Preparation method of 3-benzyloxy-2-chloropropionic acid potassium salt

Abstract

The invention discloses a preparation method of 3-benzyloxy-2-chloropropionic acid potassium salt. The preparation method comprises the following steps: preparing a sodium benzyl alcohol solution by taking sodium hydroxide as a sodium source; dropwise adding methyl 2, 3-dichloropropionate into the sodium benzyl alcohol solution to carry out etherification reaction; adding a sodium hydroxide solution into the etherification reaction solution for hydrolysis, and then adding hydrochloric acid to adjust the pH value of the reaction system; standing the reaction system to obtain an organic layer containing the 3-benzyloxy-2-chloropropionic acid; and washing the organic layer with water, adding a potassium hydroxide solution for neutralization, and then carrying out crystallization purification by using lower alcohol to obtain the target product 3-benzyloxy-2-chloropropionic acid potassium salt. According to the method, the reaction conditions are easy to control, the energy consumption is low, and the prepared product is high in purity and yield.

Description

Technical Field

[0001] The invention relates to the technical field of organic reactions, and in particular to a method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt. Background Art

[0002] Potassium 3-benzyloxy-2-chloropropionate is a white or off-white powder used as an intermediate for the preparation of magnetic resonance contrast agent gadobenate dimeglumine. Currently, there are few studies on the synthesis of potassium 3-benzyloxy-2-chloropropionate.

[0003] Patent EP230893 discloses the following technical solution: using diethylenetriamine and 2-chloro-3-benzyloxypropionic acid as key raw materials, gadobenate dimeglumine is prepared by N-alkylation reaction, carboxymethylation reaction, ion exchange resin separation and purification, and chelation reaction. The disadvantages of the above method are: the product purity of the intermediate raw material 2-chloro-3-benzyloxypropionic acid is low, which affects the purity of the final product, and ion exchange resin is used when converting the salt form, which requires the use of a large amount of hydrochloric acid and potassium hydroxide, and it is easy to produce cyclized 6-membered lactam byproducts.

[0004] Patent CN1307558 discloses the following technical solution: using methyl acrylate as the starting material, high-purity 2-chloro-3-benzyloxypropionic acid is prepared by chlorination, etherification reaction, and isobutyl alcohol recrystallization; by changing the alkaline conditions of the ion exchange resin, the shortcomings of the original synthesis method are preliminarily solved, but the above synthesis method still has the following technical problems: (1) 3-benzyloxy-2-chloropropionic acid potassium salt is an oily substance after being concentrated from the reaction system, which is difficult to crystallize, mainly because of the viscosity of benzyl alcohol and the high sodium ions contained; (2) in order to achieve thorough desalination, the reaction process requires special milli-nanofiltration filtration equipment for concentration and desalination. The reaction condition control, equipment requirements, and energy consumption are relatively strict and complicated. Therefore, the equipment investment in this step of the reaction is large, which greatly increases the preparation cost of the product. Summary of the invention

[0005] The technical problem to be solved by the present invention is: in view of the shortcomings of the prior art, a method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt is provided, the reaction conditions of the method are easy to control, the energy consumption is low, and the purity and yield of the prepared product are high.

[0006] In order to solve the above technical problems, the technical solution of the present invention is:

[0007] A method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt comprises the following steps:

[0008] Sodium benzyl alcohol solution was prepared using sodium hydroxide as a sodium source;

[0009] Add methyl 2,3-dichloropropionate dropwise to the sodium benzyl alcohol solution to carry out etherification reaction;

[0010] Add sodium hydroxide solution to the above etherification reaction solution for hydrolysis, and then add hydrochloric acid to adjust the pH of the reaction system;

[0011] The reaction system is allowed to stand to obtain an organic layer containing 3-benzyloxy-2-chloropropionic acid;

[0012] The organic layer is washed with water, neutralized by adding potassium hydroxide solution, and then crystallized and purified by using lower alcohol to obtain the target product 3-benzyloxy-2-chloropropionic acid potassium salt.

[0013] Preferably, in the step of preparing the sodium benzyl alcohol solution, the solution is prepared by azeotropic dehydration with toluene.

[0014] Preferably, the process of preparing the sodium benzyl alcohol solution by azeotropic dehydration of toluene is as follows: toluene is added to a mixed solution of sodium hydroxide solution and benzyl alcohol, the mixture is evenly mixed and then heated to react, azeotropic dehydration is performed during the reaction, the azeotropic toluene layer re-enters the reaction system, the water in the reaction system is separated, the temperature is increased to evaporate the toluene, and then concentrated to obtain the sodium benzyl alcohol solution.

[0015] Preferably, the concentration of the sodium hydroxide solution is 20-40wt%, and the mass ratio of the sodium hydroxide solution, benzyl alcohol and toluene is (0.5-5):(2-20):(1-10).

[0016] Preferably, the temperature of the azeotropic dehydration is 100° C. and the time is 5-10 h.

[0017] Preferably, the temperature for distilling toluene is 120°C.

[0018] Preferably, the concentration conditions are: temperature of 60° C. and vacuum degree of -0.09 to -0.1 MPa.

