically as follows:

[0062] 1. Raw material pretreatment: After treating the hydroxymethionine analogue with n-heptane to remove water, 300g of the water-treated hydroxymethionine analogue and 170g of isopropanol were mixed and ultrasonically vibrated under a nitrogen atmosphere. The ultrasonic vibration frequency was controlled at 30kHz, the time was 2.5h, and the temperature was 25℃. After ultrasonic vibration was completed, the raw material mixture was obtained.

[0063] The composition of the hydroxymethionine analogue, by weight, includes: 85 parts of 2-hydroxy-4-methylthio-butyric acid, 7 parts of 2-hydroxy-4-methylthio-butyric acid dimer, and 12 parts of water.

[0064] 2. Esterification reaction: 420g of raw material mixture and 900g of dichloromethane were added to a four-necked flask equipped with a condenser. The temperature of the four-necked flask was controlled at 90℃ and the stirring speed was controlled at 300rpm. Then, 4.5g of solid acid catalyst and 260g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added and stirred for 7h to obtain the reaction solution.

[0065] The preparation method of the solid acid catalyst is as follows:

[0066] (1) Preparation of the carrier: 3g of ferric chloride and 1050g of deionized water were added to a four-necked flask. The temperature of the four-necked flask was controlled at 35℃, and the stirring speed was controlled at 200rpm. After stirring for 40min, a ferric chloride solution was obtained. 25g of graphene oxide and 1050g of deionized water were added to a four-necked flask. The temperature of the four-necked flask was controlled at 35℃, and the stirring speed was controlled at 200rpm. After stirring for 50min, ultrasonic vibration was performed. The frequency of ultrasonic vibration was controlled at 30kHz for 40min. After ultrasonic vibration, a graphene oxide sol was obtained. 42g of tetraethyl orthosilicate, 370g of anhydrous ethanol, 45g of deionized water, and 3g of 25% ammonia solution were added to a four-necked flask. The temperature of the four-necked flask was controlled at 50℃, and the stirring speed was controlled at 200rpm. After stirring for 3h, ultrasonic vibration was performed. The ultrasonic oscillation frequency was 30 kHz for 60 min, and silica sol was obtained after ultrasonic oscillation. The graphene oxide sol was added to a four-necked flask equipped with a reflux condenser. The temperature of the four-necked flask was controlled at 50 °C and the stirring speed was controlled at 200 rpm. Then, ferric chloride solution was added dropwise to the four-necked flask at a rate of 12 g / min. After the addition was completed, the temperature of the four-necked flask was controlled at 125 °C for reflux reaction. After 7 h, silica sol was added dropwise to the four-necked flask at a rate of 8 g / min. After the addition was completed, the reflux reaction was continued for 5-6 h. Then, heating and stirring were stopped, and the mixture was allowed to cool naturally to room temperature. The mixture was filtered, and the filter residue was washed 5 times with 6 times the mass of the filter residue using deionized water. After drying at 130 °C, the mixture was calcined at 550 °C for 2.5 h under a nitrogen atmosphere to obtain the carrier.

[0067] (2) One-time impregnation modification: 2.2g tungstic acid, 6.8g citric acid and 92g deionized water were added to a four-necked flask. The temperature of the four-necked flask was controlled at 70℃ and the stirring speed was controlled at 300rpm. After stirring for 50min, 25% ammonia water was added to adjust the pH to 9.5. After stirring for 20h, a one-time impregnation solution was obtained. 22g of the carrier was added to the one-time impregnation solution and impregnated at 50℃ for 4h. Then the carrier was calcined at 750℃ for 5.5h to obtain a one-time impregnation modified carrier.

[0068] (3) Secondary impregnation modification: 10g of perfluorosulfonic acid resin, 15g of dimethyl sulfoxide and 90g of isopropanol were added to a four-necked flask. The temperature of the four-necked flask was controlled at 35℃ and the stirring speed was controlled at 200rpm. After stirring for 40min, a secondary impregnation solution was obtained. 22g of the primary impregnation modified carrier was added to the secondary impregnation solution and impregnated at 50℃ for 30min. Then the carrier was freeze-dried at -30℃ for 8h to obtain a solid acid catalyst.

