CN115536518B - Preparation method of R- (+) -2- (4-hydroxyphenoxy) propionic acid - Google Patents
Preparation method of R- (+) -2- (4-hydroxyphenoxy) propionic acid Download PDFInfo
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Abstract
The invention relates to a preparation method of R- (+) -2- (4-hydroxyphenoxy) propionic acid, which comprises the following steps: adding p-hydroxybenzaldehyde into water, adding an alkali solution, heating, adding S- (-) -2-halopropionate or a derivative thereof, carrying out heat preservation reaction, and treating to obtain R- (+) -2- (4-aldehyde phenoxy) propionic acid; adding R- (+) -2- (4-aldehyde phenoxy) propionic acid into water, adding an alkali solution, heating, dropwise adding an oxidant, heating after dropwise adding, carrying out heat preservation reaction, and treating to obtain a finished product of the R- (+) -2- (4-hydroxy phenoxy) propionic acid. The preparation method has the advantages of easily available raw materials, few reaction byproducts, high product yield, high product purity, average yield of the whole process not lower than 80 percent, product purity of more than 99.0 percent, simple and easy post-treatment, and suitability for industrial production.
Description
Technical Field
The invention relates to a preparation method of R- (+) -2- (4-hydroxyphenoxy) propionic acid, belonging to the technical field of compound preparation.
Background
R- (+) -2- (4-hydroxyphenoxy) propionic acid is an important intermediate for synthesizing phenoxy propionic acid herbicides such as cyhalofop-butyl, clodinafop-propargyl, haloxyfop-R-methyl and the like.
The preparation method reported in the literature and the patent at present mainly takes hydroquinone as a starting material to prepare R- (+) -2- (4-hydroxyphenoxy) methyl propionate, and has the defects of low conversion rate of the raw material and more byproducts.
In CN202011608317.5, phenol reacts with S- (-) -2-halopropionic acid to synthesize R- (+) -2-phenoxypropionic acid, and the R- (+) -2- (4-hydroxyphenoxy) propionic acid is obtained after oxidation. The reaction utilizes a strong oxidizing reagent to directly add hydroxyl on a benzene ring, the reaction condition is complex, and byproducts and waste water are more.
In CN202010216837.5, hydroquinone and D-lactic acid are used as raw materials, nitrogen is used as carrier gas, hydroquinone and D-lactic acid are completely gasified and then enter a fixed bed reactor, and R- (+) -2- (4-hydroxyphenoxy) propionic acid is continuously synthesized in a gas phase manner under the catalysis of a supported heteropolyacid catalyst. The process needs special catalyst and has harsh preparation conditions. Hydroquinone is completely gasified in the reaction, the energy consumption is high, and the method is not suitable for industrial production.
In CN201711334123.9, hydroquinone is added to a sodium hydroxide solution containing an organic solvent in batches to obtain a sodium p-hydroxyphenol suspension; simultaneously dissolving S- (-) -2-chloropropionic acid in an organic solvent, and slowly adding Na under the condition of ice-water bath 2 CO 3 Carrying out solid reaction to obtain a S- (-) -2-sodium chloropropionate solution; and finally, mixing the two solutions, and carrying out reduced pressure distillation, dissolution acidification, extraction and reduced pressure distillation on the obtained reaction solution to obtain the R- (+) -2- (4-hydroxyphenoxy) propionic acid. The method still can not avoid excessive alkylation reaction, has more impurities, adopts a large amount of organic solvent, has a heterogeneous reaction system and has unsatisfactory reaction effect.
The applicant has been working diligently in this respect and has applied for 6 inventions (CN 108129303A, CN110105201A, CN110803987A, CN112062671A, CN114057575A, CN 114085145A). The applicant has obtained different research results from the above technical solutions through further research, and has applied for the present invention patent.
Disclosure of Invention
The main purposes of the invention are: the preparation method of the R- (+) -2- (4-hydroxyphenoxy) propionic acid overcomes the problems in the prior art, has the advantages of high conversion rate of reaction raw materials, less byproducts, high product purity, simple and easy post-treatment, and is suitable for industrial production.
