CN108191784B - 5-difluoroethyl [4,5] dihydroisoxazole derivative and preparation method thereof - Google Patents
5-difluoroethyl [4,5] dihydroisoxazole derivative and preparation method thereof Download PDFInfo
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Abstract
The invention provides a 5-difluoroethyl [4,5] dihydroisoxazole derivative, wherein the 5-difluoroethyl [4,5] dihydroisoxazole derivative has a structure shown in a formula I. The invention provides a preparation method of a 5-difluoroethyl [4,5] dihydroisoxazole derivative, which takes 3-butene-1-oxime and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate as raw materials to prepare the 5-difluoroethyl [4,5] dihydroisoxazole compound through addition reaction under the action of a copper-based catalyst. The invention takes S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate as a difluoroalkylation reagent, thereby avoiding the use of a highly toxic fluorination reagent; meanwhile, the copper-based catalyst is used for catalyzing addition reaction, so that the use of expensive catalyst is avoided, and the production cost is reduced.
Description
Technical Field
The invention relates to the technical field of fluorine-containing compound intermediates, in particular to a 5-difluoroethyl [4,5] dihydroisoxazole derivative and a preparation method thereof.
Background
Fluorine-containing compounds have very broad and important applications in the fields of medicine, pesticides and materials due to the unique properties of fluorine atoms. Among the numerous fluoroalkyl groups, difluoromethyl (CF)2H) Generally considered as bioisosteres of hydroxyl and sulfhydryl groups, which can mimic hydroxyl or sulfhydryl groups in their physiological activities and are important fluoroalkyl groups in the design of drug molecules. The difluoromethyl group is selectively introduced into the aromatic ring of the bioactive molecule, so that the biological metabolic stability, the oral bioavailability and the like of the bioactive molecule can be obviously improved, and the difluoromethylation of the bioactive molecule becomes an effective means for modifying the bioactivity of the bioactive molecule.
Isoxazole and its derivatives are a very important class of organic heterocyclic compounds and are widely applied to organic synthesis. The compounds have good biological activity and pharmacological activity, and therefore, have extremely high application value in the fields of pesticides, medicines and the like. In the prior art, the difluoromethylation of isoxazole derivatives is reported to obtain isoxazole derivatives containing difluoromethylene, but the existing types of the compounds are few, and the diversity requirements of pesticide and medicine fields on the compounds cannot be met.
Disclosure of Invention
The invention aims to provide a 5-difluoroethyl [4,5] dihydroisoxazole derivative and a preparation method thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a 5-difluoroethyl [4,5] dihydroisoxazole derivative which has a structure shown in a formula I:
in the formula I, R1including-Ph, 4-CH3-Ph-、4-F-Ph-、4-Cl-Ph-、4-Br-Ph-、4-CF3-Ph-、3-CH3-Ph-, 3-F-Ph-, 3-Cl-Ph-, 2-F-Ph-, 2-Cl-Ph-, or 2-naphthyl; r2comprising-H, -CH3or-F.
Preferably, the 5-difluoroethyl [4,5] dihydroisoxazole derivative comprises
The invention provides a preparation method of a 5-difluoroethyl [4,5] dihydroisoxazole derivative in the technical scheme, which comprises the following steps:
mixing 1, 3-disubstituted 3-butene-1-oxime, S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate, an alkaline reagent, a copper-based catalyst and an organic solvent, and carrying out addition reaction under a protective atmosphere to obtain a 5-difluoroethyl [4,5] dihydroisoxazole derivative;
the 1, 3-disubstituted 3-butene-1-oximes have the structure shown in formula II:
in the formula II R1including-Ph, 4-CH3-Ph-、4-F-Ph-、4-Cl-Ph-、4-Br-Ph-、4-CF3-Ph-、3-CH3-Ph-, 3-F-Ph-, 3-Cl-Ph-, 2-F-Ph-, 2-Cl-Ph-, or 2-naphthyl; r2comprising-H, -CH3or-F.
Preferably, the volume ratio of the 1, 3-disubstituted 3-butene-1-oxime, the S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate, the alkaline reagent, the copper-based catalyst and the organic solvent is 1mmol (1.2-2.5) mmol: (2-4) mmol: (0.01-0.05) mmol, (8-12) mL.
Preferably, the alkaline agent comprises potassium carbonate, sodium bicarbonate, potassium dihydrogen phosphate, potassium phosphate, sodium acetate, potassium acetate, triethylamine or diisopropylethylamine.
Preferably, the organic solvent includes fluorobenzene, chlorobenzene, acetonitrile, dichloroethane, dichloromethane, dimethyl sulfoxide, N-dimethylformamide or tetrahydrofuran.
Preferably, the copper-based catalyst comprises cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, cuprous sulfate or cuprous oxide.
Preferably, the temperature of the addition reaction is 40-60 ℃ and the time is 24-36 h.
Preferably, the method further comprises the following steps: and (3) carrying out column chromatography separation on the obtained addition reaction material to obtain the 5-difluoroethyl [4,5] dihydroisoxazole derivative.
The invention provides a 5-difluoroethyl [4,5] dihydroisoxazole derivative which has a structure shown in a formula I.
