CN109735582B - Method for synthesizing cyclohexanol beta-amino alcohol derivatives on line by lipase catalysis - Google Patents
Method for synthesizing cyclohexanol beta-amino alcohol derivatives on line by lipase catalysis Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 44
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- 239000002994 raw material Substances 0.000 claims abstract description 32
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing cyclohexanol beta-amino alcohol derivatives on line by lipase catalysis, which comprises the following steps: the method comprises the steps of taking methanol as a reaction solvent, aniline compounds and cyclohexene oxide as raw materials, taking lipase Lipozyme RM IM as a catalyst, placing the raw materials and the reaction solvent into an injector, uniformly filling the lipase Lipozyme RM IM into a reaction channel of a microfluidic channel reactor, and continuously introducing the raw materials and the reaction solvent into the reaction channel reactor under the driving of an injection pump for ring-opening reaction, wherein the inner diameter of the reaction channel of the microfluidic channel reactor is 0.8-2.4 mm, and the length of the reaction channel is 0.5-1.0 m; controlling the ring-opening reaction temperature to be 30-50 ℃, controlling the ring-opening reaction time to be 10-30 min, collecting reaction liquid on line through a product collector, and carrying out conventional aftertreatment on the reaction liquid to obtain the cyclohexanol beta-alkamine derivative. The invention has the advantages of short reaction time, high selectivity and high yield.
Description
Technical Field
The invention relates to a method for synthesizing cyclohexanol beta-amino alcohol derivatives on line by lipase catalysis.
Background
Beta-amino alcohol is an organic synthesis intermediate with wide application, is widely applied to synthesis of natural substances with biological activity, unnatural amino acids, medicinal chemistry, chiral auxiliaries, ligands and the like, plays an important role in medicinal chemistry and biology, and contains beta-amino alcohol structural units in a plurality of clinically and widely applied medicaments, such as antihypertensive medicaments, antidiabetic medicaments, antiasthmatic medicaments, antimalarial medicaments and the like. More than 75% of the drugs or drug intermediates in the organic molecule contain amino functional groups. The chiral amino alcohol with both amino and hydroxyl functional groups shows good chiral induction capability in the field of asymmetric catalysis. The N atom and O atom with good coordination ability in the chiral amino alcohol can form a complex with various elements (such as B, Li, Zn and the like) to form a chiral catalyst with excellent performance, and has high stereoselectivity and catalytic activity. Therefore, the exploration of a new green synthesis technology for synthesizing the beta-amino alcohol compound has important significance.
Typical methods for the synthesis of beta-aminoalcohols are nucleophilic ring-opening reactions of epoxy compounds and aromatic amines, which require large amounts of amine and high temperatures for their application, which are detrimental to some sensitive functional groups and which are accompanied by large amounts of side reactions. The epoxy compound is easily subjected to a ring-opening reaction due to the presence of a ring tension and a polarized carbon-oxygen bond, but is hardly subjected to a reaction with an amine having a weak nucleophilic property and an amine having a large steric hindrance. In this transformation, there are selectivity problems such as regioselectivity, diastereoselectivity and enantioselectivity. In the conventional synthesis method, an epoxy compound and an excessive amount of amine react at high temperature, and the high temperature causes side reaction and limits the use of some substrates sensitive to high temperature, so that a catalyst with high efficiency and good selectivity needs to be found to promote the nucleophilic ring-opening reaction of the epoxy compound. At present, domestic researches on epoxide ring-opening aminolysis reaction are still in the beginning stage, but many foreign researches are carried out, and the application prospect of the method is quite wide. Metal halides, metal triflates, transition metals, etc. are used as catalysts for the catalytic synthesis of beta-aminoalcohols. However, the preparation process of the catalytic system of the catalyst is complex, the cost is high, the catalyst is easy to run off, and substances harmful to the environment can be generated. In addition, it has been reported that graphite, montmorillonite-K10 clay or a metal organic skeleton is used for the reaction, but these reactions have disadvantages such as a long reaction time and poor regioselectivity. Therefore, the research on green synthesis methods of beta-amino alcohol becomes a hot research field in drug synthesis.
