Method for preparing R-2-(4-hydroxyphenoxy) propionic acid step by step

Abstract

The invention belongs to the technical field of compound preparation, and particularly relates to a method for preparing R-2-(4-hydroxyphenoxy) propionic acid step by step. According to the method, a continuous flow micro-reaction system is adopted to replace a traditional kettle type process, accurate temperature control and efficient mass transfer of rapid strong exothermic reactions such as diazotization and chlorination are achieved through the synergistic effect of a micro-mixer and a micro-packed bed, the reaction time is remarkably shortened, side reactions and product racemization are inhibited, and therefore the yield and optical purity are improved at the same time. Secondly, a bifunctional solid base catalyst is developed, and uniform distribution and structure stabilization of active sites are realized through a template-oriented modification and distribution load strategy. The green solvent gamma-valerolactone is adopted in the etherification step, and the good thermal stability and low volatility of the gamma-valerolactone are beneficial to reaction and efficient recovery. The whole process effectively improves the yield and purity of the product, and greatly reduces the use of volatile organic solvents and the emission of wastes.

Description

Technical Field

[0001] This invention belongs to the field of compound preparation technology, specifically relating to a stepwise method for preparing R-2-(4-hydroxyphenoxy)propionic acid (DHPPA). Background Technology

[0002] R-2-(4-hydroxyphenoxy)propionic acid (DHPPA) is an important chiral organic intermediate. The benzene ring hydroxyl group and chiral propionic acid unit in its structure make it widely applicable in the fields of medicine, pesticides and polymer materials. For example, it is a key building block for the synthesis of certain anti-inflammatory drugs, herbicides or liquid crystal materials.

[0003] In the synthesis process of R-2-(4-hydroxyphenoxy)propionic acid (DHPPA), the traditional method usually uses L-alanine as the starting material, which is diazotized and chlorinated to obtain R-chloropropionic acid, and then etherified with hydroquinone. However, this route has the following problems: (1) The diazotization and chlorination reactions are rapid and strongly exothermic processes, which cause local overheating in the traditional batch reactor, resulting in racemization of the product and a decrease in yield; (2) The etherification step often uses liquid strong base catalysis, which can easily cause excessive ionization of hydroquinone, increase the generation of diether by-products, and generate a large amount of saline wastewater, which is complicated to post-treatment and has a heavy environmental burden; (3) Conventional organic solvents have low recovery rates and high volatility, which does not conform to the development trend of green chemistry.

[0004] Based on this, we propose a stepwise method for preparing R-2-(4-hydroxyphenoxy)propionic acid (DHPPA), hoping to overcome the shortcomings of the existing technology. Summary of the Invention

[0005] The purpose of this invention is to address existing problems by providing a stepwise method for preparing R-2-(4-hydroxyphenoxy)propionic acid (DHPPA).

[0006] This invention is achieved through the following technical solution:

[0007] A method for stepwise preparation of R-2-(4-hydroxyphenoxy)propionic acid (DHPPA) includes the following steps:

[0008] S1. Preparation of R-chloropropionic acid by continuous flow diazotization-chlorination:

[0009] L-alanine hydrochloride solution prepared by L-alanine and hydrochloric acid was subjected to diazotization reaction with sodium nitrite solution under continuous flow conditions. The reaction solution was then subjected to chlorination reaction with HCl-glacial acetic acid solution under continuous flow conditions. After quenching and continuous centrifugation, the organic phase was purified by vacuum short-path distillation to obtain R-chloropropionic acid.

[0010] S2, Preparation of DHPPA by catalytic etherification-reactive extraction and crystallization:

[0011] Under N2 protection, R-chloropropionic acid, hydroquinone, bifunctional solid base catalyst obtained in step S1 are mixed with green solvent γ-valerol to carry out etherification reaction. After recovering the catalyst, the filtrate is acidified, separated into layers, cooled and crystallized, and dried to obtain DHPPA product.

[0012] Further, the L-alanine hydrochloride solution mentioned in step S1 is prepared by mixing L-alanine with 15-20% by mass hydrochloric acid at a molar ratio of 1:(1.0-1.2), with a system pH of 1.5-2.5 and a concentration of 0.8-1.2 mol / L;

[0013] The sodium nitrite solution has a concentration of 1.0~1.5mol / L and is stored at a low temperature of 0~5℃ for later use.

[0014] The HCl-glacial acetic acid solution has a mass fraction of 20-25% and is sealed and refrigerated at 0-5°C for later use.

[0015] Furthermore, the continuous flow conditions described in step S1 are achieved through a two-stage reaction system, which includes a diazotization reaction unit and a chlorination reaction unit arranged in series.

[0016] Furthermore, the diazotization reaction temperature in step S1 is 0~3℃, the residence time is 1.5~2.5min, and the molar ratio of L-alanine hydrochloride solution to sodium nitrite solution is 1:(1.05~1.1).

[0017] The chlorination reaction temperature is 5~8℃, the residence time is 3~4min, and the molar ratio of HCl to L-alanine is (1.2~1.4):1;

[0018] The quenching treatment uses deionized water at 0~5℃, with the amount being 10~15% of the reaction liquid volume. After quenching, the system temperature is ≤10℃.

[0019] Further, the conditions for vacuum short-path distillation in step S1 are: absolute pressure 5~10 Pa, evaporator wall temperature 60~80℃, feed rate 5~8 mL / min; the yield of purified R-chloropropionic acid ≥85%, ee value ≥99.3%, and HPLC purity ≥99.2%.

[0020] Furthermore, the reaction process in step S1 is as follows:

[0021] .

[0022] Further, the molar ratio of R-chloropropionic acid to hydroquinone in step S2 is 1:(1.1~1.3);

[0023] The mass ratio of γ-valerol to reactants (R-chloropropionic acid + hydroquinone) is (2.5~3):1;

[0024] The bifunctional solid base catalyst is a supported KOH / mesoporous SiO2, and its dosage is 5-8% of the mass of hydroquinone.