The technical scheme for solving the technical problems of the invention is as follows:
a preparation method of R- (+) -2- (4-hydroxyphenoxy) propionic acid is characterized by comprising the following steps:
under the protection of inert gas, adding p-hydroxybenzaldehyde into water, adding an alkali solution, heating, adding a compound shown in the formula A, carrying out heat preservation reaction, cooling after the reaction is finished, adjusting the pH value with acid, cooling, crystallizing, carrying out suction filtration, rinsing a filter cake, and drying to obtain R- (+) -2- (4-aldehyde phenoxy) propionic acid;
wherein the compound of formula A is S- (-) -2-halopropionic acid ester or a derivative thereof;
in the formula A, X is selected from fluorine, chlorine, bromine and iodine, R is selected from-OH, -OCH 3 ，-OCH 2 CH 3 ，-NH 2 ，Na + ，K + ；
Secondly, under the protection of inert gas, adding R- (+) -2- (4-aldehyde phenoxy) propionic acid into water, adding an alkali solution, heating, dropwise adding an oxidant, heating after dropwise adding, carrying out heat preservation reaction, cooling after the reaction is finished, adjusting the pH value with acid, cooling, crystallizing, and carrying out suction filtration to obtain a solid product; and refining the crude product with water, performing suction filtration, rinsing a filter cake, and drying to obtain a finished product of the R- (+) -2- (4-hydroxyphenoxy) propionic acid.
According to the method, under the protection of inert gas, p-hydroxybenzaldehyde and S- (-) -2-halopropionate or derivatives thereof are subjected to Williamson etherification and hydrolysis reaction to prepare an intermediate R- (+) -2- (4-aldehyde phenoxy) propionic acid, and then under an alkaline condition, the intermediate is subjected to Dakin oxidation reaction to prepare optically pure R- (+) -2- (4-hydroxy phenoxy) propionic acid. Compared with the preparation process adopting hydroquinone as the starting material in the prior art, the method adopts p-hydroxybenzaldehyde as the starting material, only one phenolic hydroxyl group is adopted, excessive alkylation impurities cannot be generated, and the generation of impurities is effectively avoided; the method has the advantages of less side reaction, simple and convenient post-treatment, high product yield and high product purity, the average yield is not lower than 80%, and the product purity is more than 99.0%.
The technical scheme of the invention is further perfected as follows:
preferably, in the first step, the compound of formula A is one of S- (-) -2-chloropropionic acid, S- (-) -2-bromopropionic acid methyl ester, S- (-) -2-chloropropionic acid ethyl ester, S- (-) -2-chloropropanamide, S- (-) -2-bromopropionic acid ethyl ester, S- (-) -2-chloropropionic acid sodium, and S- (-) -2-chloropropionic acid potassium.
Preferably, in the second step, the oxidant is one of hydrogen peroxide, peracetic acid, perbenzoic acid, sodium persulfate, potassium persulfate, and sodium percarbonate.
More preferably, in the first step, the compound of formula a is methyl S- (-) -2-chloropropionate; in the second step, the oxidant is hydrogen peroxide.
With the above preferred embodiment, the compound of formula a in the first step, and the oxidizing agent in the second step, can be further optimized. When the hydrogen peroxide is used as the oxidant, the main byproducts in the reaction process are water and carbon dioxide, so that the discharge of three wastes can be further effectively reduced, and the reaction process is green and environment-friendly.
Preferably, in the first step, the equivalent ratio of the base contained in the p-hydroxybenzaldehyde, the compound of formula A and the alkaline solution is 1:1.0 to 1.5:1.0 to 2.0; adding an alkali solution, heating to 30-70 ℃, and adding the compound of the formula A; during the heat preservation reaction, the reaction temperature is 30-70 ℃, and the reaction time is 5-10 hours; when the content of p-hydroxybenzaldehyde is less than or equal to 1.0 percent by HPLC detection, the reaction is finished; after the reaction is finished, cooling to the ambient temperature, adjusting the pH to be less than or equal to 2 by using acid, and cooling to 0-5 ℃ for crystallization.
More preferably, in the first step, the equivalent ratio of the base contained in the p-hydroxybenzaldehyde, the compound of formula A and the alkaline solution is 1:1.1 to 1.2:1.4 to 1.6; adding an alkali solution, heating to 50-60 ℃, and adding the compound of the formula A; during the heat preservation reaction, the reaction temperature is 50-60 ℃, and the reaction time is 6-8 hours; when the content of p-hydroxybenzaldehyde is less than or equal to 0.5 percent by HPLC detection, the reaction is finished; rinsing the filter cake with ice water; vacuum drying is adopted during drying.
By adopting the preferable scheme, the main specific technical characteristics in the first step can be further optimized.
Preferably, in the second step, the equivalent ratio of the base contained by the R- (+) -2- (4-aldehyde phenoxy) propionic acid, the oxidant and the alkali solution is 1:1.5 to 2.0:2.0 to 3.0; after adding the alkali solution, heating to 30-50 ℃ and then dropwise adding an oxidant; during the heat preservation reaction, the reaction temperature is 60-80 ℃, and the reaction time is 5-10 hours; when the HPLC detects that the content of R- (+) -2- (4-aldehyde phenoxy) propionic acid is less than or equal to 1.0 percent, the reaction is finished; after the reaction is finished, cooling to the ambient temperature, adjusting the pH to be less than or equal to 1 by using acid, and cooling to 0-5 ℃ for crystallization.