The enzyme catalysis reaction is a key point of green chemical research due to high efficiency, green and strong specificity. The enzymatic reaction is widely applied in the fields of industrial biosynthesis, medical care, food industry and the like because of less waste, mild conditions, high selectivity and good product stability. However, the enzymatic reaction has the constraints of solvent dissolution on the substrate, solvent polarity inhibition on enzyme activity and the like, the reaction time is usually long (24-96 h), and the conversion rate of a specific substrate is not very high, so that the development of a novel synthesis technology of an enzymatic beta-aminoalcohol compound based on a microfluidic technology based on the traditional enzymatic reaction becomes a research target.
Compared with the conventional chemical reactor, the microfluidic reactor has the characteristics of high mixing efficiency, fast mass and heat transfer, accurate parameter control, high reaction selectivity, good safety and the like, and is widely applied to organic synthesis reaction. In a continuous flow micro-reactor, a plurality of reactions can realize rapid screening of the conditions of micro-reactions, and safe reactions can be carried out even under harsh experimental conditions, so that reaction raw materials are greatly saved, the screening efficiency is improved, and the concept of green chemistry is more attached.
So far, the enzymatic synthesis of beta-amino alcohols by ring opening of epoxides has been relatively little studied. Candida rugosa lipase CRL (CCandida rugosa lipase from Candida rugosa) The method can effectively catalyze the reaction, but the method needs longer reaction time (8-12 h), and the conversion rate of the specific substrate reaction is not particularly ideal.In order to develop a new technology for synthesizing a beta-amino alcohol compound with high efficiency, green color, good regioselectivity, economy and environmental protection, a method for synthesizing 2- (3-methylphenylamino) cyclohexanol on line by lipase catalysis in a microchannel reactor is researched, and the new technology for synthesizing the 2- (3-methylphenylamino) cyclohexanol on line with high regioselectivity is aimed at being found out.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel process for synthesizing cyclohexanol beta-amino alcohol derivatives on line by lipase catalysis in a microfluidic channel reactor, and the novel process has the advantages of short reaction time, high yield and good selectivity.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method for synthesizing cyclohexanol beta-amino alcohol derivatives on line under catalysis of lipase adopts a microfluidic channel reactor, wherein the microfluidic channel reactor comprises an injector, a reaction channel and a product collector which are sequentially connected, the injector is installed in an injection pump, the injector is connected with an inlet of the reaction channel through a first connecting pipeline, the product collector is connected with an outlet of the reaction channel through a second connecting pipeline, 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 comprises the following steps: taking methanol as a reaction solvent, aniline compounds and cyclohexene oxide shown in formula 1 as raw materials, taking lipase Lipozyme RM IM as a catalyst, placing the raw materials and the reaction solvent in an injector, uniformly filling the lipase Lipozyme RM IM in a reaction channel, continuously introducing the raw materials and the reaction solvent into the reaction channel under the driving of an injection pump for ring-opening reaction, controlling the reaction temperature to be 30-50 ℃ and the reaction time to be 10-30 min, collecting reaction liquid on line through a product collector, and carrying out post-treatment on the reaction liquid to obtain cyclohexanol beta-amino alcohol derivatives shown in formula 2; the mass ratio of the aniline compound shown in the formula 1 to cyclohexene oxide is 1: 0.6-1.4; the catalyst is added in an amount of 0.025-0.05 g/mL based on the volume of the reaction solvent within the maximum limit that the reaction channel can accommodate the filled catalyst; in the reaction system, the concentration of the cyclohexene oxide is 0.12-0.28 mmol/mL,
in the formula 1 or the formula 2, R is 3-CH3Or 4-CH3。
Further, the present invention adopts a microfluidic channel reactor, wherein the number of the injectors can be one or more, depending on the specific reaction requirements. The reaction raw materials of the invention are two, preferably two injectors are used, specifically, the injectors are respectively a first injector and a second injector, the first connecting pipeline is a Y-shaped or T-shaped pipeline, the first injector and the second injector are respectively connected with two interfaces of the Y-shaped or T-shaped pipeline and are connected with the reaction channel in series through the Y-shaped or T-shaped pipeline, and the probability of contact and collision of reactant molecules passing through the microchannel is increased, so that two reactant liquid flows are mixed and react in the common reaction channel.
