Preparation method of difluoromethyl aromatic hydrocarbon compound

Abstract

The invention discloses a preparation method of a difluoromethyl aromatic hydrocarbon compound, which comprises the following steps: (1) in a nitrogen atmosphere, sequentially adding an aryl mono-substituted malonic acid substrate, a silver catalyst, alkali and a selective fluorine reagent into a reaction tube, adding a solvent, and reacting at corresponding temperature for 11-13 hours, wherein the molar ratio of the aryl mono-substituted malonic acid substrate to the silver catalyst to the alkali to the selective fluorine reagent is 1: (0.1-1): (0.5-5): (4-10); and (2) carrying out quenchingreaction by using 3M hydrochloric acid, and sequentially carrying out extraction, organic phase combination, washing, drying, organic phase spin-drying and purification on the reaction product to obtain the difluoromethyl aromatic hydrocarbon compound. The preparation method disclosed by the invention is simple to operate, simple and cheap in raw materials, easy in preparation, mild in conditions,good in functional group compatibility and very practical.

Description

technical field [0001] The invention belongs to the technical field of organic fluorine chemistry, and in particular relates to a preparation method of difluoromethyl aromatic compounds. Background technique [0002] There are two fluorine atoms and one hydrogen atom in the difluoromethyl group. The electron-withdrawing effect of the fluorine atom makes the hydrogen atom have weak acidity, which can be used as a lipophilic hydrogen bond donor to form hydrogen bonds with electron-rich systems in biomacromolecules. It is conducive to the selective combination of drugs and receptors, thereby improving the activity of drugs or lead compounds; and this structural fragment is highly valued in the field of medicinal chemistry, often used as bioelectronics for primary alcohols, thiols, hydroxamic acids and amides, etc. Exosomes are used in the design of drugs and bioactive molecules. [0003] Conventional methods for the preparation of difluoromethyl aromatic compounds are: (1) by ...

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Problems solved by technology

[0003] Conventional methods for the preparation of difluoromethyl aromatic compounds are: (1) by aromatic aldehydes and diethylaminosulfur trifluoride (DAST) [1.F.S.Fawcett, C.W.Yullock, D.D.Coffman, J.Am.Chem. Soc.84,4275-4285(1962).], but this method is not compatible with carbonyl, hydroxyl, carboxyl and other groups, and the substrates are relatively limited; (2) under the participation of metals or catalysis, functionalized arenes and difluoro Coupling with methyl reagents is also a method for preparing difluoromethylarenes [2.P.S.Fire, J.F.Harwig, J.Am.Chem.Soc.134, 5524-5527 (2012); 3.Y.Gu, X .Leng, Q.L.Shen, Nat.Commun.5,5405-5411(2014); 4.Z.Feng, Q.Q.Min, X.G.Zhang, Nat.Chem.9,918-923(2017)], but this method is due to the use of metal , making the reaction system more sensitive to water and oxygen; (3) the addition of difluoromethyl free radicals to simple arenes is the most direct method for preparing difluoromethyl arenes [5.Y.Fujiwara, J.A.Dixon, P.S.Baran , J.Am.Chem.Soc.134,1494-1497(2012); 6.T.T.Tung, S.B.Christensen, J.nielsen, Chem.Eur.J.23,18125-18128(2017)], but the method exists Reaction site selectivity problem, unable to obtain a single product

[0004] All in all, although the above-mentioned methods can obtain difluoromethyl aromatic compounds, the disadvantages are also obvious

In addition, the preparation of gem-difluoromethylene from malonic acid derivatives has been reported [7.Z.Wang, C.Y.Guo, C.Yang, J.P.Chen, J.Am.Chem.Soc.141,5617-5622( 2019)], but the reaction raw materials are mainly limited to disubstituted malonic acid derivatives, and it is very difficult to prepare difluoromethyl compounds from monosubstituted malonic acid derivatives

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