[0025] Furthermore, the specific surface area of ​​the bifunctional solid base catalyst is ≥250 m². 2 / g, with a KOH loading of 10~15%.

[0026] Furthermore, the preparation of the bifunctional solid base catalyst includes the following steps:

[0027] (1) Pretreatment of the carrier: The mesoporous SiO2 carrier is refluxed and stirred with 3-7% dilute hydrochloric acid for 1-3 hours at a stirring temperature of 55-65℃ and a stirring speed of 180-220 rpm. After washing until pH=6-7, it is dried at 100-140℃ for 3-5 hours to obtain pretreated mesoporous SiO2.

[0028] The mesoporous SiO2 support is of type MCM-41 or SBA-15, with a specific surface area ≥750~850m². 2 / g, pore size 2~5nm, particle size 10~20μm;

[0029] (2) Template-guided modification: Pretreated mesoporous SiO2 is dispersed in anhydrous ethanol, and template agent polyvinylpyrrolidone (PVP) is added. The mixture is stirred at 40~60℃ for 1~3h, and then crosslinking agent γ-aminopropyltriethoxysilane (APTES) is added dropwise. The mixture is heated to 60~80℃ and stirred under reflux for 3~5h. After washing, it is vacuum dried at 90~110℃ for 5~7h to obtain template-modified mesoporous SiO2.

[0030] The mass ratio of PVP to pretreated mesoporous SiO2 is 1:(8~12);

[0031] The mass ratio of APTES to pretreated mesoporous SiO2 is 1:(18~22);

[0032] The liquid-to-solid ratio of anhydrous ethanol to pretreated mesoporous SiO2 is 4~6 L / kg;

[0033] (3) Stepwise loading of KOH: Dissolve KOH in deionized water to prepare a KOH aqueous solution with a concentration of 120~150g / L, and impregnate the template modified mesoporous SiO2 in 2~3 times, each time for 3~5h, with ultrasonic dispersion for 5~15min in between, and dry at 70~90℃ for 6~10h after each impregnation to obtain secondary / tertiary loading intermediates;

[0034] The mass ratio of KOH to template-modified mesoporous SiO2 is 1:(4~6);

[0035] The volume of KOH aqueous solution used for each impregnation is 40-60% of the total loading liquid volume;

[0036] The power of ultrasonic dispersion is 400~600W;

[0037] (4) In-situ crosslinking: The supported intermediate is dispersed in anhydrous ethanol, APTES is added dropwise, and the mixture is kept at 60~70℃ and stirred for 2~4h. After washing, it is vacuum dried at 90~110℃ for 5~7h to obtain the crosslinked intermediate.

[0038] The mass ratio of APTES to KOH is 1:(12~14);

[0039] (5) Gradient calcination activation: The cross-linked intermediate was placed in a calcination furnace and calcined according to the following procedure: room temperature → 180~220℃ (heating rate 4~6℃ / min, holding for 1~3h) → 380~420℃ (heating rate 2~4℃ / min, holding for 2~4h) → 580~620℃ (heating rate 1~3℃ / min, holding for 3~5h). After cooling, the mixture was sieved to obtain a bifunctional solid base catalyst (supported KOH / mesoporous SiO2).

[0040] The sieving process uses a 20-40 mesh sieve, and the residue is the target catalyst.

[0041] Furthermore, the etherification reaction in step S2 is carried out at a temperature of 65~75℃ for 4~5 hours.

[0042] Further, the process of acidification, stratification, cooling crystallization, and drying of the filtrate in step S2 is as follows: after filtering the hot filtrate after recovering the catalyst, add 1.5 to 2 times its volume of deionized water, add 10% by mass dilute hydrochloric acid to adjust the pH to 2.5 to 3.0, and let it stand to separate into layers;

[0043] Separate the upper γ-valerol phase, cool it to 0-3℃ at a cooling rate of 5-10℃ / h, and maintain the temperature for crystallization for 2-4h;

[0044] After filtration, the crystals were washed 2-3 times with γ-valerol at 0-5℃, and then vacuum dried at 40-50℃ and 0.09-0.1MPa for 4-6 hours.

[0045] Furthermore, it also includes the recycling of solvents and unreacted raw materials, as well as the resource utilization of wastewater;

[0046] The γ-valerol was recovered by vacuum distillation at 120-150℃ and 0.08-0.09MPa, with a recovery rate of ≥93%.

[0047] Unreacted hydroquinone in the aqueous phase was acidified to pH 1-2 and then extracted with ethyl acetate, with a recovery rate of ≥92% and a purity of ≥98.8%.

[0048] Furthermore, the wastewater generated in steps (1) and (2) is combined and then treated by neutralization, flocculation sedimentation and membrane separation. The water quality meets the standards for "washing water" or "cooling water" in the "Water Quality Standard for Industrial Water Reuse of Urban Wastewater" (GB / T 19923-2005) and is used for preliminary flushing of equipment or replenishment of circulating cooling system.

[0049] Furthermore, all equipment, piping, and fittings that come into contact with HCl-glacial acetic acid solution shall be made of Hastelloy C276 or lined with polytetrafluoroethylene (PTFE).

[0050] Furthermore, the reaction process in step S2 is as follows:

[0051] .

