阅读说明：本技术 利用连续流微通道反应器氧化合成(±)-萘普生的方法 (Method for synthesizing (+/-) -naproxen by oxidation through continuous flow microchannel reactor ) 是由 陈恬 陈冲 车大庆 王后勇 杜小华 王乃星 鞠馥璟 于 2021-09-28 设计创作，主要内容包括：本发明公开了一种利用连续流微通道反应器氧化合成萘普生的方法,属于医药中间体技术领域。将2-(6-甲氧基-2-萘基)丙醛与溶剂形成的均相溶液再与氧化剂分别经计量泵打入微通道反应器中,在微通道中混合接触进行氧化反应,得到(±)-2-(6-甲氧基-2-萘基)丙酸,即为萘普生。本发明所述方法解决了现有反应时间长,反应条件要求高,工艺安全系数低,成本高等问题,并具有操作简单、工艺安全性高、反应时间短、转化率和选择性好、产物纯度高、可连续化生产、可快速工业化放大等优点,反应结束后物料可以直接进入后处理操作,后处理简单,产物收率达到95％以上,纯度99％以上。(The invention discloses a method for synthesizing naproxen by oxidizing a continuous flow microchannel reactor, belonging to the technical field of medical intermediates. And pumping homogeneous solution formed by 2- (6-methoxy-2-naphthyl) propionaldehyde and a solvent and an oxidant into a microchannel reactor through a metering pump respectively, and carrying out mixed contact in a microchannel for oxidation reaction to obtain (+/-) -2- (6-methoxy-2-naphthyl) propionic acid, namely naproxen. The method solves the problems of long reaction time, high requirement on reaction conditions, low process safety coefficient, high cost and the like in the prior art, and has the advantages of simple operation, high process safety, short reaction time, good conversion rate and selectivity, high product purity, continuous production, rapid industrial amplification and the like, materials can directly enter post-treatment operation after the reaction is finished, the post-treatment is simple, the product yield reaches more than 95 percent, and the purity is more than 99 percent.)

1. A method for preparing (+/-) -2- (6-methoxy-2-naphthyl) propionic acid by continuous flow microchannel reaction oxidation is characterized by comprising the following steps:

(1) preparation of material a mixed solution: adding a reaction auxiliary agent into the material A solution, and stirring for dissolving;

(2) preparing a material B mixed solution: adjusting the pH value of an oxidant aqueous solution to 2-6 at room temperature;

(3) and pumping the mixed solution of the material A and the mixed solution of the material B into a microchannel reactor through a metering pump, mixing the two materials in the microchannel reactor, carrying out continuous oxidation reaction at the reaction temperature of 0-100 ℃, the reaction pressure of 0.15-0.5 MPa and the reaction residence time of 1-300 s, carrying out quenching reaction on the reacted materials, and processing to obtain the (+/-) -2- (6-methoxy-2-naphthyl) propionic acid.

2. The method of claim 1, wherein: in the step (1), 6-methoxy-2-acetyl naphthalene and chloroacetate are used as raw materials, potassium alkoxide is used as alkali, and a material solution A is obtained by condensation, hydrolysis, decarboxylation and liquid separation or a material solid A is dissolved in a reaction solvent to obtain a material solution A.

3. The method of claim 1, wherein: in the step (1), the adopted reaction auxiliary agent is 2-methyl-1-butene, 2-methyl-2-butene or 2-methyl-1, 3-butadiene; wherein the molar ratio of 2-methyl-1-butene, 2-methyl-2-butene or 2-methyl-1, 3-butadiene to 2- (6-methoxy-2-naphthyl) propanal is 1.0-3.0: 1, preferably 1.1-1.8: 1.

4. The method of claim 3, wherein: in the step (1), dissolving a compound 2- (6-methoxy-2-naphthyl) propionaldehyde in a solvent, adding 2-methyl-1-butene, 2-methyl-2-butene or 2-methyl-1, 3-butadiene, stirring and dissolving to prepare a material solution A; wherein the mass-volume ratio of the compound 2- (6-methoxy-2-naphthyl) propionaldehyde to the solvent is 1: 4-15 g/mL, preferably 1: 4-10 g/mL.

5. The method of claim 4, wherein: in the step (1), the solvent used is sec-butyl alcohol, tert-butyl alcohol, isopropanol or n-butyl alcohol, preferably sec-butyl alcohol or isopropanol.

6. The method of claim 1, wherein: in the step (2), the oxidizing agent comprises NaClO₂、NaClO、NaNO₂、KClO₂、KClO、KNO₂、KMnO₄Or H₂O₂Preferably NaClO, preferably NaClO₂。

7. The method of claim 6, wherein: in the step (2), acid, alkali or buffer salt is adopted to adjust the pH value of the solution; the acid comprises one or more of hydrochloric acid, sulfuric acid or acetic acid, and is preferably acetic acid; the alkali comprises one or more of sodium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate, and is preferably sodium bicarbonate; the buffer salt comprises one or more of potassium dihydrogen phosphate, sodium acetate, potassium acetate, ammonium acetate, sodium formate or potassium formate, and is preferably potassium dihydrogen phosphate.

8. The method of claim 7, wherein: in the step (2), adding water into an oxidant to dilute the oxidant to obtain a 10-30% aqueous solution by mass, preferably 12-25% by mass; acetic acid or potassium dihydrogen phosphate is added at room temperature to adjust the pH to 2.0 to 6.0, preferably 3.0 to 4.0.

9. The method of claim 1, wherein: in the step (3), the molar ratio of the material A2- (6-methoxy-2-naphthyl) propionaldehyde to the material B oxidant is 1: 1.1-2.5, and the preferred molar ratio is 1: 1.3-2.0.

