An α-difluoromethylstyrene derivative and a preparation method thereof

Abstract

The present invention discloses an α-difluoromethylstyrene derivative and a preparation method thereof. The structure of the α-difluoromethylstyrene derivative of the present invention is as shown in formula (I), and the α-difluoromethylstyrene derivative is formed by reacting 3,3-difluoroallyl hydrazine, a transition metal salt and an additive in a solvent. The α-difluoromethylstyrene derivative of the present invention contains both gem-difluoromethylene and double bond structural units, and can be used as a potential pharmaceutical lead compound or a synthetic intermediate of a drug active molecule, providing an opportunity for the synthesis of macromolecular drugs. At the same time, the present invention provides a preparation method of the compound. The method is direct, simple, efficient, has a wide range of substrate applicability, and the raw materials are economically available and easy to obtain, and is suitable for large-scale production of α-difluoromethylstyrene derivatives.

Description

Technical Field

[0001] The present invention belongs to the technical fields of pharmaceutical intermediates and organic synthesis, and particularly relates to an α-difluoromethylstyrene derivative and a preparation method thereof. Background Art

[0002] Fluorinated compounds are a unique structural motif and have important applications in the fields of drug discovery, agrochemical science, and materials science. In many cases, the difluoromethyl group has been proven to be a lipophilic hydrogen bond donor. Due to the high polarization of the C-H bond, it can be recognized as a methyl group or a hydroxyl group in vivo. After introducing the difluoromethyl group into the molecular scaffold, the lipophilicity and binding affinity of bioactive molecules are significantly enhanced, so it has many important biological properties. α-Difluoromethylstyrene, due to its carbon-carbon double bond and difluoromethyl unit, is a general precursor for various difluoromethyl-containing compounds and fluorinated polymers. And due to its good stability and the ability to participate in a variety of organic chemical reactions, it is widely used in the synthesis of fluorine-containing compounds with biological activity in the fields of biomedicine and pesticides.

[0003] Therefore, in view of the special properties of fluorine-containing groups and their wide application value, the synthesis of a new type of α-difluoromethylstyrene derivative is very attractive both in the field of biomedicine and organic synthesis. However, in the past few decades, although considerable progress has been made in the fluorination, trifluoromethylation, and difluoromethylation of organic substrates, so far, the synthetic strategies of α-difluoromethylstyrene derivatives have been explored very little. Although there are few reports on obtaining α-difluoromethyl derivatives, they use expensive fluorinated ketones, which are characterized by harsh, strong base, and ultra-low temperature conditions, severely limiting their wide synthetic applications. Therefore, it is crucial to explore a preparation method of α-difluoromethylstyrene derivatives with mild reaction conditions, simple operation, and wide substrate applicability. Summary of the Invention

[0004] The purpose of the present invention is to provide an α-difluoromethylstyrene derivative and a preparation method thereof in view of the deficiencies of the above-mentioned prior art.

[0005] To achieve the above purpose, the technical scheme adopted by the present invention is as follows: An α-difluoromethylstyrene derivative, whose structure is shown in formula (I):

[0006]

[0007] In formula (I), n is the number of H on the benzene ring substituted by the substituent R 1 The number of substitutions, n is a natural number from 1 to 5; when n = 2 - 5, it means that multiple hydrogens on the benzene ring are substituted by multiple substituents R 1 Substituted, and the substituents at different substitution positions are the same or different groups; R 1is one of phenyl, methyl, tert-butyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, acetyl, benzodiazole, naphthalene, thiophene;

[0008] The α-difluoromethylstyrene derivative is formed by reacting 3,3-difluoroallyl hydrazine, a transition metal salt and an additive in a solvent.

[0009] Firstly, the α-difluoromethylstyrene derivative of the present invention contains both gem-difluoromethylene and double bond structural units, and can be used as a potential pharmaceutical lead compound or a synthetic intermediate for bioactive molecules, providing an opportunity for the synthesis of macromolecular drugs. Secondly, the α-difluoromethylstyrene derivative prepared by the cheap metal-mediated dehydrohydrazination using 3,3-difluoroallyl hydrazine as a raw material has high purity, high yield, good selectivity and stable physical properties. Moreover, the method of the present invention has a wide range of substrate applicability, simple process operation, and easily available raw materials, overcoming the disadvantages of using expensive fluorinated ketones and harsh, strong base and ultra-low temperature preparation conditions in traditional methods. Therefore, the preparation method of the present invention is more convenient for large-scale production.

