CN109706194B - Method for synthesizing phenethyl alcohol beta-amino alcohol derivatives on line based on mobile chemical enzymatic ammonolysis reaction - Google Patents
Method for synthesizing phenethyl alcohol beta-amino alcohol derivatives on line based on mobile chemical enzymatic ammonolysis reaction Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 49
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- -1 aniline compound Chemical class 0.000 claims description 44
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 32
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- 238000003786 synthesis reaction Methods 0.000 claims description 19
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- 239000003960 organic solvent Substances 0.000 description 20
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 18
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing phenethyl alcohol beta-amino alcohol derivatives on line based on a mobile chemical enzymatic ammonolysis reaction, which comprises the following steps: methanol is used as a reaction solvent, aniline compounds and styrene oxide with a molar ratio of 1: 0.6-1.4 are used as raw materials, lipase Lipozyme RM IM is used as a catalyst, the raw materials and the reaction solvent are placed in an injector, the lipase Lipozyme RM IM is uniformly filled in a reaction channel of a microfluidic channel reactor, the raw materials and the reaction solvent are continuously introduced into the reaction channel reactor under the driving of an injection pump for ring-opening reaction, 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 phenethyl alcohol beta-amino alcohol derivative. The invention has the advantages of short reaction time, high selectivity and high yield.
Description
(I) technical field
The invention relates to a method for synthesizing phenethyl alcohol beta-amino alcohol derivatives on line based on a mobile chemical enzymatic aminolysis reaction.
(II) background of the invention
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.
The usual method for synthesizing beta-aminoalcohols is the nucleophilic ring-opening reaction of an epoxy compound and an aromatic amine, which often requires a large amount of amine and a high reaction temperature, which is detrimental to some sensitive functional groups and is accompanied by a large number 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, the domestic research on epoxide ring-opening aminolysis reaction is still in the initial stage, but more foreign researches are carried out, and the application prospect 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. Thus, the search for green synthesis methods of β -aminoalcohols has been a field of intense research in organic synthesis.
The enzyme catalysis reaction is a key point of green chemical research due to high efficiency, green and strong specificity. The enzymatic reaction has been widely used in the fields of industrial biosynthesis, medical care and food industry because of its mild reaction conditions, high selectivity and good product stability. However, the enzymatic reaction has the restriction of solvent to substrate dissolution, solvent polarity to enzyme activity inhibition and the like, the reaction time is often 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 enzyme-catalyzed ring-opening synthesis of beta-amino alcohols from epoxides has been relatively less studied. Candida rugosa lipase CRL (Candida rugosa lipase from Candida rugosa) can catalyze the reaction effectively, but the method requires a long reaction time (8-12 h), and the conversion rate for a specific substrate reaction is not particularly ideal. In order to develop a new technology for synthesizing beta-amino alcohol compounds with high efficiency, green color, good regioselectivity, economy and environmental protection, a method for synthesizing 2- (2-methylphenylamino) phenethyl alcohol on line by lipase catalysis in a microchannel reactor is researched, and the new technology for synthesizing the 2- (2-methylphenylamino) phenethyl alcohol with high regioselectivity on line is aimed at being found out.
Disclosure of the invention
The technical problem to be solved by the invention is to provide a novel process for synthesizing the phenethyl alcohol 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 phenethyl alcohol type 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 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, taking aniline compounds shown in a formula 1 and styrene oxide 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 ℃, reacting for 10-30 min, collecting reaction liquid on line through a product collector, and carrying out post-treatment on the reaction liquid to obtain the phenethyl alcohol beta-amino alcohol derivative shown in the formula 2; the mass ratio of the aniline compound shown in the formula 1 to the styrene 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 styrene oxide is 0.12-0.28 mmol/mL,
in formula 1 or formula 2, R is1Is H or CH3；
When said R is1When is H, said R2Is H or CH3；
When said R is1Is CH3When R is said2Is H.
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 aniline compound represented by the formula 1 and styrene oxide with the mass ratio of 1: 0.6-1.4 are used as raw materials, the lipase Lipozyme RM IM is uniformly filled in a reaction channel by taking the lipase Lipozyme RM IM as a catalyst and methanol as a reaction solvent, firstly, dissolving aniline compound shown in formula 1 with methanol, then filling the aniline compound into a first syringe, dissolving styrene oxide with methanol, then filling a second syringe into the same syringe pump, then under the synchronous push of an injection pump, the raw materials and the reaction solvent are converged through the Y-shaped or T-shaped pipeline and then enter a reaction channel for reaction, the reaction temperature is controlled to be 30-50 ℃, the reaction time is 10-30 min, collecting reaction liquid on line by a product collector, and carrying out aftertreatment on the reaction liquid to obtain the phenethyl alcohol type 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 styrene 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 food grade lipase (ec3.1.1.3) specific to 1,3 sites on granular silica gel, which is commercially available from novozymes (novozymes). It is produced by submerged fermentation of a genetically modified Aspergillus oryzae (Aspergillus oryzae) microorganism obtained from Rhizomucormihei.
