CN109735582B - A kind of method of lipase-catalyzed online synthesis of cyclohexanol β-amino alcohol derivatives - Google Patents

Abstract

The invention discloses a method for on-line synthesis of cyclohexanol β-amino alcohol derivatives catalyzed by lipase: methanol is used as a reaction solvent, aniline compounds and cyclohexene oxide are used as raw materials, and lipase Lipozyme RM IM is used as a catalyst. , put the raw material and the reaction solvent in the syringe, evenly fill the lipase Lipozyme RM IM in the reaction channel of the microfluidic channel reactor, and make the raw material and the reaction solvent continuously pass into the reaction channel device under the push of the syringe pump. For the ring-opening reaction, the inner diameter of the reaction channel of the microfluidic channel reactor is 0.8-2.4mm, and the length of the reaction channel is 0.5-1.0m; the temperature of the ring-opening reaction is controlled to be 30-50°C, and the ring-opening reaction time is 10-30min , the reaction solution is collected online by a product collector, and the reaction solution is subjected to conventional post-processing to obtain cyclohexanol β-amino alcohol derivatives. The present invention has the advantages of short reaction time, high selectivity and high yield.

Description

A kind of method of lipase-catalyzed online synthesis of cyclohexanol β-amino alcohol derivatives

technical field

The invention relates to a method for on-line synthesis of cyclohexanol β-amino alcohol derivatives catalyzed by lipase.

Background technique

β-Amino alcohol is a versatile organic synthesis intermediate, which is widely used in the synthesis of biologically active natural substances, unnatural amino acids, medicinal chemistry, chiral auxiliaries and ligands, etc., in medicinal chemistry and biology. Occupying a very important position, many clinically widely used drugs, such as antihypertensive drugs, antidiabetic drugs, antiasthma drugs and antimalarial drugs, contain β-amino alcohol structural units. More than 75% of drugs or drug intermediates in organic molecules contain amino functional groups. Chiral amino alcohols with both amino and hydroxyl functional groups show good chirality-inducing ability in the field of asymmetric catalysis. The N and O atoms with good coordination ability in chiral amino alcohols can form complexes with various elements (such as B, Li, Zn, etc.) to become chiral catalysts with excellent performance, with high stereoselectivity and catalytic activity. Therefore, it is of great significance to explore new green synthesis techniques for synthesizing β-amino alcohols.

The typical method for synthesizing β-amino alcohols is the nucleophilic ring-opening reaction between epoxy compounds and aromatic amines. These methods all require a large amount of amines and high temperature in application, and high temperature is unfavorable for some sensitive functional groups. accompanied by a large number of side reactions. Due to the existence of ring tension and polarized carbon-oxygen bonds in epoxy compounds, ring-opening reactions are easy to occur, but it is difficult for epoxy compounds to react with weakly nucleophilic amines and sterically hindered amines. In this transformation, there are many selectivity problems such as regioselectivity, diastereoselectivity and enantioselectivity. In the traditional synthesis method, the epoxy compound and excess amine are reacted at high temperature, and high temperature will lead to the occurrence of side reactions, and also limit the use of some substrates sensitive to high temperature, so it is necessary to find some efficient and good options. It can be used as a catalyst to promote the nucleophilic ring-opening reaction of epoxy compounds. At present, the domestic research on epoxide ring-opening amination reaction is still in its infancy, but there are many foreign researches, and its application prospect is quite broad. Metal halides, metal triflates, transition metals, etc. are used as catalysts to catalyze the synthesis of β-amino alcohols. However, the preparation process of the catalytic system of this type of catalyst is complicated, expensive, easy to run off, and produces substances harmful to the environment. Another report uses graphite, montmorillonite-K10 clay or metal organic framework to carry out the reaction, but these reactions have the disadvantages of long reaction time and poor regioselectivity. Therefore, exploring green synthesis methods of β-amino alcohols has become a hot research field in drug synthesis.

Enzyme-catalyzed reactions have become a focus of green chemistry research due to their high efficiency, greenness and specificity. Enzymatic reactions have been widely used in industrial biosynthesis, medical care and food industry due to their low waste, mild conditions, high selectivity and good product stability. However, the enzymatic reaction has constraints on the dissolution of the substrate by the solvent and the inhibition of the enzyme activity by the polarity of the solvent. The reaction time is often very long (24h~96h), and the conversion rate of specific substrates is not very high. On the basis of the development of a new technology for the synthesis of enzymatic β-amino alcohol compounds based on microfluidic technology has become our research goal.