[0019] Preferably, during the etherification reaction, the amount of methyl 2,3-dichloropropionate added is 0.1-1 times the amount of toluene used.

[0020] Preferably, during the etherification reaction, when methyl 2,3-dichloropropionate is added dropwise, the temperature of the sodium benzyl alcohol solution is controlled to be below 5° C., and the temperature of the reaction system is controlled to be below 10° C. during the entire adding process.

[0021] Preferably, during the etherification reaction, after the dropwise addition of methyl 2,3-dichloropropionate is completed, the reaction is stirred at 5-10° C. for 2-3 hours.

[0022] Preferably, during hydrolysis, the concentration of the sodium hydroxide solution is 20-40 wt %, and the temperature of the reaction system is controlled to be below 5° C. when the sodium hydroxide solution is added, and the pH of the hydrolysis system is controlled to be greater than 12 during hydrolysis.

[0023] Preferably, the hydrolysis temperature is room temperature, and sampling and analysis are performed during the hydrolysis. The hydrolysis reaction endpoint is when the content of methyl 3-benzyloxy-2-chloropropionate in the reaction system is ≤1.0wt%.

[0024] Preferably, hydrochloric acid solution is added to adjust the pH of the reaction system to 2-4, the concentration of the hydrochloric acid solution is 10-30 wt % and the temperature of the reaction system is controlled to be below 15° C. when hydrochloric acid is added.

[0025] Preferably, the concentration of the potassium hydroxide solution is 40-50wt%.

[0026] Preferably, the dehydration step is further included after the potassium hydroxide solution is used for dehydration, the temperature during dehydration is 75-85° C., and the vacuum degree during dehydration is -0.09 to -0.1 MPa.

[0027] The benzyl alcohol / propionic acid solution was adjusted to pH 7.0-7.5 with a 50% potassium hydroxide aqueous solution, and then dehydrated under reduced pressure at high vacuum (-0.099 MPa) and 80° C. until the water content was ≦1.0%, which was the dehydration end point.

[0028] Preferably, the crystallization purification includes primary crystallization and recrystallization, and both the primary crystallization and the recrystallization use lower alcohol as the crystallization solvent.

[0029] Preferably, the lower alcohol is a fatty alcohol having six carbon atoms or less; preferably, it is one of a straight-chain alcohol, a branched alcohol and a cyclic alcohol having six carbon atoms or less; further, preferably, it is a mixture of one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 2-butanol, n-pentanol and its isomers, cyclopentanol, n-hexanol and its isomers, and cyclohexanol.

[0030] Preferably, during primary crystallization and recrystallization, the volume ratio of the crystallization solvent is 1-20 times the weight of the crude product; more preferably, the volume ratio of the crystallization solvent is 1-5 times.

[0031] Preferably, the temperature during the primary crystallization and recrystallization is 0° C., and the time is 1-3 h.

[0032] The synthetic route of the present invention is as follows:

[0033]

[0034] Due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0035] 1. In the preparation process of sodium benzyl alcohol, sodium hydroxide is used as the sodium source to avoid the use of high-risk metallic sodium blocks and metallic sodium bars; and toluene azeotropic dehydration is adopted, the water generated by the reaction is quickly taken away, and after the water is removed, all the toluene is evaporated, so that the reaction is more thorough.

[0036] 2. The whole reaction process of the present invention adopts benzyl alcohol as the reaction solvent, which simplifies the synthesis process and reduces the preparation cost. In addition, the reaction conditions of the present invention are easy to control and have low requirements on equipment.

[0037] 3. The present invention adopts lower alcohol as a crystallization solvent, and adopts lower alcohol as a crystallization solvent; it avoids isopropyl ether and tetrahydrofuran that can produce peroxide, reduces the generation of by-products, improves the purity of the product, and solves the problem of high viscosity and difficult crystallization of benzyl alcohol.

[0038] 4. The present invention washes the organic layer with water before purification, and controls the ratio of water to benzyl alcohol, thereby effectively removing the sodium ions in the organic layer, facilitating subsequent crystallization. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0040] Figure 1 This is the GC spectrum of the crude product after primary crystallization in Example 1;

[0041] Figure 2 It is the GC spectrum of the refined product after recrystallization in Example 1. DETAILED DESCRIPTION

[0042] In order to more clearly understand the above-mentioned objectives, features and advantages of the present invention, the scheme of the present invention will be further described below. It should be noted that the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

[0043] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein; it is obvious that the embodiments in the specification are only part of the embodiments of the present invention, rather than all of the embodiments.

[0044] In order to solve the problems in the background technology, the present invention provides the following technical solutions:

[0045] A method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt comprises the following steps:

[0046] (1) preparing a sodium benzyl alcohol solution using sodium hydroxide as a sodium source;

[0047] (2) adding methyl 2,3-dichloropropionate dropwise to the sodium benzyl alcohol solution to carry out an etherification reaction;

[0048] (3) adding sodium hydroxide solution to the etherification reaction solution for hydrolysis, and then adding hydrochloric acid to adjust the pH of the reaction system; allowing the reaction system to stand to obtain an organic layer containing 3-benzyloxy-2-chloropropionic acid;

[0049] (4) washing the organic layer with water, and neutralizing it with potassium hydroxide solution to obtain a crude product solution;

[0050] (5) Using lower alcohol for crystallization purification, the target product 3-benzyloxy-2-chloropropionic acid potassium salt is obtained.

