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

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: 2017-12-19
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 often require a long reaction time (12-24h), and the conversion rate and selectivity of the reaction are not high. The method for synthesizing N-(5-glucosyl valeryl) mexiletine aims to find an efficient and environmentally friendly online controllable selective synthesis method of N-(5-glucosyl pentanoyl) mexiletine

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: the synthesis of N-(5-glucosyl valeryl) mexiletine

[0029]

[0030] Dissolve N-(5-vinylvaleryl) mexiletine (0.1 mmol) in 0.70 mL DMSO and 9.30 mL tert-amyl alcohol, glucose (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.

[0031] 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...

Embodiment 2-7

[0036] 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:

[0037] Table 1: The effect of the amount of DMSO in the reaction medium on the reaction

[0038]

[0039]

[0040] 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 glucose 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

[0042] Change the ratio of the amount of N-(5-vinylvaleryl) mexiletine to the substrate substance of glucose 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 :

[0043] Table 2: Effect of the ratio of the amount of N-(5-vinylvaleryl) mexiletine to the glucose substrate substance on the reaction

[0044]

[0045]

[0046] 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%, the conversion rate of the reaction also increases with the increase of the reactant glucose amount. 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 lipase-catalyzed online synthesis of N-(5-glucose ester valeryl)mexiletine. The method, adopting N-(5-vinyl ester valeryl)mexiletine and glucose with a molar ratio of 1:(1-10) as raw materials, dimethyl sulphoxide and tertiary amyl alcohol 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 esterification reaction at a temperature of 20-60 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-glucose 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-glucosyl valeryl) 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P19/26C12M1/40C12M1/00
CPCC12M21/18C12M23/16C12M33/04C12M41/22C12P19/26
Inventor 杜理华蒋志鹏龙瑞杰沈佳鸿罗锡平
Owner ZHEJIANG UNIV OF TECH
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