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Method for on-line synthesis of N-(5-vinyl ester valeryl) metoprolol through catalysis by lipase

A vinyl ester valeryl and lipase technology, applied in biochemical equipment and methods, biological material sampling methods, biochemical instruments, etc., can solve the problems of long reaction time, low conversion rate and selectivity, and reduce the reaction cost , short reaction time, high conversion and selectivity

Inactive Publication Date: 2017-12-22
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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) metoprolol, aiming to find an efficient and environmentally friendly online controllable selection of N-(5-vinylvaleryl) metoprolol synthetic method

Method used

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  • Method for on-line synthesis of N-(5-vinyl ester valeryl) metoprolol through catalysis by lipase
  • Method for on-line synthesis of N-(5-vinyl ester valeryl) metoprolol through catalysis by lipase
  • Method for on-line synthesis of N-(5-vinyl ester valeryl) metoprolol through catalysis by lipase

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Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0029]

[0030] Dissolve metoprolol (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 fill them into 10mL syringes in spare. 0.87g of lipase Lipozyme TLIM 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 entered the reaction channel through the "Y" joint for reaction, and the temperature of the reactor was controlled at 50°C by a water bath thermostat. The reaction solution was continuously flowed in the reaction channel for 30 minutes, and the reaction results were tracked and detected by thin-layer chromatography (TLC).

[0031] The reaction solution was collected online by the product collector, the solvent was removed by distillation under reduced pressure, and the column was wet packed wi...

Embodiment 2-7

[0036] Change organic solvent (DMSO: tert-amyl alcohol) volume ratio in microfluidic channel reactor, control temperature is 50 ℃, other is the same as embodiment 1, and reaction result is as 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 ℃, the ratio of the amount of reactant metoprolol and divinyl adipate is 1:2, and the conversion rate varies with the organic solvent (DMSO: tert-amyl Alcohol) volume ratio increases and increases, and when DMSO: tert-amyl alcohol volume ratio is 1:3, reaction conversion rate is the best, is 82%, if continue to increase the amount of tert-amyl alcohol in the reaction system now, will The incomplete dissolution of the reactants leads to a decrease in the conversion rate of the reaction. Therefore, the optimal reaction medium volume ratio in...

Embodiment 8-12

[0041] Change the ratio of the amount of substrate substance of metoprolol and divinyl adipate in the microfluidic microchannel reactor, control temperature 50 DEG C, other are with embodiment 1, and result is as shown in table 2:

[0042] Table 2: the impact of the ratio of the amount of metoprolol 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 on-line synthesis of N-(5-vinyl ester valeryl) metoprolol through catalysis by lipase. According to the method, metoprolol and diethenyl adipate with the mole ratio being 1:(1 to 6) are used as raw materials; dimethyl sulfoxide and tert-amyl alcohol with the volume ratio being 1:(1 to 10) are used as reaction solvents; lipase lipozyme TL IM is used as a catalyst; the raw materials and the reaction solvents are put into an injector; the lipase lipozyme TL IM is uniformly filled in a reaction channel of a microfluidic channel reactor; under the pushing effect of an injection pump, the raw materials and the reaction solvents are continuously introduced into the channel reactor to take an acylation reaction, wherein the inner diameter of the reaction passage of the microfluidic channel reactor is 0.8 to 2.4mm, the length of the reaction channel is 0.5 to 1.0m, the acylation temperature is controlled to be 30 to 70 DEG C, and the acylation reaction time is controlled to be 20 to 40 min; collecting reaction liquid on line through a product collector; and performing conventional treatment on the obtained reaction liquid to obtain N-(5-vinyl ester valeryl) metoprolol. The method has the advantages that the reaction time is short; the selectivity is high; and the yield is high.

Description

(1) Technical field [0001] The invention relates to a lipase-catalyzed online controllable selective synthesis of N-(5-vinylvaleryl) metoprolol. (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 present, most drugs are faced with 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. For this reason, researchers increase the water solubility of drugs and their oral bioavailability through water solubility mod...

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 杜理华蒋志鹏董振罗锡平
Owner ZHEJIANG UNIV OF TECH
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