[0052] The present invention has the following advantages over the prior art:

[0053] This invention first employs a continuous flow microreactor system to replace the traditional batch process, achieving precise temperature control and efficient mass transfer for rapid, strongly exothermic reactions such as diazotization and chlorination. This significantly shortens reaction time, suppresses side reactions and product racemization, thereby simultaneously improving yield and optical purity. Secondly, a bifunctional solid base catalyst was developed. Through template-guided modification and distributed loading strategies, uniform distribution of active sites and structural stabilization were achieved. Compared to liquid bases, this solid catalyst not only effectively promotes etherification reactions and inhibits excessive ionization of hydroquinone and the formation of dual ether byproducts, but also allows for simple filtration recovery and multiple recycling, avoiding the large amounts of saline wastewater generated by traditional base catalysis processes. It combines high catalytic activity with green process characteristics. Furthermore, this invention uses the green solvent γ-valerol in the etherification step. Its good thermal stability and low volatility facilitate the reaction and enable efficient recovery. Subsequent acidification layering and programmed cooling crystallization achieve high-purity product separation and solvent recycling. The entire process effectively improves product yield and purity while significantly reducing the use of volatile organic solvents and waste emissions. Attached Figure Description

[0054] Figure 1 The reaction formula of this invention;

[0055] Figure 2 The color, state after dissolving in ethanol, and color of DHPPA prepared in Example 2 of this invention;

[0056] Figure 2In the image: (a) shows the color of DHPPA prepared in Example 2 of the present invention; (b) shows the state of DHPPA prepared in Example 2 of the present invention after being dissolved in ethanol; (c) shows the color of DHPPA prepared in Example 2 of the present invention after being dissolved in ethanol.

[0057] Figure 3 The liquid phase spectrum of R-chloropropionic acid in Example 2 of this invention;

[0058] Figure 4 This is a liquid phase diagram of R-2-(4-hydroxyphenoxy)propionic acid in Example 2 of the present invention. Detailed Implementation

[0059] To further explain the present invention, the following specific embodiments are described.

[0060] Raw material pretreatment and solution preparation

[0061] Preparation of L-alanine hydrochloride solution: Mix industrial-grade L-alanine with 15-20% (mass fraction) hydrochloric acid at a molar ratio of 1:(1.0-1.2), stir and dissolve at 25-30℃ for 30-40 min, adjust the pH of the system to 1.5-2.5, and obtain an L-alanine hydrochloride solution with a concentration of 0.8-1.2 mol / L for later use;

[0062] Preparation of sodium nitrite solution: Dissolve industrial grade sodium nitrite in deionized water, stir to dissolve and obtain a sodium nitrite aqueous solution with a concentration of 1.0~1.5mol / L. Store at low temperature (0~5℃) for later use to avoid decomposition.

[0063] Preparation of hydrogen chloride solution: Pass dry hydrogen chloride gas into glacial acetic acid to prepare a 20-25% HCl-glacial acetic acid solution by mass fraction. Seal and refrigerate (0-5℃) for later use to prevent HCl from evaporating.

[0064] Equipment preparation

[0065] The first micro-mixer is a plate reactor with a serrated or staggered herringbone microchannel structure, with an inner diameter of 0.8~1.2 mm and an effective volume of 50~100 mL; the second micro-packed bed reactor is a tubular reactor filled with silica or alumina ceramic balls with a diameter of 0.5~1.0 mm, with an inner diameter of 2.0~3.0 mm, an effective volume of 80~120 mL, and a ceramic ball filling rate of 60~70%.

[0066] Preparation Example 1

[0067] The preparation of bifunctional solid base catalyst I includes the following steps:

[0068] (1) Pretreatment of the carrier: The mesoporous SiO2 carrier was refluxed and stirred for 1 hour with 3% dilute hydrochloric acid at a stirring temperature of 55°C and a stirring speed of 180 rpm. After washing until pH=6, it was dried at 100°C for 3 hours to obtain pretreated mesoporous SiO2.

[0069] The mesoporous SiO2 carrier is of type SBA-15, with a specific surface area ≥750~850m². 2 / g, pore size 2~5nm, particle size 10~20μm;

[0070] (2) Template-guided modification: Pretreated mesoporous SiO2 was dispersed in anhydrous ethanol, and the template agent polyvinylpyrrolidone (PVP) was added. The mixture was stirred at 40°C for 1 h, and then the crosslinking agent γ-aminopropyltriethoxysilane (APTES) was added dropwise. The mixture was heated to 60°C and stirred under reflux for 3 h. After washing, the mixture was vacuum dried at 90°C for 5 h to obtain template-modified mesoporous SiO2.

[0071] The mass ratio of PVP to pretreated mesoporous SiO2 is 1:8;

[0072] The mass ratio of APTES to pretreated mesoporous SiO2 is 1:18;

[0073] The liquid-to-solid ratio of anhydrous ethanol to pretreated mesoporous SiO2 was 4 L / kg;

[0074] (3) Stepwise loading of KOH: KOH was dissolved in deionized water to prepare a KOH aqueous solution with a concentration of 120 g / L. The template-modified mesoporous SiO2 was impregnated twice, each time for 3 h, with an interval of 5 min of ultrasonic dispersion. After each impregnation, it was dried at 70 °C for 6 h to obtain the secondary / tertiary loading intermediate.

[0075] The mass ratio of KOH to template-modified mesoporous SiO2 is 1:4;

[0076] The volume of KOH aqueous solution used for each impregnation is 40% of the total load liquid volume;

[0077] The power of ultrasonic dispersion is 400W;

[0078] (4) In-situ crosslinking: The supported intermediate was dispersed in anhydrous ethanol, APTES was added dropwise, and the mixture was stirred at 60°C for 2 hours. After washing, it was vacuum dried at 90°C for 5 hours to obtain the crosslinked intermediate.

[0079] The mass ratio of APTES to KOH is 1:12;

[0080] (5) Gradient calcination activation: The cross-linked intermediate was placed in a calcination furnace and calcined according to the following procedure: room temperature → 180℃ (heating rate 4℃ / min, holding for 1h) → 380℃ (heating rate 2℃ / min, holding for 2h) → 580℃ (heating rate 1℃ / min, holding for 3h). After cooling, it was sieved to obtain bifunctional solid base catalyst I (supported KOH / mesoporous SiO2).

[0081] The sieving process uses a 20-mesh sieve, and the residue on the sieve is the target catalyst.