Still further, more specifically, the method of the present invention comprises the steps of: the method comprises the following steps: the preparation method comprises the steps of taking an aniline compound shown in a formula 1 and cyclohexene oxide with the mass ratio of 1: 0.6-1.4 as raw materials, taking lipase Lipozyme RM IM as a catalyst, taking methanol as a reaction solvent, uniformly filling the lipase Lipozyme RM IM into a reaction channel, dissolving the aniline compound shown in the formula 1 with methanol, and filling the aniline compound into a first injector; dissolving cyclohexene oxide in methanol and filling the solution into a second injector; then, the first injector and the second injector are arranged in the same injection pump, then under the synchronous pushing of the injection pump, raw materials and a reaction solvent are gathered through the Y-shaped or T-shaped pipeline and enter a reaction channel for reaction, the reaction temperature is controlled to be 30-50 ℃, the reaction time is 10-30 min, a reaction solution is collected on line through a product collector, and the reaction solution is subjected to post-treatment to prepare the cyclohexanol beta-amino alcohol derivative shown in the formula 2; the addition amount of the catalyst is 0.5-1 g; in the reaction system, the concentration of the cyclohexene oxide is 0.12-0.28 mmol/mL.
In the present invention, the first syringe and the second syringe have the same specification, and the concentration of the aniline compound represented by formula 1 in the first syringe is usually 0.2 mmol/mL.
Furthermore, the microfluidic channel reactor also comprises a thermostat, and the reaction channel is arranged in the thermostat, so that the reaction temperature can be effectively controlled. The constant temperature box can be selected according to the reaction temperature requirement, such as a water bath constant temperature box and the like.
The material of the reaction channel is not limited, and green and environment-friendly materials such as a silicone tube are recommended; the shape of the reaction channel is preferably curved, so that the reaction liquid can be ensured to stably pass through at a constant speed.
In the present invention, the lipase Lipozyme RM IM is a preparation prepared from microorganisms, using a commercial product manufactured by Novozymes (novozymes), which is a food-grade lipase (EC 3.1.1.3) specific to 1, 3-position on granular silica gel. It is fromRhizomucor mieheiObtained Aspergillus oryzae modified with a gene (Aspergillus oryzae) The microorganism is produced by deep fermentation.
The method of the invention uniformly fills the lipase Lipozyme RM IM in the reaction channel, and can directly and uniformly fix the granular catalyst in the reaction channel by a physical method.
Further, the amount ratio of the aniline compound represented by the formula 1 to cyclohexene oxide is preferably 1:0.8 to 1.2, and most preferably 1: 1.
Further, the ring-opening reaction temperature is preferably 30-40 ℃, and most preferably 35 ℃.
Further, the ring-opening reaction time is preferably 15-25 min, and most preferably 20 min.
The reaction product can be collected on line, and the obtained reaction liquid can be used for obtaining the cyclohexanol beta-alkamine derivative by a conventional post-treatment method. The conventional post-treatment method may be: and distilling the obtained reaction solution under reduced pressure to remove the solvent, filling the reaction solution into a column by using a 200-mesh 300-mesh silica gel wet method, wherein the volume ratio of an eluting reagent to ethyl acetate is =9:1, dissolving the obtained sample by using a small amount of eluting reagent, then filling the sample into the column by using the wet method, collecting the eluent, tracking the elution process by using TLC (thin layer chromatography), and merging and evaporating the obtained eluent containing a single product to dryness to obtain the cyclohexanol beta-amino alcohol derivative.
Compared with the prior art, the invention has the beneficial effects that:
the invention synthesizes the cyclohexanol beta-alkamine derivative on line by using lipase catalysis in a microfluidic channel reactor, and the method not only greatly shortens the reaction time, but also has high conversion rate and selectivity; meanwhile, the ring-opening reaction of the epoxy compound and the amine is catalyzed by using the economic lipase Lipozyme RM IM for the first time, so that the reaction cost is reduced, and the method has the advantages of economy and high efficiency.