10. The method of claim 1, wherein: in the step (3), the microchannel reactor is a microreactor or a micromixer of a double-feeding single-discharging module, and single modules or multiple modules are connected in series.

11. The method of claim 1, wherein: in the step (3), the residence time of the microchannel reaction is 60-300 s, preferably 80-180 s.

12. The method of claim 1, wherein: in the step (3), the materials after the reaction are quenched by sodium thiosulfate or sodium bisulfite.

13. The method of claim 12, wherein: in the step (3), during the quenching reaction, the mass ratio of the oxidant to the sodium thiosulfate or the sodium bisulfite is 1: 0.3-4.5; preferably 1: 0.5-3.0; the mass volume ratio of the sodium thiosulfate to the water in the sodium thiosulfate solution is 1: 4-30 g/mL, preferably 1: 8-20 g/mL; the mass volume ratio of the sodium bisulfite to the water in the sodium bisulfite solution is 1: 4-30 g/mL, preferably 1: 8-1: 20 g/mL.

14. The method of claim 1, wherein: in the step (3), the flow rate of the mixed solution for conveying the material A is 5-60 mL/min; the flow rate of the mixed solution for conveying the material B is 5-80 mL/min.

Technical Field

The invention belongs to the technical field of medical intermediates, and relates to a method for synthesizing (+/-) -naproxen in a continuous flow microchannel reactor by oxidation, in particular to a continuous flow synthesis method for synthesizing naproxen by oxidizing 2- (6-methoxy-2-naphthyl) propionaldehyde in a microchannel reactor.

Background

Naproxen (naproxen), chemical name S- (+) -2- (6-methoxy-2-naphthyl) propionic acid, a nonsteroidal anti-inflammatory analgesic (NSIND) developed by syntex corporation, has the effects of anti-inflammation, antipyresis and analgesia, has the advantages of complete oral absorption, low toxicity, small side effect and the like, and is an important medicine in the field of anti-inflammation and antibiosis.

The original research patent of naproxen expires in 1993, and in recent years, new synthetic process routes are infinite, and the process routes reported in literatures are more than ten, and the overall process can be divided into two categories: firstly, racemic naproxen is synthesized, and then S-naproxen with optical activity is obtained by resolution through a chiral resolving agent; the other is an asymmetric synthesis method, which directly synthesizes the S-naproxen with a single configuration by using a chiral auxiliary agent or a chiral catalyst.

At present, the only processes for really realizing industrial production are acetylation process and propionylation process, and the industrial production processes reported in documents are the first method, namely, the process of firstly synthesizing raceme and then splitting. Representative patents of acetylation processes include US4423244B, WO2001049053a1, CN 102731295B; propionylation process patents are CN101234963A, CN108530278A, CN109485561A, CN 110183323A. However, the current propionylation process has the disadvantages of long synthesis reaction flow, complex process, more high-risk processes, high safety risk and high cost. The common synthesis and acetylation process of naproxen is introduced as follows:

the acetylation process comprises the steps of taking acetyl naphthyl methyl ether as a starting material, and obtaining (+/-) -naproxen through condensation, hydrolysis, decarboxylation, oxidation or oximation hydrolysis, wherein the synthetic route is as follows:

the acetylation process is divided into two different process routes, the first two steps are basically identical, and the third step isThe difference is that 2- (6-methoxy-2-naphthyl) propionaldehyde is firstly oximated, then hydrolyzed and acidified to obtain (+/-) -naproxen, and the patents WO2001049053A1 and CN102731295B disclose that 6-methoxy-2-acetonaphthalene is used as a starting material and applied to industrial production through a synthesis route A, but the use of hydroxylamine in the process route increases the production cost and reduces the additional value of products, and meanwhile, a large amount of industrial waste gas, waste water and waste residues are generated in the oximation and hydrolysis processes, thereby increasing the three-waste treatment cost of enterprises, and being not in line with the concept of 'green chemistry'. The process B directly oxidizes the 2- (6-methoxy-2-naphthyl) propionaldehyde in one step to obtain the (+/-) -naproxen, is a process route with good atom utilization rate and higher economic added value, and the common oxidant in the process is KMnO₄、H₅IO₆、CrO₃、KHSO₅、AgNO₃Copper salt and other oxidants, but the process needs to solve the three wastes problem of heavy metal salt pollution and the economic problem of expensive oxidant price and the like. Meanwhile, the oxidation reaction belongs to high-risk reaction in the traditional kettle type reactor, the safety coefficient is low, and the controllability is poor; in addition, most of the oxidation reactions are exothermic reactions, and the reaction system is removed when the released heat is not in time, so that the reaction is out of control and even explodes; and the oxidation reaction time in the traditional tank reactor is longer, and the product can have the problems of excessive oxidation and oxidative degradation, which leads to the reduction of the product quality.

The Pinnick oxidation uses sodium chlorite as an oxidant with medium polarity to oxidize aldehydes to corresponding carboxylic acids, and is widely applied to organic synthesis and natural product total synthesis due to the reaction characteristics of high efficiency and high selectivity, the cheap and easily available oxidant and the convenient operation of reaction conditions. Patent CN105294667B reports that the method of Pinnick oxidation oxidizes 2- (6-methoxy-2-naphthyl) propionaldehyde to obtain naproxen, and the yield is as high as 91%; journal (New Journal of chemistry,2018, 42: 10414-; there are many reports of this type, but most share common disadvantages: the use of the byproduct hypochlorous acid scavenger (or called trapping agent) -2-methyl-2-butene with more than 10 times of equivalent or even dozens of equivalents limits the application of the Pinnick oxidation in industrialization because the cost of the 2-methyl-2-butene is high, and the boiling point of the 2-methyl-2-butene is low and the 2-methyl-2-butene is easy to volatilize, and the consumption of the byproduct hypochloric acid is high.