[0051] Regarding step (1):

[0052] In some embodiments of the present invention, toluene is prepared by azeotropic dehydration, and the specific process is: toluene is added to a mixed solution of sodium hydroxide solution and benzyl alcohol, mixed evenly and then heated to react, azeotropic dehydration is performed during the reaction, the azeotropic toluene layer re-enters the reaction system, and after separating the water in the reaction system, the temperature is increased to evaporate the toluene, and then part of the benzyl alcohol is removed to obtain a sodium benzyl alcohol solution. Specifically, the removal of part of the benzyl alcohol is controlled so that the subsequent reaction system ensures a suitable viscosity, and the mass ratio of benzyl alcohol to methyl 2,3-dichloropropionate in the subsequent reaction system is 4:1.

[0053] In the process of preparing sodium benzyl alcohol, sodium hydroxide is used as the sodium source, avoiding the use of high-risk metallic sodium blocks and metallic sodium bars, thereby ensuring the safety of production. In addition, in the process of synthesizing the sodium benzyl alcohol solution, the process is carried out in a mode of toluene with water, so that benzyl alcohol and sodium hydroxide are fully contacted and reacted, the water generated by the reaction can be quickly removed, and all toluene is evaporated, so that the reaction is more thorough.

[0054] In some embodiments of the present invention, the concentration of the sodium hydroxide solution is 20-40 wt %, and the mass ratio of the sodium hydroxide solution, benzyl alcohol and toluene is (0.5-5):(2-20):(1-10).

[0055] In some embodiments of the present invention, the temperature of the azeotropic dehydration is 100° C. and the time is 5-10 h.

[0056] In some embodiments of the present invention, the temperature for distilling toluene is 120° C., and distillation is performed until no gas is discharged, indicating that the toluene is completely distilled out.

[0057] In some embodiments of the present invention, the conditions for removing part of the benzyl alcohol are a temperature of 60° C. and a vacuum degree of -0.09 to -0.1 MPa.

[0058] Regarding step (2):

[0059] The intermediate product methyl 3-benzyloxy-2-chloropropionate was prepared by reacting methyl 2,3-dichloropropionate with sodium benzyl alcohol.

[0060] In some embodiments of the present invention, when methyl 2,3-dichloropropionate is added dropwise, the temperature of the sodium benzyl alcohol solution is controlled to be below 5°C, and the temperature of the reaction system is controlled to be below 10°C during the entire addition process; after the addition of methyl 2,3-dichloropropionate is completed, the reaction is stirred at 5-10°C for 2-3h.

[0061] In some embodiments of the present invention, the amount of methyl 2,3-dichloropropionate added is 0.1-1 times the amount of toluene used.

[0062] Regarding step (3):

[0063] The intermediate product 3-benzyloxy-2-chloropropionic acid methyl ester is mixed with a sodium hydroxide solution for hydrolysis to prepare the intermediate product 3-benzyloxy-2-chloropropionic acid. During the hydrolysis process, the pH of the solution is controlled to be greater than 12 to ensure thorough hydrolysis.

[0064] In some embodiments of the present invention, the concentration of the sodium hydroxide solution is 20-40 wt %, and the temperature of the reaction system is controlled to be below 5° C. when the sodium hydroxide solution is added.

[0065] In some embodiments of the present invention, the hydrolysis temperature is room temperature, sampling and analysis are performed during the hydrolysis, and the hydrolysis reaction endpoint is when the content of methyl 3-benzyloxy-2-chloropropionate in the reaction system is ≦1.0 wt %.

[0066] In some embodiments of the present invention, the concentration of the hydrochloric acid solution is 10-30 wt %, and the pH of the reaction system is adjusted to 2-4 by adding the hydrochloric acid solution; when the hydrochloric acid is added, the temperature of the reaction system is controlled to be below 15° C.

[0067] Regarding step (4):

[0068] In some embodiments of the present invention, when washing the organic layer with water, the amount of water added is 20 wt % to 60 wt % of the organic layer.

[0069] By controlling the ratio of benzyl alcohol to water, the sodium ions enter the water phase during water washing, thereby removing the sodium ions in the organic layer through water washing, without the need to use ion exchange resin for exchange and removal, thereby reducing the preparation cost of the product and reducing energy consumption.

[0070] In some embodiments of the present invention, the concentration of the potassium hydroxide solution is 40-50 wt %. Potassium hydroxide reacts with the intermediate product 3-benzyloxy-2-chloropropionic acid to form a salt; and the potassium hydroxide solution is used to adjust the pH of the reaction system to 7.0-7.5.

