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Continuous synthetic method for 2-fluorophenylboronic acid compound

A technology of fluorophenylboronic acid and compounds, which is applied in the field of continuous synthesis of 2-fluorophenylboronic acid compounds, can solve the problems of high cost and low yield, and achieve low cost, high yield, and improved purity and yield Effect

Active Publication Date: 2019-01-04
天津凯诺医药科技发展有限公司
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Problems solved by technology

[0014] The main purpose of the present invention is to provide a continuous synthesis method of 2-fluorophenylboronic acid compounds, so as to solve the problems of high cost and low yield in the existing methods for preparing 2-fluorophenylboronic acid compounds

Method used

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  • Continuous synthetic method for 2-fluorophenylboronic acid compound
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  • Continuous synthetic method for 2-fluorophenylboronic acid compound

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preparation example Construction

[0038] As described in the background art, the existing methods for preparing 2-fluorophenylboronic acid compounds have the problems of high cost and low yield. In order to solve the above-mentioned technical problems, the application provides a continuous synthesis method of 2-fluorobenzene boronic acid compounds, the continuous synthesis method comprises: the fluorobenzene compound, the first organic solvent and the alkyl lithium reagent in the first The continuous lithiation reaction is carried out in the continuous reaction device to obtain the lithiated product; the continuous borated reaction is carried out on the lithiated product and the alkyl borate in the second continuous reaction device to obtain 2-fluorophenylboronic acid compounds.

[0039] 2-fluorophenylboronic acid compounds include one or more of the compounds shown in formulas (I) to (IV):

[0040]

[0041] Among them, A includes but not limited to -H, -F, -Cl, methyl, ethyl, isopropyl, methoxy, ethoxy, is...

Embodiment 1

[0083] Dissolve 2-fluorophenylboronic acid (1 equivalent) in the first organic solvent (tetrahydrofuran, 8 mL / g), then add the basic ligand PMDTA (pentamethyldiethylenetriamine, 1.1 equivalent) and mix well to form solution A. n-Butyllithium (22.5 wt% n-hexane solution, 1.6 equivalents) was used as solution B without any dilution. As solution C, isopropyl borate (2.0 equiv) was diluted with THF (2 mL / g).

[0084] according to figure 1 As shown, the continuous reaction equipment is installed and debugged. Solution A, solution B and solution C are sequentially connected to the first material pump 11, the second material pump 13 and the third material pump 41, and the flow rate is automatically controlled by the automatic feeding system. The delivery pipeline of solution A has a first one-way valve 12, and the delivery pipeline of solution B has a second one-way valve 14 (to prevent backflow, solution C decides whether to install a one-way valve as required).

[0085] According...

Embodiment 2

[0092] Dissolve 2-fluorophenylboronic acid (1 equivalent) in the first organic solvent (tetrahydrofuran, 8mL / g), and then add the basic ligand PMDTA (pentamethyldiethylenetriamine, CAS#:3030-47-5, 1.1 Equivalent) mixed uniformly as solution A. n-Butyllithium (22.5 wt% n-hexane solution, 1.6 equivalents) was used as solution B without any dilution. As solution C, isopropyl borate (2.0 equiv) was diluted with THF (2 mL / g).

[0093] according to figure 2 As shown, the continuous reaction equipment is installed and debugged. Solution A, solution B and solution C are sequentially connected to the first material pump 11, the second material pump 13 and the third material pump 41, and the flow rate is automatically controlled by the automatic feeding system. The delivery pipeline of solution A has a first one-way valve 12, and the delivery pipeline of solution B has a second one-way valve 14 (to prevent backflow, solution C decides whether to install a one-way valve as required). ...

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Abstract

The invention provides a continuous synthetic method for a 2-fluorophenylboronic acid compound. The continuous synthetic method comprises the following steps: carrying out continuous lithiation reactions on a fluorobenzene compound, a first organic solvent and an alkyl lithium reagent in a first continuous reaction device to obtain a lithiated product; and carrying out boric acid reactions on thelithiated product and alkyl borate in a second continuous reaction device to obtain the 2-fluorophenylboronic acid compound. The fluorophenylboronic acid compound is prepared by taking fluorophenylboronic and derivatives thereof as raw materials which are easily available and quite cheap, so that the synthetic method is suitable for amplified production. In the whole synthetic process, a continuous synthetic process is adopted, and the reaction times in stages can be controlled precisely, so that the reaction time of the lithiation stage is controlled and the output of impurities is reduced favorably, and therefore, the purity and yield of the 2-fluorophenylboronic acid compound are improved. In a word, the continuous synthetic method for the 2-fluorophenylboronic acid compound provided bythe invention has the advantages of being low in cost, high in yield and the like.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a continuous synthesis method of 2-fluorophenylboronic acid compounds. Background technique [0002] Aryl boronic acid is a class of organic synthesis, pharmaceutical and chemical intermediates that are relatively stable in the air, insensitive to moisture, can be stored for a long time and have high reactivity. The position selectivity and stereoselectivity of the Suzuki coupling reaction of aryl boronic acid and halogenated aromatic hydrocarbons are good, various chemical functional groups do not change during the reaction, the reaction conditions are mild, and the yield is high, which is an important factor for the formation of C—C bonds. way. Arylboronic acid has a very important application in organic synthesis reactions such as the formation of C—O bonds, C—N bonds, and C—S bonds. [0003] Fluorine-containing phenylboronic acid and its derivatives, because the atomic radi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02
CPCC07F5/025
Inventor 洪浩卢江平丰惜春刘金光蒋缓
Owner 天津凯诺医药科技发展有限公司
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