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 the styrene 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 of the invention can be collected on line, and the obtained reaction liquid can be used for preparing the phenethyl alcohol beta-amino alcohol derivative by a conventional post-treatment method. The conventional post-treatment method may be: and (2) distilling the obtained reaction liquid under reduced pressure to remove the solvent, filling the reaction liquid into a column by using a 200-mesh 300-mesh silica gel wet method, wherein the volume ratio of an elution reagent to ethyl acetate is 9:1, dissolving the obtained sample by using a small amount of elution reagent, then loading the sample into the column by using the wet method, collecting the eluent, tracking the elution process by using TLC (thin layer chromatography), combining the obtained eluents containing a single product, and evaporating to dryness to obtain a light yellow oily substance, namely the phenethyl alcohol beta-alkamine derivative shown in the formula 2.
Compared with the prior art, the invention has the beneficial effects that:
the method utilizes lipase to catalyze and synthesize the phenethyl alcohol beta-alkamine derivative shown in the formula 2 on line in the microfluidic channel reactor, greatly shortens the reaction time, and 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.
(IV) description of the 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.
(V) detailed description of the preferred embodiments
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- (2-methylphenylamino) phenethyl alcohol
The device is shown in figure 1: o-toluidine (2.0mmol) was dissolved in 10mL of NaOH, and styrene oxide (2.0mmol) was dissolved in 10mL of NaOH, and the solution was filled in a 10mL syringe for use. 0.87g of lipase lipozymeRM IM is uniformly filled in the reaction channel, and two paths of reaction liquid are respectively driven by a PHD2000 injection pump to be 15.6 mu L/min-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 20min, 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, dissolving a sample in a small amount of an elution reagent, namely petroleum ether and ethyl acetate which are 9:1, wherein the column height is 35cm, the column diameter is 4.5cm, filling the sample into the column by using the wet method, and collecting eluent at the flow rate of 2 mL/min-1And simultaneously tracking the elution process by TLC (thin layer chromatography), merging the obtained eluates containing single products, evaporating to obtain a light yellow oily substance to obtain 2- (2-methylphenylamino) phenethyl alcohol, and detecting the conversion rate of the 2- (2-methylphenylamino) phenethyl alcohol by HPLC (high performance liquid chromatography) and the selectivity of the 2- (2-methylphenylamino) phenethyl alcohol to be 100%.
The nuclear magnetic characterization results were as follows:
1H NMR(500MHz,CDCl3):δ＝7.42-7.26(m,5H),7.16-6.94(m, 1H),6.69(t,J＝7.4Hz,1H),6.30(d,J＝8.3Hz,1H),4.57-4.53(m,1 H),3.77-3.83(m,2H),2.23(s,3H).13C NMR(125MHz,CDCl3):δ＝ 145.5,140.2,138.9,129.8,129.5,127.6,121.5,116.9,110.9,66.3,61.5, 22.2.
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:
TABLE 1 Effect of solvent on the reaction
The results in Table 1 show that when the amount ratio of o-toluidine to styrene oxide substrate substance was 1:1, the flow rate was 15.6. mu.L.min-1The reaction time is 20min, the reaction temperature is 35 ℃, and the conversion rate and the selectivity of the reaction are 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 temperature was controlled at 35 ℃ by varying the ratio of the amounts of the substrate substances of o-toluidine and styrene oxide in the microfluidic microchannel reactor based on the amount of o-toluidine, and the results are shown in Table 2, which is otherwise the same as in example 1:
TABLE 2 influence of the ratio of the amounts of o-toluidine and styrene oxide substrate substances on the reaction
| Examples | O-toluidine and styrene oxide | Conversion rate [ 2 ]％] | Selectivity [% ]] |
| 6 | 1:0.6 | 53 | 87 |
| 7 | 1:0.8 | 78 | 98 |
| 1 | 1:1 | 92 | 100 |
| 8 | 1:1.2 | 86 | 97 |
| 9 | 1:1.4 | 80 | 87 |
The results in Table 2 show that the flow rate was 15.6. mu.L.min-1The reaction time is 20min, 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 styrene oxide, and when the ratio of the substrate to the o-toluidine to the styrene oxide is 1:1, the conversion rate and the selectivity of the reaction are optimal, so that the optimal amount of the substrate substance in the microfluidic microchannel reactor is the optimal amount in the inventionThe ratio 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:
table 3: influence of temperature on the reaction
| Examples | Temperature [ deg.C ]] | Conversion [% ]] | Selectivity [% ]] |
| 10 | 30 | 80 | 100 |
| 1 | 35 | 92 | 100 |
| 11 | 40 | 87 | 98 |
| 12 | 45 | 82 | 97 |
| 13 | 50 | 77 | 95 |
The results in Table 3 show that the flow rate was 15.6. mu.L.min-1The reaction time is 20min, the MeOH is used as an organic solvent in the reactor, the quantity ratio of reactants o-toluidine to styrene oxide is 1:1, the conversion rate and the selectivity of the reaction are optimal when the reaction temperature is 35 ℃, and the activity of the enzyme is influenced when the temperature 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:
table 4: influence of reaction time on the reaction
| Examples | Time [ min ]] | Conversion [% ]] | Selectivity [% ]] |
| 14 | 10 | 36 | 100 |
| 15 | 15 | 75 | 100 |
| 1 | 20 | 92 | 100 |
| 16 | 25 | 88 | 98 |
| 17 | 30 | 82 | 97 |
The results in Table 4 show that when MeOH is used as the organic solvent in the reactor, the amounts of the reactants o-toluidine and styrene oxide are 1:1, the reaction temperature is 35 ℃, and the reaction time is 20min, the reaction conversion is 92% 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.