Compared with conventional chemical reactors, microfluidic reactors have the characteristics of high mixing efficiency, fast mass and heat transfer, accurate parameter control, high reaction selectivity and good safety, and are widely used in organic synthesis reactions. In the continuous flow microreactor, many reactions can be quickly screened for micro-reaction conditions, and safe reactions can be carried out even under harsh experimental conditions, which greatly saves reaction raw materials, improves screening efficiency, and makes it more suitable for green. Chemistry concept.

So far, there are relatively few studies on enzyme-catalyzed ring-opening of epoxy compounds to synthesize β-amino alcohols. Candida rugosa lipase CRL ( Candida rugosa lipase from Candida rugosa ) can effectively catalyze the reaction, but this method requires a long reaction time (8h~12h), and the conversion rate for a specific substrate reaction is not particularly ideal. In order to develop a new technology for efficient, green, regioselective, and economical and environmentally friendly synthesis of β-aminoalcohols, we investigated the on-line synthesis of 2-(3-methylanilino) ring catalyzed by lipase in a microchannel reactor. The method of hexanol aims to find a new technology for the high regioselectivity on-line synthesis of 2-(3-methylanilino)cyclohexanol with high efficiency and environmental protection.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide a new process for on-line synthesis of cyclohexanol β-amino alcohol derivatives catalyzed by lipase in a microfluidic channel reactor, which has the advantages of short reaction time, high yield and good selectivity advantage.

In order to solve the above-mentioned technical problems, the present invention adopts the following technical solutions:

A method for on-line synthesis of cyclohexanol β-amino alcohol derivatives catalyzed by lipase, the method adopts a microfluidic channel reactor, and the microfluidic channel reactor comprises a syringe, a reaction channel and a product connected in sequence Collector, the syringe is installed in the syringe pump, the syringe is connected with the inlet of the reaction channel through the first connecting pipe, the product collector is connected with the outlet of the reaction channel through the second connecting pipe, and the inner diameter of the reaction channel is 0.8 ~2.4 mm, the length of the reaction channel is 0.5~1.0 m; the method includes: using methanol as a reaction solvent, using the aniline compound shown in formula 1 and cyclohexene oxide as raw materials, and using lipase Lipozyme RM IM as a catalyst, The raw material and the reaction solvent are placed in a syringe, the lipase Lipozyme RM IM is evenly filled in the reaction channel, and the raw material and the reaction solvent are used continuously under the push of a syringe pump. Pass into the reaction channel to carry out the ring-opening reaction, control the reaction temperature to be 30-50 °C, and the reaction time to be 10-30 min, collect the reaction solution online through the product collector, and the reaction solution is post-treated to obtain the formula shown in formula 2. Cyclohexanol β-aminoalcohol derivative; the ratio of the amount of the aniline compound represented by the formula 1 to the cyclohexene oxide is 1:0.6~1.4; the catalyst can be filled in the reaction channel Within the maximum limit, the amount of the catalyst added is 0.025 ~ 0.05 g/mL in terms of the volume of the reaction solvent; in the reaction system, the concentration of the cyclohexene oxide is 0.12 ~ 0.28 mmol/mL,

In Formula 1 or Formula 2, the R is 3-CH ₃ or 4-CH ₃ .

Further, in the microfluidic channel reactor used in the present invention, the number of the syringes may be one or more, depending on the specific reaction requirements. There are two kinds of reaction raw materials in the present invention, and two syringes are preferably used. Specifically, the syringes are the first syringe and the second syringe respectively, the first connecting pipeline is a Y-shaped or T-shaped pipeline, and the third A syringe and a second syringe are respectively connected to the two ports of the Y-shaped or T-shaped pipeline, and are connected in series with the reaction channel through the Y-shaped or T-shaped pipeline, and the reactant molecules through the microchannel are in contact with each other. The probability of collision is increased, so that the two reaction streams are mixed and reacted in the common reaction channel.