More preferably, in the second step, the equivalent ratio of the alkali contained in the R- (+) -2- (4-aldehyde phenoxy) propionic acid, the oxidant and the alkali solution is 1:1.6 to 1.8:2.5 to 2.6; after adding the alkali solution, heating to 40-45 ℃ and then dropwise adding an oxidant; during the heat preservation reaction, the reaction temperature is 70-75 ℃, and the reaction time is 6-8 hours; when the HPLC detects that the content of R- (+) -2- (4-aldehyde phenoxy) propionic acid is less than or equal to 0.5 percent, the reaction is finished; the crude product is refined by water for one time; rinsing the filter cake with ice water; vacuum drying is adopted during drying.
By adopting the preferred scheme, the main specific technical characteristics in the second step can be further optimized.
Preferably, in the first step and the second step, the inert gas is nitrogen or argon, respectively; the alkali solution is one of or a mixed solution of at least two of a sodium hydroxide solution, a potassium hydroxide solution and a calcium hydroxide solution; the adopted acid is one of or the combination of at least two of hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid; in the first step, when the p-hydroxybenzaldehyde is added into water, the weight ratio of the p-hydroxybenzaldehyde to the water is 1:2 plus or minus 0.5; in the second step, when the R- (+) -2- (4-aldehyde phenoxy) propionic acid is added into water, the weight ratio of the R- (+) -2- (4-aldehyde phenoxy) propionic acid to the water is 1:1.5 plus or minus 0.5; when the crude product is refined by water, the weight ratio of the R- (+) -2- (4-aldehyde phenoxy) propionic acid to the water is 1:1 plus or minus 0.5.
More preferably, in the first step and the second step, the inert gas is nitrogen, respectively; the alkali solutions are respectively liquid alkali; the acids used are respectively hydrochloric acid.
By adopting the preferred scheme, the other specific technical characteristics of the first step and the second step can be further optimized.
Compared with the prior art, the method prepares the intermediate R- (+) -2- (4-aldehyde phenoxy) propionic acid by the etherification and hydrolysis reaction of the p-hydroxybenzaldehyde, and then prepares the finished product of the optical pure R- (+) -2- (4-hydroxyl phenoxy) propionic acid by the Dakin oxidation reaction. The preparation method has the advantages of easily available raw materials, few reaction byproducts, high product yield, high product purity, average yield of the whole process not lower than 80 percent, product purity of more than 99.0 percent, simple and easy post-treatment, and suitability for industrial production.
Drawings
FIG. 1 is a reaction scheme of the present invention.
Detailed Description
As shown in fig. 1, the preparation method of R- (+) -2- (4-hydroxyphenoxy) propionic acid embodied in the present invention comprises the following steps:
under the protection of inert gas, adding p-hydroxybenzaldehyde into water, adding an alkali solution, heating, adding a compound shown in the formula A, carrying out heat preservation reaction, cooling after the reaction is finished, adjusting the pH value with acid, cooling, crystallizing, carrying out suction filtration, rinsing a filter cake, and drying to obtain R- (+) -2- (4-aldehyde phenoxy) propionic acid;
wherein the compound of formula A is S- (-) -2-halopropionic acid ester or a derivative thereof;
in the formula A, X is selected from fluorine, chlorine, bromine and iodine, R is selected from-OH, -OCH 3 ，-OCH 2 CH 3 ，-NH 2 ，Na + ，K + ；
Secondly, under the protection of inert gas, adding R- (+) -2- (4-aldehyde phenoxy) propionic acid into water, adding an alkali solution, heating, dropwise adding an oxidant, heating after dropwise adding, carrying out heat preservation reaction, cooling after the reaction is finished, adjusting the pH value with acid, cooling, crystallizing, and carrying out suction filtration to obtain a solid product; and refining the crude product with water, performing suction filtration, rinsing a filter cake, and drying to obtain a finished product of the R- (+) -2- (4-hydroxyphenoxy) propionic acid.
Specifically, in the first step, the compound shown in the formula A is one of S- (-) -2-chloropropionic acid, S- (-) -2-bromopropionic acid methyl ester, S- (-) -2-chloropropionic acid ethyl ester, S- (-) -2-chloropropionamide, S- (-) -2-bromopropionic acid ethyl ester, S- (-) -2-chloropropionic acid sodium and S- (-) -2-chloropropionic acid potassium; methyl S- (-) -2-chloropropionate is preferred.
In the second step, the oxidant is one of hydrogen peroxide, peracetic acid, peroxybenzoic acid, sodium persulfate, potassium persulfate and sodium percarbonate; hydrogen peroxide is preferred.