Table 5: effect of different enzymes on reaction conversion and selectivity
The results in Table 5 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- (2-methylphenylamino) phenethyl alcohol was 44%. By using Novozym 435 as a catalytic reaction, the conversion rate of 2- (2-methyl phenylamino) phenethyl alcohol is only 15%. From the results in table 5, 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 a conversion of 92% and a selectivity of 100% for o-toluidine.
Example 18: synthesis of 2- (3-methylphenylamino) phenethyl alcohol
The device is shown in figure 1: m-toluidine (2.0mmol) was dissolved in 10mL of MeOH, and styrene oxide (2.0mmol) was dissolved in 10mL of MeOH, which were then separately filled in a 10mL syringe for use. 0.87g of lipase lipozymeRM IM is uniformly filled in the reaction channel, and two paths of reaction liquid are respectively driven by a PHD2000 injection pump to be 15.6 mu L/min-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 20min, 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, dissolving a sample in a small amount of an elution reagent, namely petroleum ether and ethyl acetate which are 9:1, wherein the column height is 35cm, the column diameter is 4.5cm, filling the sample into the column by using the wet method, and collecting eluent at the flow rate of 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- (3-methylphenylamino) phenethyl alcohol, and detecting the conversion rate of the 2- (3-methylphenylamino) phenethyl alcohol by HPLC (high performance liquid chromatography) and the selectivity of the 2- (3-methylphenylamino) phenethyl alcohol to be 98 percent.
The nuclear magnetic characterization results were as follows:
1H NMR(500MHz,CDCl3):δ＝7.46-7.25(m,5H),7.08(t,J＝7.8 Hz,1H),6.82-6.65(m,3H),4.52-4.48(m,1H),3.95-3.90(m,1H), 3.77-3.70(m,1H),2.30(s,3H).13C NMR(125MHz,CDCl3):δ＝145.8, 140.2,138.9,129.8,129.5,127.6,127.0,121.5,116.9,110.9,66.3,61.5, 22.2.
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:
TABLE 6 influence of solvent on the reaction
| Examples | Solvent(s) | Conversion [% ]] | Selectivity [% ]] |
| 19 | Ethanol | 93 | 99 |
| 18 | Methanol | 98 | 100 |
| 20 | N-octane | 89 | 98 |
| 21 | N-hexane | 85 | 93 |
| 22 | Petroleum ether | 76 | 95 |
The results in Table 6 show that when the amount ratio of m-toluidine to styrene oxide substrate substance was 1:1, the flow rate was 15.6. mu.L.min-1The reaction time is 20min, the reaction temperature is 35 ℃, and the conversion rate and the selectivity of the reaction are 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 ratio of the amounts of toluidine and styrene oxide as substrate materials in the microfluidic microchannel reactor was varied based on the amount of m-toluidine, and the temperature was controlled at 35 ℃ as in example 18, and the results are shown in Table 7:
TABLE 7 influence of the ratio of the amounts of m-toluidine and styrene oxide substrate substances on the reaction
| Examples | M-toluidine and styrene oxide | Conversion [% ]] | Selectivity [% ]] |
| 23 | 1:0.6 | 56 | 88 |
| 24 | 1:0.8 | 77 | 98 |
| 18 | 1:1 | 98 | 100 |
| 25 | 1:1.2 | 91 | 98 |
| 26 | 1:1.4 | 84 | 87 |
TABLE 7The results showed that the flow rate was 15.6. mu.L.min-1The reaction time is 20min, 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 styrene oxide, and when the substrate ratio of m-toluidine to styrene oxide is 1:1, the conversion rate and the selectivity of the reaction are optimal, so that the optimal substrate mass ratio 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:
table 8: influence of temperature on the reaction
| Examples | Temperature [ deg.C ]] | Conversion [% ]] | Selectivity [% ]] |
| 27 | 30 | 89 | 100 |
| 18 | 35 | 98 | 100 |
| 28 | 40 | 95 | 99 |
| 29 | 45 | 90 | 98 |
| 30 | 50 | 86 | 93 |
The results in Table 8 show that the flow rate was 15.6. mu.L.min-1The reaction time is 20min, the MeOH is used as an organic solvent in the reactor, the quantity ratio of reactants of m-toluidine and styrene oxide is 1:1, the conversion rate and the selectivity of the reaction are optimal when the reaction temperature is 35 ℃, and the activity of the enzyme is influenced when the temperature 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:
table 9: influence of reaction time on the reaction
| Examples | Time [ min ]] | Transformation ofRate [% ]] | Selectivity [% ]] |
| 31 | 10 | 43 | 100 |
| 32 | 15 | 82 | 100 |
| 18 | 20 | 98 | 100 |
| 33 | 25 | 96 | 99 |
| 34 | 30 | 92 | 98 |
The results in Table 9 show that when MeOH is used as the organic solvent in the reactor, the amounts of the reactants m-toluidine and styrene oxide were 1:1, the reaction temperature was 35 ℃ and the reaction time was 20min, the reaction conversion was 98% and the selectivity was 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.