The invention provides a preparation method of 5-difluoroethyl [4,5] dihydro isoxazole derivatives, which takes 1, 3-disubstituted 3-butene-1-oxime and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate as raw materials to prepare the 5-difluoroethyl [4,5] dihydro isoxazole compounds through addition reaction under the action of a copper-based catalyst, and the product yield can reach 55-78%. The invention takes S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate as a difluoroalkylation reagent, thereby avoiding the use of highly toxic fluorination reagents (such as Selectfluor, NFSI and the like); meanwhile, the copper-based catalyst is used for catalyzing addition reaction, so that the use of expensive catalyst (such as Pd or Ir catalyst) is avoided, and the production cost is reduced.
Detailed Description
The invention provides a 5-difluoroethyl [4,5] dihydroisoxazole derivative which has a structure shown in a formula I:
in the formula I, R1including-Ph, 4-CH3-Ph-、4-F-Ph-、4-Cl-Ph-、4-Br-Ph-、4-CF3-Ph-、3-CH3-Ph-, 3-F-Ph-, 3-Cl-Ph-, 2-F-Ph-, 2-Cl-Ph-, or 2-naphthyl; r2comprising-H, -CH3or-F.
In the present invention, the 5-difluoroethyl [4,5] dihydroisoxazole derivative preferably comprises
The invention provides a preparation method of a 5-difluoroethyl [4,5] dihydroisoxazole derivative in the technical scheme, which comprises the following steps:
mixing 1, 3-disubstituted 3-butene-1-oxime, S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate, an alkaline reagent, a copper-based catalyst and an organic solvent, and carrying out addition reaction under a protective atmosphere to obtain a 5-difluoroethyl [4,5] dihydroisoxazole derivative;
the 1, 3-disubstituted 3-butene-1-oximes have the structure shown in formula II:
in the formula II R1including-Ph, 4-CH3-Ph-、4-F-Ph-、4-Cl-Ph-、4-Br-Ph-、4-CF3-Ph-、3-CH3-Ph-, 3-F-Ph-, 3-Cl-Ph-, 2-F-Ph-, 2-Cl-Ph-, or 2-naphthyl; r2comprising-H, -CH3or-F.
In the invention, the reaction process of the addition reaction is as follows:
in the present invention, the ratio of the amount of the 1, 3-disubstituted 3-butene-1-oxime, S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate, the alkaline agent, the copper-based catalyst and the organic solvent is preferably 1mmol (1.2 to 2.5) mmol: (2-4) mmol: (0.01-0.05) mmol, (8-12) mL, more preferably 1mmol, (1.5-2.2) mmol: (2.5-3.5) mmol: (0.02-0.04) mmol, (9-11) mL, most preferably 1mmol, (1.8-2.0) mmol: (2.7-3.2) mmol: (0.025-0.035) mmol, (9.5-10.5) mL.
In the present invention, the basic agent preferably includes potassium carbonate, sodium bicarbonate, potassium dihydrogen phosphate, potassium phosphate, sodium acetate, potassium acetate, triethylamine or diisopropylethylamine.
In the present invention, the organic solvent preferably includes fluorobenzene, chlorobenzene, acetonitrile, dichloroethane, dichloromethane, dimethyl sulfoxide, N-dimethylformamide, or tetrahydrofuran.
In the present invention, the copper-based catalyst preferably comprises cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, cuprous sulfate or cuprous oxide.
The present invention has no particular requirement for the sources of the 1, 3-disubstituted 3-butene-1-oxime, S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate, the alkaline agent, the copper-based catalyst and the organic solvent, and those known to those skilled in the art as well as those commercially available can be used.
In the present invention, the 1, 3-disubstituted 3-butene-1-oxime, S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate, the alkaline agent, the copper-based catalyst and the organic solvent are preferably mixed in the order of addition, by mixing the 3-butene-1-oxime and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate first and then adding the alkaline agent, the copper-based catalyst and the organic solvent in this order.
The type of the protective gas for providing the protective atmosphere is not particularly limited in the present invention, and a protective gas known to those skilled in the art, such as nitrogen, may be used.
In the invention, the temperature of the addition reaction is preferably 40-60 ℃, more preferably 45-55 ℃, and most preferably 48-52 ℃; the time of the addition reaction is preferably 24-36 h, more preferably 26-34 h, and most preferably 28-30 h.
In the present invention, it is preferable that the addition reaction further comprises: and (3) carrying out column chromatography separation on the obtained addition reaction material to obtain the 5-difluoroethyl [4,5] dihydroisoxazole derivative. After the addition reaction is finished, the solvent in the obtained addition reaction material is preferably removed, then the obtained residues are washed, extracted and concentrated in sequence, and finally the obtained concentrated material is subjected to column chromatography separation to obtain the 5-difluoroethyl [4,5] dihydroisoxazole derivative.
The method for removing the solvent in the addition reaction material is not particularly limited, and the technical scheme for removing the solvent, which is well known by the technical personnel in the field, can be adopted; in the examples of the present invention, the solvent in the addition reaction mass was removed by distillation under reduced pressure. In the present invention, the washing is preferably water washing; the number of times of washing and the amount of water required for each washing are not particularly limited, and the technical scheme of washing known to those skilled in the art can be adopted. In the invention, the extracting agent used for the extraction is preferably dichloromethane or ethyl acetate. In the present invention, the concentration is preferably to concentrate the organic phase obtained after the extraction to 5% of the original volume; the concentration is preferably carried out using a rotary evaporator according to the invention.