Specifically, in the first step:
the equivalent ratio of the alkali contained in the p-hydroxybenzaldehyde, the compound shown in the formula A and the alkali solution is 1:1.0 to 1.5:1.0 to 2.0 (preferably 1.1 to 1.2; adding an alkali solution, heating to 30-70 ℃ (preferably 50-60 ℃), and adding the compound of the formula A; during the heat preservation reaction, the reaction temperature is 30-70 ℃ (preferably 50-60 ℃), and the reaction time is 5-10 hours (preferably 6-8 hours); when the content of p-hydroxybenzaldehyde is less than or equal to 1.0 percent (preferably less than or equal to 0.5 percent) detected by HPLC, the reaction is ended; after the reaction is finished, cooling to the ambient temperature, adjusting the pH to be less than or equal to 2 by using acid, and cooling to 0-5 ℃ for crystallization. Rinsing the filter cake with ice water; vacuum drying is adopted during drying.
Specifically, in the second step:
the equivalent ratio of the alkali contained in the R- (+) -2- (4-aldehyde phenoxy) propionic acid, the oxidant and the alkali solution is 1:1.5 to 2.0:2.0 to 3.0 (preferably 1.6 to 1.8; after adding the alkali solution, firstly heating to 30-50 ℃ (preferably 40-45 ℃), and then dropwise adding an oxidant; during the heat preservation reaction, the reaction temperature is 60-80 ℃ (preferably 70-75 ℃), and the reaction time is 5-10 hours (preferably 6-8 hours); when the HPLC detects that the content of R- (+) -2- (4-aldehyde phenoxy) propionic acid is less than or equal to 1.0 percent (preferably less than or equal to 0.5 percent), the reaction is finished; after the reaction is finished, cooling to the ambient temperature, adjusting the pH to be less than or equal to 1 by using acid, and cooling to 0-5 ℃ for crystallization. The crude product is refined by water once; rinsing the filter cake with ice water; vacuum drying is adopted during drying.
Specifically, in the first step, when parahydroxyben-zaldehyde is added into water, the weight ratio of parahydroxyben-zaldehyde to water is 1:2 plus or minus 0.5; in the second step, when the R- (+) -2- (4-aldehyde phenoxy) propionic acid is added into water, the weight ratio of the R- (+) -2- (4-aldehyde phenoxy) propionic acid to the water is 1:1.5 plus or minus 0.5; when the crude product is refined by water, the weight ratio of the R- (+) -2- (4-aldehyde phenoxy) propionic acid to the water is 1:1 + -0.5.
Further, in the first step and the second step, the inert gas is nitrogen or argon (preferably nitrogen), respectively; the alkali solution is one of or a mixed solution of at least two of sodium hydroxide solution, potassium hydroxide solution or calcium hydroxide solution (preferably liquid alkali); the acid used is one of hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid or the combination of at least two of the hydrochloric acid, the sulfuric acid, the phosphoric acid and the acetic acid (preferably hydrochloric acid).
The present invention will be described in further detail with reference to examples. The invention is not limited to the examples given.
Example 1
This example is a specific example of the preparation of R- (+) -2- (4-hydroxyphenoxy) propionic acid.
The basic process of this embodiment is the specific implementation technical solution of the present invention described above.
Some specific details of this embodiment are as follows:
the first step is as follows: preparation of R- (+) -2- (4-aldehyde phenoxy) propionic acid
Under the protection of nitrogen, the mass ratio of p-hydroxybenzaldehyde: 122g (1.0 mol) of water: 244g of 30% liquid base was added with stirring: 200g (1.5 mol), heating to 50-60 ℃, and dropwise adding S- (-) -2-methyl chloropropionate: 141g (1.15 mol), about 2 h. After the S- (-) -2-methyl chloropropionate is dripped, the reaction is carried out for 6 to 8 hours at the temperature of 50 to 60 ℃, the sampling is controlled in a middle way, the p-hydroxybenzaldehyde is less than or equal to 0.5 percent (HPLC), and the reaction is finished. Cooled to room temperature, treated with 31% hydrochloric acid: 295g, and adjusting the pH value to be less than or equal to 2. Cooling to 0-5 ℃, crystallizing for 30min, performing suction filtration, and using a small amount of ice water for a filter cake: rinsing 50g, and drying in vacuum at 40-45 ℃ to obtain an intermediate with the purity of 99.5 percent and the R- (+) -2- (4-aldehyde phenoxy) propionic acid content of 180.6g, yield: 93% (theoretical weight of 194.19 g).