[0071] In some embodiments of the present invention, after neutralization with potassium hydroxide solution, a dehydration step is further included, the temperature during dehydration is 75-85°C, the vacuum degree during dehydration is -0.09 to -0.1 MPa, and specifically, the dehydration end point is when the water content in the product is ≤1.0%. After dehydration, it is convenient for subsequent crystallization and purification of the product.

[0072] Regarding step (5):

[0073] In some embodiments of the present invention, the lower alcohol is a fatty alcohol having six or less carbon atoms; specifically, the fatty alcohol includes a mixture of one or more of a straight-chain alcohol, a branched alcohol and a cyclic alcohol; further, the fatty alcohol includes at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 2-butanol, n-pentanol and its isomers, cyclopentanol, n-hexanol and its isomers, and cyclohexanol.

[0074] In some embodiments of the present invention, the lower alcohol includes at least one of ethanol, isopropanol, cyclopentanol, and cyclohexanol, and the volume of the crystallization solvent is 1-20 times the weight of the crude product; at least one of ethanol and cyclopentanol is further preferred, and the volume ratio of the crystallization solvent is further preferred to be 1-5 times.

[0075] During crystallization purification, benzyl alcohol has a large viscosity and will appear as an oily substance during the concentration process, thereby causing difficulty in crystallization. To solve the above problem, the present invention first uses a lower alcohol as a crystallization solvent to make 3-benzyloxy-2-chloropropionic acid potassium salt easy to precipitate, and then recrystallizes it in the lower alcohol to obtain a target product with a purity of more than 99%, and the residual benzyl alcohol in the product is very low.

[0076] In some embodiments of the present invention, the temperature during the primary crystallization and the recrystallization is 0° C., and the time is 1-3 h.

[0077] In order to further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0078] Unless otherwise specified, the materials in the following examples and comparative examples are all commercially available; the conditions described are all conventional conditions in the art unless otherwise specified.

[0079] The yield calculation method of the target product 3-benzyloxy-2-chloropropionic acid potassium salt is as follows:

[0080] Yield (%) = (actual yield of target product / theoretical yield of target product) × 100%.

[0081] Example 1

[0082] A method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt comprises the following steps:

[0083] (1) Preparation of sodium benzyl alcohol solution:

[0084] Add 70g of 30wt% sodium hydroxide solution, 600g of benzyl alcohol and 300g of toluene into a 2000ml three-necked flask, stir evenly, heat to 100°C and keep warm for 8h, during which azeotropic dehydration is carried out and the azeotropic toluene layer re-enters the reaction system; after no water is removed, heat to 120°C to completely evaporate toluene; then cool to 60°C, remove 250g of benzyl alcohol at -0.097MPa, and finally cool to room temperature to obtain a sodium benzyl alcohol solution;

[0085] (2) Preparation of 3-benzyloxy-2-chloropropionic acid methyl ester:

[0086] The sodium benzyl alcohol solution was cooled to 4°C, and 78.5 g (0.500 mol) of methyl 2,3-dichloropropionate was added dropwise. During the addition, the liquid temperature was controlled below 10°C until the addition was completed. After the addition was completed, the reaction was continued at 5°C with stirring for 2 hours to obtain a solution containing methyl 3-benzyloxy-2-chloropropionate;

[0087] (3) Preparation of 3-benzyloxy-2-chloropropionic acid:

[0088] The above solution containing methyl 3-benzyloxy-2-chloropropionate was cooled to 4°C, 80.0g of 30wt% sodium hydroxide solution was slowly added dropwise, hydrolysis reaction was carried out at room temperature, sampling and analysis were performed, and the end point of the hydrolysis reaction was when the content of methyl 3-benzyloxy-2-chloropropionate in the reaction system was ≤1.0wt%; then the temperature of the reaction solution was controlled below 15°C, a 30wt% hydrochloric acid solution was slowly added dropwise to the reaction solution to adjust the pH to 3, and then the reaction solution was allowed to stand for stratification, and the organic layer was collected, 150ml of water was added to the organic layer for washing, and the mixture was stirred for 30min, and the reaction solution was allowed to stand for stratification, and the organic layer containing 3-benzyloxy-2-chloropropionic acid was collected;

[0089] (4) Preparation of crude 3-benzyloxy-2-chloropropionic acid potassium salt:

[0090] A 50 wt % potassium hydroxide aqueous solution was added to the organic layer containing 3-benzyloxy-2-chloropropionic acid to adjust the pH to 7.0, and then dehydrated under reduced pressure at -0.099 MPa and 80° C. to a water content of ≤1.0%. After dehydration, the mixture was cooled to room temperature and benzyl alcohol was added to maintain the system weight at 300 g to obtain a crude product of 3-benzyloxy-2-chloropropionic acid potassium salt;

[0091] (5) Preparation of high-purity 3-benzyloxy-2-chloropropionic acid potassium salt:

[0092] Heat the crude potassium salt of 3-benzyloxy-2-chloropropionic acid to 40°C, slowly add 450g of cyclopentanol while stirring, stir at 40°C for 30min, cool to 0°C, stir and crystallize for 2h, filter after crystallization, and dry at 50°C to obtain 130.0g of crude product. Figure 1 As shown, the content of 3-benzyloxy-2-chloropropionic acid potassium salt is 89.8%;

[0093] The crude product and anhydrous ethanol were mixed and heated to 50°C, then cooled to 0°C, stirred for crystallization for 2h, filtered after the crystallization, and the solid was dried at 50°C to obtain 101.2g of high-purity 3-benzyloxy-2-chloropropionic acid potassium salt, with a 3-benzyloxy-2-chloropropionic acid potassium salt content of 99.5%. Figure 2 As shown, the yield is 80.1%.