[0010] As a preferred embodiment of the present invention, the molar ratio of 3,3-difluoroallyl hydrazine, transition metal salt, additive and solvent is 3,3-difluoroallyl hydrazine: transition metal salt: additive: solvent = 1: (1-4): (0.5-2): (10-100).

[0011] As a preferred embodiment of the present invention, the structural formula of the 3,3-difluoroallyl hydrazine is shown in formula (II):

[0012]

[0013]

[0014] In formula (II), n is the number of H on the benzene ring substituted by the substituent R 1 The number of substitutions, n is a natural number from 1 to 5; when n = 2-5, it means that multiple hydrogens on the benzene ring are substituted by multiple substituents R 1 Substituted, and the substituents at different substitution positions are the same or different groups; R 1 is one of phenyl, methyl, tert-butyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, acetyl, benzodiazole, naphthalene, thiophene.

[0015] As a preferred embodiment of the present invention, the transition metal salt is one of ZnCl2, CuCl2, CuI, FeCl3, CuCl, NiCl2.

[0016] As a preferred embodiment of the present invention, the solvent is one of methanol, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, toluene, and 1,2-dichloroethane.

[0017] The solvent of the present invention is unique, and using the solvent defined in the present invention can successfully synthesize α-difluoromethylstyrene derivatives with high yield and high purity.

[0018] As a preferred embodiment of the present invention, the additive is one of cesium carbonate, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and trifluoroacetic acid.

[0019] As a preferred embodiment of the present invention, the reaction temperature is 60-85 °C and the reaction time is 2-5 hours.

[0020] The present invention also claims to protect a method for preparing the α-difluoromethylstyrene derivative, which includes the following steps:

[0021] (1) Add 3,3-difluoroallyl hydrazine, a transition metal salt, and an additive to a solvent for reaction to obtain a reaction solution;

[0022] (2) Subject the reaction solution to vacuum distillation to obtain a crude product, and then perform column chromatography to obtain the α-difluoromethylstyrene derivative.

[0023] As a preferred embodiment of the present invention, the temperature of the vacuum distillation is 35-40 °C; the eluent for column chromatography is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 10:1 or petroleum ether.

[0024] Compared with the prior art, the present invention has the following beneficial effects: The α-difluoromethylstyrene derivative of the present invention contains both gem-difluoromethylene and double bond structural units, and can be used as a potential pharmaceutical lead compound or a synthetic intermediate for drug active molecules, providing an opportunity for the synthesis of macromolecular drugs. And the present invention uses 3,3-difluoroallyl hydrazine as a raw material, adopts mild reaction conditions, and obtains α-difluoromethylstyrene derivatives with high yield and high purity through dehydrozination hydrogenation. Compared with the traditional preparation method, the preparation conditions of the present invention are simple, the synthesis conditions are mild, the substrate applicability is wide, and it is more convenient for large-scale production and commercial operation. Specific Embodiments

[0025] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0026] Example 1

[0027] The preparation of 4-(3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl in this example includes the following steps:

[0028] According to the ratio of tert-butyl 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylate: zinc dichloride: N,N-diisopropylethylamine: acetonitrile = 1:3:1:100 in molar ratio, 0.4 mmol of tert-butyl 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 1.2 mmol of zinc dichloride, 0.4 mmol of N,N'-diisopropylethylamine, and 40 mmol of acetonitrile were successively added to the reactor and reacted at 60 °C for 2 hours; the solvent was removed by distillation under reduced pressure at 40 °C to obtain the crude product, and then column chromatography was carried out using petroleum ether as the eluent. The silica gel for column chromatography was 200-300 mesh, and 72 mg of 4-(3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl was obtained with a yield of 78%.

[0029] The reaction equation is as follows:

[0030]

[0031] The characterization data of the 1H NMR, 13C NMR, and 19F NMR of the product are as follows: 1 H NMR(600MHz,CDCl3)δ7.64(ddd,J=24.2,6.6,2.0Hz,6H),7.49(dd,J=13.8,7.2Hz,2H),7.41(td,J=7.2,1.2Hz,1H),6.47(t,J=55.2Hz,1H),5.83(s,1H),5.72(s,1H). 13 C NMR(151MHz,CDCl3)δ141.57,141.54(t,J=20.1Hz),140.50,133.59,128.99,127.72,127.43,127.40,127.19,119.04(t,J=9.5Hz),115.70(t,J=239.6Hz). 19 F NMR(471MHz,CDCl3)δ-112.94(s,1F),-113.06(s,1F).

