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Micro-reactor tandem synthesis method of indole anticancer drug molecules

A technology of microreactors and anticancer drugs, applied in drug combinations, chemical/physical/physicochemical reactors, chemical instruments and methods, etc., can solve unseen problems, achieve mild conditions, simple production process, and side effects and the effect of fewer separation steps

Active Publication Date: 2019-11-26
FUDAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are no relevant patents and research papers on the microreactor series reaction of sulfonamidation reaction and Suzuki reaction, especially the microreactor series synthesis method of benzenesulfonamide pyridine diazaindole candidate target anticancer drug molecules check-in

Method used

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  • Micro-reactor tandem synthesis method of indole anticancer drug molecules
  • Micro-reactor tandem synthesis method of indole anticancer drug molecules
  • Micro-reactor tandem synthesis method of indole anticancer drug molecules

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] This embodiment takes N-{2-chloro-5-[1H-pyrrole(2,3-b)pyridin-5-yl]pyridin-3-yl}benzenesulfonamide as the preparation target, and the structural formula is

[0064](1) 5-bromo-3-amino-2-chloropyridine (0.10g, 0.48mmol), pyridine (0.057g, 0.72mmol), dissolved in dichloromethane (0.77mL) to prepare reaction solution 1, take Benzenesulfonyl chloride (0.10g, 0.58mmol) was made into reaction solution 2, and the flow rate (0.4mL / min) set by the intelligent numerical control injector was simultaneously introduced into the first three-way mixer (environment temperature 0°C), and then flow out under its own pressure, enter a pickle tube with an inner diameter of 500 μm at a set temperature control (25°C), and complete the sulfonamidation reaction under the set residence time t1 (1min) condition, Then through the back pressure valve, the first effluent is obtained;

[0065] (2) Dissolve bis-linked pinacolate diboron (0.18g, 0.72mmol), tetrakistriphenylphosphine palladium (0.01...

Embodiment 2

[0069] The preparation method is specifically shown in Example 1. In this example, N-{2-chloro-5-[2-methyl-1H-pyrrole (2,3-b)pyridin-5-yl]pyridin-3-yl }Benzenesulfonamide is the preparation target, and the structural formula is

[0070] (1) 5-bromo-3-amino-2-chloropyridine (0.10g, 0.48mmol), pyridine (0.057g, 0.72mmol), dissolved in dichloromethane (0.77mL) to prepare reaction solution 1, take Benzenesulfonyl chloride (0.10g, 0.58mmol) was made into reaction solution 2, and the flow rate (0.4mL / min) set by the intelligent numerical control injector was simultaneously introduced into the first three-way mixer (environment temperature 0°C), and then flow out under its own pressure, enter a pickle tube with an inner diameter of 500 μm at a set temperature control (25°C), and complete the sulfonamidation reaction under the set residence time t1 (1min) condition, Then through the back pressure valve, the first effluent is obtained;

[0071] (2) Dissolve bis-linked pinacolate dib...

Embodiment 3

[0075] The preparation method is specifically shown in Example 1. In this example, N-{2-chloro-5-[2-ethyl-1H-pyrrole (2,3-b)pyridin-5-yl]pyridin-3-yl }Benzenesulfonamide is the preparation target, and the structural formula is

[0076] (1) 5-bromo-3-amino-2-chloropyridine (0.10g, 0.48mmol), pyridine (0.076g, 0.96mmol), dissolved in dichloromethane (0.92mL) to prepare reaction solution 1, take Benzenesulfonyl chloride (0.10g, 0.58mmol) was made into reaction solution 2, and the flow rate (0.5mL / min) set by the intelligent numerical control sampler was introduced into the first three-way mixer (environment temperature 5°C), and then flow out under its own pressure, into a pickle tube with an inner diameter of 1000 μm at a set temperature control (25°C), and complete the sulfonamidation reaction under the set residence time t1 (0.5min) , and then through the back pressure valve to obtain the first effluent;

[0077] (2) Dissolve bis-pinacolyl diboron (0.18g, 0.72mmol), tetraki...

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PUM

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Abstract

The invention relates to a micro-reactor tandem synthesis method of indole anticancer drug molecules. The method comprises the following steps: a reaction liquid 1 and a reaction liquid 2 are mixed, then are introduced into a first micro-reactor, and are reacted to obtain a first effluent, the first effluent and a reaction liquid 3 are mixed, then are introduced into a second micro-reactor, and are reacted to obtain a second effluent, the second effluent and a reaction liquid 4 are mixed, then are introduced into a third micro-reactor, and are reacted to obtain a final effluent, and the finaleffluent is concentrated and separated to obtain the indole anticancer drug molecules, wherein the reaction liquid 1 is a mixed solution containing 5-bromine-3-amino-2-substituted (R1)-pyridine, the reaction liquid 2 is substituted (R2)-benzenesulfonyl chloride, the reaction liquid 3 is a mixed solution containing bis(pinacolato)diboron, the reaction liquid 4 is a mixed solution containing a 5-bromo-7-azaindole derivative, and the indole anticancer drug molecules are benzenesulfonamidopyridylazaindole compounds. Compared with the prior art, the method of the invention has the advantages of high reaction efficiency, few side reactions and simple production process.

Description

technical field [0001] The invention relates to the technical field of synthesis technology, in particular to a microreactor series synthesis method of indole anticancer drug molecules. Background technique [0002] The benzenesulfonamide pyridine diazaindole compound is a class of important azasulfonamide compounds with potential biomedical activity, and its structural formula is: It has potential wide application in the field of medicine. For example: GSK2126458 developed by GlaxoSmithKline, UK, has high-efficiency PI3K kinase inhibitory activity. The compound is a potent inhibitor of p110α / β / γ / δ and mTORC1 / 2 with enzyme activities of 0.019nM / 0.13nM / 0.024nM / 0.06nM and 0.18nM / 0.3nM (ACS Med.Chem.Lett.2010, 1,39-43); B11-B14 four new benzenesulfonamide pyridine diazaindole compounds developed by Zhou Yaming's team from the Department of Chemistry, Fudan University showed anti-cancer effects on common cancer cells NCI-H460, MCF-7, T47D, U87MG, KARPAS -422 etc. have high i...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61P35/00B01J19/00
CPCA61P35/00B01J19/0093C07D471/04
Inventor 凌云周亚明贾瑜邓名莉刘小锋杨永泰陈珍霞
Owner FUDAN UNIV
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