[0094] Example 2

[0095] A method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt comprises the following steps:

[0096] (1) Preparation of sodium benzyl alcohol solution:

[0097] Add 150g of 30wt% sodium hydroxide solution, 600g of benzyl alcohol and 400g of toluene into a 2000ml three-necked flask, stir evenly, heat to 100°C and keep warm for 8h, during which azeotropic dehydration is carried out and the azeotropic toluene layer re-enters the reaction system; after no water is removed, heat to 120°C to completely evaporate toluene; then cool to 60°C, remove 250g of benzyl alcohol at -0.097MPa, and finally cool to room temperature to obtain a sodium benzyl alcohol solution;

[0098] (2) Preparation of 3-benzyloxy-2-chloropropionic acid methyl ester:

[0099] The sodium benzyl alcohol solution was cooled to 4°C, and 78.5 g (0.500 mol) of methyl 2,3-dichloropropionate was added dropwise. During the addition, the liquid temperature was controlled below 10°C until the addition was completed. After the addition was completed, the reaction was continued at 7°C with stirring for 3 hours to obtain a solution containing methyl 3-benzyloxy-2-chloropropionate;

[0100] (3) Preparation of 3-benzyloxy-2-chloropropionic acid:

[0101] The above solution containing methyl 3-benzyloxy-2-chloropropionate was cooled to 4°C, 150g of 30wt% sodium hydroxide solution was slowly added dropwise, hydrolysis reaction was carried out at room temperature, sampling and analysis were performed, and the end point of the hydrolysis reaction was when the content of methyl 3-benzyloxy-2-chloropropionate in the reaction system was ≤1.0wt%; then the temperature of the reaction solution was controlled below 15°C, a 30wt% hydrochloric acid solution was slowly added dropwise to the reaction solution to adjust the pH to 3, then the reaction solution was allowed to stand for stratification, an organic layer was collected, 200ml of water was added to the organic layer for washing, stirring for 30min, and the reaction solution was allowed to stand for stratification, and an organic layer containing 3-benzyloxy-2-chloropropionic acid was collected;

[0102] (4) Preparation of crude 3-benzyloxy-2-chloropropionic acid potassium salt:

[0103] A 50 wt % potassium hydroxide aqueous solution was added to the organic layer containing 3-benzyloxy-2-chloropropionic acid to adjust the pH to 7.0, and then dehydrated under reduced pressure at -0.099 MPa and 80° C. to a water content of ≤1.0%. After dehydration, the mixture was cooled to room temperature and benzyl alcohol was added to maintain the system weight at 280 g to obtain a crude product of 3-benzyloxy-2-chloropropionic acid potassium salt;

[0104] (5) Preparation of high-purity 3-benzyloxy-2-chloropropionic acid potassium salt:

[0105] Heat the crude potassium salt of 3-benzyloxy-2-chloropropionic acid to 40°C, slowly add 450g of cyclopentanol while stirring, stir at 40°C for 30min, cool to 0°C, stir and crystallize for 2h, filter after crystallization, and dry at 50°C to obtain 124.3g of crude product;

[0106] The above crude product and anhydrous ethanol were mixed and heated to 50°C, then cooled to 0°C, stirred for crystallization for 2 hours, filtered after the crystallization, and the solid was dried at 50°C to obtain 101.07 g of high-purity 3-benzyloxy-2-chloropropionic acid potassium salt, with a 3-benzyloxy-2-chloropropionic acid potassium salt content of 99.3% and a yield of 80%.

[0107] Example 3

[0108] A method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt comprises the following steps:

[0109] (1) Preparation of sodium benzyl alcohol solution:

[0110] Add 100g of 20wt% sodium hydroxide solution, 600g of benzyl alcohol and 300g of toluene into a 2000ml three-necked flask, stir evenly, heat to 100°C and keep warm for 8h, during which azeotropic dehydration is carried out and the azeotropic toluene layer re-enters the reaction system; after no water is removed, heat to 120°C to completely evaporate toluene; then cool to 60°C, remove 250g of benzyl alcohol at -0.097MPa, and finally cool to room temperature to obtain a sodium benzyl alcohol solution;

[0111] (2) Preparation of 3-benzyloxy-2-chloropropionic acid methyl ester:

[0112] The sodium benzyl alcohol solution was cooled to 4°C, and 78.5 g (0.500 mol) of methyl 2,3-dichloropropionate was added dropwise. During the addition, the liquid temperature was controlled below 10°C until the addition was completed. After the addition was completed, the reaction was continued at 6°C with stirring for 3 hours to obtain a solution containing methyl 3-benzyloxy-2-chloropropionate;

