Method for lipase-catalyzed online synthesis of N-(5-vinyl ester valeryl)mexiletine

A technology for vinyl ester valeryl and mexiletine, 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: 2017-12-19
ZHEJIANG UNIV OF TECH
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  • Summary
  • 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 synthes

Method used

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  • Method for lipase-catalyzed online synthesis of N-(5-vinyl ester valeryl)mexiletine
  • Method for lipase-catalyzed online synthesis of N-(5-vinyl ester valeryl)mexiletine
  • Method for lipase-catalyzed online synthesis of N-(5-vinyl ester valeryl)mexiletine

Examples

Experimental program
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Effect test

Example Embodiment

[0028] Example 1: Synthesis of N-(5-vinyl valeryl) mexiletine

[0029]

[0030] Device reference figure 1 : Dissolve mexiletine (1.0mmol) in 2.50mL of DMSO and 7.50mL of tert-amyl alcohol, and dissolve divinyl adipate (4.0mmol) in 2.50mL of DMSO and 7.50mL of tert-amyl alcohol, and then put them in a 10mL syringe respectively In the spare. 0.87g lipase Lipozyme TLIM is evenly filled in the reaction channel. Driven by the PD 1200 syringe pump, the two reaction solutions are respectively 10.4μL·min -1 The flow rate of the reactor enters the reaction channel through the "Y" connector for reaction, and the temperature of the reactor is controlled at 50 ℃ through the water bath thermostat. The reaction liquid flows continuously in the reaction channel for 30 minutes. The reaction result is tracked and detected by thin layer chromatography TLC.

[0031] Collect the reaction liquid online through the product collector, remove the solvent by distillation under reduced pressure, and pack t...

Example Embodiment

[0035] Example 2-7

[0036] The volume ratio of the organic solvent (DMSO: tert-amyl alcohol) in the microfluidic channel reactor was changed, and the temperature was controlled to 50°C. Others were the same as in Example 1. The reaction results are shown in Table 1:

[0037] Table 1: The influence of the reaction medium on the reaction

[0038] Example

[0039] The results in Table 1 show that when the flow rate is 10.4μL·min -1 , The reaction time is 30min, the reaction temperature is 50℃, the ratio of the reactant mexiletine to the amount of divinyl adipate is 1:2, the conversion rate varies with the organic solvent in the reaction system (DMSO: tert-amyl alcohol ) The volume ratio increases. When the volume ratio of DMSO: tert-amyl alcohol is 1:3, the reaction conversion rate is the best, which is 90%. At this time, if you continue to increase the amount of tert-amyl alcohol in the reaction system, it will cause If the reactants are not completely dissolved, the conversion ra...

Example Embodiment

[0040] Examples 8-12

[0041] The ratio of the amount of mexiletine to divinyl adipate substrate in the microfluidic microchannel reactor was changed, and the temperature was controlled to 50°C. Others were the same as in Example 1. The results are shown in Table 2:

[0042] Table 2: The effect of the ratio of the amount of mexiletine to divinyl adipate substrate substances on the reaction

[0043]

[0044] The results in Table 2 show that when the flow rate is 10.4μL·min -1 The reaction time is 30 minutes, the reaction temperature is 50 ℃, the volume ratio of organic solvent DMSO: tert-amyl alcohol in the reactor is 1:3, with the increase of reactant divinyl adipate, the conversion rate of the reaction is also With the increase, when the ratio of the amount of substrate material is 1:4, the conversion rate of the reaction is optimal, so the optimal ratio of the amount of substrate material in the microfluidic microchannel reactor of the present invention is 1:4 .

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Abstract

The invention discloses a method for lipase-catalyzed online synthesis of N-(5-vinyl ester valeryl)mexiletine. The method, adopting mexiletine and divinyl adipate with a molar ratio of 1:(1-6) as raw materials, dimethyl sulphoxide and tertiary amyl alcohol with a volume ratio of 1:(1-10) as a reaction solvent and lipase Lipozyme TL IM as a catalyst, comprises the following steps: placing the raw materials and the reaction solvent in a syringe, uniformly filling the reaction channel of a micro-fluidic channel reactor with the lipase Lipozyme TL IM, and continuously introducing the raw materials and the reaction solvent into the reaction channel reactor under the push of a syringe pump, wherein the internal diameter of the reaction channel of the micro-fluidic channel reactor is 0.8-2.4 mm, and the length of the reaction channel is 0.5-1.0 m; and carrying out an acylation reaction at a temperature of 30-70 DEG C for 20-40 min, online collecting the obtained reaction solution through a product collector, and routinely post-processing the reaction to obtain the N-(5-vinyl ester valeryl)mexiletine. The method 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-vinylvaleryl) mexiletine on-line with controllable selectivity catalyzed by lipase. (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 wat...

Claims

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Application Information

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IPC IPC(8): C12P13/02C12M1/40C12M1/00
CPCC12M21/18C12M23/16C12M33/04C12M41/22C12P13/02
Inventor 杜理华沈乐蒋志鹏龙瑞杰罗锡平
Owner ZHEJIANG UNIV OF TECH
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