Still further, more specifically, the method of the present invention includes the following steps: the method includes the following steps: the aniline compound shown in formula 1 and the oxidized ring with the ratio of the amount of substances being 1:0.6~1.4 Hexene is used as raw material, lipase Lipozyme RM IM is used as catalyst, methanol is used as reaction solvent, the lipase Lipozyme RM IM is evenly filled in the reaction channel, and the aniline compound shown in formula 1 is first dissolved in methanol and loaded into the reaction channel. In the first syringe; dissolving cyclohexene oxide with methanol and loading it in the second syringe; then loading the first syringe and the second syringe in the same syringe pump, and then under the synchronous push of the syringe pump, the raw materials and the reaction The solvent is collected through the Y-shaped or T-shaped pipeline and then enters the reaction channel for reaction. The reaction temperature is controlled to be 30 to 50 °C, and the reaction time is 10 to 30 min. The cyclohexanol β-aminoalcohol derivative shown in formula 2 is obtained by post-treatment of the liquid; the addition amount of the catalyst is 0.5~1g; in the reaction system, the concentration of the cyclohexene oxide is 0.12~0.28 mmol/mL.

The specifications of the first syringe and the second syringe in the present invention are consistent, and the concentration of the aniline compound represented by the formula 1 in the first syringe is usually 0.2 mmol/mL.

Further, the microfluidic channel reactor further includes a constant temperature box, and the reaction channel is placed in the constant temperature box, so that the reaction temperature can be effectively controlled. The incubator can be selected according to the reaction temperature requirements, such as a water bath incubator and the like.

The present invention is not limited to the material of the reaction channel, and it is recommended to use a green and environmentally friendly material, such as a silicone tube; the shape of the reaction channel is preferably curved, which can ensure the uniform and stable passage of the reaction liquid.

In the present invention, the lipase Lipozyme RM IM is a commodity produced by Novozymes, which is a 1,3 position-specific, food-grade lipase (EC 3.1.1.3) prepared by microorganisms. Formulation on granular silica gel. It is obtained from Rhizomucor miehei and is produced by submerged fermentation with a genetically modified Aspergillus oryzae microorganism.

In the method of the present invention, the lipase Lipozyme RM IM is uniformly filled in the reaction channel, and the granular catalyst can be directly and uniformly fixed in the reaction channel by a physical method.

Further, the ratio of the amount of the aniline compound represented by the formula 1 to the amount of cyclohexene oxide is preferably 1:0.8 to 1.2, most preferably 1:1.

Further, the ring-opening reaction temperature is preferably 30 to 40 °C, most preferably 35 °C.

Further, the ring-opening reaction time is preferably 15-25 min, most preferably 20 min.

The reaction product of the present invention can be collected online, and the obtained reaction solution can obtain cyclohexanol β-amino alcohol derivatives through conventional post-processing methods. The conventional post-processing method can be as follows: the obtained reaction solution is distilled under reduced pressure to remove the solvent, 200-300 mesh silica gel is used for wet packing, the elution reagent is petroleum ether: ethyl acetate volume ratio=9:1, and the obtained sample is After dissolving a small amount of elution reagent, apply wet method to the column, collect the eluate, and track the elution process by TLC. The obtained eluate containing a single product is combined and evaporated to dryness, which is a cyclohexanol β-amino alcohol derivative.

Compared with the prior art, the beneficial effects of the present invention are:

The invention utilizes lipase to catalyze the online synthesis of cyclohexanol β-amino alcohol derivatives in a microfluidic channel reactor, the method not only greatly shortens the reaction time, but also has high conversion rate and selectivity; The economical lipase Lipozyme RM IM catalyzes the ring-opening reaction of epoxy compounds and amines, which reduces the reaction cost and has the advantages of economical efficiency.

Description of drawings

FIG. 1 is a schematic structural diagram of a microfluidic channel reactor used in an embodiment of the present invention.

In the figure, 1, 2-syringe, 3-reaction channel, 4-product collector, 5-water bath incubator.

Detailed ways

The protection scope of the present invention is further described below with specific embodiments, but the protection scope of the present invention is not limited thereto:

Referring to FIG. 1, the structure of the microfluidic channel reactor used in the embodiment of the present invention includes a syringe pump (not shown), two syringes 1 and 2, a reaction channel 3, and a water bath incubator (5, only a schematic plan view thereof is shown) and product collector 4; two syringes 1 and 2 are installed in the syringe pump, connected with the inlet of reaction channel 3 through a Y-type interface, the reaction channel 3 is placed in a water bath incubator 5, and the reaction is controlled by the water bath incubator 5 temperature, the inner diameter of the reaction channel 3 is 2.0 mm, the pipe length is 1.0 m, and the outlet of the reaction channel 3 is connected to the product collector 4 through an interface.

