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A Method for Online Synthesis of Phenylalcohol β-Amino Alcohol Derivatives Based on Flow Chemistry Enzymatic Aminolysis Reaction

A technology of phenylethyl alcohol and amino alcohol, applied in biochemical equipment and methods, enzyme production/bioreactors, enzymology/microbiology devices, etc., can solve problems such as long reaction time and unsatisfactory conversion rate, and achieve reduction Effects of reaction cost, high conversion rate and selectivity, and shortened reaction time

Active Publication Date: 2021-04-06
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Candida rugosalipase from Candida rugosa lipase CRL (Candida rugosalipase from Candida rugosa) can effectively catalyze the reaction, but this method requires a long reaction time (8h ~ 12h), and the conversion rate for specific substrate reactions is not particularly ideal

Method used

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  • A Method for Online Synthesis of Phenylalcohol β-Amino Alcohol Derivatives Based on Flow Chemistry Enzymatic Aminolysis Reaction
  • A Method for Online Synthesis of Phenylalcohol β-Amino Alcohol Derivatives Based on Flow Chemistry Enzymatic Aminolysis Reaction
  • A Method for Online Synthesis of Phenylalcohol β-Amino Alcohol Derivatives Based on Flow Chemistry Enzymatic Aminolysis Reaction

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: the synthesis of 2-(2-methylanilino) phenethyl alcohol

[0037]

[0038] device reference figure 1 : Dissolve o-toluidine (2.0mmol) in 10mLMeOH, styrene oxide (2.0mmol) in 10mLMeOH, and then put them in 10mL syringes for use. 0.87g of lipase LipozymeRM IM was evenly filled in the reaction channel, driven by the PHD2000 syringe pump, the two reaction solutions were separated at 15.6 μL min -1 The flow rate enters the reaction channel through the "Y" joint for reaction, and the temperature of the reactor is controlled at 35°C by a water bath thermostat. The reaction solution flows continuously in the reaction channel for 20 minutes, and the reaction results are tracked and detected by thin-layer chromatography (TLC).

[0039] Collect the reaction solution online by the product collector, remove the solvent by distillation under reduced pressure, use 200-300 mesh silica gel wet packing column, elution reagent is sherwood oil: ethyl acetate=9:1, column hei...

Embodiment 2-5

[0043] The solvent in the microfluidic microchannel reactor was changed, and the temperature was controlled at 35°C. Others were the same as in Example 1. The results are shown in Table 1:

[0044] Table 1: Effect of solvent on reaction

[0045]

[0046]

[0047] The results in Table 1 show that when the ratio of the amount of o-toluidine and styrene oxide substrate is 1:1, the flow rate is 15.6 μL min -1 , the reaction time is 20min, and the reaction temperature is 35°C. When the reactor uses MeOH as the organic solvent, the conversion rate and selectivity of the reaction are optimal, so the best solvent in the microfluidic microchannel reactor in the present invention is methanol.

Embodiment 6-9

[0049] Based on the amount of o-toluidine, change the ratio of the amount of o-toluidine to the substrate substance of styrene oxide in the microfluidic microchannel reactor, and control the temperature at 35°C. Others are the same as in Example 1, and the results are shown in Table 2. Show:

[0050] Table 2: The impact of the ratio of the amount of o-toluidine and styrene oxide substrate substance on the reaction

[0051] Example o-toluidine and styrene oxide Conversion rate[%] 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

[0052] The results in Table 2 show that when the flow rate is 15.6 μL min -1 , the reaction time is 20min, and the reaction temperature is 35°C. The reactor uses MeOH as the organic solvent. With the increase of the reactant styrene oxide, the conversion rate of the reaction also increases. When the ratio of ethylene is 1:1, the conversion rate and selectivity ...

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Abstract

The invention discloses a method for on-line synthesis of phenylethanol β-amino alcohol derivatives based on flow chemical enzymatic aminolysis reaction: using methanol as a reaction solvent, aniline compounds and benzene oxide with a molar ratio of 1:0.6-1.4 Ethylene is used as a raw material, and lipase Lipozyme RM IM is used as a catalyst. The raw material and reaction solvent are placed in a syringe, and the lipase Lipozyme RM IM is evenly filled in the reaction channel of the microfluidic channel reactor, driven by a syringe pump. The raw materials and the reaction solvent are continuously fed into the reaction channel to carry out 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 ring-opening reaction temperature is controlled at 30 ~50°C, the ring-opening reaction time is 10-30min, the reaction solution is collected online by the product collector, and the reaction solution is subjected to conventional post-treatment to obtain phenylethyl alcohol β-amino alcohol derivatives. The invention has the advantages of short reaction time, high selectivity and high yield.

Description

[0001] (1) Technical field [0002] The invention relates to a method for online synthesis of phenethyl alcohol β-amino alcohol derivatives based on flow chemical enzymatic aminolysis reaction. [0003] (2) Background technology [0004] β-Amino alcohol is a widely used 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 aminoalcohols with both amino and hydroxyl functional groups have shown good chiral induction in the field of asymmetric catalysis. N atoms and O atoms with good coordination a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P13/00C12M1/40C12M1/00
Inventor 杜理华陈平锋龙瑞杰罗锡平周娜妮薛苗陶佳丽郑泽灿陈昱晗
Owner ZHEJIANG UNIV OF TECH
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