In the invention, the eluent used in the column chromatography separation process is preferably a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate in the eluent is preferably (14-16): 1, and more preferably 15: 1. In the present invention, the column chromatography is preferably performed using silica gel column chromatography.
The 5-difluoroethyl [4,5] dihydroisoxazole derivatives provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
1, 3-Diphenyl-3-butene-1-oxime (1.0mmol) and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate (1.5mmol) were mixed, followed by the addition of sodium bicarbonate (2.0mmol), cuprous chloride (0.02mmol) and acetonitrile (10.0mL), N2Protecting, and carrying out addition reaction for 24 hours at 50 ℃; after the addition reaction is finished, distilling under reduced pressure to remove the solvent in the obtained addition reaction material, washing, extracting the obtained washed material by using dichloromethane, concentrating the obtained organic phase to 1.0mL by using a rotary evaporator, performing silica gel column separation on the obtained concentrated material (the eluent is a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate in the eluent is 15:1), and removing the eluent by using the rotary evaporator to obtain the target product, wherein the yield is 76%.
And (3) characterizing the obtained target product, wherein the characterization data are as follows:
1HNMR(500MHz,CDCl3):δ7.68-7.66(m,2H),7.51-7.49(m,2H),7.44-7.41(m,5H),7.36-7.33(m,1H),5.93(tt,1H,J1＝56.0Hz,J2＝4.5Hz),3.79(d,1H,J＝16.5Hz),3.60(d,1H,J＝16.5Hz),2.68-2.61(m,2H).13CNMR(125MHz,CDCl3):δ156.8,143.4,130.4,129.2,128.83,128.75,128.0,126.7,124.7,115.3(t,J＝237.5Hz),86.9(t,J＝5.9Hz),47.0,45.1(t,J＝21.3Hz).19FNMR(470MHz,CDCl3):δ-113.3(d,1F,J＝291.9Hz),-113.9(d,1F,J＝291.9Hz)。
from the above data, the obtained target product is 5- (2, 2-difluoroethyl) -3, 5-diphenyl-4, 5-dihydroisoxazole, and the structural formula is as follows:
example 2
1-p-methylphenyl-3-phenyl-3-butene-1-oxime (1.0mmol) and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate (1.2mmol) were mixed, followed by the addition of sodium carbonate (2.5mmol), cuprous bromide (0.02mmol) and dimethyl sulfoxide (10.0mL), N2Protecting, and carrying out addition reaction for 22h at 50 ℃; after the addition reaction is finished, the reaction is reducedRemoving the solvent in the obtained addition reaction material by pressure distillation, washing with water, extracting the obtained washed material with ethyl acetate, concentrating the obtained organic phase to 1.0mL by using a rotary evaporator, separating the obtained concentrated material by using a silica gel column (the eluent is a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate in the eluent is 15:1), and removing the eluent by using the rotary evaporator to obtain the target product, wherein the yield is 78%.
And (3) characterizing the obtained target product, wherein the characterization data are as follows:
1HNMR(500MHz,CDCl3):δ7.56(d,2H,J＝8.0Hz),7.50(d,2H,J＝8.0Hz),7.42(t,2H,J＝7.5Hz),7.34(d,1H,J＝7.5Hz),7.22(d,2H,J＝7.5Hz),5.93(tt,1H,J1＝56.0Hz,J2＝4.5Hz),3.76(d,1H,J＝16.5Hz),3.58(d,1H,J＝16.5Hz),2.67-2.60(m,2H),2.40(s,3H).13CNMR(125MHz,CDCl3):δ156.7,143.5,140.7,129.4,128.8,127.9,126.6,126.3,124.7,115.4(t,J＝237.5Hz),86.7(t,J＝5.9Hz),47.1,45.1(t,J＝21.1Hz),21.4.19FNMR(470MHz,CDCl3):δ-113.2(d,1F,J＝291.4Hz),-113.9(d,1F,J＝291.4Hz)。
from the above data, the obtained target product is 5- (2, 2-difluoroethyl) -5-phenyl-3-p-methylphenyl-4, 5-dihydroisoxazole, and the structural formula is as follows:
example 3
1-p-fluorophenyl-3-phenyl-3-butene-1-oxime (1.0mmol) and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate (1.6mmol) were mixed, and triethylamine (3.0mmol), cuprous iodide (0.02mmol) and tetrahydrofuran (10.0mL), N, were added in that order2Protecting, and carrying out addition reaction for 28h at 50 ℃; after the addition reaction is finished, distilling under reduced pressure to remove the solvent in the obtained addition reaction material, washing, extracting the obtained washed material by using dichloromethane, concentrating the obtained organic phase to 1.0mL by using a rotary evaporator, and separating the obtained concentrated material by using a silica gel column (the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the eluent is a mixed solvent of petroleum ether and ethyl acetateThe volume ratio of petroleum ether to ethyl acetate in the eluent was 15:1), and the eluent was removed by a rotary evaporator to obtain the target product with a yield of 73%.