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-injector, 3-reaction channel, 4-product collector, 5-water bath incubator.
Detailed Description
The scope of the invention is further illustrated by the following examples, but is not limited thereto:
referring to fig. 1, a microfluidic channel reactor used in an embodiment of the present invention includes a syringe pump (not shown), two syringes 1 and 2, a reaction channel 3, a water bath incubator (5, only a schematic plan view thereof is shown), and a product collector 4; two injectors 1 and 2 are installed in the injection pump and are connected with an inlet of a reaction channel 3 through a Y-shaped interface, the reaction channel 3 is arranged in a water bath thermostat 5, the reaction temperature is controlled through the water bath thermostat 5, the inner diameter of the reaction channel 3 is 2.0mm, the length of a tube is 1.0m, and an outlet of the reaction channel 3 is connected with a product collector 4 through an interface.
Example 1: synthesis of 2- (3-methylphenylamino) cyclohexanol
The device is shown in figure 1: m-toluidine (2.0 mmol) was dissolved in 10mL of MeOH, cyclohexene oxide (2.0 mmol) was dissolved in 10mL of MeOH, and the resulting solution was taken up in a 10mL syringe for further use. 0.87 g of lipase Lipozyme RM IM is uniformly filled in the reaction channel, and two paths of reaction liquid are respectively 15.6 mu L.min under the push of a PHD 2000 injection pump-1The flow rate of the reaction solution enters a reaction channel through a Y joint for reaction, the temperature of the reactor is controlled at 35 ℃ through a water bath thermostat, the reaction solution continuously and continuously reacts in the reaction channel for 20 min, and the reaction result is tracked and detected through thin-layer chromatography TLC.
Collecting reaction liquid on line through a product collector, distilling under reduced pressure to remove a solvent, filling the reaction liquid into a column by using a 200-mesh 300-mesh silica gel wet method, wherein an elution reagent is petroleum ether, ethyl acetate =9:1, the column height is 35 cm, the column diameter is 4.5 cm, a sample is dissolved by using a small amount of the elution reagent and then is loaded into the column by using the wet method, and the eluent collection flow rate is 2 mL.min−1Meanwhile, TLC tracks the elution process, the obtained eluents containing single products are merged and evaporated to dryness to obtain a light yellow oily substance, 2- (3-methylphenylamino) cyclohexanol is obtained, the conversion rate of the 2- (3-methylphenylamino) cyclohexanol is detected by HPLC, and the selectivity is 100%.
The nuclear magnetic characterization results were as follows:
1H NMR (500 MHz, CDCl3): 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). 13C NMR (125 MHz, CDCl3): 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.
examples 2 to 5
The solvent in the microfluidic microchannel reactor was changed, the temperature was controlled at 35 ℃, and the results are shown in table 1, otherwise the same as in example 1:
the results in Table 1 show that when m-toluidine and oxidized ringThe amount of hexene substrate material was 1:1 at a flow rate of 15.6 μ L.min-1The reaction time is 20 min, the reaction temperature is 35 ℃, and the conversion rate of the reaction is optimal when the reactor takes MeOH as an organic solvent, so that the optimal solvent in the microfluidic microchannel reactor is the methanol.
Examples 6 to 9
The ratio of the amounts of the toluidine and the cyclohexene oxide substrate in the middle of the microfluidic microchannel reactor was changed based on the amount of m-toluidine, and the temperature was controlled at 35 ℃, as in example 1, and the results are shown in table 2:
the results in Table 2 show that when the flow rate is 15.6 μ L.min-1The reaction time is 20 min, the reaction temperature is 35 ℃, the MeOH is used as an organic solvent in the reactor, the reaction conversion rate is increased along with the increase of the reactant cyclohexene oxide, and when the ratio of the substrate to the m-toluidine to the substrate to the cyclohexene oxide is 1:1, the reaction conversion rate is optimal, so that the ratio of the optimal substrate substance in the microfluidic microchannel reactor is 1: 1.
