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Method for online synthesis of N-(5-sucrose ester valeryl)metoprolol by means of catalysis of lipase

A technology of ester valeryl and vinyl ester valeryl, applied in the field of lipase catalyzed on-line controllable selective synthesis of N-metoprolol, can solve the problems of low bioavailability, short half-life, long reaction time, etc. Effect of reaction time, reduced reaction cost, high conversion and selectivity

Inactive Publication Date: 2017-12-01
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 metoprolol compound drugs, improving its pharmacological activity, and solving the half-life of its clinical use. Short, need continuous administration, low bioavailability and other limitations
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, we found that lipase catalyzed online synthesis of N-(5 - the method of sucrose valeryl) metoprolol, aiming to find an online controllable selective synthesis method of N-(5-sucrose valeryl) metoprolol with high efficiency and environmental protection

Method used

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  • Method for online synthesis of N-(5-sucrose ester valeryl)metoprolol by means of catalysis of lipase
  • Method for online synthesis of N-(5-sucrose ester valeryl)metoprolol by means of catalysis of lipase
  • Method for online synthesis of N-(5-sucrose ester valeryl)metoprolol by means of catalysis of lipase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0029]

[0030] Dissolve N-(5-vinylvaleryl)metoprolol (0.1 mmol) in 0.70 mL DMSO and 9.30 mL tert-amyl alcohol, and dissolve sucrose (0.5 mmol) in 0.70 mL DMSO and 9.30 mL tert-amyl alcohol , and then packed in 10mL syringes for 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 col...

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] 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 35 ° C, the ratio of the amount of reactant N-(5-vinylvaleryl) metoprolol to sucrose is 1:5, and the conversion rate varies with the reaction system (DMSO / tert-amyl alcohol) in DMSO volume ratio increases and increases, when the amount of DMSO in DMSO and tert-amyl alcohol mixed solvent is 7%, reach optimum, then continue to increase the amount of DMSO in mixed solvent, will affect enzyme The activity affects the conversion and selectivity of the reaction. Therefore, the optimal reaction ...

Embodiment 8-13

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

[0042] Table 2: Effect of the ratio of the amount of N-(5-vinylvaleryl) metoprolol and sucrose 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 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 online synthesis of N-(5-sucrose ester valeryl)metoprolol by means of catalysis of lipase. The method comprises the following steps: putting N-(5-vinyl ester valeryl)metoprolol and sucrose, which is taken as raw materials, as well as dimethyl sulfoxide (DMSO) and tert-amyl alcohol, taken as reaction solvents, into an injector, wherein the ratio of amount of substance of the N-(5-vinyl ester valeryl)metoprolol to the sucrose is equal to 1 to (1-10); evenly filling a reaction channel of a microfluidic channel reactor with the lipase Lipozyme TL IM taken as a catalyst; continuously injecting the raw materials and the reaction solvents into the reaction channel under the propelling of an injection pump, and carrying out an esterification reaction, wherein the inner diameter of the reaction channel of the microfluidic channel reactor is 0.8-2.4mm, and the length of the reaction channel is 0.5-1.0m; controlling the temperature of the esterification reaction to be 20-60 DEG C and the time of the esterification reaction to be 20-40min, collecting reaction liquid in an online way by using a product collector, and carrying conventional aftertreatment on the reaction liquid to obtain the N-(5-sucrose ester valeryl)metoprolol. The method provided by the invention has the advantages of being short in reaction time, high in selectivity and high in yield.

Description

(1) Technical field [0001] The invention relates to a method for synthesizing N-(5-sucrose ester pentanoyl) metoprolol 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 ...

Claims

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Application Information

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IPC IPC(8): C12P19/26C12P19/12
CPCC12P19/12C12P19/26
Inventor 杜理华蒋志鹏周娜妮沈乐罗锡平
Owner ZHEJIANG UNIV OF TECH
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