And (3) characterizing the obtained target product, wherein the characterization data are as follows:
1HNMR(500MHz,CDCl3):δ7.69-7.65(m,2H),7.50(d,2H,J＝7.5Hz),7.43(t,2H,J＝8.0Hz),7.35(t,1H,J＝8.0Hz),7.11(t,2H,J＝8.5Hz),5.93(tt,1H,J1＝56.0Hz,J2＝5.0Hz),3.76(d,1H,J＝17.0Hz),3.57(d,1H,J＝16.5Hz),2.68-2.60(m,2H).13CNMR(125MHz,CDCl3):δ163.9(d,J＝249.8Hz),155.8,143.3,128.9,128.7(d,J＝8.5Hz),128.0,125.4(d,J＝3.5Hz),124.6,115.9(d,J＝21.8Hz),115.3(t,J＝237.5Hz),87.0(t,J＝5.8Hz),47.0(t,J＝1.9Hz),45.1(t,J＝21.4Hz).19FNMR(470MHz,CDCl3):δ-109.4(s,1F),-113.4(d,1F,J＝291.9Hz),-114.0(d,1F,J＝291.9Hz)。
from the data, the obtained target product is 5- (2, 2-difluoroethyl) -5-phenyl-3-p-fluorophenyl-4, 5-dihydroisoxazole, and the structural formula is as follows:
example 4
1-p-chlorophenyl-3-phenyl-3-butene-1-oxime (1.0mmol) and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate (1.5mmol) were mixed, followed by the addition of potassium phosphate (2.5mmol), cuprous acetate (0.03mmol) and dichloromethane (10.0mL), N, in that order2Protecting, and carrying out addition reaction for 25h at 50 ℃; after the addition reaction is finished, distilling under reduced pressure to remove the solvent in the obtained addition reaction material, washing, extracting the obtained washed material by using ethyl acetate, concentrating the obtained organic phase to 1.0mL by using a rotary evaporator, separating the obtained concentrated material by using a silica gel column (the eluent is a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate in the eluent is 15:1), and removing the eluent by using the rotary evaporator to obtain the target product with the yield of 75%.
And (3) characterizing the obtained target product, wherein the characterization data are as follows:
1HNMR(500MHz,CDCl3):δ7.62-7.59(m,2H),7.50-7.48(m,2H),7.45-7.39(m,4H),7.36-7.34(m,1H),5.92(tt,1H,J1＝56.0Hz,J2＝4.5Hz),3.75(d,1H,J＝16.5Hz),3.57(d,1H,J＝16.5Hz),2.67-2.60(m,2H).13CNMR(125MHz,CDCl3):δ155.9,143.2,136.4,129.0,128.9,128.1,127.9,127.7,124.6,115.3(t,J＝237.8Hz),87.2(t,J＝5.6Hz),46.8,45.1(t,J＝21.4Hz).19FNMR(470MHz,CDCl3):δ-113.4(d,1F,J＝291.9Hz),-114.0(d,1F,J＝291.9Hz)。
from the above data, the obtained target product is 5- (2, 2-difluoroethyl) -5-phenyl-3-p-chlorophenyl-4, 5-dihydroisoxazole, and the structural formula is as follows:
example 5
1-p-bromophenyl-3-phenyl-3-butene-1-oxime (1.0mmol) and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate (2.0mmol) were mixed, followed by the addition of potassium acetate (4.0mmol), cuprous sulfate (0.04mmol) and fluorobenzene (10.0mL), N2Protecting, and carrying out addition reaction for 26h at 50 ℃; after the addition reaction is finished, distilling under reduced pressure to remove the solvent in the obtained addition reaction material, washing, extracting the obtained washed material by using dichloromethane, concentrating the obtained organic phase to 1.0mL by using a rotary evaporator, performing silica gel column separation on the obtained concentrated material (the eluent is a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate in the eluent is 15:1), and removing the eluent by using the rotary evaporator to obtain a target product, wherein the yield is 72%.
And (3) characterizing the obtained target product, wherein the characterization data are as follows:
1HNMR(500MHz,CDCl3):δ7.57-7.52(m,4H),7.49(d,2H,J＝8.0Hz),7.44-7.42(m,2H),7.36-7.34(m,1H),5.91(tt,1H,J1＝55.5Hz,J2＝4.5Hz),3.75(d,1H,J＝17.0Hz),3.57(d,1H,J＝16.5Hz),2.67-2.60(m,2H).13CNMR(125MHz,CDCl3):δ156.0,143.2,132.0,128.9,128.11,128.08,124.7,124.6,115.2(t,J＝237.9Hz),87.3(t,J＝5.6Hz),46.7,45.1(t,J＝21.1Hz).19FNMR(470MHz,CDCl3):δ-113.4(d,1F,J＝291.9Hz),-114.0(d,1F,J＝291.9Hz)。
from the above data, the obtained target product is 5- (2, 2-difluoroethyl) -5-phenyl-3-p-bromophenyl-45-dihydroisoxazole, and the structural formula is as follows:
example 6
1-p-trifluoromethylphenyl-3-phenyl-3-butene-1-oxime (1.0mmol) and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate (2.0mmol) were mixed, followed by the addition of diisopropylethylamine (3.0mmol), cuprous oxide (0.03mmol) and chlorobenzene (10.0mL), N2Protecting, and carrying out addition reaction for 30h at 50 ℃; after the addition reaction is finished, distilling under reduced pressure to remove the solvent in the obtained addition reaction material, washing, extracting the obtained washed material by using dichloromethane, concentrating the obtained organic phase to 1.0mL by using a rotary evaporator, performing silica gel column separation on the obtained concentrated material (the eluent is a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate in the eluent is 15:1), and removing the eluent by using the rotary evaporator to obtain a target product, wherein the yield is 73%.