Example 1: Synthesis of 2-(3-methylanilino)cyclohexanol

Refer to Figure 1 for the device: m-toluidine (2.0 mmol) was dissolved in 10 mL of MeOH, and cyclohexene oxide (2.0 mmol) was dissolved in 10 mL of MeOH, and then loaded into 10 mL syringes for use. 0.87 g of lipase Lipozyme RM IM was evenly filled in the reaction channel. Driven by the PHD 2000 syringe pump, the two reaction solutions entered the reaction channel through the "Y" joint at a flow rate of 15.6 µL·min ^-1 respectively, and the reaction was carried out through the water bath. The temperature of the reactor was controlled by a thermostat at 35 °C, the reaction solution was continuously flowed in the reaction channel for 20 min, and the reaction results were tracked and detected by thin-layer chromatography (TLC).

The reaction solution was collected online through a product collector, the solvent was distilled off under reduced pressure, and the column was wet-packed with 200-300 mesh silica gel. The elution reagent was petroleum ether:ethyl acetate=9:1, the column height was 35 cm, and the column diameter was 4.5 cm. , the sample was dissolved with a small amount of elution reagent, and then loaded onto the column by wet method. The eluent was collected at a flow rate of 2 mL·min ⁻¹ . At the same time, the elution process was tracked by TLC. The oily substance was obtained as 2-(3-methylanilino)cyclohexanol. The conversion rate of 2-(3-methylanilino)cyclohexanol was detected by HPLC to be 82%, and the selectivity was 100%.

The NMR characterization results are as follows:

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.16 (t, J =7.6 Hz, 1 H), 6.69 - 6.54 (m, 3 H), 3.48 - 3.35 (m, 1 H), 3.17 - 3.09 ( m, 1 H), 2.31 (s, 3 H), 2.23 - 2.09(m, 2 H), 1.88 - 1.73(m, 2 H), 1.39 - 1.27 (m, 4 H), 1.16 - 1.03 (m, 1 H). ¹³ CNMR (125 MHz, CDCl ₃ ): δ = 147.8, 139.5, 129.4, 120.2, 115.7, 112.1, 74.1, 60.6, 32.9, 30.1, 24.9, 24.2, 21.4.

Example 2-5

The solvent in the microfluidic microchannel reactor was changed, and the temperature was controlled to 35 °C. Others were the same as those in Example 1. The results are shown in Table 1:

The results in Table 1 show that when the ratio of m-toluidine and cyclohexene oxide substrate substances is 1:1, the flow rate is 15.6 µL·min ^-1 , the reaction time is 20 min, and the reaction temperature is 35 °C, The conversion rate of the reaction is the best when the reactor uses MeOH as the organic solvent, so methanol is the best solvent in the microfluidic microchannel reactor in the present invention.

Examples 6-9

Based on the consumption of m-toluidine, change the ratio of the amount of the substrate substance of m-toluidine and cyclohexene oxide in the microfluidic micro-channel reactor, and control the temperature to 35 ° C, and the others are the same as in Example 1, and the results are shown in Table 2. Show:

The results in Table 2 show that when the flow rate is 15.6 µL•min ^-1 , the reaction time is 20 min, the reaction temperature is 35 °C, and MeOH is used as the organic solvent in the reactor, with the increase of cyclohexene oxidation of the reactant, the reaction The conversion rate of the reaction also increases with the increase. When the ratio of the substrate to m-toluidine and cyclohexene oxide is 1:1, the conversion rate of the reaction is optimal, so the optimal substrate material in the microfluidic microchannel reactor in the present invention is The ratio of the quantity is 1:1.

Examples 10-13

Change the temperature of the microfluidic channel reactor, and the others are the same as in Example 1, and the reaction results are shown in Table 3:

The results in Table 3 show that when the flow rate is 15.6 µL·min ^-1 , the reaction time is 20 min, the reactor uses MeOH as the organic solvent, and the ratio of m-toluidine and cyclohexene oxide is 1: 1. When the reaction temperature is 35°C, the conversion rate of the reaction is the best, and the activity of the enzyme will be affected if the temperature is too high or too low. Therefore, the optimum temperature in the microfluidic microchannel reactor of the present invention is 35°C.

