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Lipozyme-catalyzed on-line synthesizing method for 5'-O-ethylene hexanedioyl-5-methyluridine

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 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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  • Summary
  • 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 method of online synthesis of 5'-O-ethylene adipyl-5-methyluridine catalyzed by lipase in a microchannel reactor, aiming to find an efficient and environmentally friendly On-line controllable selective synthesis of 5'-O-ethylene adipyl-5-methyluridine

Method used

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  • Lipozyme-catalyzed on-line synthesizing method for 5'-O-ethylene hexanedioyl-5-methyluridine
  • Lipozyme-catalyzed on-line synthesizing method for 5'-O-ethylene hexanedioyl-5-methyluridine
  • Lipozyme-catalyzed on-line synthesizing method for 5'-O-ethylene hexanedioyl-5-methyluridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0026]

[0027] device reference figure 1 : Dissolve 5-methyluridine (1.0mmol) in 1.33mL of DMSO and 8.67mL of tert-amyl alcohol, and dissolve divinyl adipate (9.0mmol) in 10mL of tert-amyl alcohol, and then fill them in 10mL syringes spare. 0.87g of lipase Lipozyme TLIM was evenly filled in the reaction channel, driven by the PD1200 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 colum...

Embodiment 2-6

[0033] Change the organic solvent DMSO in the microfluidic channel reactor: the volume ratio of tert-amyl alcohol, the control temperature is 50 ° C, the others are the same as in Example 1, and the reaction results are as 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 divinyl adipate is 1:9, and the concentration of 5-methyluridine in the reaction system is 0.05 During mmol / mL, conversion rate increases with the increase of organic solvent volume ratio in the reactor, reaches optimum when DMSO: tert-amyl alcohol volume ratio reaches 1:14, continues to increase volume ratio and will cause reactant to dissolve insufficiency Completely reduce the conversion rate. Therefore, the optimal organic solvent volume ratio in the microfluidic microchannel...

Embodiment 7-11

[0038] Change the substrate molar ratio of 5-methyluridine to divinyl adipate 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 5-methyluridine and divinyl adipate substrate molar ratio 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 the concentration of 5-methyluridine in the reaction system is 0.05mmol / mL, Along with the increase of reactant divinyl adipate, the conversion rate of reaction also increases, and when 5-methyluridine: the divinyl adipate substrate mol ratio is 1:9, the conversion rate of reaction Optimum, so the optimal substrate molar ratio in the microfluidic microchannel reactor in the present invention is 1:9.

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Abstract

The invention discloses a lipozyme-catalyzed on-line synthesizing method for 5'-O-ethylene hexanedioyl-5-methyluridine. The lipozyme-catalyzed on-line synthesizing method comprises the following steps that dimethyl sulfoxide and tert-amyl alcohol with the volume ratio being 1:8-16 are taken as a reaction solvent, 5-methyluridine and adipic acid divinyl ester with the molar ration being 1:5-13 are taken as raw materials, 0.5-1.0 gram of lipozyme TLIM is taken as a catalyst, the raw materials and the reaction solvent are placed in a syringe, a reaction channel of a microfluidic channel reactor is evenly filled with the lipozyme TLIM, the raw materials and the reaction solvent are continuously injected into the reaction channel for acylation reaction under driving of an injection pump, the inner diameter of the reaction channel of the microfluidic channel reactor is 0.8-2.4 mm, the length of the reaction channel is 0.5-1.0 m; and the temperature of the acylation reaction is controlled to be at 15-50 DEG C, the time for the acylation reaction is 20-35 minutes, a reaction solution is collected on line by a product collector, and the 5'-O-ethylene hexanedioyl-5-methyluridine is obtained after conventional treatment is conducted on the reaction solution. The lipozyme-catalyzed on-line synthesizing method has the advantages of being short in reaction time, high in selectivity and high in yield.

Description

(1) Technical field [0001] The invention relates to a lipase-catalyzed online controllable selective synthesis method of 5'-O-ethylene adipyl-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---esterificat...

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 杜理华徐亮亮罗锡平
Owner ZHEJIANG UNIV OF TECH
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