And (3) characterizing the obtained target product, wherein the characterization data are as follows:
1HNMR(500MHz,CDCl3):δ7.79(d,2H,J＝8.5Hz),7.68(d,2H,J＝8.5Hz),7.50(d,2H,J＝7.5Hz),7.46-7.43(m,2H),7.38-7.35(m,1H),5.92(tt,1H,J1＝56.0Hz,J2＝4.5Hz),3.80(d,1H,J＝17.0Hz),3.61(d,1H,J＝17.0Hz),2.69-2.62(m,2H).13CNMR(125MHz,CDCl3):δ155.8,143.0,132.6(d,J＝1.0Hz),132.0(q,J＝32.5Hz),128.9,128.2,126.9,125.9(q,J＝270.4Hz),125.7(q,J＝3.9Hz),124.6,115.2(t,J＝237.8Hz),87.6(t,J＝5.8Hz),46.6,45.1(t,J＝21.3Hz).19FNMR(470MHz,CDCl3):δ-63.0(s,3F),-113.5(d,1F,J＝292.3Hz),-114.1(d,1F,J＝292.8Hz)。
from the above data, the obtained target product is 5- (2, 2-difluoroethyl) -5-phenyl-3-p-trifluoromethylphenyl-4, 5-dihydroisoxazole, and the structural formula is as follows:
example 7
1-m-methylphenyl-3-phenyl-3-butene-1-oxime (1.0mmol) and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate (2.0mmol) were mixed, followed by the addition of potassium carbonate (4.0mmol), cuprous chloride (0.05mmol) and dichloroethane (10.0mL), N2Protecting, and carrying out addition reaction for 24 hours at 50 ℃; after the addition reaction is finished, distilling under reduced pressure to remove the solvent in the obtained addition reaction material, washing, extracting the obtained washed material by using ethyl acetate, concentrating the obtained organic phase to 1.0mL by using a rotary evaporator, separating the obtained concentrated material by using a silica gel column (the eluent is a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate in the eluent is 15:1), and removing the eluent by using the rotary evaporator to obtain a target product, wherein the yield is 63%.
And (3) characterizing the obtained target product, wherein the characterization data are as follows:
1HNMR(500MHz,CDCl3):δ7.48-7.46(m,3H),7.43-7.38(m,3H),7.32-7.25(m,2H),7.21(d,1H,J＝7.5Hz),5.90(tt,1H,J1＝56.0Hz,J2＝5.0Hz),3.74(d,1H,J＝17.0Hz),3.55(d,1H,J＝16.5Hz),2.64-2.57(m,2H),2.36(s,3H).13CNMR(125MHz,CDCl3):δ156.9,143.5,138.5,131.2,129.1,128.8,128.6,127.9,127.3,124.7,123.9,115.3(t,J＝237.6Hz),86.8(t,J＝5.8Hz),47.1,45.0(t,J＝21.3Hz),21.3.19FNMR(470MHz,CDCl3):δ-113.2(d,1F,J＝291.9Hz),-113.9(d,1F,J＝291.9Hz)。
from the above data, the target product is 5- (2, 2-difluoroethyl) -5-phenyl-3-m-methylphenyl-4, 5-dihydroisoxazole, and the structural formula is as follows:
example 8
1-m-fluorophenyl-3-phenyl-3-butene-1-oxime (1.0mmol) and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate (2.0mmol) were mixed, followed by the addition of sodium acetate (3.0mmol), cuprous bromide (0.03mmol) and N, N-dimethylformamide (10.0mL), N2Protecting, and carrying out addition reaction for 23h at 50 ℃; after the addition reaction is finished, distilling under reduced pressure to remove the solvent in the obtained addition reaction material, washing, extracting the obtained washed material by using dichloromethane, concentrating the obtained organic phase to 1.0mL by using a rotary evaporator, performing silica gel column separation on the obtained concentrated material (the eluent is a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate in the eluent is 15:1), and removing the eluent by using the rotary evaporator to obtain the target product, wherein the yield is 55%.