[0113] (3) Preparation of 3-benzyloxy-2-chloropropionic acid:

[0114] The above solution containing methyl 3-benzyloxy-2-chloropropionate was cooled to 4°C, 100g of 20wt% sodium hydroxide solution was slowly added dropwise, hydrolysis reaction was carried out at room temperature, sampling and analysis were performed, and the hydrolysis reaction end point was when the content of methyl 3-benzyloxy-2-chloropropionate in the reaction system was ≤1.0wt%; then the temperature of the reaction solution was controlled below 15°C, a 10wt% hydrochloric acid solution was slowly added dropwise to the reaction solution to adjust the pH to 3, and then the reaction solution was allowed to stand for stratification, and the organic layer was collected, 150ml of water was added to the organic layer for washing, and the mixture was stirred for 30min, and the reaction solution was allowed to stand for stratification, and the organic layer containing 3-benzyloxy-2-chloropropionic acid was collected;

[0115] (4) Preparation of crude 3-benzyloxy-2-chloropropionic acid potassium salt:

[0116] A 40 wt % potassium hydroxide aqueous solution was added to the organic layer containing 3-benzyloxy-2-chloropropionic acid to adjust the pH to 7.0, and then dehydrated under reduced pressure at -0.099 MPa and 80° C. to a water content of ≤1.0%. After dehydration, the mixture was cooled to room temperature and benzyl alcohol was added to maintain the system weight at 300 g to obtain a crude product of 3-benzyloxy-2-chloropropionic acid potassium salt;

[0117] (5) Preparation of high-purity 3-benzyloxy-2-chloropropionic acid potassium salt:

[0118] Heat the crude product of 3-benzyloxy-2-chloropropionic acid potassium salt to 40°C, slowly add 450g of cyclopentanol while stirring, stir at 40°C for 30min, cool to 0°C, stir and crystallize for 2h, filter after crystallization, and dry at 50°C to obtain 121.5g of crude product;

[0119] The above crude product and anhydrous ethanol were mixed and heated to 50°C, then cooled to 0°C, stirred for crystallization for 2 hours, filtered after the crystallization, and the solid was dried at 50°C to obtain 100.44 g of high-purity 3-benzyloxy-2-chloropropionic acid potassium salt, with a 3-benzyloxy-2-chloropropionic acid potassium salt content of 99.2% and a yield of 79.5%.

[0120] Example 4

[0121] A method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt comprises the following steps:

[0122] (1) Preparation of sodium benzyl alcohol solution:

[0123] Add 60g of 40wt% sodium hydroxide solution, 400g of benzyl alcohol and 300g of toluene into a 2000ml three-necked flask, stir evenly, heat to 100°C and keep warm for 8h, during which azeotropic dehydration is carried out and the azeotropic toluene layer re-enters the reaction system; after no water is removed, heat to 120°C to completely evaporate toluene; then cool to 60°C, remove 180g of benzyl alcohol at -0.097MPa, and finally cool to room temperature to obtain a sodium benzyl alcohol solution;

[0124] (2) Preparation of 3-benzyloxy-2-chloropropionic acid methyl ester:

[0125] The sodium benzyl alcohol solution was cooled to 4°C, and 78.5 g (0.500 mol) of methyl 2,3-dichloropropionate was added dropwise. During the addition, the liquid temperature was controlled below 10°C until the addition was completed. After the addition was completed, the reaction was continued at 6°C with stirring for 3 hours to obtain a solution containing methyl 3-benzyloxy-2-chloropropionate;

[0126] (3) Preparation of 3-benzyloxy-2-chloropropionic acid:

[0127] The above solution containing methyl 3-benzyloxy-2-chloropropionate was cooled to 4°C, 60.0g of 40wt% sodium hydroxide solution was slowly added dropwise, hydrolysis reaction was carried out at room temperature, sampling and analysis were performed, and the end point of the hydrolysis reaction was when the content of methyl 3-benzyloxy-2-chloropropionate in the reaction system was ≤1.0wt%; then the temperature of the reaction solution was controlled below 15°C, a 30wt% hydrochloric acid solution was slowly added dropwise to the reaction solution to adjust the pH to 3, and then the reaction solution was allowed to stand for stratification, and the organic layer was collected, 150ml of water was added to the organic layer for washing, and the mixture was stirred for 30min, and the reaction solution was allowed to stand for stratification, and the organic layer containing 3-benzyloxy-2-chloropropionic acid was collected;

[0128] (4) Preparation of crude 3-benzyloxy-2-chloropropionic acid potassium salt:

[0129] A 50 wt % potassium hydroxide aqueous solution was added to the organic layer containing 3-benzyloxy-2-chloropropionic acid to adjust the pH to 7.0, and then dehydrated under reduced pressure at -0.099 MPa and 80° C. to a water content of ≤1.0%. After dehydration, the mixture was cooled to room temperature and benzyl alcohol was added to maintain the system weight at 300 g to obtain a crude product of 3-benzyloxy-2-chloropropionic acid potassium salt;

