CN-121990972-A - Preparation method of difluoromethyl reagent and application of difluoromethyl reagent in nickel-catalyzed synthesis of alkyl difluoromethyl compound

Abstract

The invention discloses a preparation method of a difluoromethyl reagent and application thereof in nickel-catalyzed synthesis of alkyl difluoromethyl compounds. The preparation method of the difluoromethyl reagent comprises the steps of adding potassium iodide, cuprous iodide and an aqueous dimethylformamide solution into a reaction vessel under the inert gas atmosphere, heating, adding the difluorochloroacetic acid of DMF into a reaction system dropwise, collecting difluoromethane, and then adding a 1-methyl-2-pyrrolidone NMP solution into the system. The invention provides a difluoromethyl reagent which is simple and convenient to operate, low in cost, high in yield, environment-friendly and beneficial to large-scale preparation and application of the reagent in synthesis of difluoromethyl-substituted alkane compounds.

Inventors

• ZENG XIAOJUN
• ZHAO LILI
• CUI YUAN
• LI JIAMING
• ZHANG JINGHONG

Assignees

• 南昌大学

Dates

Publication Date

20260508

Application Date

20260224

Claims (9)

1. 1. A method for preparing a difluoromethyl reagent, comprising the steps of: under the inert gas atmosphere, adding potassium iodide, cuprous iodide and an aqueous dimethylformamide solution into a reaction vessel, heating, adding difluorochloroacetic acid dissolved in DMF into a reaction system, collecting difluoroiodomethane after the reaction is finished, and then adding a 1-methyl-2-pyrrolidone NMP solution into the system to prepare the difluoromethyl reagent.
2. 2. The method of claim 1 wherein the molar ratio of potassium iodide, cuprous iodide and difluorochloroacetic acid is 0.2-0.3:0.09-0.15:0.1-0.15.
3. 3. The method of claim 2 wherein the molar ratio of potassium iodide, cuprous iodide and difluorochloroacetic acid is 0.3:0.15:0.15.
4. 4. A difluoromethyl reagent obtainable by a process according to any one of claims 1 to 3.
5. 5. Use of a difluoromethyl reagent according to claim 4 for the synthesis of nickel-catalysed alkyldifluoromethyl compounds.
6. 6. The use according to claim 5, wherein the nickel-catalyzed alkyl difluoromethyl compound synthesis is as follows: in the inert gas atmosphere, adding a catalyst, a ligand, a solvent, a difluoromethyl reagent and halogenated alkane or non-activated olefin into a reaction vessel, stirring to fully react to obtain a difluoromethyl compound, wherein the reaction formula is as follows: ; Wherein X is chlorine, bromine, iodine or p-toluenesulfonyl; R is H or CH 3 .
7. 7. The use according to claim 6, wherein the catalyst is NiBr 2 and the ligand is L4 or 2-trifluoromethyl pyridine or bipyridine.
8. 8. The use according to claim 7, wherein the amount of said NiBr 2 is 5-20 mol% of the substrate, preferably 10-mol% of the substrate, and the amount of said ligand is 10-20 mol% of the substrate.
9. 9. The use according to claim 7 or 8, characterized in that the solvent is 1-methyl-2-pyrrolidone NMP or N, N-dimethylacetamide DMA or 1, 4-dioxane, or any mixture thereof.