The by-product hypochlorous acid in the reaction system mainly has the following effects: 1. relative to ClO₂ ^-The electrode potential of the HOCl/Cl-is higher than that of the HO Cl redox ion pair, and the ion pair with stronger oxidizing property brings a plurality of over-oxidation side reactions; 2. hypochlorous acid can further consume chlorite ions to generate chlorine dioxide with free radical oxidation activity, so that a plurality of side reactions are brought; 3. hypochlorous acid reacts with the carbon-carbon double bond of the electron-rich methoxy naphthalene ring to form chlorinated byproducts. The continuous flow microchannel reactor has the characteristics of short reaction time, low requirement on reaction conditions, simple operation, high safety and the like, so the continuous flow microchannel reactor has great advantages in the technology when being applied to the oxidative synthesis of (+/-) -naproxen: firstly, the safety of the oxidation reaction is high, and secondly, the consumption of the byproduct hypochlorous acid scavenger is greatly reduced due to the short reaction time and the continuous reaction; and finally, the generation of byproducts such as over-oxidation, chlorination and the like is greatly reduced because the reaction time is short, so that the product yield and the product quality are improved.

Disclosure of Invention

The invention aims to provide a method for preparing (+/-) -2- (6-methoxy-2-naphthyl) propionic acid by oxidation in a continuous flow microchannel reactor on the basis of the prior art, which is prepared by taking 2- (6-methoxy-2-naphthyl) propionaldehyde as a raw material and carrying out oxidation reaction with an oxidant in the microchannel reactor.

The technological process of the invention is shown as the attached figure 1, and the adopted technical scheme is as follows: a method for preparing (+/-) -2- (6-methoxy-2-naphthyl) propionic acid by oxidation in a continuous flow microchannel reactor comprises the following steps:

(1) preparation of material a mixed solution: adding a reaction auxiliary agent into the material A solution, and stirring for dissolving;

(2) preparing a material B mixed solution: adjusting the pH value of an oxidant aqueous solution to 2-6 at room temperature;

(3) and pumping the mixed solution of the material A and the mixed solution of the material B into a microchannel reactor through a metering pump, mixing the two materials in the microchannel reactor, carrying out continuous oxidation reaction at the reaction temperature of 0-100 ℃, the reaction pressure of 0.15-0.5 MPa and the reaction residence time of 1-300 s, carrying out quenching reaction on the reacted materials, and processing to obtain the (+/-) -2- (6-methoxy-2-naphthyl) propionic acid.

Further, in the step (1) of the technical scheme, 6-methoxy-2-acetylnaphthalene and chloroacetate are used as raw materials, potassium alkoxide is used as alkali, and a material solution A is obtained by condensation, hydrolysis, decarboxylation and liquid separation or a material solid A is dissolved in a reaction solvent to obtain a material solution A.

Further, in the step (1) of the technical scheme, the adopted reaction auxiliary agent is 2-methyl-1-butene, 2-methyl-2-butene or 2-methyl-1, 3-butadiene; wherein the molar ratio of 2-methyl-1-butene, 2-methyl-2-butene or 2-methyl-1, 3-butadiene to 2- (6-methoxy-2-naphthyl) propanal is 1.0-3.0: 1, preferably 1.1-1.8: 1.

Further, in the step (1) of the technical scheme, a compound 2- (6-methoxy-2-naphthyl) propionaldehyde is firstly dissolved in a solvent, and then 2-methyl-1-butene, 2-methyl-2-butene or 2-methyl-1, 3-butadiene is added and stirred for dissolution to prepare a material solution A; wherein the mass-volume ratio of the compound 2- (6-methoxy-2-naphthyl) propionaldehyde to the solvent is 1: 4-15 g/mL, preferably 1: 4-10 g/mL.

Further, in the step (1) of the above technical scheme, the solvent used is sec-butyl alcohol, tert-butyl alcohol, isopropanol or n-butyl alcohol, preferably sec-butyl alcohol or isopropanol.

Further, in the step (2) of the above technical solution, the oxidizing agent comprises NaClO₂、NaClO、NaNO₂、KClO₂、KClO、KNO₂、KMnO₄Or H₂O₂Preferably NaClO, preferably NaClO₂。

Further, in the step (2) of the technical scheme, acid, alkali or buffer salt is adopted to adjust the pH value of the solution; the acid comprises one or more of hydrochloric acid, sulfuric acid or acetic acid, and is preferably acetic acid;

the alkali comprises one or more of sodium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate, and is preferably sodium bicarbonate;

the buffer salt comprises one or more of potassium dihydrogen phosphate, sodium acetate, potassium acetate, ammonium acetate, sodium formate or potassium formate, and is preferably potassium dihydrogen phosphate.

Further, in the step (2) of the technical scheme, the oxidant is diluted by adding water to obtain an aqueous solution with the mass fraction of 10-30%, preferably 12-25%; acetic acid or potassium dihydrogen phosphate is added at room temperature to adjust the pH to 2.0-6.0, preferably 3.0-4.0.

Further, in the step (3) of the technical scheme, the molar ratio of the material A2- (6-methoxy-2-naphthyl) propionaldehyde to the material B oxidant is 1: 1.1-2.5, and the preferred molar ratio is 1: 1.3-2.0.

The research finds that: the reaction molar ratio of the 2- (6-methoxy-2-naphthyl) propionaldehyde to the oxidant has great influence on the yield and purity of a target product, and the low amount of the oxidant causes incomplete reaction of the raw material 2- (6-methoxy-2-naphthyl) propionaldehyde, so that the yield and quality of the target product are low; higher amounts of oxidizing agents result in increased side reaction products, increased amounts of quenching agents, and increased costs.