The second step is that: preparation of R- (+) -2- (4-hydroxyphenoxy) propionic acid
Under the protection of nitrogen, adding R- (+) -2- (4-aldehyde phenoxy) propionic acid: 180.6g (0.93 mol) of water: 271g of sodium hydroxide solution is added with stirring: 316g (2.37 mol), heating to 40-45 ℃, and slowly dropwise adding 25% hydrogen peroxide: 215g (1.58 mol), and the solution is dripped into the solution for about 3 to 4 hours. After the dropping of the hydrogen peroxide is finished, heating to 70-75 ℃, carrying out heat preservation reaction for 6-8 h, sampling and analyzing, wherein the content of R- (+) -2- (4-aldehyde phenoxy) propionic acid is less than or equal to 0.5 percent (HPLC), and finishing the reaction. Cooled to room temperature, treated with 31% hydrochloric acid: adjusting the pH value to be less than or equal to 1 by 395g, cooling to 0-5 ℃, crystallizing, and performing suction filtration to obtain a crude product: 166.5g.
And (3) mixing the crude product: 166.5g of water: 166.5g, activated charcoal: 8g, heating to 80-85 ℃ for decolorization for 1h, performing suction filtration while the solution is hot, slowly cooling the filtrate to 0-5 ℃ for crystallization for 30min, performing suction filtration, and using ice water for filter cakes: rinsing 50g, and drying the wet product at 50-60 ℃ in vacuum to obtain the product with the purity of 99.7 percent, the content of 159.8g of R- (+) -2- (4-hydroxyphenoxy) propionic acid and the yield of 94.3 percent (the theoretical weight is 169.46 g).
Example 2
This example is a specific example of the preparation of the intermediate R- (+) -2- (4-formylphenoxy) propionic acid.
The basic process of this embodiment is the first step of the above-mentioned specific implementation scheme of the present invention.
Some specific details of this embodiment are as follows:
under the protection of nitrogen, the mass ratio of p-hydroxybenzaldehyde: 122g (1.0 mol) of water: 244g of 30% liquid base was added with stirring: 200g (1.5 mol), heating to 50-60 ℃, and dropwise adding S- (-) -2-chloropropionic acid: 125g (1.15 mol), about 2 h. And (3) after the S- (-) -2-chloropropionic acid is dripped, carrying out heat preservation reaction at 50-60 ℃ for 6-8h, and finishing the reaction. Cool to room temperature, add 31% hydrochloric acid: 300g, and the pH is adjusted to be less than or equal to 2. Cooling to 0-5 ℃, crystallizing for 30min, performing suction filtration, and using a small amount of ice water for a filter cake: rinsing 50g, and drying in vacuum at 40-45 ℃ to obtain an intermediate with the purity of 99.1 percent and the yield of 175.4g of R- (+) -2- (4-aldehyde phenoxy) propionic acid: 90.3% (theoretical weight 194.19 g).
Example 3
This example is a specific example of the preparation of the intermediate R- (+) -2- (4-formylphenoxy) propionic acid.
The basic process of this embodiment is the first step of the above-described embodiment of the present invention.
Some specific details of this embodiment are as follows:
under the protection of nitrogen, the mass ratio of p-hydroxybenzaldehyde: 122g (1.0 mol) of water: 244g of 30% liquid base was added with stirring: 200g (1.5 mol), heating to 50-60 ℃, and dropwise adding S- (-) -2-bromopropionic acid methyl ester: 192g (1.15 mol), about 2 h. And (3) after the S- (-) -2-bromomethyl propionate is dripped, keeping the temperature at 50-60 ℃ for reaction for 6-8 h, and finishing the reaction. Cooled to room temperature, treated with 31% hydrochloric acid: 300g, and the pH is adjusted to be less than or equal to 2. Cooling to 0-5 ℃, crystallizing for 30min, performing suction filtration, and using a small amount of ice water for a filter cake: rinsing 50g, and drying in vacuum at 40-45 ℃ to obtain an intermediate with the purity of 99.0 percent and containing 180.4g of R- (+) -2- (4-aldehyde phenoxy) propionic acid, wherein the yield is as follows: 92.9% (theoretical weight 194.19 g).
Example 4
This example is a specific example of the preparation of R- (+) -2- (4-hydroxyphenoxy) propionic acid.
The basic process of this embodiment is the second step of the above-described embodiment of the present invention.
Some specific details of this embodiment are as follows:
under the protection of nitrogen, adding R- (+) -2- (4-aldehyde phenoxy) propionic acid: 97.1g (0.5 mol) of water: 148g, 30% lye was added with stirring: 170g (1.27 mol), raising the temperature to 40-45 ℃, and slowly dropwise adding a 40% sodium persulfate solution: 506g (0.85 mol), and the solution is dripped for about 3 to 4 hours. After the 40 percent sodium persulfate solution is dripped, the temperature is raised to 70-75 ℃, and the reaction is carried out for 6-8h under the condition of heat preservation. Cool to room temperature, add 31% hydrochloric acid: regulating the pH value to be less than or equal to 1 by 225g, cooling to 0-5 ℃, crystallizing, and performing suction filtration to obtain a crude product: 72.6g.