Description

Preparation method of difluoromethyl reagent and application of difluoromethyl reagent in nickel-catalyzed synthesis of alkyl difluoromethyl compound Technical Field The invention relates to a difluoromethyl reagent and a preparation method thereof, in particular to a preparation method of a difluoromethyl reagent and application thereof in nickel-catalyzed synthesis of alkyl difluoromethyl compounds. Background Fluorine atoms have an irreplaceable role in drug molecule design due to their unique physicochemical properties. By introducing fluorine-containing groups, the lipophilicity and metabolic stability of the compound can be remarkably improved, and the characteristic enables organofluorine chemistry to develop into an important branch for promoting drug development, material science and pesticide innovation. The difluoromethyl (CF 2 H) is taken as a key fluorine-containing building block, and multiple advantages are shown in the field of pharmaceutical chemistry, namely, firstly, the CF 2 H group can effectively prolong the half life of a drug by enhancing the metabolic oxidation resistance, secondly, the fat-soluble characteristic of the CF 2 H group can optimize the absorption and distribution of the drug in a body, and more importantly, the CF 2 H can be taken as a bioisostere of hydroxyl (-OH), amino (-NH 2), sulfhydryl (-SH) and other groups, and the chemical stability and the bioavailability are obviously improved while the interaction between the drug and a target is maintained. This unique dual attribute makes the CF 2 H group an ideal alternative to traditional hydrogen bond donors. It not only can be used as hydrogen bond donor to maintain interaction of pharmacophore, but also can be used for improving pharmacokinetic property by enhancing cell membrane permeability. The anti-obstructive pulmonary disease drug roflumilast has the advantages that the metabolic stability is obviously improved by substituting the CF 2 H for the hydroxy, and in addition, the development of the pesticide benzovindiflupyr further proves the obvious advantage of the CF 2 H group in improving the performance of the compound. Difluoromethane is a common electrophilic difluoromethylating agent and is also a direct or indirect source of other difluoromethylating agents. As difluoromethane and difluorochloromethane are commercially available, research into both gases is currently focused mainly. Whereas difluoromethane is expensive and there is no purchase channel for a while, which results in relatively few studies of the reagent. And the electrophilicity of the difluoroiodomethane is stronger than that of the other two reagents in terms of reactivity. During the course of the investigation, many studies have been made on difluoromethylation of aromatic halides, and few studies have been made on aliphatic compounds, especially on difluoromethyl substitution of secondary halides. Researchers often use equivalent copper and excess difluoromethylating agent to difluoromethylate aliphatic halogenated hydrocarbons during an aliphatic difluoromethylating study (J. Org. Chem.2021.86,2854);(Angew Chem Int Ed.2022,61, e202201064);(Chem. Sci.2024, 15, 11550–11556). Disclosure of Invention The invention aims to overcome the defects of the prior art, and provides a difluoromethyl reagent which is simple to operate, low in cost, high in yield, environment-friendly and beneficial to large-scale preparation and application of the reagent in synthesis of difluoromethyl-substituted alkane compounds. The preparation method of the difluoromethyl reagent comprises the following steps: under the inert gas atmosphere, adding potassium iodide, cuprous iodide and an aqueous dimethylformamide solution into a reaction vessel, heating, adding difluorochloroacetic acid dissolved in DMF into a reaction system, collecting difluoroiodomethane after the reaction is finished, and then adding a 1-methyl-2-pyrrolidone solution into the system to prepare the difluoromethyl reagent. Further, the molar ratio of the potassium iodide to the cuprous iodide to the difluorochloroacetic acid is 0.2-0.3:0.09-0.15:0.1-0.15. Further, the molar ratio of potassium iodide, cuprous iodide and difluorochloroacetic acid is 0.3:0.15:0.15. The difluoromethyl reagent prepared by the method. The application of the difluoromethyl reagent in synthesizing the alkyl difluoromethyl compound is provided. Further, the synthesis method of the nickel-catalyzed alkyl difluoromethyl compound comprises the following steps: in the inert gas atmosphere, adding a catalyst, a ligand, a solvent, a difluoromethyl reagent and halogenated alkane or non-activated olefin into a reaction vessel, stirring to fully react to obtain a difluoromethyl compound, wherein the reaction formula is as follows: Wherein X is chlorine, bromine, iodine or p-toluenesulfonyl; R is H or CH 3. The catalyst is NiBr 2, and the ligand is L4 or 2-trifluoromethyl pyridine or bipyridine. The amount of NiBr 2 is 5-20-mol%