Method for synthesizing 5'-O-ethylene hexanedioyl-5-floxuridine on line through catalyzing of lipase

Abstract

The invention discloses a method for synthesizing 5'-O-ethylene hexanedioyl-5-floxuridine 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-floxuridine and adipic acid divinyl ester are used as raw materials, wherein the mole ratio of the 5-floxuridine to the adipic acid divinyl ester 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-ethylene hexanedioyl-5-floxuridine 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-ethylene adipyl-5-fluorouridine (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 prote...

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Problems solved by technology

[0006] In recent years, 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). Moreover, 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-fluorouridine 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-fluorouridine

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