Examples 14-17

Change the reaction time of the microfluidic channel reactor, and the others are the same as in Example 1, and the reaction results are shown in Table 4:

The results in Table 4 show that when the reactor uses MeOH as the organic solvent, the ratio of the amount of the reactants m-toluidine and cyclohexene oxide is 1:1, the reaction temperature is 35 °C, and when the reaction time is 20 min At this time, the reaction conversion was 82% and the selectivity was 100%. Therefore, the optimal reaction time in the microfluidic microchannel reactor of the present invention is 20 min.

Comparative Examples 1-4

The catalysts in the microfluidic microchannel reactor were changed to porcine pancreatic lipase PPL (comparative example 1), lipase Novozym 435 (comparative example 2), Bacillus subtilis alkaline protease (comparative example 3), lipase TM IM (Comparative Example 4), the others are the same as in Example 1, and the results are shown in Table 5.

The results in Table 5 show that for the enzymatic ring-opening reaction of epoxy compounds in the microfluidic channel reactor, different enzymes have very obvious effects on the reaction. The reaction was catalyzed by lipase TM IM, and the conversion of 2-(3-methylanilino)cyclohexanol was 42%. The conversion of 2-(3-methylanilino)cyclohexanol was only 14% using Novozym 435 catalyzed reaction.

From the results in Table 5, for the enzymatic ring-opening reaction of epoxy compounds in the microfluidic channel reactor, the most effective catalyst is lipase Lipozyme RM IM, the conversion rate of m-toluidine is 82%, and the selectivity is 82%. is 100%.

Example 18: Synthesis of 2-(4-methylanilino)cyclohexanol

Refer to Figure 1 for the device: p-toluidine (2.0 mmol) was dissolved in 10 mL of MeOH, and cyclohexene oxide (2.0 mmol) was dissolved in 10 mL of MeOH, and then filled in 10 mL syringes for use. 0.87 g of lipase Lipozyme RMIM was evenly filled in the reaction channel. Driven by the PHD 2000 syringe pump, the two reaction solutions entered the reaction channel through the "Y" joint at a flow rate of 15.6 µL·min ^-1 respectively. The temperature of the reactor was controlled by the box at 35 °C, the reaction solution was continuously flowed in the reaction channel for 20 min, and the reaction results were tracked and detected by thin-layer chromatography (TLC).

The reaction solution was collected online through a product collector, the solvent was distilled off under reduced pressure, and the column was wet-packed with 200-300 mesh silica gel. The elution reagent was petroleum ether:ethyl acetate=9:1, the column height was 35 cm, and the column diameter was 4.5 cm. , the sample was dissolved with a small amount of elution reagent, and then loaded onto the column by wet method. The eluent was collected at a flow rate of 2 mL·min ⁻¹ . At the same time, the elution process was tracked by TLC. The oily substance was obtained as 2-(4-methylanilino)cyclohexanol. The conversion rate of 2-(4-methylanilino)cyclohexanol was detected by HPLC to be 75% and the selectivity was 100%.

The NMR characterization results are as follows:

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.04 - 6.96 (d, J = 8.3 Hz, 2H), 6.65 -6.62 (d, J = 7.8 Hz, 2H), 3.44 - 3.33 (m, 1H), 3.16 (ddd, J = 10.9, 10.0, 4.3Hz, 1H), 2.94 (br s, 1H), 2.27 (s, 3H), 2.17 - 2.08 (m, 2H), 1.78 - 1.69 (m,2H), 1.36 - 1.25 (m, 3H), 1.13 - 1.04 (m, 1H). ¹³ C NMR (125 MHz, CDCl ₃ ): δ =143.9, 129.7, 126.8, 113.7, 74.2, 60.3, 33.0, 30.7, 24.9, 24.2, 21.4.

