Method for online synthesizing 5'-O-palmitoyl uridine in lipozyme catalysis mode

A palmitoyluridine and lipase technology, 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 achieve high conversion efficiency, shorten the reaction time, and reduce the effect of reaction cost

Active Publication Date: 2016-08-10
ZHEJIANG FORESTRY UNIVERSITY
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  • Abstract
  • Description
  • Claims
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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-palmitoyluridine in a microchannel reactor, aiming to find an efficient and environmentally friendly 5'-O-palmitoyluridine On-line controllable and selective synthesis of acyluridines

Method used

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  • Method for online synthesizing 5'-O-palmitoyl uridine in lipozyme catalysis mode
  • Method for online synthesizing 5'-O-palmitoyl uridine in lipozyme catalysis mode
  • Method for online synthesizing 5'-O-palmitoyl uridine in lipozyme catalysis mode

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0026]

[0027] device reference figure 1 : Uridine (1.0mmol) was dissolved in 1.2mL DMSO and 8.8mL tert-amyl alcohol, vinyl palmitate (9.0mmol, 2.3mL) was dissolved in 7.7mL tert-amyl alcohol, and then filled 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 elution re...

Embodiment 2-6

[0033] Keep the total volume of the organic solvent constant, change the volume ratio of the organic solvent DMSO to tert-amyl alcohol in the microfluidic channel reactor, and control the temperature to 50°C. Others are 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 uridine to vinyl palmitate is 1:9, and the uridine concentration is 0.05mmol / mL, the conversion rate varies with the organic solvent in the reactor. The volume ratio increases and increases. When the volume ratio of DMSO and tert-butanol reaches 1:14, it reaches the optimum. Continuing to increase the volume ratio will lead to incomplete dissolution of the reactants and reduce the conversion rate. Therefore, the optimal organic solvent volume ratio in the micro...

Embodiment 7-11

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

[0039] Table 2: Effect of Uridine to Vinyl Palmitate Substrate 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 volume ratio of the organic solvent DMSO to tert-butanol in the reactor is 1:14, and the uridine concentration is 0.05mmol / mL, with the reactant vinyl palmitate As the ester increases, the conversion rate of the reaction also increases. When the substrate ratio is 1:9, the conversion rate of the reaction is optimal, so the optimum substrate molar ratio in the microfluidic microchannel reactor in the present invention is 1 :9.

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Abstract

The invention discloses a method for online synthesizing 5'-O-palmitoyl uridine in a lipozyme catalysis mode .The method includes the steps that dimethyl sulfoxide and tert-amyl alcohol with the volume ratio of 1:(8-16) serve as a reaction solvent, uridine and palmitic acid vinyl ester with the molar ratio of 1:(5-13) serve as raw materials, 0.5 g to 1.0 g of lipozyme TLIM serves as a catalyst, the raw materials and the reaction solvent are placed into an injector, a reaction channel of a microfluidics channel reactor is evenly filled with the lipozyme TLIM, and the raw materials and the reaction solvents are continuously led into a reaction channel device under pushing of an injection pump for an acylation reaction, wherein the inner diameter of the reaction channel of the microfluidics channel reactor is 0.8 mm to 2.4 mm, the length of the reaction channel is 0.5 m to 1.0 m, the temperature of the acylation reaction is controlled to be 15 DEG C to 50 DEG C, the concentration of the uridine in the reaction system is 0.03 mmol / mL to 0.07 mmol / mL, and the time of the acylation reaction is 20 min to 35 min; reacted liquid is online collected through a product collector and subjected to conventional aftertreatment, and the 5'-O-palmitoyl uridine is obtained .The method has the advantages of being short in reaction time and high in selectivity and yield.

Description

(1) Technical field [0001] The invention relates to a lipase-catalyzed online controllable selective synthesis of 5'-O-palmitoyluridine (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 be protected by "group protection——esterification——deprotection g...

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 罗锡平杜理华成柄灼
Owner ZHEJIANG FORESTRY UNIVERSITY
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