[0082] Preparation Example 2

[0083] The preparation of bifunctional solid base catalyst II includes the following steps:

[0084] (1) Pretreatment of the carrier: The mesoporous SiO2 carrier was refluxed and stirred with 5% dilute hydrochloric acid for 2 hours at a stirring temperature of 60°C and a stirring speed of 200 rpm. After washing until pH=6.5, it was dried at 120°C for 4 hours to obtain pretreated mesoporous SiO2.

[0085] The mesoporous SiO2 carrier is of type SBA-15, with a specific surface area ≥750~850m². 2 / g, pore size 2~5nm, particle size 10~20μm;

[0086] (2) Template-guided modification: Pretreated mesoporous SiO2 was dispersed in anhydrous ethanol, and the template agent polyvinylpyrrolidone (PVP) was added. The mixture was stirred at 50°C for 2 hours, and then the crosslinking agent γ-aminopropyltriethoxysilane (APTES) was added dropwise. The mixture was heated to 70°C and stirred under reflux for 4 hours. After washing, the mixture was vacuum dried at 100°C for 6 hours to obtain template-modified mesoporous SiO2.

[0087] The mass ratio of PVP to pretreated mesoporous SiO2 is 1:10;

[0088] The mass ratio of APTES to pretreated mesoporous SiO2 is 1:20;

[0089] The liquid-to-solid ratio of anhydrous ethanol to pretreated mesoporous SiO2 was 5 L / kg;

[0090] (3) Stepwise loading of KOH: KOH was dissolved in deionized water to prepare a KOH aqueous solution with a concentration of 130 g / L. The template-modified mesoporous SiO2 was impregnated twice, each time for 4 h, with an interval of 10 min of ultrasonic dispersion. After each impregnation, it was dried at 80 °C for 8 h to obtain the secondary / tertiary loading intermediate.

[0091] The mass ratio of KOH to template-modified mesoporous SiO2 is 1:5;

[0092] The volume of KOH aqueous solution used for each impregnation is 50% of the total load liquid volume;

[0093] The power of ultrasonic dispersion is 500W;

[0094] (4) In-situ crosslinking: The supported intermediate was dispersed in anhydrous ethanol, APTES was added dropwise, and the mixture was kept at 65°C and stirred for 3 hours. After washing, it was dried under vacuum at 100°C for 6 hours to obtain the crosslinked intermediate.

[0095] The mass ratio of APTES to KOH is 1:13;

[0096] (5) Gradient calcination activation: The cross-linked intermediate was placed in a calcination furnace and calcined according to the following procedure: room temperature → 200℃ (heating rate 5℃ / min, holding for 2h) → 400℃ (heating rate 3℃ / min, holding for 3h) → 600℃ (heating rate 2℃ / min, holding for 4h). After cooling, it was sieved to obtain bifunctional solid base catalyst II (supported KOH / mesoporous SiO2).

[0097] The sieving process uses a 20-mesh sieve, and the residue on the sieve is the target catalyst.

[0098] Preparation Example 3

[0099] The preparation of bifunctional solid base catalyst III includes the following steps:

[0100] (1) Pretreatment of the carrier: The mesoporous SiO2 carrier was refluxed and stirred for 3 hours with 7% dilute hydrochloric acid at a stirring temperature of 65°C and a stirring speed of 220 rpm. After washing until pH=7, it was dried at 140°C for 5 hours to obtain pretreated mesoporous SiO2.

[0101] The mesoporous SiO2 support is of type MCM-41 or SBA-15, with a specific surface area ≥750~850m². 2 / g, pore size 2~5nm, particle size 10~20μm;

[0102] (2) Template-guided modification: Pretreated mesoporous SiO2 was dispersed in anhydrous ethanol, and the template agent polyvinylpyrrolidone (PVP) was added. The mixture was stirred at 60°C for 3 hours, and then the crosslinking agent γ-aminopropyltriethoxysilane (APTES) was added dropwise. The mixture was heated to 80°C and stirred under reflux for 5 hours. After washing, the mixture was vacuum dried at 110°C for 7 hours to obtain template-modified mesoporous SiO2.

[0103] The mass ratio of PVP to pretreated mesoporous SiO2 is 1:12;

[0104] The mass ratio of APTES to pretreated mesoporous SiO2 is 1:22;

[0105] The liquid-to-solid ratio of anhydrous ethanol to pretreated mesoporous SiO2 was 6 L / kg.

[0106] (3) Stepwise loading of KOH: KOH was dissolved in deionized water to prepare a KOH aqueous solution with a concentration of 150 g / L. The template-modified mesoporous SiO2 was impregnated in three steps, each time for 5 h, with an interval of 15 min of ultrasonic dispersion. After each impregnation, it was dried at 90 °C for 10 h to obtain the secondary / tertiary loading intermediate.

[0107] The mass ratio of KOH to template-modified mesoporous SiO2 is 1:6;

[0108] The volume of KOH aqueous solution used for each impregnation is 60% of the total loading liquid volume;

[0109] The power of ultrasonic dispersion is 600W;

[0110] (4) In-situ crosslinking: The supported intermediate was dispersed in anhydrous ethanol, APTES was added dropwise, and the mixture was kept at 70°C and stirred for 4 hours. After washing, it was vacuum dried at 110°C for 7 hours to obtain the crosslinked intermediate.

[0111] The mass ratio of APTES to KOH is 1:14;

[0112] (5) Gradient calcination activation: The cross-linked intermediate was placed in a calcination furnace and calcined according to the following procedure: room temperature → 220℃ (heating rate 6℃ / min, holding for 3h) → 420℃ (heating rate 4℃ / min, holding for 4h) → 620℃ (heating rate 3℃ / min, holding for 5h). After cooling, it was sieved to obtain bifunctional solid base catalyst III (supported KOH / mesoporous SiO2).