And (3) characterizing the obtained target product, wherein the characterization data are as follows:
1HNMR(500MHz,CDCl3):δ7.49(d,2H,J＝7.5Hz),7.45-7.34(m,6H),7.15-7.12(m,1H),5.92(tt,1H,J1＝56.0Hz,J2＝4.5Hz),3.76(d,1H,J＝16.5Hz),3.57(d,1H,J＝16.5Hz),2.68-2.61(m,2H).13CNMR(125MHz,CDCl3):δ162.8(d,J＝245.6Hz),155.9(d,J＝2.9Hz),143.2,131.3(d,J＝8.0Hz),130.4(d,J＝8.1Hz),128.9,128.1,124.6,122.4(d,J＝3.1Hz),117.3(d,J＝21.1Hz),115.2(t,J＝237.6Hz),113.5(d,J＝23.0Hz),87.3(t,J＝5.8Hz),46.8,45.0(t,J＝21.3Hz).19FNMR(470MHz,CDCl3):δ-112.0(s,1F),-113.4(d,1F,J＝291.9Hz),-114.0(d,1F,J＝291.9Hz)。
from the data, the obtained target product is 5- (2, 2-difluoroethyl) -5-phenyl-3-m-fluorophenyl-4, 5-dihydroisoxazole, and the structural formula is as follows:
example 9
1-m-chlorophenyl-3-phenyl-3-butene-1-oxime (1.0mmol) and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate (2.0mmol) were mixed, followed by the sequential addition of phosphorusPotassium (3.0mmol), cuprous iodide (0.02mmol) and tetrahydrofuran (10.0mL), N2Protecting, and carrying out addition reaction for 32h at 50 ℃; after the addition reaction is finished, distilling under reduced pressure to remove the solvent in the obtained addition reaction material, washing, extracting the obtained washed material by using ethyl acetate, concentrating the obtained organic phase to 1.0mL by using a rotary evaporator, separating the obtained concentrated material by using a silica gel column (the eluent is a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate in the eluent is 15:1), and removing the eluent by using the rotary evaporator to obtain the target product with the yield of 58%.
And (3) characterizing the obtained target product, wherein the characterization data are as follows:
1HNMR(500MHz,CDCl3):δ7.63(t,1H,J＝1.5Hz),7.53(d,1H,J＝7.5Hz),7.47-7.45(m,2H),7.42-7.36(m,3H),7.34-7.31(m,2H),5.89(tt,1H,J1＝56.0Hz,J2＝4.5Hz),3.73(d,1H,J＝16.5Hz),3.54(d,1H,J＝16.5Hz),2.65-2.58(m,2H).13CNMR(125MHz,CDCl3):δ155.8,143.1,134.8,130.9,130.3,130.0,128.9,128.1,126.7,124.7,124.6,115.2(t,J＝237.8Hz),87.3(t,J＝5.6Hz),46.7(t,J＝1.9Hz),45.0(t,J＝21.3Hz).19FNMR(470MHz,CDCl3):δ-113.4(d,1F,J＝291.9Hz),-114.0(d,1F,J＝291.9Hz)。
from the above data, the obtained target product is 5- (2, 2-difluoroethyl) -5-phenyl-3-m-chlorophenyl-4, 5-dihydroisoxazole, and the structural formula is as follows:
example 10
1-o-fluorophenyl-3-phenyl-3-butene-1-oxime (1.0mmol) and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate (2.0mmol) were mixed, followed by the addition of triethylamine (3.0mmol), cuprous acetate (0.04mmol) and dichloroethane (10.0mL), N2Protecting, and carrying out addition reaction for 26h at 50 ℃; after the addition reaction is finished, removing the solvent in the obtained addition reaction material by reduced pressure distillation, washing with water, extracting the obtained washed material with dichloromethane, and performing rotary evaporationConcentrating the obtained organic phase to 1.0mL, performing silica gel column separation on the obtained concentrated material (the eluent is a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate in the eluent is 15:1), and removing the eluent by using a rotary evaporator to obtain the target product, wherein the yield is 65%.
And (3) characterizing the obtained target product, wherein the characterization data are as follows:
1HNMR(500MHz,CDCl3):δ7.85(td,1H,J1＝7.5Hz,J2＝2.0Hz),7.48-7.46(m,2H),7.42-7.36(m,3H),7.34-7.30(m,1H),7.19-7.15(m,1H),7.11-7.07(m,1H),5.89(tt,1H,J1＝55.5Hz,J2＝4.5Hz),3.83(dd,1H,J1＝17.5Hz,J2＝2.5Hz),3.68-3.65(m,1H),2.65-2.57(m,2H).13CNMR(125MHz,CDCl3):δ160.3(d,J＝251.1Hz),153.5(d,J＝3.0Hz),143.2,132.0(d,J＝8.6Hz),128.9(d,J＝2.9Hz),128.8,128.0,124.7,124.5(d,J＝3.4Hz),117.3(d,J＝11.4Hz),116.4(d,J＝21.9Hz),115.3(t,J＝237.5Hz),87.1(td,J1＝5.8Hz,J2＝2.1Hz),48.7(d,J＝6.9Hz),45.1(t,J＝21.3Hz).19FNMR(470MHz,CDCl3):δ-112.5(s,1F),-113.3(d,1F,J＝291.4Hz),-114.0(d,1F,J＝291.4Hz)。
from the data, the obtained target product is 5- (2, 2-difluoroethyl) -5-phenyl-3-o-fluorophenyl-4, 5-dihydroisoxazole, and the structural formula is as follows:
example 11
1-o-chlorophenyl-3-phenyl-3-butene-1-oxime (1.0mmol) and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate (2.5mmol) were mixed, followed by the addition of sodium dihydrogen phosphate (2.5mmol), cuprous bromide (0.03mmol) and acetonitrile (10.0mL), N, in that order2Protecting, and carrying out addition reaction for 24 hours at 50 ℃; after the addition reaction is finished, distilling under reduced pressure to remove the solvent in the obtained addition reaction material, washing, extracting the obtained washed material by using ethyl acetate, concentrating the obtained organic phase to 1.0mL by using a rotary evaporator, and separating the obtained concentrated material by using a silica gel column (the eluent is the mixed solution of petroleum ether and ethyl acetate)And (3) removing the eluent by using a rotary evaporator to obtain a target product, wherein the volume ratio of the petroleum ether to the ethyl acetate in the eluent is 15:1, and the yield is 65%.