And (3) mixing a crude product: 72.6g of input water: 72g, adding activated carbon: 4g, heating to 80-85 ℃, decoloring for 1h, performing suction filtration while hot, slowly cooling the filtrate to 0-5 ℃, crystallizing for 30min, performing suction filtration, and using ice water for a filter cake: rinsing 25g, and drying the wet product at 50-60 ℃ in vacuum to obtain a product with the purity of 99.1 percent, the R- (+) -2- (4-hydroxyphenoxy) propionic acid content of 84.1g and the yield of 92.3 percent (the theoretical weight of 91.1 g).
Example 5
This example is a specific example of the preparation of R- (+) -2- (4-hydroxyphenoxy) propionic acid.
The basic process of this embodiment is the second step of the above-mentioned embodiment of the present invention.
Some specific details of this embodiment are as follows:
under the protection of nitrogen, adding R- (+) -2- (4-aldehyde phenoxy) propionic acid: 97.1g (0.5 mol) of water: 148g, 30% lye was added with stirring: 170g (1.27 mol), raising the temperature to 40-45 ℃, and slowly adding peroxyacetic acid: 65g (0.85 mol), and the solution is dripped for about 3 to 4 hours. After the dripping of the peroxyacetic acid is finished, heating to 70-75 ℃, and reacting for 6-8h under the condition of heat preservation. Cool to room temperature, add 31% hydrochloric acid: regulating the pH value to be less than or equal to 1 by 225g, cooling to 0-5 ℃, crystallizing, and performing suction filtration to obtain a crude product: 67.8g.
And (3) mixing the crude product: 67.8g of water: 68g, adding activated carbon: 4g, heating to 80-85 ℃, decoloring for 1h, performing suction filtration while hot, slowly cooling the filtrate to 0-5 ℃, crystallizing for 30min, performing suction filtration, and using ice water for a filter cake: rinsing 25g, and drying the wet product at 50-60 ℃ in vacuum to obtain a product with the purity of 99.0 percent, the R- (+) -2- (4-hydroxyphenoxy) propionic acid content of 84.3g and the yield of 92.5 percent (the theoretical weight is 91.1 g).
Comparative example 1
This comparative example is a comparative example of the preparation of R- (+) -2- (4-hydroxyphenoxy) propionic acid.
The specific details of this comparative example are as follows:
the first step is as follows: preparation of R- (+) -2- (4-aldehyde phenoxy) propionic acid
Under the protection of nitrogen, the mass ratio of p-hydroxybenzaldehyde: 122g (1.0 mol) of water: 244g of 30% liquid base was added with stirring: 120g (0.9 mol), heating to 50-60 ℃, and dropwise adding S- (-) -2-methyl chloropropionate: 122.5g (1.0 mol), about 2 h. And (3) after the S- (-) -2-methyl chloropropionate is dripped, carrying out heat preservation reaction at 50-60 ℃ for 6-8h, and finishing the reaction. Cooled to room temperature, treated with 31% hydrochloric acid: 225g, and adjusting the pH value to be less than or equal to 2. Cooling to 0-5 ℃, crystallizing for 30min, performing suction filtration, and using a small amount of ice water for a filter cake: rinsing 50g, and drying in vacuum at 40-45 ℃ to obtain an intermediate with the purity of 99.1 percent and containing 167.1g of R- (+) -2- (4-aldehyde phenoxy) propionic acid, wherein the yield is as follows: 86% (theoretical weight 194.2 g).
Compared with the previous embodiment of the invention and example 1, in the first step, the addition amount of 30% liquid alkali is too low, which results in a significant decrease in the yield of R- (+) -2- (4-aldehyde phenoxy) propionic acid.
The second step: preparation of R- (+) -2- (4-hydroxyphenoxy) propionic acid
Under the protection of nitrogen, adding R- (+) -2- (4-aldehyde phenoxy) propionic acid: 167.1g (0.86 mol) of water: 250g, adding 30% alkali liquor under stirring: 229g (1.7 mol), heating to 40-45 ℃, and slowly dropwise adding 25% hydrogen peroxide: 150g (1.1 mol) and dripping for about 3 to 4 hours. After the dropping of the hydrogen peroxide is finished, heating to 70-75 ℃, and carrying out heat preservation reaction for 6-8h. Cool to room temperature, add 31% hydrochloric acid: adjusting the pH value to be less than or equal to 1 by 300g, cooling to 0-5 ℃, crystallizing, and performing suction filtration to obtain a crude product: 150.1g.
And (3) mixing the crude product: 150.1g of input water: 150g, adding activated carbon: 8g, heating to 80-85 ℃ for decolorization for 1h, performing suction filtration while the solution is hot, slowly cooling the filtrate to 0-5 ℃ for crystallization for 30min, performing suction filtration, and using ice water for filter cakes: rinsing 50g, and drying the wet product at 50-60 ℃ in vacuum to obtain a product with the purity of 99.3 percent and the content of R- (+) -2- (4-hydroxyphenoxy) propionic acid: 142.6g, yield 91.0% (theoretical weight 156.7 g).