[0113] The sieving process uses a 40-mesh sieve, and the residue on the sieve is the target catalyst.

[0114] Example 1

[0115] A method for stepwise preparation of R-2-(4-hydroxyphenoxy)propionic acid (DHPPA) includes the following steps:

[0116] S1. Preparation of R-chloropropionic acid by continuous flow diazotization-chlorination:

[0117] A 0.8 mol / L L-alanine hydrochloride solution prepared by L-alanine and hydrochloric acid was reacted with a 1.0 mol / L sodium nitrite solution in the first microreactor of a two-stage microreactor for diazotization. The reaction solution flowed into the second micro-packed bed reactor and was subjected to chlorination with a 20% HCl-glacial acetic acid solution. After quenching and continuous centrifugation, the organic phase was purified by vacuum short-path distillation to obtain R-chloropropionic acid.

[0118] The two-stage microreactor consists of a first micromixer and a second micro-packed bed reactor connected in series.

[0119] The diazotization reaction was carried out at a temperature of 1°C and a residence time of 1.5 min, with a molar ratio of L-alanine hydrochloride solution to sodium nitrite solution of 1:1.05.

[0120] The chlorination reaction temperature was 5℃, the residence time was 3 min, and the molar ratio of HCl to L-alanine was 1.2:1.

[0121] The quenching treatment uses 1℃ deionized water, which is 10% of the volume of the reaction liquid. The system temperature after quenching is ≤10℃.

[0122] The conditions for the vacuum short-path distillation were: absolute pressure 5 Pa, evaporator wall temperature 60 °C, and feed rate 5 mL / min; the yield of purified R-chloropropionic acid was ≥85%, ee value was ≥99.3%, and HPLC purity was ≥99.2%.

[0123] The reaction process in step S1 is as follows:

[0124] ;

[0125] S2, Preparation of DHPPA by catalytic etherification-reactive extraction and crystallization:

[0126] Under N2 protection, R-chloropropionic acid, hydroquinone, bifunctional solid base catalyst obtained in step S1 are mixed with green solvent γ-valerol to carry out etherification reaction. After recovering the catalyst, the filtrate is acidified, separated into layers, cooled and crystallized, and dried to obtain DHPPA product.

[0127] The molar ratio of R-chloropropionic acid to hydroquinone is 1:1.1;

[0128] The mass ratio of γ-valerol to reactants (R-chloropropionic acid + hydroquinone) is 2.5:1;

[0129] The bifunctional solid base catalyst is the bifunctional solid base catalyst I prepared by method 1, and its amount is 5% of the mass of hydroquinone;

[0130] The specific surface area of ​​the bifunctional solid base catalyst is ≥250 m². 2 / g, KOH loading is 10%;

[0131] The etherification reaction was carried out at 65°C for 4 hours.

[0132] The specific steps of acidification, stratification, cooling crystallization, and drying of the filtrate are as follows: the hot filtrate after filtration and catalyst recovery is mixed with 1.5 times its volume of deionized water, and 10% by mass dilute hydrochloric acid is added dropwise to adjust the pH to 2.5. The mixture is then allowed to stand and separate into layers.

[0133] The upper γ-valerol phase was separated and cooled to 0°C at a cooling rate of 5°C / h, and crystallized at this temperature for 2h.

[0134] After filtration, the crystals were washed twice with γ-valerol at 0℃ and then dried under vacuum at 40℃ and 0.09MPa for 4 hours.

[0135] The reaction process in step S2 is as follows:

[0136] .

[0137] Example 2

[0138] A method for stepwise preparation of R-2-(4-hydroxyphenoxy)propionic acid (DHPPA) includes the following steps:

[0139] S1. Preparation of R-chloropropionic acid by continuous flow diazotization-chlorination:

[0140] A 1 mol / L L-alanine hydrochloride solution prepared by L-alanine and hydrochloric acid was reacted with a 1.2 mol / L sodium nitrite solution in the first microreactor of a two-stage microreactor for diazotization. The reaction solution flowed into the second micro-packed bed reactor and was subjected to chlorination with a 22% HCl-glacial acetic acid solution. After quenching and continuous centrifugation, the organic phase was purified by vacuum short-path distillation to obtain R-chloropropionic acid.

[0141] The two-stage microreactor consists of a first micromixer and a second micro-packed bed reactor connected in series.

[0142] The diazotization reaction was carried out at a temperature of 2°C for 2 minutes, with a molar ratio of L-alanine hydrochloride solution to sodium nitrite solution of 1:1.1.

[0143] The chlorination reaction temperature was 6℃, the residence time was 3 min, and the molar ratio of HCl to L-alanine was 1.3:1.

[0144] Quenching treatment uses 3℃ deionized water, with a volume of 12% of the reaction liquid volume, and the system temperature after quenching is ≤10℃.

[0145] The conditions for the vacuum short-path distillation were: absolute pressure 8 Pa, evaporator wall temperature 70 °C, and feed rate 6 mL / min; the yield of purified R-chloropropionic acid was ≥85%, ee value was ≥99.3%, and HPLC purity was ≥99.2%.

[0146] The reaction process in step S1 is as follows:

[0147] ;

[0148] S2, Preparation of DHPPA by catalytic etherification-reactive extraction and crystallization:

[0149] Under N2 protection, R-chloropropionic acid, hydroquinone, bifunctional solid base catalyst obtained in step S1 are mixed with green solvent γ-valerol to carry out etherification reaction. After recovering the catalyst, the filtrate is acidified, separated into layers, cooled and crystallized, and dried to obtain DHPPA product.

[0150] The molar ratio of R-chloropropionic acid to hydroquinone is 1:1.2;

[0151] The mass ratio of γ-valerol to reactants (R-chloropropionic acid + hydroquinone) was 2.8:1;

[0152] The bifunctional solid base catalyst is bifunctional solid base catalyst II prepared by method 1, and its dosage is 7% of the mass of hydroquinone;

[0153] The specific surface area of ​​the bifunctional solid base catalyst is ≥250 m². 2 / g, KOH loading is 12%;

[0154] The etherification reaction was carried out at 70°C for 4.5 hours.