And (3) characterizing the obtained target product, wherein the characterization data are as follows:
1HNMR(500MHz,CDCl3):δ7.62-7.60(m,1H),7.48-7.46(m,2H),7.43-7.40(m,3H),7.36-7.32(m,2H),7.30-7.27(m,1H),5.90(tt,1H,J1＝56.0Hz,J2＝4.5Hz),3.89(d,1H,J＝17.0Hz),3.72(d,1H,J＝17.0Hz),2.67-2.59(m,2H).13CNMR(125MHz,CDCl3):δ156.8,142.9,132.8,131.1,130.6,130.5,128.8,128.7,128.0,127.0,124.7,115.3(t,J＝237.8Hz),87.5(t,J＝5.5Hz),49.3,44.9(t,J＝21.3Hz).19FNMR(470MHz,CDCl3):δ-113.3(d,1F,J＝291.4Hz),-113.9(d,1F,J＝291.4Hz)。
from the data, the obtained target product is 5- (2, 2-difluoroethyl) -5-phenyl-3-o-chlorophenyl-45-dihydroisoxazole, and the structural formula is as follows:
example 12
1-phenyl-3-p-methylphenyl-3-butene-1-oxime (1.0mmol) and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate (2.0mmol) were mixed, followed by the addition of sodium bicarbonate (2.0mmol), cuprous iodide (0.03mmol) and N, N-dimethylformamide (10.0mL), N2Protecting, and carrying out addition reaction for 30h at 50 ℃; after the addition reaction is finished, distilling under reduced pressure to remove the solvent in the obtained addition reaction material, washing, extracting the obtained washed material by using dichloromethane, concentrating the obtained organic phase to 1.0mL by using a rotary evaporator, performing silica gel column separation on the obtained concentrated material (the eluent is a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate in the eluent is 15:1), and removing the eluent by using the rotary evaporator to obtain a target product, wherein the yield is 68%.
And (3) characterizing the obtained target product, wherein the characterization data are as follows:
1HNMR(500MHz,CDCl3):δ7.65-7.63(m,2H),7.41-7.38(m,3H),7.36-7.35(m,2H),7.20(d,2H,J＝8.0Hz),5.89(tt,1H,J1＝55.5Hz,J2＝4.5Hz),3.73(d,1H,J＝16.5Hz),3.55(d,1H,J＝16.5Hz),2.64-2.56(m,2H),2.35(s,3H).13CNMR(125MHz,CDCl3):δ156.8,140.4,137.7,130.3,129.4,129.2,128.7,126.7,124.6,115.4(t,J＝237.5Hz),86.9(t,J＝5.5Hz),46.9,45.1(t,J＝21.3Hz),21.0.19FNMR(470MHz,CDCl3):δ-113.3(d,1F,J＝291.4Hz),-113.9(d,1F,J＝291.9Hz)。
from the above data, the obtained target product is 5- (2, 2-difluoroethyl) -3-phenyl-5-p-methylphenyl-4, 5-dihydroisoxazole, and the structural formula is as follows:
example 13
1-phenyl-3-p-fluorophenyl-3-butene-1-oxime (1.0mmol) and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate (2.0mmol) were mixed, followed by the addition of diisopropylamine (2.0mmol), cuprous acetate (0.02mmol) and dichloromethane (10.0mL), N2Protecting, and carrying out addition reaction for 28h at 50 ℃; after the addition reaction is finished, distilling under reduced pressure to remove the solvent in the obtained addition reaction material, washing, extracting the obtained washed material by using ethyl acetate, concentrating the obtained organic phase to 1.0mL by using a rotary evaporator, separating the obtained concentrated material by using a silica gel column (the eluent is a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate in the eluent is 15:1), and removing the eluent by using the rotary evaporator to obtain the target product, wherein the yield is 71%.
And (3) characterizing the obtained target product, wherein the characterization data are as follows:
1HNMR(500MHz,CDCl3):δ7.68-7.66(m,2H),7.49-7.47(m,2H),7.45-7.41(m,3H),7.11(t,2H,J＝9.0Hz),5.93(tt,1H,J1＝55.5Hz,J2＝4.5Hz),3.78(d,1H,J＝16.5Hz),3.56(d,1H,J＝16.5Hz),2.67-2.59(m,2H).13CNMR(125MHz,CDCl3):δ162.3(d,J＝245.8Hz),156.8,139.2(d,J＝3.1Hz),130.5,129.0,128.8,126.7,126.6(d,J＝8.1Hz),115.7(d,J＝21.4Hz),115.2(t,J＝237.6Hz),86.5(t,J＝5.8Hz),47.2,45.1(t,J＝21.3Hz).19FNMR(470MHz,CDCl3):δ-113.3(d,1F,J＝291.9Hz),-114.0(d,1F,J＝291.9Hz),-114.2(s,1F)。
from the data, the obtained target product is 5- (2, 2-difluoroethyl) -3-phenyl-5-p-fluorophenyl-4, 5-dihydroisoxazole, and the structural formula is as follows:
example 14
1-naphthyl-3-phenyl-3-butene-1-oxime (1.0mmol) and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate (1.5mmol) were mixed, followed by the addition of potassium carbonate (2.5mmol), cuprous chloride (0.03mmol) and dimethyl sulfoxide (10.0mL), N2Protecting, and carrying out addition reaction for 24 hours at 50 ℃; after the addition reaction is finished, distilling under reduced pressure to remove the solvent in the obtained addition reaction material, washing, extracting the obtained washed material by using ethyl acetate, concentrating the obtained organic phase to 1.0mL by using a rotary evaporator, separating the obtained concentrated material by using a silica gel column (the eluent is a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate in the eluent is 15:1), and removing the eluent by using the rotary evaporator to obtain the target product, wherein the yield is 59%.