Examples 10 to 13
The temperature of the microfluidic channel reactor was changed, and the reaction results are shown in Table 3 as in example 1:
the results in Table 3 show that when the flow rate is 15.6 μ L.min-1The reaction time is 20 min, the MeOH is used as an organic solvent in the reactor, the quantity ratio of reactants of m-toluidine and cyclohexene oxide is 1:1, the conversion rate of the reaction is optimal when the reaction temperature is 35 ℃, and the enzyme activity is influenced by the temperature which is too high or too low. Therefore, the optimal temperature in the microfluidic microchannel reactor is 35 ℃.
Examples 14 to 17
The reaction time of the microfluidic channel reactor was changed, and the reaction results are shown in Table 4 as in example 1:
the results in Table 4 show that when MeOH is used as the organic solvent in the reactor, the amount ratio of the reactants m-toluidine and cyclohexene oxide is 1:1, the reaction temperature is 35 ℃, and the reaction time is 20 min, the reaction conversion rate is 82%, and the selectivity is 100%. Therefore, the optimal reaction time in the microfluidic microchannel reactor is 20 min.
Comparative examples 1 to 4
The results are shown in Table 5 for the same samples as example 1 except that the catalysts in the microfluidic microchannel reactor were changed to porcine pancreatic lipase PPL (comparative example 1), lipase Novozym 435 (comparative example 2), subtilisin alkaline protease (comparative example 3) and lipase TM IM (comparative example 4), respectively.
The results in table 5 show that for the enzymatic epoxide ring-opening reaction in the microfluidic channel reactor, different enzymes have a very significant effect on the reaction. The reaction was catalyzed by lipase TM IM and the conversion of 2- (3-methylphenylamino) cyclohexanol was 42%. Whereas with the Novozym 435 catalyzed reaction, the conversion of 2- (3-methylphenylamino) cyclohexanol was only 14%.
From the results in table 5, the most effective catalyst for the ring-opening reaction of enzymatic epoxy compounds in microfluidic channel reactors was lipase Lipozyme RM IM with a conversion of 82% and a selectivity of 100% for m-toluidine.
Example 18: synthesis of 2- (4-methylphenylamino) cyclohexanol
Device parameterReferring to fig. 1: p-toluidine (2.0 mmol) was dissolved in 10mL MeOH, and cyclohexene oxide (2.0 mmol) was dissolved in 10mL MeOH, which were then separately taken up in a 10mL syringe for use. 0.87 g of lipase Lipozyme RM IM is uniformly filled in the reaction channel, and two paths of reaction liquid are respectively 15.6 mu L.min under the push of a PHD 2000 injection pump-1The flow rate of the reaction solution enters a reaction channel through a Y joint for reaction, the temperature of the reactor is controlled at 35 ℃ through a water bath thermostat, the reaction solution continuously and continuously reacts in the reaction channel for 20 min, and the reaction result is tracked and detected through thin-layer chromatography TLC.
Collecting reaction liquid on line through a product collector, distilling under reduced pressure to remove a solvent, filling the reaction liquid into a column by using a 200-mesh 300-mesh silica gel wet method, wherein an elution reagent is petroleum ether, ethyl acetate =9:1, the column height is 35 cm, the column diameter is 4.5 cm, a sample is dissolved by using a small amount of the elution reagent and then is loaded into the column by using the wet method, and the eluent collection flow rate is 2 mL.min−1And simultaneously tracking the elution process by TLC (thin layer chromatography), merging the obtained eluents containing the single product and evaporating to obtain a light yellow oily substance to obtain 2- (4-methylphenylamino) cyclohexanol, and detecting the conversion rate of the 2- (4-methylphenylamino) cyclohexanol and the selectivity of the 2- (4-methylphenylamino) cyclohexanol by HPLC (high performance liquid chromatography) to be 75%.
The nuclear magnetic characterization results were as follows:
1H NMR (500 MHz, CDCl3): 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, 4.3 Hz, 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). 13C NMR (125 MHz, CDCl3): 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 to 22
The solvent in the microfluidic microchannel reactor was changed, the temperature was controlled at 35 ℃, and the results are shown in table 6, which is otherwise the same as in example 18:
results table of Table 6It is clear that when the amount ratio of p-toluidine to cyclohexene oxide substrate substances is 1:1, the flow rate is 15.6 muL.min-1The reaction time is 20 min, the reaction temperature is 35 ℃, and the conversion rate of the reaction is optimal when the reactor takes MeOH as an organic solvent, so that the optimal solvent in the microfluidic microchannel reactor is the methanol.