[0130] (5) Preparation of high-purity 3-benzyloxy-2-chloropropionic acid potassium salt:

[0131] Heat the crude potassium salt of 3-benzyloxy-2-chloropropionic acid to 40°C, slowly add 450g of cyclopentanol while stirring, stir at 40°C for 30min, cool to 0°C, stir and crystallize for 2h, filter after crystallization, and dry at 50°C to obtain 120.6g of crude product;

[0132] The above crude product and anhydrous ethanol were mixed and heated to 50°C, then cooled to 0°C, stirred for crystallization for 2 hours, filtered after the crystallization, and the solid was dried at 50°C to obtain 101.7 g of high-purity 3-benzyloxy-2-chloropropionic acid potassium salt, with a 3-benzyloxy-2-chloropropionic acid potassium salt content of 99.4% and a yield of 80.5%.

[0133] Example 5

[0134] A method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt comprises the following steps:

[0135] (1) Preparation of sodium benzyl alcohol solution:

[0136] 70 g of 30 wt% sodium hydroxide solution, 400 g of benzyl alcohol and 200 g of toluene were added to a 2000 ml three-necked flask, stirred evenly, heated to 100° C. and kept warm for 8 h, during which azeotropic dehydration was performed and the azeotropic toluene layer re-entered the reaction system; after no water was removed, the temperature was raised to 120° C. to completely evaporate the toluene; then the temperature was lowered to 60° C., 180 g of benzyl alcohol was removed at -0.097 MPa, and finally cooled to room temperature to obtain a sodium benzyl alcohol solution;

[0137] (2) Preparation of 3-benzyloxy-2-chloropropionic acid methyl ester:

[0138] The sodium benzyl alcohol solution was cooled to 4°C, and 78.5 g (0.500 mol) of methyl 2,3-dichloropropionate was added dropwise. During the addition, the liquid temperature was controlled below 10°C until the addition was completed. After the addition was completed, the reaction was continued at 7°C with stirring for 3 hours to obtain a solution containing methyl 3-benzyloxy-2-chloropropionate;

[0139] (3) Preparation of 3-benzyloxy-2-chloropropionic acid:

[0140] The above solution containing methyl 3-benzyloxy-2-chloropropionate was cooled to 4°C, 80.0g of 30wt% sodium hydroxide solution was slowly added dropwise, hydrolysis reaction was carried out at room temperature, sampling and analysis were performed, and the end point of the hydrolysis reaction was when the content of methyl 3-benzyloxy-2-chloropropionate in the reaction system was ≤1.0wt%; then the temperature of the reaction solution was controlled below 15°C, a 30wt% hydrochloric acid solution was slowly added dropwise to the reaction solution to adjust the pH to 3, and then the reaction solution was allowed to stand for stratification, and the organic layer was collected, 150ml of water was added to the organic layer for washing, and the mixture was stirred for 30min, and the reaction solution was allowed to stand for stratification, and the organic layer containing 3-benzyloxy-2-chloropropionic acid was collected;

[0141] (4) Preparation of crude 3-benzyloxy-2-chloropropionic acid potassium salt:

[0142] A 50 wt % potassium hydroxide aqueous solution was added to the organic layer containing 3-benzyloxy-2-chloropropionic acid to adjust the pH to 7.0, and then dehydrated under reduced pressure at -0.099 MPa and 80° C. to a water content of ≤1.0%. After dehydration, the mixture was cooled to room temperature and benzyl alcohol was added to maintain the system weight at 280 g to obtain a crude product of 3-benzyloxy-2-chloropropionic acid potassium salt;

[0143] (5) Preparation of high-purity 3-benzyloxy-2-chloropropionic acid potassium salt:

[0144] Heat the crude potassium salt of 3-benzyloxy-2-chloropropionic acid to 40°C, slowly add 250g of cyclopentanol while stirring, stir at 40°C for 30min, cool to 0°C, stir and crystallize for 2h, filter after crystallization, and dry at 50°C to obtain 112.8g of crude product;

[0145] The above crude product and anhydrous ethanol were mixed and heated to 50°C, then cooled to 0°C, stirred for crystallization for 2 hours, filtered after the crystallization, and the solid was dried at 50°C to obtain 99.8g of high-purity 3-benzyloxy-2-chloropropionic acid potassium salt, with a 3-benzyloxy-2-chloropropionic acid potassium salt content of 99.2% and a yield of 79%.

[0146] Comparative Example 1

[0147] Compared with Example 1, the difference is that in step (3), hydrochloric acid solution is added to adjust the pH of the solution to 5, and the other conditions are the same as those in Example 1, and 52.3 g of 3-benzyloxy-2-chloropropionic acid potassium salt is obtained, the 3-benzyloxy-2-chloropropionic acid potassium salt content is 94.7%, and the yield is 41.4%.

[0148] Comparative Example 2

[0149] Compared with Example 1, the difference is that in step (4), no benzyl alcohol is added after decompression dehydration, and other conditions are the same as in Example 1, to obtain 70.9 g of 3-benzyloxy-2-chloropropionic acid potassium salt, with a 3-benzyloxy-2-chloropropionic acid potassium salt content of 98.2% and a yield of 56.1%.