Table 10: effect of different enzymes on reaction conversion and selectivity
| Comparative example | Enzyme source | Conversion [% ]] | Selectivity [% ]] |
| 5 | PPL | 25 | 75 |
| 6 | Novozym 435 | 18 | 96 |
| 7 | Bacillus subtilis alkaline protease | 30 | 88 |
| 8 | Lipozyme TMIM | 51 | 86 |
| Example 18 | Lipozyme RM IM | 98 | 100 |
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- (3-methylphenylamino) phenethyl alcohol was 51%. The conversion of 2- (3-methylphenylamino) phenethyl alcohol by Novozym 435 catalysis was only 18%. From the results in table 5, 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 98% conversion and 100% selectivity for m-toluidine.
Example 35: synthesis of 2- (4-methylphenylamino) phenethyl alcohol
The device is shown in figure 1: p-toluidine (2.0mmol) was dissolved in 10mL of MeOH, and styrene oxide (2.0mmol) was dissolved in 10mL of MeOH, which were then separately filled in a 10mL syringe for use. 0.87g of lipase lipozymeRM IM is uniformly filled in the reaction channel, and two paths of reaction liquid are respectively driven by a PHD2000 injection pump to be 15.6 mu L/min-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 20min, and the reaction result is tracked and detected through thin-layer chromatography TLC.
Collecting reaction liquid on line by a product collector, and distilling under reduced pressureRemoving solvent, loading into 200-mesh 300-mesh silica gel wet column with petroleum ether as eluting reagent, ethyl acetate 9:1, column height 35cm, column diameter 4.5cm, dissolving sample with small amount of eluting reagent, loading into the column by wet method, collecting eluent at flow rate of 2 mL/min-1And simultaneously tracking the elution process by TLC (thin layer chromatography), merging the obtained eluates containing single products, evaporating to obtain a light yellow solid, obtaining 2- (4-methylphenylamino) phenethyl alcohol, and detecting the conversion rate of the 2- (4-methylphenylamino) phenethyl alcohol by HPLC (high performance liquid chromatography) and the selectivity of the 2- (4-methylphenylamino) phenethyl alcohol to be 100%.
The nuclear magnetic characterization results were as follows:
1H NMR(500MHz,CDCl3):δ＝7.31-7.22(m,5H),6.91(d,J＝ 8.5Hz,2H),6.47(d,J＝8.4Hz,2H),4.46(m,1H),3.91(dd,J＝10.8, 4.0Hz,1H),3.73(dd,J＝11.3,7.3Hz,1H),2.19(s,3H).13C NMR (125MHz,CDCl3):δ＝144.9,140.2,129.8,128.6,128.0,127.1,126.7, 113.7,66.1,61.5,22.3.
examples 36 to 39
The solvent in the microfluidic microchannel reactor was changed, the temperature was controlled at 35 ℃, and the results are shown in table 11, which is otherwise the same as in example 35:
TABLE 11 influence of solvent on the reaction
| Examples | Solvent(s) | Conversion [% ]] | Selectivity [% ]] |
| 36 | Ethanol | 91 | 98 |
| 35 | Methanol | 97 | 100 |
| 37 | N-octane | 87 | 98 |
| 38 | N-hexane | 82 | 96 |
| 39 | Petroleum ether | 73 | 95 |
The results in Table 11 show that when the amount ratio of p-toluidine to styrene oxide substrate substance was 1:1, the flow rate was 15.6. mu.L.min-1The reaction time is 20min, the reaction temperature is 35 ℃, and the conversion rate and the selectivity of the reaction are optimal when the reactor takes MeOH as an organic solvent, so that the optimal solvent in the microfluidic microchannel reactor is the methanol.