Further, in the step (3) of the above technical solution, the microchannel reactor is a microreactor or a micromixer of a dual-feed single-discharge module, and single modules or multiple modules are connected in series. The microchannel reactor was a silicon carbide reactor, model CSD 1005. The reaction temperature is precisely controlled by an external heat exchanger.

Further, in the step (3) of the technical scheme, the residence time of the microchannel reaction is 60-300 s, preferably 80-180 s.

Further, in the step (3) of the above technical scheme, the reacted materials are quenched by sodium thiosulfate or sodium bisulfite.

In the prior art, an oxidant is quenched by a sodium thiosulfate aqueous solution, water is added into an organic phase after liquid separation, the pH value is adjusted to be 7-13, liquid separation is carried out after stirring, the pH value of an aqueous phase is adjusted to be 2-6, stirring, suction filtration and vacuum drying are carried out until the weight is constant, and a crude (+/-) -2- (6-methoxy-2-naphthyl) propionic acid product is obtained.

Further, in the step (3) of the technical scheme, when the quenching reaction is carried out, the mass ratio of the oxidant to the sodium thiosulfate or the sodium bisulfite is 1: 0.3-4.5; preferably 1: 0.5-3.0; the mass volume ratio of the sodium thiosulfate to the water in the sodium thiosulfate solution is 1: 4-30 g/mL, preferably 1: 8-20 g/mL; the mass volume ratio of the sodium bisulfite to the water in the sodium bisulfite solution is 1: 4-30 g/mL, preferably 1: 8-1: 20 g/mL.

Further, in the step (3) of the technical scheme, the flow rate of the mixed solution for conveying the material A is 5-60 mL/min; the flow rate of the mixed solution for conveying the material B is 5-80 mL/min.

The invention adopts the microchannel reactor to carry out continuous flow type reaction, the materials staying in the microchannel reactor are few, the materials are fully mixed, the reaction time is short, the reaction time and the reaction temperature can be accurately controlled, the generation of a large amount of byproducts caused by excessive oxidation due to local overheating or prolonged reaction time is avoided, and the problems of long reaction time, more byproducts, complex post-treatment operation and low yield and purity in the prior art are avoided; the preparation method can accurately control the feeding proportion of reaction materials, greatly shortens the reaction time, has high safety, low cost and simple post-treatment, ensures that the product yield reaches more than 95 percent and the purity reaches more than 99 percent, and is particularly suitable for industrial large-scale production.

The invention adopts the microchannel reactor to produce the target product (+/-) -2- (6-methoxy-2-naphthyl) propionic acid, can accurately control the proportion of feeding, accurately control the pH value, the reaction temperature and the reaction time of a reaction system, basically does not generate new impurities, can save raw materials, save the cost, greatly shorten the reaction time and improve the safety of the process.

The invention has the beneficial effects that:

compared with the existing synthesis method, the method adopts continuous flow type reaction, has less materials staying in the microchannel reactor, accurate feeding proportion of each reaction material, full reaction mixing, accurate control of pH, reaction temperature and time of the reaction materials, reduction of byproducts, raw material saving, cost reduction, great reduction of reaction time and high safety.

The preparation method of the invention can be used for continuous production, the materials after the reaction can be directly subjected to post-treatment operation, the post-treatment is simple, the yield of the product is more than 95%, the purity is more than 99%, and the preparation method is particularly suitable for industrial large-scale production, so that the production is more economic and environment-friendly.

The micro-channel reactor adopted by the invention is acid and alkali resistant, can be conveniently assembled and disassembled, and can be adjusted according to actual requirements.

Drawings

FIG. 1 is a process flow diagram of the preparation method of the present invention.

Detailed Description

The process for the oxidative preparation of (+ -) -2- (6-methoxy-2-naphthyl) propionic acid according to the present invention is further illustrated by the following examples, which are not intended to limit the present invention in any way.

Example 1:

model of microchannel reactor, silicon carbide reactor model CSD1005

(1) Preparation of material a mixed solution: dissolving 50.1g (0.234mol) of 2- (6-methoxy-2-naphthyl) propionaldehyde (solid) with 300mL of sec-butyl alcohol (the mass-to-volume ratio is 1:6.0), adding 26.1mL of 2-methyl-1, 3-butadiene (1.1eq) into a raw material tank A (the bottom of the raw material tank is connected with a corresponding feeding pipeline of a micro-channel through a valve), stirring and dissolving, and then placing at a low temperature for later use;

(2) preparing a material B mixed solution: adding NaClO₂23.3g (0.258mol, molar ratio)1:1.1), adding 170.9g of water, stirring and diluting to prepare NaClO with the mass fraction of 12%₂Adding potassium dihydrogen phosphate into the aqueous solution at room temperature to adjust the pH value to 3.0-4.0, wherein the total volume of the solution is 187 mL. Placing the mixture in a raw material tank B (the bottom of the raw material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving the mixture, and then placing the mixture at a low temperature for later use;

(3) 20.3g of sodium thiosulfate (mass ratio of oxidant to sodium thiosulfate is 1:0.9) was dissolved in 163mL of water (mass to volume ratio of sodium thiosulfate to water is 1:8), placed at the outlet of the microchannel reactor and stirred continuously.