Examples 19-22

The solvent in the microfluidic microchannel reactor was changed, and the temperature was controlled to 35°C, and the others were the same as in Example 18. The results are shown in Table 6:

The results in Table 6 show that when the ratio of p-toluidine and cyclohexene oxide substrate substances is 1:1, the flow rate is 15.6 µL·min ^-1 , the reaction time is 20 min, and the reaction temperature is 35 ℃, The conversion rate of the reaction is the best when the reactor uses MeOH as the organic solvent, so methanol is the best solvent in the microfluidic microchannel reactor in the present invention.

Examples 23-26

Based on the consumption of p-toluidine, change the ratio of the amount of p-toluidine and the substrate substance of cyclohexene oxide in the microfluidic microchannel reactor, and control the temperature to 35 ° C, and the other is the same as in Example 18, and the results are shown in Table 7 shown:

The results in Table 7 show that when the flow rate is 15.6 µL·min ^-1 , the reaction time is 20 min, the reaction temperature is 35 °C, and MeOH is used as the organic solvent in the reactor, with the increase of cyclohexene oxidation of the reactant, the reaction The conversion rate of the reaction also increases with the increase. When the substrate ratio of p-toluidine and cyclohexene oxide is 1:1, the conversion rate of the reaction is optimal, so the optimal substrate material in the microfluidic microchannel reactor in the present invention is The ratio of the quantity is 1:1.

Examples 27-30

Change the temperature of the microfluidic channel reactor, and the others are the same as in Example 18, and the reaction results are shown in Table 8:

The results in Table 8 show that when the flow rate is 15.6 µL·min ^-1 , the reaction time is 20 min, the reactor uses MeOH as the organic solvent, and the ratio of the amount of reactants to toluidine and cyclohexene oxide is 1: 1. When the reaction temperature is 35 °C, the conversion rate of the reaction is the best, and the temperature is too high or too low will affect the activity of the enzyme. Therefore, the optimum temperature in the microfluidic microchannel reactor in the present invention is 35°C.

Examples 31-34

Change the reaction time of the microfluidic channel reactor, and the others are the same as in Example 18, and the reaction results are shown in Table 9:

The results in Table 9 show that when the reactor uses MeOH as the organic solvent, the ratio of the amount of the reactants to toluidine and cyclohexene oxide is 1:1, and the reaction temperature is 35 °C. When the reaction time is 20 min At this time, the reaction conversion was 75% and the selectivity was 100%. Therefore, the optimal reaction time in the microfluidic microchannel reactor of the present invention is 20 min.

Comparative Examples 5-8

The catalysts in the microfluidic microchannel reactor were changed to porcine pancreatic lipase PPL (comparative example 5), lipase Novozym 435 (comparative example 6), Bacillus subtilis alkaline protease (comparative example 7), lipase TM IM (Comparative Example 8), the others are the same as in Example 18, and the results are shown in Table 10.

The results in Table 10 show that for the enzymatic ring-opening reaction of epoxy compounds in the microfluidic channel reactor, different enzymes have very obvious effects on the reaction. Using lipase TM IM to catalyze the reaction, the conversion of 2-(4-methylanilino)cyclohexanol was 41%. While using Novozym 435 catalyzed reaction, the conversion of 2-(4-methylanilino)cyclohexanol was only 15%. From the results in Table 10, for the enzymatic ring-opening reaction of epoxy compounds in the microfluidic channel reactor, the most effective catalyst is lipase Lipozyme RM IM, the conversion rate of p-toluidine is 75%, and the selectivity is 75%. is 100%.

Claims (8)

1. a method for lipase catalyzed online synthesis of cyclohexanol β-amino alcohol derivatives, is characterized in that: described method adopts microfluidic channel reactor, and described microfluidic channel reactor comprises sequentially connected A syringe, a reaction channel and a product collector, the syringe is installed in a syringe pump, the syringe is connected to the inlet of the reaction channel through a first connection pipe, and the product collector is connected to the outlet of the reaction channel through a second connection pipe, so The inner diameter of the reaction channel is 0.8-2.4 mm, and the length of the reaction channel is 0.5-1.0 m; the method includes: using methanol as a reaction solvent, using the aniline compound shown in formula 1 and cyclohexene oxide as raw materials, using lipase Lipozyme RM IM is a catalyst, the raw materials and the reaction solvent are placed in a syringe, the lipase Lipozyme RM IM is evenly filled in the reaction channel, and the raw materials and The reaction solvent is continuously passed into the reaction channel to carry out the ring-opening reaction, the reaction temperature is controlled to be 30-50 °C, the reaction time is 10-30 min, the reaction solution is collected online through a product collector, and the reaction solution is post-treated. The cyclohexanol β-amino alcohol derivative shown in formula 2 is obtained; the ratio of the amount of the aniline compound shown in formula 1 to the cyclohexene oxide is 1:0.6~1.4; in the reaction Within the maximum limit that the channel can accommodate the filled catalyst, the added amount of the catalyst is 0.025-0.05 g/mL in terms of the volume of the reaction solvent; in the reaction system, the concentration of the cyclohexene oxide is 0.12-0.28 g/mL mmol/mL,