[0155] The specific steps of acidification, stratification, cooling crystallization, and drying of the filtrate are as follows: the hot filtrate after filtration and catalyst recovery is mixed with 1.8 times its volume of deionized water, and 10% by mass dilute hydrochloric acid is added dropwise to adjust the pH to 2.8. The mixture is then allowed to stand and separate into layers.

[0156] The upper γ-valerol phase was separated, cooled to 2℃ at a cooling rate of 7℃ / h, and crystallized at this temperature for 3h.

[0157] After filtration, the crystals were washed twice with γ-valerol at 2℃ and then vacuum dried at 45℃ and 0.095MPa for 5 hours.

[0158] The reaction process in step S2 is as follows:

[0159] .

[0160] Example 3

[0161] A method for stepwise preparation of R-2-(4-hydroxyphenoxy)propionic acid (DHPPA) includes the following steps:

[0162] S1. Preparation of R-chloropropionic acid by continuous flow diazotization-chlorination:

[0163] A 1.2 mol / L L-alanine hydrochloride solution prepared by L-alanine and hydrochloric acid was reacted with a 1.5 mol / L sodium nitrite solution in the first microreactor of a two-stage microreactor for diazotization. The reaction solution flowed into the second micro-packed bed reactor and was subjected to chlorination with a 25% HCl-glacial acetic acid solution. After quenching and continuous centrifugation, the organic phase was purified by vacuum short-path distillation to obtain R-chloropropionic acid.

[0164] The two-stage microreactor consists of a first micromixer and a second micro-packed bed reactor connected in series.

[0165] The diazotization reaction was carried out at a temperature of 3°C, with a residence time of 2.5 min, and the molar ratio of L-alanine hydrochloride solution to sodium nitrite solution was 1:1.1.

[0166] The chlorination reaction temperature was 8℃, the residence time was 4 min, and the molar ratio of HCl to L-alanine was 1.4:1.

[0167] The quenching treatment uses 5℃ deionized water, which accounts for 15% of the volume of the reaction liquid. The system temperature after quenching is ≤10℃.

[0168] The conditions for the vacuum short-path distillation were: absolute pressure 10 Pa, evaporator wall temperature 80 °C, and feed rate 8 mL / min; the yield of purified R-chloropropionic acid was ≥85%, ee value was ≥99.3%, and HPLC purity was ≥99.2%.

[0169] The reaction process in step S1 is as follows:

[0170] ;

[0171] S2, Preparation of DHPPA by catalytic etherification-reactive extraction and crystallization:

[0172] Under N2 protection, R-chloropropionic acid, hydroquinone, bifunctional solid base catalyst obtained in step S1 are mixed with green solvent γ-valerol to carry out etherification reaction. After recovering the catalyst, the filtrate is acidified, separated into layers, cooled and crystallized, and dried to obtain DHPPA product.

[0173] The molar ratio of R-chloropropionic acid to hydroquinone is 1:1.3;

[0174] The mass ratio of γ-valerol to reactants (R-chloropropionic acid + hydroquinone) is 3:1;

[0175] The bifunctional solid base catalyst is bifunctional solid base catalyst III prepared by method 1, and the amount used is 8% of the mass of hydroquinone.

[0176] The specific surface area of ​​the bifunctional solid base catalyst is ≥250 m². 2 / g, KOH loading is 15%;

[0177] The etherification reaction was carried out at 75°C for 5 hours.

[0178] The specific process of acidification, stratification, cooling crystallization, and drying of the filtrate is as follows: After filtering and recovering the catalyst, the hot filtrate is added with twice its volume of deionized water, and 10% by mass dilute hydrochloric acid is added dropwise to adjust the pH to 3.0. The filtrate is then allowed to stand and separate into layers.

[0179] The upper γ-valerol phase was separated, cooled to 3℃ at a cooling rate of 10℃ / h, and crystallized at this temperature for 4h.

[0180] After filtration, the crystals were washed three times with γ-valerol at 5℃ and then dried under vacuum at 50℃ and 0.1MPa for 6 hours.

[0181] The reaction process in step S2 is as follows:

[0182] .

[0183] Example 4

[0184] A method for stepwise preparation of R-2-(4-hydroxyphenoxy)propionic acid (DHPPA) includes the following steps:

[0185] S1. Preparation of R-chloropropionic acid by continuous flow diazotization-chlorination:

[0186] A 1 mol / L L-alanine hydrochloride solution prepared by L-alanine and hydrochloric acid was reacted with a 1.2 mol / L sodium nitrite solution in the first tubular reactor of a two-stage continuous flow tubular reaction system for diazotization. The reaction solution flowed into the second tubular reactor and was subjected to chlorination with a 22% HCl-glacial acetic acid solution. After quenching and continuous centrifugation, the organic phase was purified by vacuum short-path distillation to obtain R-chloropropionic acid.

[0187] The two-stage continuous flow tubular reaction system consists of a first tubular reactor and a second tubular reactor connected in series.

[0188] The diazotization reaction was carried out at a temperature of 2°C for 2 minutes, with a molar ratio of L-alanine hydrochloride solution to sodium nitrite solution of 1:1.1.

[0189] The chlorination reaction temperature was 6℃, the residence time was 3 min, and the molar ratio of HCl to L-alanine was 1.3:1.

[0190] Quenching treatment uses 3℃ deionized water, with a volume of 12% of the reaction liquid volume, and the system temperature after quenching is ≤10℃.

[0191] The conditions for the vacuum short-path distillation were: absolute pressure 8 Pa, evaporator wall temperature 70 °C, and feed rate 6 mL / min; the yield of purified R-chloropropionic acid was ≥85%, ee value was ≥99.3%, and HPLC purity was ≥99.2%.