Examples 40 to 43
The temperature was controlled at 35 ℃ by varying the ratio of the amounts of the substrate substances p-toluidine and styrene oxide in the microfluidic microchannel reactor based on the amount of p-toluidine, and the results are shown in Table 12 in the same manner as in example 35:
TABLE 12 influence of the ratio of the amounts of p-toluidine and styrene oxide substrate substances on the reaction
The results in Table 12 show that the flow rate was 15.6. mu.L.min-1The reaction time is 20min, 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 styrene oxide, and when the ratio of the substrate to the toluidine to the styrene oxide is 1:1, the conversion rate and the selectivity of the reaction are optimal, so that the ratio of the optimal substrate substance in the microfluidic microchannel reactor is 1: 1.
Examples 44 to 47
The temperature of the microfluidic channel reactor was changed, and the reaction results are shown in Table 13 in the same manner as in example 35:
table 13: influence of temperature on the reaction
| Examples | Temperature [ deg.C ]] | Conversion [% ]] | Selectivity [% ]] |
| 44 | 30 | 86 | 96 |
| 35 | 35 | 97 | 99 |
| 45 | 40 | 93 | 99 |
| 46 | 45 | 88 | 96 |
| 47 | 50 | 83 | 95 |
The results in Table 13 show that the flow rate was 15.6. mu.L.min-1The reaction time is 20min, the reactor uses MeOH as an organic solvent, the quantity ratio of reactants p-toluidine and styrene oxide is 1:1, the conversion rate of the reaction is optimal when the reaction temperature is 35 ℃, and the activity of the enzyme is influenced by the temperature which is too high or too low. Therefore, the optimal temperature in the microfluidic microchannel reactor is 35 ℃.
Examples 48 to 51
The reaction time of the microfluidic channel reactor was changed, and the reaction results are shown in Table 14 in the same manner as in example 35:
table 14: influence of reaction time on the reaction
| Examples | Time [ min ]] | Conversion [% ]] | Selectivity [% ]] |
| 48 | 10 | 42 | 94 |
| 49 | 15 | 80 | 95 |
| 35 | 20 | 97 | 99 |
| 50 | 25 | 94 | 98 |
| 51 | 30 | 89 | 97 |
The results in Table 14 show that when MeOH is used as the organic solvent in the reactor, the amounts of p-toluidine and styrene oxide are 1:1, the reaction temperature is 35 ℃ and the reaction time is 20min, the reaction conversion is 97% and the selectivity is 100%. Therefore, the optimal reaction time in the microfluidic microchannel reactor is 20 min.
Comparative examples 9 to 12
The results are shown in Table 15 for the same examples 35 except that the catalysts in the microfluidic microchannel reactor were changed to porcine pancreatic lipase PPL (comparative example 9), lipase Novozym 435 (comparative example 10), subtilisin alkaline protease (comparative example 11), and lipase TM IM (comparative example 12), respectively.
Table 15: effect of different enzymes on reaction conversion and selectivity
| Comparative example | Enzyme source | Conversion [% ]] | Selectivity [% ]] |
| 9 | PPL | 24 | 76 |
| 10 | Novozym 435 | 16 | 96 |
| 11 | Bacillus subtilis alkaline protease | 28 | 87 |
| 12 | Lipozyme TMIM | 50 | 88 |
| Example 35 | Lipozyme RM IM | 97 | 100 |
The results in Table 15 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- (4-methylphenylamino) phenethyl alcohol was 50%. The conversion of 2- (4-methylphenylamino) phenethyl alcohol by Novozym 435 catalysis was only 16%. From the results in table 5, 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 a conversion of 97% and a selectivity of 100% for p-toluidine.
Example 52: synthesis of 2- (N-methylphenylamino) phenethyl alcohol
The device is shown in figure 1: n-methylaniline (2.0mmol) was dissolved in 10mL of MeOH, and styrene oxide (2.0mmol) was dissolved in 10mL of MeOH, which were then separately filled in 10mL syringes. 0.87g Lipase LipThe ozymeRM IM is uniformly filled in the reaction channel, and the two paths of reaction liquid are respectively 15.6 mu L/min under the driving of a PHD2000 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 20min, 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, dissolving a sample in a small amount of an elution reagent, namely petroleum ether and ethyl acetate which are 9:1, wherein the column height is 35cm, the column diameter is 4.5cm, filling the sample into the column by using the wet method, and collecting eluent at the flow rate of 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- (N-methylanilino) phenethyl alcohol, and detecting the conversion rate of the 2- (N-methylanilino) phenethyl alcohol by HPLC (high performance liquid chromatography) and the selectivity of the 2- (N-methylanilino) phenethyl alcohol is 90 percent.
The nuclear magnetic characterization results were as follows:
1H NMR(500MHz,CDCl3):δ＝7.26-7.32(m,5H),7.16-7.14(m, 2H),6.96(d,J＝7.9Hz,2H),6.84(m,1H),5.11(dd,J＝8.7,6.0Hz,1 H),4.16(m,2H),2.70(s,3H).13C NMR(125MHz,CDCl3):δ＝149.1, 138.2,129.4,128.5,127.7,127.2,117.9,113.3,65.4,61.9,33.1.
examples 53 to 56
The solvent in the microfluidic microchannel reactor was changed, the temperature was controlled at 35 ℃, and the results are shown in table 16 in the same manner as in example 52:
TABLE 16 influence of solvent on the reaction
The results in Table 16 show that when the amount ratio of N-methylaniline to styrene oxide substrate material was 1:1The flow rate is 15.6 mu L/min-1The reaction time is 20min, the reaction temperature is 35 ℃, and the conversion rate and the selectivity of the reaction are optimal when the reactor takes MeOH as an organic solvent, so that the optimal solvent in the microfluidic microchannel reactor is the methanol.