[0150] Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method of the present invention and its core ideas, including the best mode, and also enable any technician in the field to practice the present invention, including making and using any device or system, and implementing any combined method. It should be pointed out that for ordinary technicians in this technical field, without departing from the principle of the present invention, the present invention can also be improved and modified, and these improvements and modifications also fall within the scope of protection of the claims of the present invention. The scope of patent protection of the present invention is defined by the claims and may include other embodiments that can be thought of by those skilled in the art. If these other embodiments have structural elements similar to the literal expression of the claims, or if they include equivalent structural elements that are not substantially different from the literal expression of the claims, then these other embodiments should also be included in the scope of the claims.

Claims

1. A method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt, characterized in that: The following steps are involved: Sodium benzyl alcohol solution was prepared using sodium hydroxide as a sodium source; Add methyl 2,3-dichloropropionate dropwise to the sodium benzyl alcohol solution to carry out etherification reaction; Add sodium hydroxide solution to the above etherification reaction solution for hydrolysis, and then add hydrochloric acid solution to adjust the pH of the reaction system; The reaction system is allowed to stand to obtain an organic layer containing 3-benzyloxy-2-chloropropionic acid; The organic layer is washed with water, neutralized by adding potassium hydroxide solution, and then crystallized and purified by using lower alcohol to obtain the target product 3-benzyloxy-2-chloropropionic acid potassium salt.

2. The method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt according to claim 1, characterized in that: In the step of preparing the sodium benzyl alcohol solution, toluene azeotropic dehydration is adopted for preparation; specifically, the following steps are included: toluene is added into a mixed solution of sodium hydroxide solution and benzyl alcohol, the mixture is evenly mixed and then the temperature is raised for reaction, azeotropic dehydration is carried out during the reaction, the azeotropic toluene layer re-enters the reaction system, the water in the reaction system is separated, the temperature is raised again to evaporate the toluene, and then the solution is concentrated to obtain the sodium benzyl alcohol solution.

3. The method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt according to claim 2, characterized in that: The concentration of the sodium hydroxide solution is 20-40 wt %, and the mass ratio of the sodium hydroxide solution, benzyl alcohol and toluene is (0.5-5):(2-20):(1-10).

4. The method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt according to claim 1, characterized in that: The temperature of the azeotropic dehydration is 100°C and the time is 5-10h; and / or the temperature of distilling toluene is 120°C; and / or the conditions for concentration are: temperature is 60°C and vacuum degree is -0.09 to -0.1MPa.

5. The method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt according to claim 1, characterized in that: When methyl 2,3-dichloropropionate is added dropwise, the temperature of the sodium benzyl alcohol solution is controlled to be below 5° C., the temperature of the reaction system is controlled to be below 10° C. during the entire dropping process, and the amount of methyl 2,3-dichloropropionate added is 0.1-1 times the amount of toluene used; and / or after the addition of methyl 2,3-dichloropropionate is completed, the reaction is stirred at 5-10° C. for 2-3 hours.

6. The method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt according to claim 1, characterized in that: During hydrolysis, the concentration of the sodium hydroxide solution is 20-40 wt %, and the temperature of the reaction system is controlled to be below 5° C. when the sodium hydroxide solution is added, and the pH of the reaction solution is controlled to be greater than 12 during the hydrolysis process; And / or the hydrolysis temperature is room temperature, sampling and analysis are performed during the hydrolysis process, and the end point of the hydrolysis reaction is when the content of 3-benzyloxy-2-chloropropionic acid methyl ester in the reaction system is ≤1.0wt%.

7. The method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt according to claim 1, characterized in that: The pH of the reaction system is adjusted to 2-4 by adding hydrochloric acid solution, wherein the concentration of the hydrochloric acid solution is 10-30 wt %; when the hydrochloric acid solution is added, the temperature of the reaction system is controlled to be below 15° C.

8. The method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt according to claim 1, characterized in that: The concentration of the potassium hydroxide solution is 40-50 wt %; the potassium hydroxide solution is added to neutralize the solution until the pH value is 7.0-7.

5.

9. The method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt according to claim 1, characterized in that: The method further comprises a dehydration step after the potassium hydroxide solution is used for dehydration. The temperature during dehydration is 75-85° C., the vacuum degree during dehydration is -0.09 to -0.1 MPa, and the dehydration end point is when the water content is ≤1.0 wt %.

10. The method for preparing 3-benzyloxy-2-chloropropionic acid potassium salt according to claim 1, characterized in that: The lower alcohol is a fatty alcohol having six or less carbon atoms; the fatty alcohol includes a mixture of one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 2-butanol, n-pentanol and its isomers, cyclopentanol, n-hexanol and its isomers, and cyclohexanol; And / or crystallization purification includes primary crystallization and recrystallization, and both the primary crystallization and recrystallization use lower alcohol as crystallization solvent; during the primary crystallization and recrystallization, the volume of the crystallization solvent is 1-20 times the weight of the crude product; the temperature during the primary crystallization and recrystallization is 0°C, and the time is 1-3h.

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