[0192] The reaction process in step S1 is as follows:

[0193] ;

[0194] S2, Preparation of DHPPA by catalytic etherification-reactive extraction and crystallization:

[0195] Under N2 protection, R-chloropropionic acid, hydroquinone, bifunctional solid base catalyst obtained in step S1 are mixed with green solvent γ-valerol to carry out etherification reaction. After recovering the catalyst, the filtrate is acidified, separated into layers, cooled and crystallized, and dried to obtain DHPPA product.

[0196] The molar ratio of R-chloropropionic acid to hydroquinone is 1:1.2;

[0197] The mass ratio of γ-valerol to reactants (R-chloropropionic acid + hydroquinone) was 2.8:1;

[0198] The bifunctional solid base catalyst is bifunctional solid base catalyst II prepared by method 1, and its dosage is 7% of the mass of hydroquinone;

[0199] The specific surface area of ​​the bifunctional solid base catalyst is ≥250 m². 2 / g, KOH loading is 12%;

[0200] The etherification reaction was carried out at 70°C for 4.5 hours.

[0201] The specific steps of acidification, stratification, cooling crystallization, and drying of the filtrate are as follows: the hot filtrate after filtration and catalyst recovery is mixed with 1.8 times its volume of deionized water, and 10% by mass dilute hydrochloric acid is added dropwise to adjust the pH to 2.8. The mixture is then allowed to stand and separate into layers.

[0202] The upper γ-valerol phase was separated, cooled to 2℃ at a cooling rate of 7℃ / h, and crystallized at this temperature for 3h.

[0203] After filtration, the crystals were washed twice with γ-valerol at 2℃ and then vacuum dried at 45℃ and 0.095MPa for 5 hours.

[0204] The reaction process in step S2 is as follows:

[0205] .

[0206] Comparative Example 1

[0207] Compared with Example 2, in Comparative Example 1, the bifunctional solid base catalyst II in step S2 was replaced with liquid base NaOH, and the amount was equal to the molar amount of KOH in the bifunctional solid base catalyst II. Other steps and parameters were the same as in Example 2.

[0208] Comparative Example 2

[0209] Compared with Example 2, Comparative Example 2 replaces the two-stage microreactor in step S1 with a conventional 500mL four-necked flask, uses a batch reactor, and a stirring rate of 300rpm. Other steps and parameters are the same as in Example 2.

[0210] Comparative Example 3

[0211] Compared with Example 2, Comparative Example 3 replaces γ-valerolactone in step S2 with the conventional solvent ethyl acetate, with a mass ratio of 2.8:1 to the reactants. Other steps and parameters are the same as in Example 2.

[0212] Comparative Example 4

[0213] Compared with Example 2, Comparative Example 4 replaced the continuous diazotization-chlorination in step S1 with a step-by-step batch reaction. The diazotization was stirred in a batch for 6 hours, and the chlorination was stirred in a batch for 4 hours. Other steps and parameters were the same as in Example 2.

[0214] Performance testing

[0215] 1. R-chloropropionic acid analysis and DHPPA analysis

[0216] 1.1 R-chloropropionic acid analysis

[0217] Yield: Gravimetric method (mass of distilled product / theoretical mass × 100%)

[0218] ee value: High performance liquid chromatography (HPLC, Agilent 1260), chiral column Chiralpak AD-H (4.6×250mm), mobile phase n-hexane-isopropanol (90:10), flow rate 1mL / min, detection wavelength 254nm, column temperature 30℃.

[0219] 1.2 DHPPA Analysis

[0220] Yield: Gravimetric method (mass of dried crystals / theoretical mass × 100%)

[0221] HPLC purity: HPLC (same as above), C18 column (4.6×250mm), mobile phase methanol-water (60:40, containing 0.1% phosphoric acid), flow rate 1mL / min, detection wavelength 280nm.

[0222] The test results are shown in Table 1 below.

[0223] Table 1: R-chloropropionic acid yield (%) R-chloropropionic acid ee value (%) DHPPA yield (%) DHPPA HPLC purity (%) Example 1 85.2 99.3 81.8 99.6 Example 2 85.5 99.4 82.3 99.7 Example 3 85.3 99.3 82.5 99.7 Example 4 85.5 99.4 82.4 99.7 Comparative Example 1 84.8 99.2 75.6 98.5 Comparative Example 2 78.6 97.5 76.2 98.8 Comparative Example 3 85.4 99.3 81.9 99.6 Comparative Example 4 76.3 96.8 73.5 98.2

[0224] As shown in Table 1 above, in Comparative Example 1, using liquid NaOH to replace the bifunctional solid base catalyst II reduced the DHPPA yield from 82.3% to 75.6%. Liquid NaOH easily leads to excessive ionization of hydroquinone, generating a diether byproduct and reducing DHPPA selectivity. Furthermore, the excess NaOH needs to be neutralized after the reaction, resulting in a large amount of NaCl wastewater. Therefore, the bifunctional solid base catalyst of this invention has significant advantages. In Comparative Example 2, the R-chloropropionic acid yield decreased to 78.6%, and the ee value decreased to 97.5, indicating that the microreactor enhances mass and heat transfer, which is beneficial for rapid reaction control. The continuous flow system reduces intermediate decomposition and avoids local overheating leading to racemization or side reactions. In Comparative Example 4, the yield and ee value further decreased, demonstrating the significant advantages of the continuous flow process in terms of reaction efficiency and selectivity.

[0225] 2. Catalyst performance

[0226] After 5 cycles, the ratio of DHPPA yield to the yield of the first use was measured as 100%.

[0227] The test results are shown in Table 2 below.

