Method for 5'-O-acetyl uridine online synthesis through lipase catalysis

A technology of acetyluridine and lipase, applied in biochemical equipment and methods, biochemical instruments, enzyme production/bioreactors, etc., can solve the problems of long reaction time, low conversion rate and selectivity, and reduce reaction cost , short reaction time, high conversion and selectivity

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

AI Technical Summary

Problems solved by technology

[0006] At present, many domestic and foreign scholars 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-acetyluridine in a microchannel reactor, aiming to find an efficient and environmentally friendly 5'-O-acetyluridine On-line controllable selective synthesis of glycosides

Method used

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  • Method for 5'-O-acetyl uridine online synthesis through lipase catalysis
  • Method for 5'-O-acetyl uridine online synthesis through lipase catalysis
  • Method for 5'-O-acetyl uridine online synthesis through lipase catalysis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0026]

[0027] device reference figure 1 : Dissolve uridine (1.0mmol) in 1.33mL of DMSO and 8.67mL of tert-amyl alcohol, and dissolve vinyl acetate (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] The reaction solution was collected online by the product collector, the solvent was removed by distillation under reduced pressure, and the column was wet packed with 200-300 mesh silica ge...

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 uridine to vinyl acetate is 1:9, and when the concentration of uridine in the reaction system is 0.05mmol / mL, the conversion rate varies with that in the reactor. The organic solvent volume ratio increases and increases, and reaches the best when the DMSO:tert-amyl alcohol volume ratio reaches 1:14, and then continuing to increase the volume ratio will result in incomplete dissolution of the reactant and reduce the conversion rate. Therefore, the optimal organic solvent volume ratio in the microfluidic microchannel rea...

Embodiment 7-11

[0038] Change the substrate molar ratio of uridine to vinyl acetate in the microfluidic microchannel reactor, control the temperature at 50°C, and the others are the same as in Example 1. The results are shown in Table 2:

[0039] Table 2: Effect of molar ratio of uridine to vinyl acetate substrate on reaction

[0040]

[0041] 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 when the uridine concentration in the reaction system is 0.05mmol / mL, with the reactant With the increase of vinyl acetate, the conversion rate of the reaction also increases, and when the substrate molar ratio is 1:9, the conversion rate of the reaction is optimal, so the optimal substrate mole in the microfluidic microchannel reactor in the present invention The ratio is 1:9.

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Abstract

The invention discloses a method for 5'-O-acetyl uridine online synthesis through lipase catalysis. The method comprises the steps that dimethyl sulfoxide and tert-amyl alcohol serve as reactive solvents, uridine and acetic acid vinyl ester serve as raw materials, and 0.5-1.0 g of a lipase, namely Lipozyme TLIM, serves as a catalyst, wherein the volume ratio of the dimethyl sulfoxide to the tert-amyl alcohol is 1:(8-16), and the molar ratio of the uridine to the acetic acid vinyl ester is 1:(5-13). The raw materials and the reactive solvents are placed into an injector, and a reaction passage of a microfluidic passage reactor is uniformly filled with the lipase, namely the Lipozyme TLIM. Under pushing of an injection pump, the raw materials and the reactive solvents are continuously pumped into the reaction passage for acylation reaction. The inner diameter of the reaction passage of the microfluidic passage reactor is 0.8-2.4 mm, the length of the reaction passage is 0.5-1.0 m, the acylation reaction temperature is controlled to be 15-50 DEG C, and the acylation reaction time is 20-35 min. Through a product collector, reactive solution online collection is conducted, and after a reactive solution is subjected to conventional after-treatment, 5'-O-acetyl uridine is obtained. The method for 5'-O-acetyl uridine online synthesis through lipase catalysis has the advantages that the reaction time is short, the selectivity is high, and the productive rate is high.

Description

(1) Technical field [0001] The invention relates to a lipase-catalyzed online controllable selective synthesis of 5'-O-acetyluridine (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 three steps of "group protection-esterification-deprotect...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12M1/40C12P19/38
CPCC12M21/18C12M23/16C12P19/385
Inventor 杜理华徐亮亮成柄灼罗锡平
Owner ZHEJIANG UNIV OF TECH
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