Examples 57 to 60
The temperature was controlled at 35 ℃ by varying the ratio of the amounts of substrate materials of N-methylaniline and styrene oxide in the microfluidic microchannel reactor based on the amount of N-methylaniline used, as in example 52, and the results are shown in Table 17:
TABLE 17 influence of the ratio of the amounts of N-methylaniline and styrene oxide substrate material on the reaction
| Examples | N-methylaniline and styrene oxide | Conversion [% ]] | Selectivity [% ]] |
| 57 | 1:0.6 | 53 | 89 |
| 58 | 1:0.8 | 75 | 97 |
| 52 | 1:1 | 90 | 100 |
| 59 | 1:1.2 | 85 | 97 |
| 60 | 1:1.4 | 79 | 85 |
The results in Table 17 show that the flow rate was 15.6. mu.L.min-1The reaction time is 20min, the reaction temperature is 35 ℃, MeOH is used as an organic solvent in the reactor, the conversion rate of the reaction is increased along with the increase of the reactant styrene oxide, and when the substrate ratio N-methylaniline to styrene oxide is 1:1, the conversion rate and the selectivity of the reaction are optimal, so that the ratio of the optimal substrate material amount in the microfluidic microchannel reactor is 1: 1.
Examples 61 to 64
The temperature of the microfluidic channel reactor was changed, and the reaction results are shown in Table 18 in the same manner as in example 52:
table 18: influence of temperature on the reaction
| Examples | Temperature [ deg.C ]] | Conversion [% ]] | Selectivity [% ]] |
| 61 | 30 | 78 | 100 |
| 52 | 35 | 90 | 100 |
| 62 | 40 | 85 | 98 |
| 63 | 45 | 78 | 96 |
| 64 | 50 | 77 | 95 |
The results in Table 18 show that the flow rate was 15.6. mu.L.min-1The reaction time is 20min, the MeOH is used as an organic solvent in the reactor, the quantity ratio of reactants of N-methylaniline and styrene oxide is 1:1, the conversion rate and the selectivity of the reaction are optimal when the reaction temperature is 35 ℃, and the activity of the enzyme is influenced when the temperature is too high or too low. Therefore, the microfluidic microchannel of the inventionThe optimum temperature in the reactor was 35 ℃.
Examples 65 to 68
The reaction time of the microfluidic channel reactor was changed, and the reaction results are shown in Table 19 in the same manner as in example 52:
table 19: influence of reaction time on the reaction
The results in Table 19 show that when the reactor uses MeOH as an organic solvent, the amounts of the reactants N-methylaniline and styrene oxide were 1:1, the reaction temperature was 35 ℃ and the reaction conversion was 90% when the reaction time was 20 min. Therefore, the optimal reaction time in the microfluidic microchannel reactor is 20 min.
Comparative examples 13 to 16
The results are shown in Table 20 for the same examples 52 except that the catalysts in the microfluidic microchannel reactor were changed to porcine pancreatic lipase PPL (comparative example 13), lipase Novozym 435 (comparative example 14), subtilisin alkaline protease (comparative example 15), and lipase TM IM (comparative example 16), respectively.
Table 20: effect of different enzymes on reaction conversion and selectivity
| Comparative example | Enzyme source | Conversion [% ]] | Selectivity [% ]] |
| 13 | PPL | 20 | 76 |
| 14 | Novozym 435 | 14 | 96 |
| 15 | Bacillus subtilis alkaline protease | 23 | 85 |
| 16 | Lipozyme TMIM | 46 | 83 |
| Example 1 | Lipozyme RM IM | 90 | 100 |
The results in Table 20 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- (N-methylphenylamino) phenethyl alcohol was 46%. The conversion of 2- (N-methylphenylamino) phenethyl alcohol by Novozym 435 catalysis was only 14%. From the results in table 5, the most effective catalyst for the ring-opening reaction of enzymatic epoxides in microfluidic channel reactors is the lipase Lipozyme RM IM with 90% conversion and 100% selectivity for N-methylaniline.
