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Device and method for performing aromatic heterocyclic lithium halide exchange reaction at room temperature

An aromatic heterocycle, lithium halide exchange technology, applied in chemical instruments and methods, chemical/physical/physical chemical processes, organic chemistry, etc. Universality, the effect of increasing the reaction temperature and shortening the reaction time

Inactive Publication Date: 2013-04-10
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The traditional lithium-halogen exchange reaction is at -78°C~-100°C by slowly adding n-butyllithium solution to the brominated aromatic heterocyclic solution. Since the reaction is a strong exothermic reaction, the addition rate must be controlled, and the reaction is not easy. control
In addition, this method is difficult to scale up, the yield is low, and it is accompanied by a large amount of by-products and easily decomposed intermediates, and its low temperature environment requires a lot of energy consumption.

Method used

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  • Device and method for performing aromatic heterocyclic lithium halide exchange reaction at room temperature
  • Device and method for performing aromatic heterocyclic lithium halide exchange reaction at room temperature
  • Device and method for performing aromatic heterocyclic lithium halide exchange reaction at room temperature

Examples

Experimental program
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Effect test

Embodiment 1

[0022] The microreactor was 500 microns internal diameter as previously described, the R1 reaction section was 20 cm, and the R2 reaction section was 150 cm. Take the raw material 5-bromo-2-trifluoromethylpyridine (362 mg, 1.6 mmol) and dissolve it in 10 mL tetrahydrofuran, draw it into a 10 mL syringe and connect it to the microautosampler P1, n-butyllithium solution (1 mL, 1.6 M ) was diluted to 0.16 M with n-hexane and drawn into a 10 mL syringe connected to a micro-volume autosampler device P3. After connecting the syringes, start the micro-injection pumps one by one, uniformly control the flow rate to 2.7 mL / min (the reaction retention time is 1 second), P1 and P2 respectively drive 5-bromo-2-trifluoromethylpyridine and n-butyllithium online After the reaction in the mixer is complete, the electrophilic substitution with P3-driven 2-chlorobenzaldehyde is completed to obtain the product. The reaction microtube was placed in a constant temperature bath at 0 °C, and the re...

Embodiment 2

[0027]The microreactor was 500 microns internal diameter as previously described, the R1 reaction section was 20 cm, and the R2 reaction section was 200 cm. Take the raw material 5-bromo-2-methoxypyridine (300 mg, 1.6 mmol) and dissolve it in 10 mL tetrahydrofuran, draw it into a 10 mL syringe and connect it to the micro autosampler P1, n-butyllithium solution (1 mL, 1.6 M) Dilute to 0.16 M with n-hexane and draw into a 10 mL syringe connected to micro autosampler P2, dissolve benzophenone (437 mg, 2.4 mmol) in 10 mL THF and draw into a 10 mL syringe connected to micro autosampler P3 . After connecting the syringes, start the micro-injection pumps in sequence, uniformly control the flow rate to 2.7 mL / min (reaction retention time is 1 second), P1 and P2 respectively drive 5-bromo-2-methoxypyridine and n-butyllithium to mix online After the reaction in the reactor is complete, the electrophilic substitution with P3-driven benzophenone is completed to obtain the product. The r...

Embodiment 3

[0032] The microreactor was 500 microns internal diameter as previously described, the R1 reaction section was 20 cm, and the R2 reaction section was 200 cm. Take the raw material 2-bromopyridine (252 mg, 1.6 mmol) and dissolve it in 10 mL tetrahydrofuran, draw it into a 10 mL syringe and connect it to the micro autosampler P1, and dilute the n-butyllithium solution (1 mL, 1.6 M) with n-hexane to 0.16 M was drawn into a 10 mL syringe connected to micro autosampler P2, methyl 2-methoxybenzoate (398 mg, 2.4 mmol) was dissolved in 10 mL THF and drawn into a 10 mL syringe connected to micro autosampler P3. After connecting the syringes, start the micro-injection pumps one by one, uniformly control the flow rate to 2.7 mL / min (the reaction retention time is 1 second), P1 and P2 respectively drive 2-bromopyridine and n-butyllithium to complete the reaction in the online mixer, Complete electrophilic substitution with P3-driven methyl 2-methoxybenzoate affords the product. The react...

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Abstract

The invention belongs to the technical field of organic chemistry and in particular relates to a device and a method for performing aromatic heterocyclic lithium halide exchange reaction at room temperature. The invention adopts a three-sampling pipeline type microreactor and a driving device thereof, wherein the microreactor consists of a pipeline with micron-level inner diameter and a three-way connector special for a high performance liquid chromatography (HPLC); and an on-line mixer is introduced into the microreactor, so the instantaneous mixing effect is achieved. The lithium halide exchange reaction is performed in the continuously flowing environment and is quenched by an electrophilic reagent quickly. The microreactor successfully realizes control of a bromo-aromatic heterocyclic and n-butyl lithium reaction system at room temperature, the reaction is finished within a few seconds, and side reaction such as decomposition and coupling can be effectively prevented, so that the reaction selectivity is greatly improved and the byproducts of the reaction are reduced. The system and the method are high in applicability and are applicable to various different aromatic heterocyclic and electrophilic reagents; the product can be obtained under the conditions that the temperature is 0 to 20 DEG C and the reaction time is 1 to 10 seconds; and the yield can reach 70 to 95 percent.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a device and a method for performing bromoaromatic heterocyclic lithium halogen exchange reaction and subsequent electrophilic substitution reaction at room temperature. Background technique [0002] Aromatic heterocyclic derivatives are widely found in natural products. Due to their special biological activities, they are important components in the synthesis of certain drugs, herbicides, and fungicides, and have important applications in pharmaceutical, industrial, and agricultural industries. value. In addition, the lithium halide exchange reaction serves as an important reaction platform for the synthesis of complex compounds containing aromatic heterocyclic ring systems. Therefore, it is of great significance to study the lithium halogen exchange reaction of aromatic heterocyclic derivatives. The traditional lithium-halogen exchange reaction is at -78...

Claims

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Application Information

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IPC IPC(8): B01J19/00C07D213/30C07D213/64C07D213/50C07D277/24C07D307/42
Inventor 贾瑜刘斌杰陈粤苏范勇杨永泰刘小锋邓名莉周亚明
Owner FUDAN UNIV
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