(4) Opening a valve at the bottom of a raw material tank, respectively conveying a material A mixed solution in the raw material tank A and a material B mixed solution in the raw material tank B through a digital display metering pump, setting for 6 minutes, finishing feeding, setting a flow rate of 55mL/min in the raw material tank A and a flow rate of 31mL/min in the raw material tank B through the metering pump, simultaneously conveying the two materials to a micro-channel reactor for reaction by using a feeding pump according to the set flow rates, keeping the reaction for 60s in a channel, controlling the temperature of the micro-channel reactor to be 0-30 ℃ through an ice water heat exchanger outside, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium thiosulfate solution in a stirring state for quenching reaction. Introducing the quenched materials into a transfer reaction container for standing and liquid separation; after 0.5h, liquid separation is carried out, 200mL of drinking water is added to the organic phase after liquid separation, the pH of the solution is adjusted to 9-10 by potassium hydroxide, stirring is carried out for 1 hour, standing and liquid separation are carried out, after 0.5h, liquid separation is carried out, the pH is adjusted to 3-4 by 2.0mol/L hydrochloric acid, stirring is carried out for 1 hour, suction filtration and vacuum drying are carried out until the weight is constant, and 52.7g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid is obtained, the yield is 98.0%, and the purity is 99.31% by high performance liquid chromatography.

Example 2:

model of microchannel reactor, silicon carbide reactor model CSD1005

(1) Preparation of material a mixed solution: dissolving 50.1g (0.234mol) of 2- (6-methoxy-2-naphthyl) propionaldehyde (solid) in 300mL of isopropanol (the mass-volume ratio is 1:6.0), adding 25.6mL of 2-methyl-1, 3-butadiene (1.5eq) into a raw material tank A (the bottom of the raw material tank is connected with a corresponding feeding pipeline of a microchannel through a valve), stirring and dissolving, and then placing at a low temperature for later use;

(2) preparing a material B mixed solution: adding NaClO₂27.5g (0.304mol, molar ratio 1:1.3), adding 110.0g of water, stirring and diluting to prepare NaClO with mass fraction of 20%₂Adding acetic acid into the aqueous solution at room temperature to adjust the pH value to be 3.0-4.0, wherein the total volume of the solution is 136 mL. Placing the mixture in a raw material tank B (the bottom of the raw material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving the mixture, and then placing the mixture at a low temperature for later use;

(3) 50.1g of sodium thiosulfate (the mass ratio of the oxidizing agent to the sodium thiosulfate is 1:1.8) is dissolved in 701.4mL of water (the mass-volume ratio of the sodium thiosulfate to the water is 1:14), and the solution is placed at the outlet of the microchannel reactor and is continuously stirred.

(4) Opening a valve at the bottom of a raw material tank, respectively conveying a material A mixed solution in the raw material tank A and a material B mixed solution in the raw material tank B through a digital display metering pump, setting 8 minutes for finishing feeding, setting the flow rate of the raw material tank A to be 40mL/min and the flow rate of the raw material tank B to be 17mL/min through the metering pump, simultaneously conveying the two materials to a micro-channel reactor for reaction according to the set flow rates by using a feeding pump, keeping the reaction in a channel for 120s, controlling the temperature of the micro-channel reactor to be 10-50 ℃ through an ice water heat exchanger outside, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium thiosulfate solution in a stirring state for quenching reaction. Introducing the quenched materials into a transfer reaction container for standing and liquid separation; after 0.5h, liquid separation is carried out, 200ml of drinking water is added into the organic phase after liquid separation, 2.0mol/L potassium hydroxide is used for adjusting the pH value of the solution to 9-10, stirring is carried out for 1 h, standing and liquid separation are carried out, liquid separation is carried out after 0.5h, 2.0mol/L hydrochloric acid is used for adjusting the pH value to 3-4, stirring is carried out for 1 h, suction filtration is carried out, vacuum drying is carried out until the weight is constant, 52.3g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid is obtained, the yield is 97.2%, and the purity is 99.17% by high performance liquid chromatography.

Example 3:

model of microchannel reactor, silicon carbide reactor model CSD1005

(1) Preparation of material a mixed solution: dissolving 100.3g (0.469mol) of 2- (6-methoxy-2-naphthyl) propionaldehyde (solid) in 400mL of sec-butyl alcohol (the mass-volume ratio is 1:4.0), adding 52.2mL of 2-methyl-1, 3-butadiene (1.1eq) into a raw material tank A (the bottom of the raw material tank is connected with a corresponding feeding pipeline of a micro-channel through a valve), stirring and dissolving, and then placing at a low temperature for later use;

(2) preparation of material B solution: adding NaClO₂63.58g (0.703mol, mol ratio 1:1.5), adding 466.2g of water, stirring and diluting to prepare NaClO with mass fraction of 12%₂Adding potassium dihydrogen phosphate into the aqueous solution at room temperature to adjust the pH value to 3.0-4.0, wherein the total volume of the solution is 514 mL. Placing the mixture in a raw material tank B (the bottom of the raw material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving the mixture, and then placing the mixture at a low temperature for later use;

(3) 44.5g of sodium bisulfite (the mass ratio of the oxidizing agent to the sodium bisulfite is 1:0.7) is dissolved in 445mL of water (the mass-to-volume ratio of the sodium bisulfite to the water is 1:10), placed at the outlet of the microchannel reactor and stirred continuously.

(4) Opening a valve at the bottom of a raw material tank, respectively conveying a material A mixed solution in the raw material tank A and a material B mixed solution in the raw material tank B through a digital display metering pump, setting for 8 minutes, finishing feeding, setting a flow rate of 55mL/min in the raw material tank A and a flow rate of 65mL/min in the raw material tank B through the metering pump, simultaneously conveying the two materials to a micro-channel reactor for reaction by using a feeding pump according to the set flow rates, keeping the reaction for 100s in a channel, controlling the temperature of the micro-channel reactor to be 30-50 ℃ through an ice water heat exchanger outside, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium bisulfite solution under a stirring state for quenching reaction. Introducing the quenched materials into a transfer reaction container for standing and liquid separation; after 0.5h, liquid separation is carried out, 400mL of drinking water is added to the organic phase after liquid separation, 2.0mol/L potassium hydroxide is used for adjusting the pH of the solution to 9-10, stirring is carried out for 1 h, standing and liquid separation are carried out, liquid separation is carried out after 0.5h, 2.0mol/L hydrochloric acid is used for adjusting the pH to 3-4, stirring is carried out for 1 h, suction filtration and vacuum drying are carried out until the weight is constant, 106.3g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid is obtained, the yield is 98.6%, and the purity is 99.41% by high performance liquid chromatography.