Example 69: synthesis of 2-phenylaminophenethyl alcohol
The device is shown in figure 1: aniline (2.0mmol) was dissolved in 10mL of MeOH and styrene oxide (2.0mmol) was dissolved in 10mL of MeOH before being separately loaded into a 10mL syringe for use. 0.87g of lipase lipozymeRM IM is uniformly filled in the reaction channel, and two paths of reaction liquid are respectively driven by a PHD2000 injection pump to be 15.6 mu L/min-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 20min, 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, dissolving a sample in a small amount of an elution reagent, namely petroleum ether and ethyl acetate which are 9:1, wherein the column height is 35cm, the column diameter is 4.5cm, filling the sample into the column by using the wet method, and collecting eluent at the flow rate of 2 mL/min-1And simultaneously tracking the elution process by TLC (thin layer chromatography), merging and evaporating the obtained eluent containing the single product to dryness to obtain a light yellow oily substance to obtain 2-phenylaminophenethyl alcohol, and detecting the conversion rate of the 2-phenylaminophenethyl alcohol by HPLC (high performance liquid chromatography) and the selectivity of the 2-phenylaminophenethyl alcohol to be 100%.
The nuclear magnetic characterization results were as follows:
1H NMR(500MHz,CDCl3):δ＝7.42-7.26(m,5H),7.14(dd,J＝ 8.5,7.5Hz,2H),6.88-6.77(m,3H),4.58(m,1H),3.99(d,J＝5.9Hz, 2H),3.70(t,J＝7.1Hz,1H).13C NMR(125MHz,CDCl3):δ＝143.6, 137.6,129.2,128.9,128.2,127.4,120.9,116.7,66.1,63.0.
examples 70 to 73
The solvent in the microfluidic microchannel reactor was changed, the temperature was controlled at 35 ℃, and the results are shown in table 21 in the same manner as in example 69:
TABLE 21 influence of solvents on the reaction
| Examples | Solvent(s) | Conversion [% ]] | Selectivity [% ]] |
| 70 | Ethanol | 90 | 98 |
| 69 | Methanol | 95 | 100 |
| 71 | N-octane | 84 | 98 |
| 72 | N-hexane | 79 | 97 |
| 73 | Petroleum ether | 68 | 95 |
The results in Table 21 show that when the amount ratio of aniline to styrene oxide substrate material was 1:1, the flow rate was 15.6. mu.L.min-1The reaction time is 20min, 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 74 to 77
The temperature was controlled at 35 ℃ by varying the ratio of the amounts of aniline and styrene oxide substrate material in the microfluidic microchannel reactor based on the amount of aniline used, as in example 69, and the results are shown in Table 22:
TABLE 22 influence of the ratio of the amounts of aniline and styrene oxide substrate substances on the reaction
| Examples | Aniline and styrene oxide | Conversion [% ]] | Selectivity [% ]] |
| 74 | 1:0.6 | 58 | 92 |
| 75 | 1:0.8 | 78 | 98 |
| 69 | 1:1 | 95 | 100 |
| 76 | 1:1.2 | 89 | 97 |
| 77 | 1:1.4 | 85 | 87 |
The results in Table 22 show that the flow rate was 15.6. mu.L.min-1The reaction time is 20min, the reaction temperature is 35 ℃, MeOH is used as an organic solvent in the reactor, the conversion rate of the reaction is increased along with the increase of the reactant styrene oxide, and when the substrate ratio aniline and styrene oxide is 1:1, the conversion rate and selectivity of the reaction are optimal, so that the ratio of the optimal substrate amount in the microfluidic microchannel reactor is 1: 1.
Examples 78 to 81
The temperature of the microfluidic channel reactor was changed, and the reaction results are shown in Table 23 in the same manner as in example 69:
table 23: influence of temperature on the reaction
The results in Table 23 show that the flow rate was 15.6. mu.L.min-1The reaction time is 20min, the MeOH is used as an organic solvent in the reactor, the quantity ratio of the aniline reactant to the styrene oxide reactant is 1:1, the conversion rate and the selectivity of the reaction are optimal when the reaction temperature is 35 ℃, and the activity of the enzyme is influenced by the temperature which is too high or too low. Therefore, the optimal temperature in the microfluidic microchannel reactor is 35 ℃.
Examples 82 to 85
The reaction time of the microfluidic channel reactor was changed, and the reaction results are shown in Table 24 in the same manner as in example 69:
table 24: influence of reaction time on the reaction
| Examples | Time [ min ]] | Conversion [% ]] | Selectivity [% ]] |
| 82 | 10 | 39 | 100 |
| 83 | 15 | 77 | 100 |
| 69 | 20 | 95 | 100 |
| 84 | 25 | 92 | 98 |
| 85 | 30 | 86 | 97 |
The results in Table 24 show that when the reactor uses MeOH as the organic solvent, the amounts of aniline and styrene oxide as the reactants were 1:1, the reaction temperature was 35 ℃ and the reaction time was 20min, the reaction conversion was 95% and the selectivity was 100%. Therefore, the optimal reaction time in the microfluidic microchannel reactor is 20 min.
Comparative examples 17 to 20
The results are shown in Table 25 for the same examples 69 except that the catalysts in the microfluidic microchannel reactor were changed to porcine pancreatic lipase PPL (comparative example 17), lipase Novozym 435 (comparative example 18), subtilisin alkaline protease (comparative example 19), and lipase TM IM (comparative example 20).