In Formula 1 or Formula 2, the R is 3-CH ₃ or 4-CH ₃ . 2. the method for online cyclohexanol β-amino alcohol derivative of lipase catalysis as claimed in claim 1, is characterized in that: described syringe has two, is respectively the first syringe and the second syringe, described The first connecting pipeline is a Y-shaped or T-shaped pipeline, and the first syringe and the second syringe are respectively connected to the two interfaces of the Y-shaped or T-shaped pipeline and pass through the Y-shaped or T-shaped pipeline. connected in parallel and in series with the reaction channel. 3. the method for on-line synthesis of cyclohexanol β-amino alcohol derivatives catalyzed by lipase as claimed in claim 2, is characterized in that: described method comprises the following steps: be 1:0.6～1 with the ratio of the amount of substance 1.4 The aniline compound shown in formula 1 and cyclohexene oxide are used as raw materials, the lipase Lipozyme RM IM is used as a catalyst, and methanol is used as a reaction solvent, and the lipase Lipozyme RM IM is uniformly filled in the reaction channel, first Dissolve the aniline compound shown in formula 1 with methanol and put it in the first syringe; dissolve cyclohexene oxide with methanol and put it in the second syringe; then put the first syringe and the second syringe in the same syringe pump , and then under the synchronous push of the syringe pump, the raw materials and the reaction solvent are aggregated through the Y-type or T-type pipeline and then enter the reaction channel to react, and the control reaction temperature is 30 ~ 50 ℃, and the reaction time is 10 ~ 30min. The product collector collects the reaction solution online, and the reaction solution is post-treated to obtain the cyclohexanol β-amino alcohol derivative shown in formula 2; the catalyst is added in an amount of 0.5-1 g; in the reaction system, The concentration of the cyclohexene oxide is 0.12-0.28 mmol/mL. 4. The method for on-line synthesis of cyclohexanol β-amino alcohol derivatives catalyzed by lipase as claimed in claim 1, wherein the microfluidic channel reactor comprises an incubator, and the reaction channel is placed in a constant temperature in the box. 5. the method for lipase catalysis on-line synthesis of cyclohexanol β-amino alcohol derivative as described in one of claim 1～4, it is characterized in that: the aniline compound shown in described formula 1 and cyclohexene oxide The ratio of the amount of substances is 1:0.8~1.2. 6. the method for on-line synthesis of cyclohexanol β-amino alcohol derivatives catalyzed by lipase as described in one of claim 1～4, it is characterized in that: described ring-opening reaction temperature is 30～40 ℃, and described open-loop reaction temperature is 30～40 ℃. The cyclic reaction time was 15-25 min. 7. the method for lipase catalysis on-line synthesis of cyclohexanol β-amino alcohol derivative as described in one of claim 1～4, it is characterized in that: the aniline compound shown in described formula 1 and cyclohexene oxide The ratio of the amount of substances is 1:1. 8. the method for on-line synthesis of cyclohexanol β-amino alcohol derivatives catalyzed by lipase as described in one of claims 1～4, it is characterized in that: the method for described aftertreatment is: gained reaction solution is removed by vacuum distillation Solvent, the obtained crude product is separated by silica gel column chromatography, and the column is packed with 200-300 mesh silica gel wet method, and the elution reagent is a mixed solvent of petroleum ether: ethyl acetate volume ratio of 9:1, and the obtained crude product is eluted with a small amount of After the reagent is dissolved, the column is wetted and the eluate is collected, and the elution process is tracked by TLC. The obtained eluates containing a single product are combined and evaporated to dryness, which is a cyclohexanol β-amino alcohol derivative.

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