Example 4:

model of microchannel reactor, silicon carbide reactor model CSD1005

(1) Preparation of material a mixed solution: dissolving 100.1g (0.467mol) of 2- (6-methoxy-2-naphthyl) propionaldehyde (solid) by using 1000mL of sec-butyl alcohol (the mass-volume ratio is 1:10), adding 50.4mL of 2-methyl-2-butene (1.2eq) into a raw material tank A (the bottom of the raw material tank is connected with a corresponding feeding pipeline of a micro-channel through a valve), stirring and dissolving, and then placing at low temperature for later use;

(2) preparing a material B mixed solution: adding NaClO₂71.8g (0.794mol, molar ratio 1:1.7), 406.9g of water is added to stir and dilute to prepare NaClO with mass fraction of 15%₂Adding potassium dihydrogen phosphate into the aqueous solution at room temperature to adjust the pH value to 3.0-4.0, wherein the total volume of the solution is 509 mL. Placing the mixture in a raw material tank B (the bottom of the raw material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving the mixture, and then placing the mixture at a low temperature for later use;

(3) 28.7g of sodium bisulfite (mass ratio of oxidant to sodium bisulfite of 1:0.4) was dissolved in 229mL of water (mass to volume ratio of sodium bisulfite to water of 1:8), placed at the outlet of the microchannel reactor and stirred continuously.

(4) Opening a valve at the bottom of a raw material tank, respectively conveying a material A mixed solution in the raw material tank A and a material B mixed solution in the raw material tank B through a digital display metering pump, setting the feeding time to be 18 minutes, finishing the feeding, setting the flow rate of the raw material tank A to be 60mL/min and the flow rate of the raw material tank B to be 29mL/min through the metering pump, simultaneously conveying the two materials to a micro-channel reactor for reaction by using a feeding pump according to the set flow rates, keeping the reaction in a channel for 80s, controlling the temperature of the micro-channel reactor to be 20-40 ℃ through an ice water heat exchanger outside, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium bisulfite solution under a stirring state for quenching reaction. Introducing the quenched materials into a transfer reaction container for standing and liquid separation; after 0.5h, liquid separation is carried out, 400mL of drinking water is added to the organic phase after liquid separation, 2.0mol/L potassium hydroxide is used for adjusting the pH of the solution to 9-10, stirring is carried out for 1 h, standing and liquid separation are carried out, liquid separation is carried out after 0.5h, 2.0mol/L hydrochloric acid is used for adjusting the pH to 3-4, stirring is carried out for 1 h, suction filtration and vacuum drying are carried out until the weight is constant, 105.0g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid is obtained, the yield is 97.60%, and the purity is 99.08% by high performance liquid chromatography.

Example 5:

model of microchannel reactor, silicon carbide reactor model CSD1005

(1) Preparation of a stock a mixed solution (one-pot method): adding 100.4g (0.501mol) of 6-methoxy-2-acetonaphthone into 82.7g sec-butyl chloroacetate (1.1eq) and stirring uniformly, adding 400mL sec-butyl alcohol and 112.2g potassium sec-butyl alcohol, reacting at room temperature for 2h, dropwise adding 294.59g of KOH aqueous solution with the mass fraction of 40%, reacting at 40 ℃ for 2h, adding 400mL drinking water, heating to reflux, decarboxylating, removing solvent while reacting, evaporating 500mL of solvent, and cooling to room temperature; adding 97.1ml of 2-methyl-1-butene (1.8eq, calculated by 6-methoxy-2-acetonaphthone) into a raw material tank A (the bottom of the raw material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring for dissolving, and then placing at a low temperature for later use;

(2) preparing a material B mixed solution: 90.18g (1.002mol, mol ratio 1:2.0) of water is added into the mixture, and then 510.0g of water is stirred and diluted to prepare NaClO with the mass concentration of 15 percent₂Adding potassium dihydrogen phosphate into the aqueous solution at room temperature to adjust the pH value to be 5.0-6.0, wherein the total volume of the solution is 576 mL. Placing the mixture in a raw material tank B (the bottom of the raw material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving the mixture, and then placing the mixture at a low temperature for later use;

(3) 90.18g of sodium sulfite (the mass ratio of the oxidant to the sodium sulfite is 1:1) is dissolved in 901.8mL of water (the mass-to-volume ratio of the sodium sulfite to the water is 1:10), and the solution is placed at the outlet of the microchannel reactor and is continuously stirred.

(4) Opening a valve at the bottom of a raw material tank, respectively conveying a material A mixed solution in the raw material tank A and a material B mixed solution in the raw material tank B through a digital display metering pump, setting 10 minutes for finishing feeding, setting the flow rate of 55mL/min of the raw material tank A and the flow rate of 58mL/min of the raw material tank B through the metering pump, simultaneously conveying the two materials into a micro-channel reactor for reaction according to the set flow rates by using a feeding pump, keeping the reaction for 180s in a channel, controlling the temperature of the micro-channel reactor to be 30-60 ℃ through an ice water heat exchanger outside, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium thiosulfate solution in a stirring state for quenching reaction. Introducing the quenched materials into a transfer reaction container for standing and liquid separation; after 0.5h, liquid separation is carried out, 400mL of drinking water is added to the organic phase after liquid separation, 2.0mol/L potassium hydroxide is used for adjusting the pH of the solution to 9-10, stirring is carried out for 1 h, standing and liquid separation are carried out, liquid separation is carried out after 0.5h, 2.0mol/L hydrochloric acid is used for adjusting the pH to 3-4, stirring is carried out for 1 h, suction filtration and vacuum drying are carried out until the weight is constant, 102.9g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid is obtained, the yield is 95.4%, and the purity is 99.07% by high performance liquid chromatography.

