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Method for synthesizing N-(5-sucrose ester valeryl)mexiletine online by lipozyme catalysis

A technology of ester valeryl and vinyl ester valeryl, which is applied in the field of lipase catalyzed on-line controllable and selective synthesis of N-mexiletine, can solve the problems of low bioavailability, short half-life, long reaction time and the like, and shorten the reaction time. Time, high conversion and selectivity, effect of reducing reaction cost

Inactive Publication Date: 2017-12-15
ZHEJIANG UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] At present, domestic and foreign studies on the enzymatic synthesis of sugar-containing amine derivatives are more concerned, especially for the synthesis and development of sugar-containing mexiletine compound drugs, to improve their pharmacological activity, and to solve the short half-life of its clinical use. , requires continuous administration, and has limitations such as low bioavailability
The reported enzymatic synthesis methods often require a long reaction time (12-24h), and the conversion rate and selectivity of the reaction are not high. Therefore, our research has found that lipase catalyzes the online synthesis of N-(5 - the method of sucrose valeryl) mexiletine, aiming to find a kind of efficient and environmentally friendly N-(5-sucrose valeryl) mexiletine online controllable selective synthesis method

Method used

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  • Method for synthesizing N-(5-sucrose ester valeryl)mexiletine online by lipozyme catalysis
  • Method for synthesizing N-(5-sucrose ester valeryl)mexiletine online by lipozyme catalysis
  • Method for synthesizing N-(5-sucrose ester valeryl)mexiletine online by lipozyme catalysis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1: the synthesis of N-(5-sucrose ester pentanoyl) mexiletine

[0028]

[0029]Dissolve N-(5-vinylvaleryl) mexiletine (0.1 mmol) in 0.70 mL DMSO and 9.30 mL tert-amyl alcohol, sucrose (0.5 mmol) in 0.70 mL DMSO and 9.30 mL tert-amyl alcohol, Then put them in 10mL syringes for later use. 0.87g of lipase Lipozyme TL IM was evenly filled in the reaction channel, 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 35 ° 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.

[0030] 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...

Embodiment 2-7

[0035] Change the content of DMSO in the reaction medium (DMSO / tert-amyl alcohol) in the microfluidic channel reactor, control the temperature to 35°C, and the others are the same as in Example 1. The reaction results are shown in Table 1:

[0036] Table 1: The effect of the amount of DMSO in the reaction medium on the reaction

[0037]

[0038]

[0039] 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 35 °C, the ratio of the amount of reactant N-(5-vinylvaleryl) mexiletine to sucrose is 1:5, and the conversion rate varies with the reaction system (DMSO / tert-amyl alcohol) in the volume ratio of DMSO increases and increases, when the amount of DMSO in DMSO and tert-amyl alcohol mixed solvent is 7%, it reaches the best, then continue to increase the amount of DMSO in the mixed solvent, will affect the enzyme activity And affect the conversion rate and selectivity of the reaction. Therefore, t...

Embodiment 8-13

[0041] Change the ratio of the amount of N-(5-vinylvaleryl) mexiletine to the substrate substance of sucrose in the microfluidic microchannel reactor, control the temperature at 35° C., and the others are the same as in Example 1. The results are shown in Table 2 :

[0042] Table 2: Effect of the ratio of the amount of N-(5-vinylvaleryl) mexiletine to the sucrose substrate substance on the reaction

[0043]

[0044]

[0045] 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 35°C, and when the DMSO content of the reaction medium is 7%, with the increase of the amount of reactant sucrose, the conversion rate of the reaction also increases. When the ratio of the amount of the substrate substance is At 1:5, the conversion rate of the reaction is optimal, so the ratio of the amount of the optimal substrate substance in the microfluidic microchannel reactor in the present invention is 1:5.

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Abstract

The invention discloses a method for synthesizing N-(5-sucrose ester valeryl)mexiletine online by lipozyme catalysis. The method takes N-(5-vinyl ester valeryl)mexiletine and sucrose as raw materials according to the amount of substance ratio of 1 to (1 to 10), dimethyl sulfoxide (DMSO) and tert-amyl alcohol as reaction solvents and lipozyme TL IM as a catalyst, and comprises the following steps: putting the raw materials and the reaction solvents into an injector; uniformly filling the lipozyme TL IM into a reaction channel of a micro-fluidic channel reactor; continuously introducing the raw materials and the reaction solvents into a reaction channel device under the pushing of the injector and carrying out esterification reaction, wherein the inner diameter of the reaction channel of the micro-fluidic channel reactor is 0.8mm to 2.4mm and the length of the reaction channel is 0.5m to 1.0m; controlling the reaction temperature to 20 DEG C to 60 DEG C and the reaction time to 20min to 40min; collecting a reaction solution online through a product collector and carrying out conventional post-treatment on the reaction solution to obtain the N-(5-sucrose ester valeryl)mexiletine. The method disclosed by the invention has the advantages of short reaction time, high selectivity and high yield.

Description

(1) Technical field [0001] The invention relates to a method for synthesizing N-(5-sucrose ester valeryl) mexiletine catalyzed by lipase on-line and selectively. (2) Background technology [0002] Currently, small-molecule drugs are the mainstream of clinically used drugs. However, small-molecule drugs have fast metabolism, short half-life and obvious peak-valley effect, which lead to frequent administration. Small-molecule drugs are prepared by chemical biology methods to prepare new drug derivatives. Or sugar-containing drug derivatives and polymer prodrugs of drugs are an effective method to improve drug sustained release and targeting. [0003] At this stage, most drugs are facing the problem of too high fat solubility or poor water solubility, and the existence of these problems leads to poor gastrointestinal absorption of drugs and poor oral bioavailability. To this end, researchers have increased the water solubility and oral bioavailability of drugs through water so...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P19/26C12P19/12
CPCC12P19/12C12P19/26
Inventor 杜理华蒋志鹏周娜妮沈佳鸿董振罗锡平
Owner ZHEJIANG UNIV OF TECH
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