And (3) characterizing the obtained target product, wherein the characterization data are as follows:
1HNMR(500MHz,CDCl3):δ8.00-7.98(m,1H),7.90-7.85(m,4H),7.57-7.52(m,4H),7.44(t,2H,J＝8.0Hz),7.35(t,1H,J＝7.5Hz),5.96(tt,1H,J1＝56.0Hz,J2＝4.5Hz),3.91(d,1H,J＝16.5Hz),3.73(d,1H,J＝16.5Hz),2.72-2.65(m,2H).13CNMR(125MHz,CDCl3):δ156.9,143.4,134.1,132.9,128.9,128.6,128.4,128.0,127.9,127.3,127.1,126.8,124.7,123.4,115.3(t,J＝237.5Hz),87.1(t,J＝5.5Hz),47.0,45.1(t,J＝21.1Hz).19FNMR(470MHz,CDCl3):δ-113.2(d,1F,J＝291.9Hz),-113.9(d,1F,J＝291.9Hz)。
from the above data, the target product obtained is 5- (2, 2-difluoroethyl) -5-p-fluorophenyl-3- (2-naphthyl) -4, 5-dihydroisoxazole, and the structural formula is as follows:
the above embodiments show that the invention provides a 5-difluoroethyl [4,5] dihydroisoxazole derivative, the invention obtains a plurality of 5-difluoroethyl [4,5] dihydroisoxazole derivatives with novel structures by the addition reaction of 3-butene-1-oxime with different structures and S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate, the product yield can reach 55% -78%, no expensive catalyst (Pd or Ir catalyst) is needed to be added, the use of highly toxic fluorinated reagents (such as Selectfluor, NFSI and the like) is avoided, and the preparation method has low production cost and is environment-friendly.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (7)
1. A preparation method of a 5-difluoroethyl [4,5] dihydroisoxazole derivative comprises the following steps:
mixing 1, 3-disubstituted 3-butene-1-oxime, S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate, an alkaline reagent, a copper-based catalyst and an organic solvent, and carrying out addition reaction under a protective atmosphere to obtain a 5-difluoroethyl [4,5] dihydroisoxazole derivative;
the 1, 3-disubstituted 3-butene-1-oximes have the structure shown in formula II:
in the formula II R1including-Ph, 4-CH3-Ph-、4-F-Ph-、4-Cl-Ph-、4-Br-Ph-、4-CF3-Ph-、3-CH3-Ph-, 3-F-Ph-, 3-Cl-Ph-, 2-F-Ph-, 2-Cl-Ph-, or 2-naphthyl; r2comprising-H, -CH3or-F;
the 5-difluoroethyl [4,5] dihydroisoxazole derivative has a structure shown in a formula I:
in the formula I, R1including-Ph, 4-CH3-Ph-、4-F-Ph-、4-Cl-Ph-、4-Br-Ph-、4-CF3-Ph-、3-CH3-Ph-, 3-F-Ph-, 3-Cl-Ph-, 2-F-Ph-, 2-Cl-Ph-, or 2-naphthyl; r2comprising-H, -CH3or-F.
2. The production method according to claim 1, wherein the volume ratio of the 1, 3-disubstituted 3-butene-1-oxime, S-difluoromethyl-S-di (p-xylyl) tetrafluoroborate, the alkaline agent, the copper-based catalyst and the organic solvent is 1mmol (1.2 to 2.5) mmol: (2-4) mmol: (0.01-0.05) mmol, (8-12) mL.
3. The method according to claim 1 or 2, wherein the basic agent comprises potassium carbonate, sodium bicarbonate, potassium dihydrogen phosphate, potassium phosphate, sodium acetate, potassium acetate, triethylamine, or diisopropylethylamine.
4. The production method according to claim 1 or 2, wherein the organic solvent comprises fluorobenzene, chlorobenzene, acetonitrile, dichloroethane, dichloromethane, dimethyl sulfoxide, N-dimethylformamide, or tetrahydrofuran.
5. The method of claim 1 or 2, wherein the copper-based catalyst comprises cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, cuprous sulfate, or cuprous oxide.
6. The preparation method according to claim 1, wherein the temperature of the addition reaction is 40-60 ℃ and the time is 24-36 h.
7. The method of claim 1, further comprising, after the addition reaction: and (3) carrying out column chromatography separation on the obtained addition reaction material to obtain the 5-difluoroethyl [4,5] dihydroisoxazole derivative.
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