Example 6:

model of microchannel reactor, silicon carbide reactor model CSD1005

(1) Preparation of a stock a mixed solution (one-pot method): adding 100.4g (0.501mol) of 6-methoxy-2-acetonaphthone into 82.7g of sec-butyl chloroacetate (1.1eq) and uniformly stirring, adding 400mL of isopropanol and 98.20g of potassium isopropoxide, reacting at room temperature for 2h, dropwise adding 294.59g of KOH aqueous solution with the mass fraction of 40%, reacting at 40 ℃ for 2h, adding 400mL of drinking water, heating to reflux, decarboxylating, desolventizing while reacting, evaporating to remove 500mL of solvent, and cooling to room temperature; adding 50.4ml of 2-methyl-2-butene (1.2eq, calculated by 6-methoxy-2-acetonaphthone) into a raw material tank A (the bottom of the raw material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring for dissolving, and then placing at a low temperature for later use;

(2) preparing a material B mixed solution: 67.94g (0.751mol, 1:1.5 mol) of water was added thereto, and the mixture was diluted with stirring to prepare 25% by mass of NaClO₂Adding potassium dihydrogen phosphate into the aqueous solution at room temperature to adjust the pH value to be 5.0-6.0, wherein the total volume of the solution is 257 mL. Placing the mixture in a raw material tank B (the bottom of the raw material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving the mixture, and then placing the mixture at a low temperature for later use;

(3) 135.88g of sodium sulfite (mass ratio of oxidant to sodium sulfite: 1:2.0) was dissolved in 1087.1mL of water (mass to volume ratio of sodium sulfite to water: 1:8.0), placed at the outlet of the microchannel reactor and stirred continuously.

(4) Opening a valve at the bottom of a raw material tank, respectively conveying a material A mixed solution in the raw material tank A and a material B mixed solution in the raw material tank B through a digital display metering pump, setting 10 minutes for finishing feeding, setting the flow rate of 55mL/min of the raw material tank A and the flow rate of 26mL/min of the raw material tank B through the metering pump, simultaneously conveying the two materials into a micro-channel reactor for reaction according to the set flow rates by using a feeding pump, keeping the reaction for 240s in a channel, controlling the temperature of the micro-channel reactor to be 40-80 ℃ through an ice water heat exchanger outside, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium thiosulfate solution in a stirring state for quenching reaction. Introducing the quenched materials into a transfer reaction container for standing and liquid separation; after 0.5h, liquid separation is carried out, 400mL of drinking water is added to the organic phase after liquid separation, 2.0mol/L potassium hydroxide is used for adjusting the pH of the solution to 9-10, stirring is carried out for 1 h, standing and liquid separation are carried out, liquid separation is carried out after 0.5h, 2.0mol/L hydrochloric acid is used for adjusting the pH to 3-4, stirring is carried out for 1 h, suction filtration and vacuum drying are carried out until the weight is constant, 102.6g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid is obtained, the yield is 95.1%, and the purity is 99.24% by high performance liquid chromatography.

Comparative example 1:

model of microchannel reactor, silicon carbide reactor model CSD1005

(1) Preparation of material a mixed solution: dissolving 50.3g (0.235mol) of 2- (6-methoxy-2-naphthyl) propionaldehyde (solid) in 300mL of sec-butyl alcohol (the mass-volume ratio is 1:6.0), placing the solution in a raw material tank A (the bottom of the raw material tank is connected with a corresponding feeding pipeline of a micro-channel through a valve), stirring and dissolving, and then placing the solution at a low temperature for later use;

(2) preparing a material B mixed solution: the mass fraction is 30 percent of H₂O₂20.0g (0.586mol, 1:2.5 mol), adding 30mL of water, stirring and diluting to prepare H with the mass fraction of 12%₂O₂Adding acetic acid into the aqueous solution at room temperature to adjust the pH value to be 4.0-5.0, wherein the total volume of the solution is 50 mL. Placing the mixture in a raw material tank B (the bottom of the raw material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving the mixture, and then placing the mixture at a low temperature for later use;

(3) 22.0g of sodium thiosulfate (the mass ratio of the oxidizing agent to the sodium thiosulfate is 1:1.1) is dissolved in 176mL of water (the mass-to-volume ratio of the sodium thiosulfate to the water is 1:8), and the solution is placed at the outlet of the microchannel reactor and is continuously stirred.

(4) Opening a valve at the bottom of a raw material tank, respectively conveying a material A mixed solution in the raw material tank A and a material B mixed solution in the raw material tank B through a digital display metering pump, setting for 6 minutes, finishing feeding, setting a flow rate of 50mL/min in the raw material tank A and a flow rate of 8mL/min in the raw material tank B through the metering pump, simultaneously conveying the two materials to a micro-channel reactor for reaction by using a feeding pump according to the set flow rates, keeping the reaction for 60s in a channel, controlling the temperature of the micro-channel reactor to be 0-30 ℃ through an ice water heat exchanger outside, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium thiosulfate solution in a stirring state for quenching reaction. Introducing the quenched materials into a transfer reaction container for standing and liquid separation; after 0.5h, liquid separation is carried out, 200mL of drinking water is added to the organic phase after liquid separation, 2.0mol/L potassium hydroxide is used for adjusting the pH of the solution to 9-10, stirring is carried out for 1 h, standing and liquid separation are carried out, liquid separation is carried out after 0.5h, 2.0mol/L hydrochloric acid is used for adjusting the pH to 3-4, stirring is carried out for 1 h, suction filtration and vacuum drying are carried out until the weight is constant, and 27.5g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid is obtained, the yield is 50.86%, and the purity is 89.31% by high performance liquid chromatography.