Table 25: effect of different enzymes on reaction conversion and selectivity
| Comparative example | Enzyme source | Conversion [% ]] | Selectivity [% ]] |
| 17 | PPL | 22 | 74 |
| 18 | Novozym 435 | 15 | 96 |
| 19 | Bacillus subtilis alkaline protease | 26 | 87 |
| 20 | Lipozyme TMIM | 43 | 85 |
| Example 69 | Lipozyme RM IM | 95 | 100 |
The results in Table 25 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 with a conversion of 43% 2-phenylaminophenethyl alcohol. While the conversion of 2-phenylaminophenethyl alcohol by Novozym 435 catalytic reaction is only 15%. From the results in table 5, the most effective catalyst for the ring-opening reaction of enzymatic epoxides in microfluidic channel reactors was the lipase Lipozyme RM IM with 95% conversion of aniline and 100% selectivity.
Claims (9)
1. A method for synthesizing phenethyl alcohol 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, taking aniline compounds shown in a formula 1 and styrene oxide 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 ℃, reacting for 10-30 min, collecting reaction liquid on line through a product collector, and carrying out post-treatment on the reaction liquid to obtain the phenethyl alcohol beta-amino alcohol derivative shown in the formula 2; the mass ratio of the aniline compound shown in the formula 1 to the styrene 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 styrene oxide is 0.12-0.28 mmol/mL
In formula 1 or formula 2, R is1Is H or CH3；
When said R is1When is H, said R2Is H or CH3；
When said R is1Is CH3When R is said2Is H.
2. The method of claim 1, wherein the lipase catalyzes an on-line phenethyl alcohol β -aminoalcohol derivative, characterized in that: 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 on-line synthesis of phenethyl alcohol beta-amino alcohol derivatives catalyzed by lipase as claimed in claim 2, characterized in that: the method comprises the following steps: the aniline compound represented by the formula 1 and styrene oxide with the mass ratio of 1: 0.6-1.4 are used as raw materials, the lipase Lipozyme RM IM is uniformly filled in a reaction channel by taking the lipase Lipozyme RM IM as a catalyst and methanol as a reaction solvent, firstly, dissolving aniline compound shown in formula 1 with methanol, then filling the aniline compound into a first syringe, dissolving styrene oxide with methanol, then filling a second syringe into the same syringe pump, then under the synchronous push of an injection pump, the raw materials and the reaction solvent are converged through the Y-shaped or T-shaped pipeline and then enter a reaction channel for reaction, the reaction temperature is controlled to be 30-50 ℃, the reaction time is 10-30 min, collecting reaction liquid on line by a product collector, and carrying out aftertreatment on the reaction liquid to obtain the phenethyl alcohol type 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 styrene oxide is 0.12-0.28 mmol/mL.
4. The method for the on-line synthesis of phenethyl alcohol beta-amino alcohol derivatives catalyzed by lipase as claimed in claim 1, characterized in that: the microfluidic channel reactor comprises a thermostat, and the reaction channel is arranged in the thermostat.
5. The method for the on-line synthesis of phenethyl alcohol beta-amino alcohol derivatives catalyzed by lipase as claimed in claim 3, characterized in that: the microfluidic channel reactor comprises a thermostat, and the reaction channel is arranged in the thermostat.
6. The method for the on-line synthesis of the phenethyl alcohol beta-amino alcohol derivatives under the catalysis of the lipase as claimed in any one of claims 1 to 5, characterized in that: the mass ratio of the aniline compound represented by the formula 1 to the styrene oxide is 1: 0.8-1.2.
7. The method for the on-line synthesis of the phenethyl alcohol beta-amino alcohol derivatives under the catalysis of the lipase as claimed in any one of claims 1 to 5, characterized in that: the ring-opening reaction temperature is 30-40 ℃, and the ring-opening reaction time is 15-25 min.
8. The method for the on-line synthesis of the phenethyl alcohol beta-amino alcohol derivatives under the catalysis of the lipase as claimed in any one of claims 1 to 5, characterized in that: the mass ratio of the aniline compound shown in the formula 1 to the styrene oxide is 1: 1.
9. The method for the on-line synthesis of the phenethyl alcohol beta-amino alcohol derivatives under the catalysis of the lipase as claimed in any one of claims 1 to 5, characterized in that: the post-treatment method of the reaction solution 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, carrying out wet column packing by using 200-mesh 300-mesh silica gel, 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, carrying out wet column packing, collecting eluent, tracking an elution process by TLC (thin layer chromatography), combining the obtained eluent containing a single product, and evaporating to dryness to obtain the phenethyl alcohol type beta-alkamine derivative.
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| CN111676255A (en) * | 2020-05-19 | 2020-09-18 | 浙江农林大学 | Method for synthesizing 3-phenylaminopropylhydroxamic acid on line under catalysis of lipase |
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