[0069] 3. Post-processing: The reaction solution is filtered, and the filter residue is used as catalyst. The catalyst is reused. The filtrate is concentrated under reduced pressure and washed with deionized water. The washed organic phase is then concentrated under reduced pressure to obtain a concentrated solution. The concentrated solution is then distilled to obtain the crude product.

[0070] 4. Purification: The crude product was completely dissolved in 1300g of n-heptane, and the pH was adjusted to 8.5 by adding saturated sodium carbonate solution. The organic phase was then distilled at a pressure of -0.09MPa and a temperature of 120℃ to obtain isopropyl 2-hydroxy-4-methylthio-butyrate. The mass of isopropyl 2-hydroxy-4-methylthio-butyrate was 332.7g, the purity was 98.4%, and the molar yield was 92.0%.

[0071] Comparative Example 1

[0072] The same modified method for the preparation and purification of isopropyl 2-hydroxy-4-methylthio-butyrate as in Example 1 was used, except that 8g of 98% concentrated sulfuric acid was used instead of 4g of solid acid catalyst in the second step of the esterification reaction.

[0073] Finally, 2-hydroxy-4-methylthio-butyrate isopropyl ester was obtained, with a mass of 285.2 g, a purity of 98.7%, and a molar yield of 80.9%.

[0074] Experimental Example 1

[0075] After applying the solid acid catalyst 50 times according to the methods in Examples 1-3, 2-hydroxy-4-methylthio-butyrate isopropyl ester was prepared and purified according to the methods in Examples 1-3, and the molar yield was calculated. The results are as follows:

[0076]

[0077] Experimental Example 2

[0078] The solid acid catalysts from Examples 1-3 were placed at 150°C and allowed to stand for 100 h, respectively. Then, 2-hydroxy-4-methylthio-butyrate isopropyl ester was prepared and purified according to the methods in Examples 1-3, and the molar yield was calculated. The results are as follows:

[0079]

[0080] Unless otherwise stated, all percentages used in this invention are mass percentages.

[0081] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An improved method for preparing isopropyl 2-hydroxy-4-methylthio-butyrate, characterized in that, include: Raw material pretreatment, esterification reaction, and post-treatment; The esterification reaction involves adding the raw material mixture and dichloromethane into a four-necked flask equipped with a condenser, controlling the temperature of the four-necked flask to 85-90°C, stirring, and then adding a solid acid catalyst and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, stirring for 6-7 hours to obtain the reaction solution. The method for preparing the solid acid catalyst includes: preparing a support, primary impregnation modification, and secondary impregnation modification; The preparation of the carrier involves adding ferric chloride and deionized water to a four-necked flask, controlling the temperature of the flask at 15-35°C, and stirring to obtain a ferric chloride solution; adding graphene oxide and deionized water to the four-necked flask, controlling the temperature of the flask at 15-35°C, stirring, and then ultrasonically vibrating to obtain a graphene oxide sol; adding tetraethyl orthosilicate, anhydrous ethanol, deionized water, and ammonia to the four-necked flask, controlling the temperature of the flask at 40-50°C, stirring, and then ultrasonically vibrating to obtain a silica sol; and then adding graphene oxide... The olefin sol was added to a four-necked flask equipped with a reflux condenser. The temperature of the four-necked flask was controlled at 40-50℃, and the mixture was stirred. Then, ferric chloride solution was added dropwise to the four-necked flask. After the addition was completed, the temperature of the four-necked flask was controlled at 115-125℃ for reflux reaction. After 6-7 hours, silica sol was added dropwise to the four-necked flask. After the addition was completed, the reflux reaction was continued for 5-6 hours. Then, heating and stirring were stopped, and the mixture was allowed to cool naturally to room temperature. The mixture was filtered, the filter residue was washed and dried, and then calcined at 500-550℃ under a nitrogen atmosphere to obtain the support. The first impregnation modification involves adding tungstic acid, citric acid, and deionized water to a four-necked flask, controlling the temperature of the flask to 60-70°C, stirring, adding ammonia water to adjust the pH to 9-9.5, and continuing stirring to obtain a first impregnation solution; adding the carrier to the first impregnation solution and impregnating it at 40-50°C, then calcining the carrier at 700-750°C to obtain a carrier modified by the first impregnation. The secondary impregnation modification involves adding perfluorosulfonic acid resin, dimethyl sulfoxide, and isopropanol to a four-necked flask, controlling the temperature of the four-necked flask to 15-35°C, and stirring to obtain a secondary impregnation solution; adding the primary impregnation modified carrier to the secondary impregnation solution, impregnating at 40-50°C, and then freeze-drying the carrier to obtain a solid acid catalyst. The post-processing involves filtering the reaction solution, using the filter residue as a catalyst, reusing the catalyst, concentrating the filtrate under reduced pressure, washing it with deionized water, concentrating the washed organic phase under reduced pressure to obtain a concentrated solution, and distilling the concentrated solution to obtain a crude product.