Examples 23 to 26
The temperature was controlled at 35 ℃ by varying the ratio of the amounts of the substrate substances p-toluidine and cyclohexene oxide in the microfluidic microchannel reactor based on the amount of p-toluidine, as in example 18, and the results are shown in Table 7:
the results in Table 7 show that when the flow rate is 15.6 μ L.min-1The reaction time is 20 min, the reaction temperature is 35 ℃, the reactor takes MeOH as an organic solvent, the conversion rate of the reaction is increased along with the increase of the reactant cyclohexene oxide, and when the ratio of the substrate to the toluidine to the cyclohexene oxide is 1:1, the conversion rate of the reaction is optimal, so that the ratio of the optimal substrate substance in the microfluidic microchannel reactor is 1: 1.
Examples 27 to 30
The temperature of the microfluidic channel reactor was changed, and the reaction results are shown in Table 8 as in example 18:
the results in Table 8 show that when the flow rate is 15.6 μ L.min-1The reaction time is 20 min, the MeOH is used as an organic solvent in the reactor, the quantity ratio of reactants p-toluidine and cyclohexene oxide is 1:1, the conversion rate of the reaction is optimal when the reaction temperature is 35 ℃, and the enzyme activity is influenced by the temperature which is too high or too low. Therefore, the optimal temperature in the microfluidic microchannel reactor is 35 ℃.
Examples 31 to 34
The reaction time of the microfluidic channel reactor was changed, and the reaction results are shown in Table 9 as in example 18:
the results in Table 9 show that when MeOH is used as the organic solvent in the reactor, the amounts of p-toluidine and cyclohexene oxide are 1:1, the reaction temperature is 35 deg.C, and the reaction time is 20 min, the reaction conversion is 75% and the selectivity is 100%. Therefore, the optimal reaction time in the microfluidic microchannel reactor is 20 min.
Comparative examples 5 to 8
The results are shown in Table 10 for the same samples as in example 18 except that the catalysts in the microfluidic microchannel reactor were changed to porcine pancreatic lipase PPL (comparative example 5), lipase Novozym 435 (comparative example 6), subtilisin alkaline protease (comparative example 7), and lipase TM IM (comparative example 8), respectively.
The results in Table 10 show that for the enzymatic epoxide ring-opening reaction in microfluidic channel reactors, different enzymes have a very significant effect on the reaction. The reaction was catalyzed by lipase TM IM and the conversion of 2- (4-methylphenylamino) cyclohexanol was 41%. Whereas the conversion of 2- (4-methylphenylamino) cyclohexanol by the Novozym 435 catalyzed reaction was only 15%. From the results in table 10, the most effective catalyst for the ring-opening reaction of the enzymatic epoxy in the microfluidic channel reactor was the lipase Lipozyme RM IM with 75% conversion and 100% selectivity for p-toluidine.
