Method for rapidly synthesizing 3-bromo-2-fluorobenzaldehyde based on continuous flow reaction technology

A technology of fluorobenzaldehyde and a synthesis method, which is applied in the field of 3-bromo-2-fluorobenzaldehyde synthesis, can solve the problems of increased side reactions, increased time consumption, obvious amplification effect, etc., achieves low cost, solved amplification effect, reduced The effect of the risk factor

A technology of fluorobenzaldehyde and a synthesis method, which is applied in the field of 3-bromo-2-fluorobenzaldehyde synthesis, can solve the problems of increased side reactions, increased time consumption, obvious amplification effect, etc., achieves low cost, solved amplification effect, reduced The effect of the risk factor

CN113264819APending Publication Date: 2021-08-17BIRDO (SHANGHAI) PHARM R&D CO LTD
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  • Method for rapidly synthesizing 3-bromo-2-fluorobenzaldehyde based on continuous flow reaction technology
  • Method for rapidly synthesizing 3-bromo-2-fluorobenzaldehyde based on continuous flow reaction technology

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Embodiment 1: as figure 1 As shown, the THF solution of o-fluorobromobenzene is put into the storage tank 1, the THF solution of LDA is put into the storage tank 2, the temperature control device 21 sets the temperature to be -80°C, the THF solution of o-fluorobromobenzene and LDA The solution is pumped into the first-stage lithium-hydrogen exchange continuous reactor 12 by the first metering pump 4 and the second metering pump 5 respectively, and reacted for 8 minutes, and is extended for 30 minutes through the second-stage and third-stage lithium-hydrogen exchange continuous reactors 13 and 14 In the reaction time, the molar equivalent ratio of o-fluorobromobenzene and LDA is 1:1.5, and the reaction generates 3-bromo-2-fluorophenyllithium intermediate; the active intermediate is passed into the first-level formylation continuous reactor 15, Simultaneously, the THF solution of N,N-dimethylformamide is pumped into reactor 15 to carry out nucleophilic aldylation reaction...

Embodiment 2

[0027] Embodiment 2: The specific preparation process is the same as that in Embodiment 1. The temperature control device 21 is set at -60° C., and the organic phase of the reaction solution is diluted and filtered, and HPLC analysis shows that the concentration of 3-bromo-2-fluorobenzaldehyde in the reaction solution is The conversion rate was 68.78%.

Embodiment 3

[0028] Example 3: The specific preparation process is the same as in Example 1, the molar equivalent ratio of o-fluorobromobenzene and LDA is adjusted to 1:1.7, and the organic phase of the reaction solution is diluted and filtered, and HPLC analysis shows that 3-bromo-2 in the reaction solution -The conversion rate of fluorobenzaldehyde is 70.84%.

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Abstract

The invention discloses a method for rapidly synthesizing 3-bromine-2-fluorobenzaldehyde based on a continuous flow reaction technology. The method comprises a lithium-hydrogen exchange reaction and a nucleophilic hydroformylation reaction, wherein the lithium-hydrogen exchange reaction comprises the following steps: pumping an o-fluorobromobenzene solution and an organic lithium reagent solution into a lithium-hydrogen exchange continuous reactor according to a certain equivalent proportion; reacting for a certain time at a certain temperature, and carrying out lithium-hydrogen exchange to generate a 3-bromo-2-fluorophenyl lithium intermediate; and the nucleophilic hydroformylation reaction comprises the steps: introducing the active intermediate obtained in the lithium-hydrogen exchange reaction into a hydroformylation continuous reactor, pumping N, N-dimethylformamide in a certain equivalent proportion into the hydroformylation continuous reactor, and reacting at a certain temperature for a certain time to generate a 3-bromo-2-fluorobenzaldehyde product. By applying the continuous flow reaction technology, the traditional kettle type reaction is improved into a continuous process, the amplification effect problem of the traditional kettle type reaction is solved, the danger level of the dangerous reaction of the metal-containing reagent is reduced, the reaction can obtain higher product purity under the controllable continuous condition, and the production efficiency is improved.

Description

technical field [0001] The invention relates to a method for synthesizing 3-bromo-2-fluorobenzaldehyde, in particular to a method for rapidly preparing 3-bromo-2-fluorobenzaldehyde by utilizing continuous flow reaction technology. Background technique [0002] 3-bromo-2-fluorobenzaldehyde, molecular formula: C7H4BrFO, is an important organic intermediate widely used in the fields of pharmaceutical molecules, fine chemicals, functional materials, etc., itself and its downstream products such as: 3-bromo- 2-fluorobenzophenone, (3-bromo-2-fluorophenyl)methanol, 7-bromo-1-benzothiophene-2-carboxylic acid, etc. all have extremely high added value. The preparation of traditional 3-bromo-2-fluorobenzaldehyde is generally carried out in a batch reactor, and the common synthetic routes are as follows: [0003] In the invention patent US2008114167A1, a kind of 3-bromo-2-fluorobenzoic acid was reported as the raw material, and the raw material acid was reduced to the corresponding 3-b...

Claims

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Application Information

Patent Timeline
17 Aug 2021
Publication
CN113264819A
IPC
C07C47/55; C07C45/45
CPC
C07C45/455; C07C47/55
Inventors
王雷; 杨文谦