Compared with the specific implementation technical scheme and the example 1, in the second step, the addition amounts of the 30% alkali liquor and the 25% hydrogen peroxide are both too low, so that the yield of the R- (+) -2- (4-hydroxyphenoxy) propionic acid is obviously reduced.
Comparative example 2
This comparative example is a comparative example of the preparation of R- (+) -2- (4-hydroxyphenoxy) propionic acid.
The specific details of this comparative example are as follows:
the first step is as follows: preparation of R- (+) -2- (4-aldehyde phenoxy) propionic acid
Under the protection of nitrogen, the mass ratio of p-hydroxybenzaldehyde: 122g (1.0 mol) of water: 244g of 30% liquid base was added with stirring: 280g (2.1 mol), heating to 50-60 ℃, and dropwise adding S- (-) -2-methyl chloropropionate: 196g (1.6 mol), about 2 h. And (3) after the S- (-) -2-methyl chloropropionate is dripped, carrying out heat preservation reaction at 50-60 ℃ for 6-8h, and finishing the reaction. Cool to room temperature, add 31% hydrochloric acid: 410g, and adjusting the pH value to be less than or equal to 2. Cooling to 0-5 ℃, crystallizing for 30min, performing suction filtration, and using a small amount of ice water for a filter cake: rinsing 50g, and drying in vacuum at 40-45 ℃ to obtain an intermediate with the purity of 98.4% and containing R- (+) -2- (4-aldehyde phenoxy) propionic acid: 178.5g, yield: 91.9% (theoretical weight 194.2 g).
Compared with the specific implementation scheme and the example 1, in the first step, the addition amounts of the 30% liquid caustic soda and the S- (-) -2-methyl chloropropionate are too high, so that the purity of the R- (+) -2- (4-aldehyde phenoxy) propionic acid is obviously reduced, and the yield is also reduced.
The second step is that: preparation of R- (+) -2- (4-hydroxyphenoxy) propionic acid
Under the protection of nitrogen, adding R- (+) -2- (4-aldehyde phenoxy) propionic acid: 178.5g (0.92 mol) of water: 268g of 30% lye was added with stirring: 374g (2.8 mol), heating to 40-45 ℃, and slowly dropwise adding 25% hydrogen peroxide: 250g (1.84 mol), and the solution is dripped for about 3 to 4 hours. After the dropping of the hydrogen peroxide is finished, heating to 70-75 ℃, and carrying out heat preservation reaction for 6-8h. Cooled to room temperature, treated with 31% hydrochloric acid: regulating the pH value to be less than or equal to 1 by 450g, cooling to 0-5 ℃, crystallizing, and performing suction filtration to obtain a crude product: 162.4g.
And (3) mixing the crude product: 162.4g of input water: 163g, activated carbon: 8g, heating to 80-85 ℃ for decolorization for 1h, performing suction filtration while the solution is hot, slowly cooling the filtrate to 0-5 ℃ for crystallization for 30min, performing suction filtration, and using ice water for filter cakes: rinsing 50g, and drying the wet product at 50-60 ℃ in vacuum to obtain a product with the purity of 99.2 percent, the R- (+) -2- (4-hydroxyphenoxy) propionic acid content of 151.2g and the yield of 90.2 percent (the theoretical weight of 167.6 g).
Compared with the previous embodiment of the invention and example 1, in the second step, the addition amount of 30% alkali liquor is too high, which results in a significant decrease in the yield of R- (+) -2- (4-hydroxyphenoxy) propionic acid.
In addition to the above embodiments, the present invention may have other embodiments. All technical solutions formed by adopting equivalent substitutions or equivalent transformations fall within the protection scope of the claims of the present invention.
