A kind of dihydronaphthalene derivative substituted by difluoromethyl and its synthetic method

The technology of a difluoromethyl group and a synthetic method is applied in the field of organic chemical synthesis, and can solve the problems of expensive fluorination reagents, difficult synthesis, harsh reaction conditions, etc., and achieves good substrate universality, simple operation, and simple operation of reaction steps. Effect

Active Publication Date: 2022-02-22
LIAONING UNIVERSITY OF PETROLEUM AND CHEMICAL TECHNOLOGY
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Problems solved by technology

[0003] At present, direct introduction of fluorine atoms into molecules usually has the disadvantages of expensive fluorinating reagents, difficult synthesis, and harsh reaction conditions. Functional groups are challenging and highly desired

Method used

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  • A kind of dihydronaphthalene derivative substituted by difluoromethyl and its synthetic method
  • A kind of dihydronaphthalene derivative substituted by difluoromethyl and its synthetic method
  • A kind of dihydronaphthalene derivative substituted by difluoromethyl and its synthetic method

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preparation example Construction

[0048] This embodiment provides a method for synthesizing dihydronaphthalene derivatives substituted with difluoromethyl, and then introducing fluorine atoms into the dihydronaphthalene derivatives. The method specifically includes the following steps:

[0049] After the reactor is evacuated, it is replaced by an inert gas such as nitrogen or argon, and then the methylenecyclopropane compound, brominated difluorocarbonyl compound, copper catalyst, ligand, pinacol diborate are added to the reactor in sequence Esters, bases and solvents are stirred and reacted at a temperature of 40-120°C;

[0050] After the reaction, the solvent was removed with a rotary evaporator to obtain a crude product, which was obtained through column chromatography, wherein the eluent used in the column chromatography was a mixed solvent of petroleum ether and ethyl acetate.

[0051] Above-mentioned copper catalyst is CuCl, CuBr, CuI, CuCl 2 、CuBr 2 and Cu(OAc) 2 One or more of them; the ligands are ...

Embodiment 1

[0068]

[0069] After the reactor was evacuated, the inert gas nitrogen or argon was replaced, and 0.2mmol (41.2mg) 1a, 0.4mmol (80.8mg) ethyl difluorobromoacetate (2a), 0.02mmol (2.9mg) CuBr, 0.02 mmol (7.1 mg) dtbbpy, 0.06 mmol (15.2 mg) B 2 pin 2 , 0.4 mmol (33.6 mg) NaHCO 3 , 1mL 1,4-dioxane, stirred at 80°C for 16h. After the reaction was completed, the solvent was removed with a rotary evaporator, and the crude product was subjected to column chromatography, and the eluent was a mixed solvent of petroleum ether and ethyl acetate to obtain 55.1 mg of dihydronaphthalene derivative 3aa substituted with difluoromethyl, which was separated and collected The rate is 84%.

[0070] see Figure 1 ~ Figure 3 , the characterization data of compound 3aa are as follows:

[0071] 1 H NMR (400MHz, CDCl 3 )δ7.33-7.28(m,3H),7.12-7.11(m,2H),7.10-7.07(m,2H),6.99-6.94(m,1H),6.53(d,J=7.6Hz,1H) , 3.87(q, J=7.2Hz, 2H), 2.89(t, J=8.0Hz, 2H), 2.58(t, J=8.0Hz, 2H), 1.13(t, J=7.2Hz, 3H)...

Embodiment 2

[0073]

[0074] After vacuumizing the reactor, replace it with inert gas nitrogen or argon, add 0.2mmol (41.6mg) 1b, 0.4mmol (80.8mg) ethyl difluorobromoacetate (2a), 0.02mmol (2.9mg) CuBr, 0.02 mmol (7.1 mg) dtbbpy, 0.06 mmol (15.2 mg) B 2 pin 2 , 0.4 mmol (33.6 mg) NaHCO 3 , 1mL 1,4-dioxane, stirred at 80°C for 16h. After the reaction was finished, the solvent was removed with a rotary evaporator, and the crude product was subjected to column chromatography, and the eluent was a mixed solvent of sherwood oil and ethyl acetate to obtain 47.5 mg of dihydronaphthalene derivative 3ba substituted with difluoromethyl, which was separated and collected. The rate is 72%.

[0075] see Figure 4 ~ Figure 6 , the characterization data of compound 3ba are as follows:

[0076] 1 H NMR (400MHz, CDCl 3 )δ7.33(dd, J=8.0,2.0Hz,1H),7.30(s,1H),7.00(d,J=8.0Hz,1H),6.82(s,1H),4.35(q,J=7.2 Hz,2H),2.85(t,J=8.0Hz,2H),2.45-2.40(m,2H),1.35(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl 3 )δ163.6(t...

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Abstract

The invention provides a dihydronaphthalene derivative substituted with a difluoromethyl group and a synthesis method thereof. The synthesis method is based on Cu / B 2 pin 2 Under the catalysis, through the process of free radical addition and three-membered ring opening and then ring closing, multiple chemical bonds were constructed in one step, and the series reaction of brominated difluoromethyl carbonyl compounds and MCPs was realized, and difluoromethyl was synthesized efficiently A substituted dihydronaphthalene derivative, the synthesis method uses cheap and easy-to-obtain copper salt as a catalyst, has the advantages of simple operation, good substrate universality, and simple operation of the reaction steps.

Description

technical field [0001] The disclosure of the invention relates to the technical field of organic chemical synthesis, in particular to a difluoromethyl-substituted dihydronaphthalene derivative and a synthesis method thereof. Background technique [0002] The fluorine atom belongs to group VIIA of the second period in the periodic table of elements, which determines that fluorine-containing organic compounds are a class of very valuable compounds, which are widely used in many fields such as pesticides, medicines, materials, and aerospace. Especially in recent years, studies have found that drug molecules containing fluorine atoms have good properties such as fat solubility, stability, and permeability, which increase the biological activity of drugs, thereby reducing the dosage of drugs to a certain extent. However, there are relatively few fluorine-containing compounds in nature, which requires artificial synthesis to meet people's growing needs. Therefore, introducing fluo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C67/347C07C69/65C07C69/757C07D295/185B01J31/22
Inventor 王贺杨艳杰刘闯李蕾周明东
Owner LIAONING UNIVERSITY OF PETROLEUM AND CHEMICAL TECHNOLOGY
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