2. The improved method for preparing isopropyl 2-hydroxy-4-methylthio-butyrate according to claim 1, characterized in that, The raw material pretreatment involves treating the hydroxymethionine analogue with water using n-heptane, then mixing the water-treated hydroxymethionine analogue with isopropanol and subjecting the mixture to ultrasonic vibration under a nitrogen atmosphere. After ultrasonic vibration, a raw material mixture is obtained.

3. The improved method for preparing isopropyl 2-hydroxy-4-methylthio-butyrate according to claim 2, characterized in that, In the raw material pretreatment, the mass ratio of the hydroxymethionine analogue after water treatment to isopropanol is 290-300:160-170. The ultrasonic oscillation frequency is 20-30kHz, the duration is 2-2.5h, and the temperature is 15-25℃; The composition of the hydroxymethionine analogue, by weight, includes: 82-85 parts of 2-hydroxy-4-methylthio-butyric acid, 5-7 parts of 2-hydroxy-4-methylthio-butyric acid dimer, and 10-12 parts of water.

4. The improved method for preparing isopropyl 2-hydroxy-4-methylthio-butyrate according to claim 1, characterized in that, In the esterification reaction, the mass ratio of the raw material mixture, dichloromethane, solid acid catalyst, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 400-420:800-900:4-4.5:240-260.

5. The improved method for preparing isopropyl 2-hydroxy-4-methylthio-butyrate according to claim 1, characterized in that, In the ferric chloride solution, the mass ratio of ferric chloride to deionized water is 2.5-3:1000-1050; In the graphene oxide sol, the mass ratio of graphene oxide to deionized water is 20-25:1000-1050; In the silica sol, the mass ratio of tetraethyl orthosilicate, anhydrous ethanol, deionized water, and ammonia is 40-42:360-370:40-45:2.5-3. The mass fraction of the ammonia solution is 22-25%. The ferric chloride solution contains ferric chloride, the graphene oxide sol contains graphene oxide, and the tetraethyl orthosilicate in the silica sol is in a ratio of 2.5-3:20-25:40-42. In the preparation of the carrier, the ferric chloride solution is added at a rate of 10-12 g / min; The dropping rate of silica sol is 6-8 g / min.

6. The improved method for preparing isopropyl 2-hydroxy-4-methylthio-butyrate according to claim 1, characterized in that, In the primary impregnation modification, the mass ratio of tungstic acid, citric acid, deionized water, and carrier is 2-2.2:6.5-6.8:90-92:20-22; The mass fraction of the ammonia solution is 22-25%.

7. The improved method for preparing isopropyl 2-hydroxy-4-methylthio-butyrate according to claim 1, characterized in that, In the secondary impregnation modification, the mass ratio of perfluorosulfonic acid resin, dimethyl sulfoxide, isopropanol, and the carrier of the primary impregnation modification is 9-10:10-15:85-90:20-22.

8. The improved method for preparing isopropyl 2-hydroxy-4-methylthio-butyrate according to claim 1, characterized in that, The preparation method further includes a purification method, wherein the crude product obtained from the post-treatment is completely dissolved in n-heptane, a saturated sodium carbonate solution is added to adjust the pH to 8-8.5, and then the organic phase is distilled to obtain isopropyl 2-hydroxy-4-methylthiobutyrate.

Images