Claims (8)
1. A method for synthesizing cyclohexanol beta-amino alcohol derivatives on line by lipase catalysis is characterized in that: the method adopts a microfluidic channel reactor, wherein the microfluidic channel reactor comprises an injector, a reaction channel and a product collector which are connected in sequence, the injector is arranged in an injection pump, the injector is connected with an inlet of the reaction channel through a first connecting pipeline, the product collector is connected with an outlet of the reaction channel through a second connecting pipeline, 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 comprises the following steps: taking methanol as a reaction solvent, aniline compounds and cyclohexene oxide shown in formula 1 as raw materials, taking lipase Lipozyme RM IM as a catalyst, placing the raw materials and the reaction solvent in an injector, uniformly filling the lipase Lipozyme RM IM in a reaction channel, continuously introducing the raw materials and the reaction solvent into the reaction channel under the driving of an injection pump for ring-opening reaction, controlling the reaction temperature to be 30-50 ℃ and the reaction time to be 10-30 min, collecting reaction liquid on line through a product collector, and carrying out post-treatment on the reaction liquid to obtain cyclohexanol beta-amino alcohol derivatives shown in formula 2; the mass ratio of the aniline compound shown in the formula 1 to the cyclohexene oxide is 1: 0.6-1.4; the catalyst is added in an amount of 0.025-0.05 g/mL based on the volume of the reaction solvent within the maximum limit that the reaction channel can accommodate the filled catalyst; in the reaction system, the concentration of the cyclohexene oxide is 0.12-0.28 mmol/mL,
in the formula 1 or the formula 2, R is 3-CH3Or 4-CH3。
2. The method of lipase-catalyzed on-line cyclohexanol- β -amino alcohol derivatives as claimed in claim 1, wherein: the device comprises a reaction channel, a Y-shaped or T-shaped pipeline, two injectors, a first connecting pipeline and a second connecting pipeline, wherein the two injectors are respectively a first injector and a second injector, the first connecting pipeline is a Y-shaped or T-shaped pipeline, the first injector and the second injector are respectively connected with two interfaces of the Y-shaped or T-shaped pipeline, are connected in parallel through the Y-shaped or T-shaped pipeline and are then connected with the reaction channel in series.
3. The method for the lipase-catalyzed on-line synthesis of cyclohexanol beta-amino alcohol derivatives as claimed in claim 2, wherein: the method comprises the following steps: the preparation method comprises the steps of taking an aniline compound shown in a formula 1 and cyclohexene oxide with the mass ratio of 1: 0.6-1.4 as raw materials, taking lipase Lipozyme RM IM as a catalyst, taking methanol as a reaction solvent, uniformly filling the lipase Lipozyme RM IM in a reaction channel, dissolving the aniline compound shown in the formula 1 with methanol, and filling the aniline compound into a first injector; dissolving cyclohexene oxide in methanol and filling the solution into a second injector; then, the first injector and the second injector are arranged in the same injection pump, then under the synchronous pushing of the injection pump, raw materials and a reaction solvent are gathered through the Y-shaped or T-shaped pipeline and enter a reaction channel for reaction, the reaction temperature is controlled to be 30-50 ℃, the reaction time is 10-30 min, a reaction solution is collected on line through a product collector, and the reaction solution is subjected to post-treatment to prepare the cyclohexanol beta-amino alcohol derivative shown in the formula 2; the addition amount of the catalyst is 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 the lipase-catalyzed on-line synthesis of cyclohexanol-type β -amino alcohol derivatives as set forth in claim 1, wherein: the microfluidic channel reactor comprises a thermostat, and the reaction channel is arranged in the thermostat.
5. The method for the lipase-catalyzed on-line synthesis of cyclohexanol beta-amino alcohol derivatives as claimed in any one of claims 1 to 4, wherein: the mass ratio of the aniline compound represented by the formula 1 to cyclohexene oxide is 1: 0.8-1.2.
6. The method for the lipase-catalyzed on-line synthesis of cyclohexanol beta-amino alcohol derivatives as claimed in any one of claims 1 to 4, wherein: the ring-opening reaction temperature is 30-40 ℃, and the ring-opening reaction time is 15-25 min.
7. The method for the lipase-catalyzed on-line synthesis of cyclohexanol beta-amino alcohol derivatives as claimed in any one of claims 1 to 4, wherein: the mass ratio of the aniline compound shown in the formula 1 to the cyclohexene oxide is 1: 1.
8. The method for the lipase-catalyzed on-line synthesis of cyclohexanol beta-amino alcohol derivatives as claimed in any one of claims 1 to 4, wherein: the post-treatment method comprises the following steps: and distilling the obtained reaction liquid under reduced pressure to remove the solvent, carrying out chromatographic separation on the obtained crude product by using a silica gel column, filling the column by using a 200-plus 300-mesh silica gel wet method, wherein an elution reagent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 9:1, dissolving the obtained crude product by using a small amount of elution reagent, then carrying out wet column loading, collecting eluent, simultaneously tracking an elution process by TLC (thin layer chromatography), and combining the obtained eluent containing a single product and evaporating to dryness to obtain the cyclohexanol beta-amino alcohol derivative.
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