[0228] Table 2: Catalyst activity retention rate after 5 cycles (%) Example 1 90.5 Example 2 92.1 Example 3 91.8 Example 4 92.0 Comparative Example 1 - Comparative Example 2 88.7 Comparative Example 3 92.0 Comparative Example 4 91.9

[0229] As shown in Table 2, the catalysts of Examples 1-3 had an activity retention rate of >90% after 5 cycles, indicating that the bond between the support and KOH was stable and that the template-directed and cross-linking steps enhanced the structural stability of the catalyst. The activity retention rate of Comparative Example 2 was slightly lower, possibly due to the mechanical stirring and uneven heating in the batch reaction, which led to accelerated catalyst wear or deactivation.

[0230] 3. Solvent recovery rate

[0231] The mass of solvent recovered after distillation / the initial amount added × 100%.

[0232] The comparison results are shown in Table 3 below.

[0233] Table 3: Solvent recovery rate (%) Example 1 92.8 Example 2 93.1 Example 3 92.9 Example 4 93.0 Comparative Example 1 92.9 Comparative Example 2 93.0 Comparative Example 3 72.5 Comparative Example 4 92.8

[0234] Table 3 shows that the recovery rate of γ-valerol solvent is >92%, indicating that this green solvent has low volatility, good thermal stability, and is easy to recover. Comparative Example 3 uses ethyl acetate, with a recovery rate of only 72.5%, mainly because ethyl acetate is highly volatile, easily lost, and may partially hydrolyze under acidic conditions.

[0235] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A process for the stepwise preparation of R-2-(4-hydroxyphenoxy)propionic acid, characterized in that, The method comprises the following steps: S1, continuously flow diazotization-chlorination to prepare R-chloropropanoic acid: Under continuous flow conditions, L-alanine hydrochloride solution prepared by mixing L-alanine with hydrochloric acid and sodium nitrite solution is subjected to diazotization reaction, and the reaction solution is then subjected to chlorination reaction with HCl-ice acetic acid solution under continuous flow conditions. After quenching and continuous centrifugal separation, the organic phase is purified by vacuum short-path distillation to obtain R-chloropropanoic acid; S2, catalytic etherification-reaction extraction crystallization to prepare DHPPA: Under N2 protection, R-chloropropanoic acid, hydroquinone, a bifunctional solid base catalyst and green solvent γ-valerolactone are mixed to perform etherification reaction. After recovering the catalyst, the filtrate is subjected to acidification, cooling crystallization and drying to obtain DHPPA product. The bifunctional solid base catalyst is a supported KOH / mesoporous SiO2, and the amount is 5-8% of the mass of hydroquinone; The specific surface area of the bifunctional solid base catalyst is ≥ 250 m 2 / g, and the KOH loading is 10-15%.

2. The process for the stepwise preparation of R-2-(4-hydroxyphenoxy)propionic acid according to claim 1, characterized in that, In step S1, the L-alanine hydrochloride solution is prepared by mixing L-alanine with 15-20% mass fraction hydrochloric acid at a molar ratio of 1:(1.0-1.2), the pH of the system is 1.5-2.5, and the concentration is 0.8-1.2 mol / L; The concentration of the sodium nitrite solution is 1.0-1.5 mol / L, and it is stored at low temperature 0-5℃; The mass fraction of the HCl-ice acetic acid solution is 20-25%, and it is stored at low temperature 0-5℃.

3. The process for the preparation of R-2-(4-hydroxyphenoxy)propionic acid in stages according to claim 1, characterized in that, In step S1, the continuous flow conditions are realized by a two-stage reaction system, which comprises diazotization reaction unit and chlorination reaction unit arranged in series.

4. The process for the preparation of R-2-(4-hydroxyphenoxy)propionic acid in stages according to claim 1, characterized in that, In step S1, the diazotization reaction temperature is 0-3℃, the residence time is 1.5-2.5 min, the molar ratio of L-alanine hydrochloride solution to sodium nitrite solution is 1:(1.05-1.1); The chlorination reaction temperature is 5-8℃, the residence time is 3-4 min, and the molar ratio of HCl to L-alanine is (1.2-1.4):

1.

5. The process for the preparation of R-2-(4-hydroxyphenoxy)propionic acid in stages according to claim 1, characterized in that, In step S1, the quenching treatment uses deionized water at 0-5℃, and the amount is 10-15% of the volume of the reaction solution. After quenching, the temperature of the system is ≤10℃.

6. The process for the preparation of R-2-(4-hydroxyphenoxy)propionic acid in stages according to claim 1, characterized in that, In step S1, the vacuum short-path distillation conditions are as follows: absolute pressure 5-10 Pa, evaporator wall temperature 60-80℃, and feeding rate 5-8 mL / min.

7. The process for the preparation of R-2-(4-hydroxyphenoxy)propionic acid in stages according to claim 1, characterized in that, In step S2, the molar ratio of R-chloropropanoic acid to hydroquinone is 1:(1.1-1.3); The mass ratio of γ-valerolactone to reaction material is (2.5-3):

1.

8. The process for the preparation of R-2-(4-hydroxyphenoxy)propionic acid in stages according to claim 1, characterized in that, In step S2, the etherification reaction temperature is 65-75℃, and the reaction is performed for 4-5 h.

9. The process for the preparation of R-2-(4-hydroxyphenoxy)propionic acid in stages according to claim 1, characterized in that, In step S2, the acidification, cooling crystallization and drying of the filtrate are as follows: after recovering the catalyst, deionized water with a volume of 1.5-2 times that of the hot filtrate is added, 10% mass fraction dilute hydrochloric acid is added dropwise to adjust the pH to 2.5-3.0, and the system is allowed to stand and separate into layers; The upper γ-valerolactone phase is separated, cooled to 0-3℃ at a cooling rate of 5-10℃ / h, and crystallized for 2-4 h; After filtration, the crystals are washed with 0-5℃ γ-valerolactone for 2-3 times, and vacuum dried at 40-50℃ and 0.09-0.1 MPa for 4-6 h.

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