Method for synthesizing 5'-O-lauroyl-5-methyluridine on line through catalyzing of lipase

A methyl uridine, lipase technology, applied in biochemical equipment and methods, biochemical instruments, enzyme production/bioreactors, etc., can solve the problems of low conversion rate and selectivity, long reaction time, etc., to shorten the time Effects of reaction time, reduced reaction cost, high conversion and selectivity

Inactive Publication Date: 2017-11-24
ZHEJIANG UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, many scholars at home and abroad have studied the enzyme-catalyzed synthesis of nucleoside acylation in organic media, but this method mostly uses acylase for catalysis, which often requires a long reaction time (12-24h), and The conversion rate and selecti

Method used

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  • Method for synthesizing 5'-O-lauroyl-5-methyluridine on line through catalyzing of lipase
  • Method for synthesizing 5'-O-lauroyl-5-methyluridine on line through catalyzing of lipase
  • Method for synthesizing 5'-O-lauroyl-5-methyluridine on line through catalyzing of lipase

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0025] Example 1: Synthesis of 5'-O-lauroyl-5-methyluridine

[0026]

[0027] Device reference figure 1 : Dissolve 5-methyluridine (1.0 mmol) in 1.33 mL of DMSO and 8.67 mL of tert-amyl alcohol, and dissolve vinyl laurate (9.0 mmol) in 10 mL of tert-amyl alcohol, and then put them in 10 mL syringes for use. 0.87g lipase Lipozyme TLIM is evenly filled in the reaction channel. Driven by the PD 1200 syringe pump, the two reaction solutions are respectively 10.4μL·min -1 The flow rate of the reactor enters the reaction channel through the "Y" connector for reaction. The temperature of the reactor is controlled at 30°C through a water bath thermostat. The reaction solution flows continuously in the reaction channel for 30 minutes. The reaction result is tracked and detected by thin layer chromatography TLC.

[0028] Collect the reaction liquid online through the product collector, distill under reduced pressure to remove the solvent, and pack the column with 200-300 mesh silica gel wet m...

Example Embodiment

[0032] Example 2-6

[0033] The volume ratio of organic solvent in the microfluidic channel reactor was changed, and the temperature was controlled to 50°C. Others were the same as in Example 1. The reaction results are shown in Table 1:

[0034] Table 1: The effect of organic solvent ratio on the reaction

[0035]

[0036] The results in Table 1 show that when the flow rate is 10.4μL·min -1 The reaction time is 30min, the reaction temperature is 50℃, the molar ratio of reactant 5-methyluridine to vinyl laurate is 1:9, and the concentration of 5-methyluridine in the reaction system is 0.05mmol / At mL, the conversion rate increases with the increase of the organic solvent volume ratio in the reactor. When the volume ratio of DMSO:tert-amyl alcohol reaches 1:14, it reaches the best value. Further increasing the volume ratio will result in incomplete dissolution of the reactants. Reduce conversion rate. Therefore, the optimal organic solvent volume ratio in the microfluidic microchann...

Example Embodiment

[0037] Example 7-11

[0038] The substrate molar ratio of 5-methyluridine to vinyl laurate in the microfluidic microchannel reactor was changed, and the temperature was controlled to 50°C. Others were the same as in Example 1. The results are shown in Table 2:

[0039] Table 2: The influence of the molar ratio of 5-methyluridine to vinyl laurate substrate on the reaction

[0040]

[0041]

[0042] The results in Table 2 show that when the flow rate is 10.4μL·min -1 When the reaction time is 30min, the reaction temperature is 50℃, the volume ratio of organic solvent DMSO: tert-amyl alcohol in the reactor is 1:14, and the concentration of 5-methyluridine in the reaction system is 0.05mmol / mL, As the reactant vinyl laurate increases, the conversion rate of the reaction also increases. When the molar ratio of 5-methyluridine to vinyl laurate substrate is 1:9, the conversion rate of the reaction is optimal, so The best substrate molar ratio in the microfluidic microchannel reactor of the...

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Abstract

The invention discloses a method for synthesizing 5'-O-lauroyl-5-methyluridine on line through catalyzing of lipase. The method comprises the steps that dimethylsulfoxide and tert-amyl alcohol are used as reactive solvents, wherein the volume ratio of the dimethylsulfoxide to the tert-amyl alcohol is 1:(8-16); 5-methyluridine and vinyl laurate are used as raw materials, wherein the mole ratio of the 5-methyluridine to the vinyl laurate is 1:(5-13); 0.5-1.0 g of the lipase Lipozyme TLIM is used as a catalyst; the raw materials and the reactive solvents are put into an injector, a reaction channel of a microfluidic channel reactor is uniformly filled with the lipase Lipozyme TLIM, and under pushing of an injection pump, the raw materials and the reaction solvents are continuously injected into the reaction channel to conduct an acylation 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; the temperature of the acylation reaction is controlled to be 15-50 DEG C, and the time of the acylation reaction is 20-35 min; and reaction liquid is collected on line through a product collector and conventionally post-processed, and thus the 5'-O-lauroyl-5-methyluridine is obtained. The method has the advantages of short reaction time, high selectivity and high yield.

Description

(1) Technical field [0001] The invention relates to a lipase-catalyzed method for on-line controllable selective synthesis of 5'-O-lauroyl-5-methyluridine (2) Background technology [0002] Nucleoside drugs play an important role in the treatment of viral diseases. Among the antiviral drugs currently used clinically, nucleoside drugs account for more than 60%. Most nucleoside compounds are polyhydroxy compounds, which have defects such as high polarity, low intestinal permeability, poor fat solubility, high toxicity and side effects, and low oral bioavailability. After the nucleoside compound is modified by esterification, its fat solubility can be enhanced, its pharmacological activity can be improved, and its oral bioavailability can be improved. In the usual chemical esterification process, multiple hydroxyl groups may participate in the esterification, and the product is a mixture of monoester and polyester, so it needs to go through "group protection---esterification-...

Claims

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Application Information

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IPC IPC(8): C12P19/38C12M1/40
CPCC12M21/18C12M23/16C12P19/385
Inventor 杜理华蒋志鹏成柄灼罗锡平
Owner ZHEJIANG UNIV OF TECH
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