Claims (6)
1. A preparation method of R- (+) -2- (4-hydroxyphenoxy) propionic acid is characterized by comprising the following steps:
under the protection of inert gas, adding p-hydroxybenzaldehyde into water, adding an alkali solution, heating, adding a compound shown in the formula A, carrying out heat preservation reaction, cooling after the reaction is finished, adjusting the pH value with acid, cooling, crystallizing, carrying out suction filtration, rinsing a filter cake, and drying to obtain R- (+) -2- (4-aldehyde phenoxy) propionic acid;
wherein the compound shown in the formula A is one of S- (-) -2-chloropropionic acid, S- (-) -2-bromopropionic acid methyl ester, S- (-) -2-chloropropionic acid ethyl ester, S- (-) -2-chloropropanamide, S- (-) -2-bromopropionic acid ethyl ester, S- (-) -2-chloropropionic acid sodium and S- (-) -2-chloropropionic acid potassium;
the equivalent ratio of the alkali contained in the p-hydroxybenzaldehyde, the compound shown in the formula A and the alkali solution is 1:1.0 to 1.5:1.0 to 2.0; adding an alkali solution, heating to 30-70 ℃, and adding the compound of the formula A; during the heat preservation reaction, the reaction temperature is 30-70 ℃, and the reaction time is 5-10 hours; when the content of p-hydroxybenzaldehyde is less than or equal to 1.0 percent by HPLC detection, the reaction is finished; after the reaction is finished, cooling to the ambient temperature, adjusting the pH to be less than or equal to 2 by using acid, and cooling to 0-5 ℃ for crystallization;
secondly, under the protection of inert gas, adding R- (+) -2- (4-aldehyde phenoxy) propionic acid into water, adding an alkali solution, heating, dropwise adding an oxidant, heating after dropwise adding, carrying out heat preservation reaction, cooling after the reaction is finished, adjusting the pH value with acid, cooling, crystallizing, and carrying out suction filtration to obtain a solid product; refining the crude product with water, performing suction filtration, rinsing a filter cake, and drying to obtain a finished product of R- (+) -2- (4-hydroxyphenoxy) propionic acid;
wherein the oxidant is one of hydrogen peroxide, peracetic acid, peroxybenzoic acid, sodium persulfate, potassium persulfate and sodium percarbonate; the equivalent ratio of the alkali contained in the R- (+) -2- (4-aldehyde phenoxy) propionic acid, the oxidant and the alkali solution is 1:1.5 to 2.0:2.0 to 3.0; after adding the alkali solution, heating to 30-50 ℃, and then dropwise adding an oxidant; during the heat preservation reaction, the reaction temperature is 60-80 ℃, and the reaction time is 5-10 hours; when the HPLC detects that the content of R- (+) -2- (4-aldehyde phenoxy) propionic acid is less than or equal to 1.0 percent, the reaction is finished; after the reaction is finished, cooling to the ambient temperature, adjusting the pH to be less than or equal to 1 by using acid, and cooling to 0-5 ℃ for crystallization;
in the first step and the second step, the inert gas is respectively nitrogen or argon; the alkali solution is one of sodium hydroxide solution, potassium hydroxide solution or calcium hydroxide solution or a mixed solution of at least two of the sodium hydroxide solution, the potassium hydroxide solution and the calcium hydroxide solution; the acid is one of hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid or the combination of at least two of the hydrochloric acid, the sulfuric acid, the phosphoric acid and the acetic acid.
2. The process of claim 1, wherein in the first step, the compound of formula A is methyl S- (-) -2-chloropropionate; in the second step, the oxidant is hydrogen peroxide.
3. The process according to claim 1, wherein the equivalent ratio of the base contained in the p-hydroxybenzaldehyde, the compound of formula A and the alkaline solution is 1:1.1 to 1.2:1.4 to 1.6; adding an alkali solution, heating to 50-60 ℃, and adding the compound of the formula A; during the heat preservation reaction, the reaction temperature is 50-60 ℃, and the reaction time is 6-8 hours; when the p-hydroxybenzaldehyde is detected by HPLC to be less than or equal to 0.5 percent, the reaction is finished; rinsing the filter cake with ice water; vacuum drying is adopted during drying.
4. The method for preparing R- (+) -2- (4-hydroxyphenoxy) propionic acid according to claim 1, wherein, in the second step, the equivalent ratio of the base contained in the R- (+) -2- (4-hydroxyphenoxy) propionic acid, the oxidant and the alkaline solution is 1:1.6 to 1.8:2.5 to 2.6; after adding the alkali solution, heating to 40-45 ℃ and then dropwise adding an oxidant; during the heat preservation reaction, the reaction temperature is 70-75 ℃, and the reaction time is 6-8 hours; when the HPLC detects that the content of R- (+) -2- (4-aldehyde phenoxy) propionic acid is less than or equal to 0.5 percent, the reaction is finished; the crude product is refined by water once; rinsing the filter cake with ice water; vacuum drying is adopted during drying.
5. The process according to any one of claims 1 to 4, wherein the weight ratio of p-hydroxybenzaldehyde to water in the first step is 1:2 plus or minus 0.5; in the second step, when the R- (+) -2- (4-aldehyde phenoxy) propionic acid is added into water, the weight ratio of the R- (+) -2- (4-aldehyde phenoxy) propionic acid to the water is 1:1.5 plus or minus 0.5; when the crude product is refined by water, the weight ratio of the R- (+) -2- (4-aldehyde phenoxy) propionic acid to the water is 1:1 + -0.5.
6. The process according to claim 5, wherein the inert gas is nitrogen in each of the first and second steps; the alkali solutions are respectively sodium hydroxide solutions; the acids used are respectively hydrochloric acid.
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