Comparative example 2:

model of microchannel reactor, silicon carbide reactor model CSD1005

(1) Preparing a material A mixed solution, namely dissolving 50.5g (0.236mol) of 2- (6-methoxy-2-naphthyl) propionaldehyde (solid) by 300ml of isopropanol (the mass-volume ratio is 1:6.0), placing the solution into a raw material tank A (the bottom of the raw material tank is connected with a corresponding feeding pipeline of a micro-channel through a valve), stirring and dissolving the solution, and placing the solution at a low temperature for later use;

(2) preparing a material B mixed solution: 41.01g of KMnO₄(0.259mol, 1:1.1 mol), adding 300.0g of water, stirring and diluting to prepare KMnO with the mass fraction of 12%₄Adding potassium dihydrogen phosphate into the aqueous solution at room temperature to adjust the pH value to 5.0-6.0, wherein the total volume of the solution is 350 ml. Placing the mixture in a raw material tank B (the bottom of the raw material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving the mixture, and then placing the mixture at a low temperature for later use;

(3) 45.1g of sodium thiosulfate (the mass ratio of the oxidizing agent to the sodium thiosulfate is 1:1.1) is dissolved in 450mL of water (the mass-volume ratio of the sodium thiosulfate to the water is 1:10), and the solution is placed at the outlet of the microchannel reactor and is continuously stirred.

(4) Opening a valve at the bottom of a raw material tank, respectively conveying a material A mixed solution in the raw material tank A and a material B mixed solution in the raw material tank B through a digital display metering pump, setting 8 minutes for finishing feeding, setting the flow rate of the raw material tank A to be 37mL/min and the flow rate of the raw material tank B to be 44mL/min through the metering pump, simultaneously conveying the two materials to a micro-channel reactor for reaction according to the set flow rates by using a feeding pump, keeping the reaction in a channel for 100s, controlling the temperature of the micro-channel reactor to be 10-50 ℃ through an ice water heat exchanger outside, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium thiosulfate solution in a stirring state for quenching reaction. Introducing the quenched materials into a transfer reaction container for standing and liquid separation; after 0.5h, liquid separation is carried out, 200mL of drinking water is added to the organic phase after liquid separation, 2.0mol/L potassium hydroxide is used for adjusting the pH of the solution to 9-10, stirring is carried out for 1 h, standing and liquid separation are carried out, liquid separation is carried out after 0.5h, 2.0mol/L hydrochloric acid is used for adjusting the pH to 3-4, stirring is carried out for 1 h, suction filtration and vacuum drying are carried out until the weight is constant, and 42.3g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid is obtained, the yield is 78.25%, and the purity is 90.71% by high performance liquid chromatography.

Comparative example 3:

model of microchannel reactor, silicon carbide reactor model CSD1005

(1) Preparation of material a mixed solution: dissolving 50.1g (0.234mol) of 2- (6-methoxy-2-naphthyl) propionaldehyde (solid) in 300mL of sec-butyl alcohol (the mass-to-volume ratio is 1:6.0), placing the solution in a raw material tank A (the bottom of the raw material tank is connected with a corresponding feeding pipeline of a micro-channel through a valve), stirring to dissolve, and then placing the solution at a low temperature for later use;

(2) preparing a material B mixed solution: NaClO22.63g (0.304mol, molar ratio 1:1.3) is added with 166.1g of water, stirred and diluted to prepare a NaClO aqueous solution with the mass fraction of 12%, acetic acid is added at room temperature to adjust the pH value to 4.0-5.0, and the total volume of the solution is 187 mL. Placing the mixture in a raw material tank B (the bottom of the raw material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving the mixture, and then placing the mixture at a low temperature for later use;

(3) 33.94g of sodium thiosulfate (mass ratio of oxidant to sodium thiosulfate is 1:1.5) was dissolved in 271.5mL of water (mass to volume ratio of sodium thiosulfate to water is 1:8), placed at the outlet of the microchannel reactor and stirred continuously.

(4) Opening a valve at the bottom of a raw material tank, respectively conveying a material A mixed solution in the raw material tank A and a material B mixed solution in the raw material tank B through a digital display metering pump, setting 8 minutes for finishing feeding, setting the flow rate of the raw material tank A to be 37mL/min and the flow rate of the raw material tank B to be 24mL/min through the metering pump, simultaneously conveying the two materials to a micro-channel reactor for reaction according to the set flow rates by using a feeding pump, keeping the reaction in a channel for 120s, controlling the temperature of the micro-channel reactor to be 10-50 ℃ through an ice water heat exchanger outside, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium thiosulfate solution in a stirring state for quenching reaction. Introducing the quenched materials into a transfer reaction container for standing and liquid separation; after 0.5h, liquid separation is carried out, 200mL of drinking water is added to the organic phase after liquid separation, 2.0mol/L potassium hydroxide is used for adjusting the pH of the solution to 9-10, stirring is carried out for 1 h, standing and liquid separation are carried out, liquid separation is carried out after 0.5h, 2.0mol/L hydrochloric acid is used for adjusting the pH to 3-4, stirring is carried out for 1 h, suction filtration and vacuum drying are carried out until the weight is constant, 35.3g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid is obtained, the yield is 65.30%, and the purity is 81.71% by high performance liquid chromatography.

The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it should be understood by those skilled in the art that various changes and modifications may be made in the embodiments described in the foregoing embodiments, or equivalent changes and modifications may be made to some of the technical features of the embodiments without departing from the scope of the embodiments of the present invention.