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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 selectivity of the reaction are not high, so we studied the lipase-catalyzed online synthesis of 5'-O-lauroyl-5-methyluridine in a microchannel reactor, aiming to find an efficient and environmentally friendly 5' On-line controllable selective synthesis of '-O-lauroyl-5-methyluridine

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

Embodiment 1

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

[0026]

[0027] device reference figure 1 : Dissolve 5-methyluridine (1.0mmol) in 1.33mL DMSO and 8.67mL of tert-amyl alcohol, and dissolve vinyl laurate (9.0mmol) in 10mL of tert-amyl alcohol, and then put them in 10mL syringes for use. 0.87g of lipase Lipozyme TLIM was evenly filled in the reaction channel, and driven by the PD 1200 syringe pump, the two reaction solutions were separated at 10.4 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 30°C by a water bath thermostat. The reaction solution flows continuously in the reaction channel for 30 minutes, and the reaction results are tracked and detected by thin-layer chromatography (TLC).

[0028] 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, the e...

Embodiment 2-6

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

[0034] Table 1: Effect of Organic Solvent Ratio on Reaction

[0035]

[0036] The results in Table 1 show that when the flow rate is 10.4 μL min -1 , the reaction time is 30min, the reaction temperature is 50°C, 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 / mL, the conversion rate increases with the increase of the organic solvent volume ratio in the reactor, and reaches the best when the DMSO: tert-amyl alcohol volume ratio reaches 1:14, and then continuing to increase the volume ratio will cause the reactant to dissolve incompletely and cause lower conversion rates. Therefore, the optimal organic solvent volume ratio in the microfluidic microchannel rea...

Embodiment 7-11

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

[0039] Table 2: Effect of 5-methyluridine and vinyl laurate substrate molar ratio on reaction

[0040]

[0041]

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

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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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