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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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  • 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 mostly use acylases for catalysis, which often require a long reaction time (12-24h), and the conversion rate and selectivity of the reaction are not high. Therefore, we have discovered the microfluidic channel reactor A lipase-catalyzed online synthesis of N-(5-vinylvaleryl) mexiletine, aiming to find an efficient and environmentally friendly online controllable selective synthesis of N-(5-vinylvaleryl) mexiletine method

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
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: the synthesis of N-(5-vinyl pentanoyl) mexiletine

[0029]

[0030] device referencefigure 1 : Mexiletine (1.0mmol) was dissolved in 2.50mL DMSO and 7.50mL tert-amyl alcohol, divinyl adipate (4.0mmol) was dissolved in 2.50mL DMSO and 7.50mL tert-amyl alcohol, and then filled into 10mL syringes in spare. 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 50 ° 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.

[0031] The reaction solution was collected online by the product collector, the solvent was distilled off under reduced pressure, and the column was wet-pac...

Embodiment 2-7

[0036] Change the volume ratio of the organic solvent (DMSO: 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:

[0037] Table 1: Influence of the reaction medium on the reaction

[0038] Example

[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 50°C, the ratio of the amount of reactant mexiletine to divinyl adipate is 1:2, and the conversion rate varies with the organic solvent (DMSO: tert-amyl alcohol) in the reaction system. ) volume ratio increases and increases, and when DMSO: tert-amyl alcohol volume ratio is 1:3, reaction transformation efficiency is optimal, is 90%, if continue to increase the amount of tert-amyl alcohol in the reaction system now, will cause If the reactants are not completely dissolved, the conversion rate of the reaction will decreas...

Embodiment 8-12

[0041] Change the ratio of the amount of mexiletine to the substrate substance of divinyl adipate 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:

[0042] Table 2: The impact of the ratio of the amount of mexiletine and divinyl adipate substrate substance on the reaction

[0043]

[0044] 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 DEG C, the organic solvent DMSO in the reactor: tert-amyl alcohol volume ratio is 1:3, along with the increase of the reactant divinyl adipate, the conversion rate of the reaction also increases. Along with increasing, when the ratio of the amount of substrate substance is 1:4, the conversion rate of reaction is optimal, so the ratio of the amount of optimum substrate substance 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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