[0032] Example 2

[0033] The synthesis of 1-(3,3-difluoroprop-1-en-2-yl)-4-methylbenzene described in this example specifically includes the following steps:

[0034] According to the ratio of tert-butyl 1-(3,3-difluoro-2-(p-tolyl)allyl)hydrazine-1-carboxylate: copper(I) chloride: cesium carbonate: methanol = 1:3:1:100, 0.4 mmol of tert-butyl 1-(3,3-difluoro-2-(p-tolyl)allyl)hydrazine-1-carboxylate, 1.2 mmol of copper(I) chloride, 0.4 mmol of cesium carbonate, and 40 mmol of methanol were successively added to a reactor, and the reaction was carried out at 70 °C for 4 hours; the solvent was removed by distillation under reduced pressure at 35 °C to obtain a crude product, and column chromatography was carried out using petroleum ether as the eluent. The silica gel for column chromatography was 200-300 mesh, and 30 mg of 1-(3,3-difluoroprop-1-en-2-yl)-4-methylbenzene was obtained with a yield of 45%.

[0035] The reaction equation is as follows:

[0036]

[0037] The characterization data of the proton nuclear magnetic resonance, carbon nuclear magnetic resonance, and fluorine nuclear magnetic resonance spectra of the product are as follows: 1 H NMR(600MHz,CDCl3)δ7.41(d,J=8.4Hz,2H),7.22(d,J=7.8Hz,2H),6.41(t,J=55.2Hz,1H),5.73(s,1H),5.64(s,1H),2.39(s,3H). 13 C NMR(151MHz,CDCl3)δ141.81(t,J=20.0Hz),138.72,131.88,129.41,126.89,118.28(t,J=9.6Hz),115.70(t,J=239.4Hz),21.32. 19 F NMR(471MHz,CDCl3)δ-113.14(s,1F),-113.25(s,1F).

[0038] Example 3

[0039] The synthesis of 1-(tert-butyl)-4-(3,3-difluoroprop-1-en-2-yl)benzene described in this example specifically includes the following steps:

[0040] According to the ratio of tert-butyl 1-(2-(4-(tert-butyl)phenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate: copper chloride: 1,8-diazabicyclo[5.4.0]undec-7-ene: N,N-dimethylformamide = 1:3:1:100, 0.4 mmol of tert-butyl 1-(2-(4-(tert-butyl)phenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 1.2 mmol of copper chloride, 0.4 mmol of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 40 mmol of N,N-dimethylformamide were successively added to a reactor and reacted at 80 °C for 2 hours; the solvent was removed by distillation under reduced pressure at 40 °C to obtain the crude product, and then column chromatography was carried out using petroleum ether as the eluent. The silica gel for column chromatography was 200-300 mesh, and 30 mg of 1-(tert-butyl)-4-(3,3-difluoroprop-1-en-2-yl)benzene was obtained with a yield of 45%.

[0041] The reaction equation is as follows:

[0042]

[0043] The characterization data of the 1H NMR, 13C NMR, and 19F NMR of the product are as follows: 1 H NMR(600MHz,CDCl3)δ7.44(d,J=8.4Hz,2H),7.43–7.39(m,2H),6.39(t,J=55.2,1H),5.73(t,J=1.8Hz,1H),5.63(t,J=1.8Hz,1H),1.34(s,9H). 13 C NMR(151MHz,CDCl3)δ151.87,141.68(t,J=20.0Hz),131.83,126.67,125.67,118.31(t,J=9.6Hz),115.70(t,J=239.5Hz),34.75,31.37. 19 F NMR(471MHz,CDCl3)δ-113.16(s,1F),-113.28(s,1F).

[0044] Example 4

[0045] The synthesis of 1-(3,3-difluoroprop-1-en-2-yl)-3-methylbenzene described in this example specifically includes the following steps:

[0046] According to the ratio of tert-butyl 1-(3,3-difluoro-2-(m-tolyl)allyl)hydrazine-1-carboxylate: anhydrous ferric trichloride: trifluoroacetic acid: 1,4-dioxane = 1:3:1:100, 0.4 mmol of tert-butyl 1-(3,3-difluoro-2-(m-tolyl)allyl)hydrazine-1-carboxylate, 1.2 mmol of anhydrous ferric trichloride, 0.4 mmol of trifluoroacetic acid, and 40 mmol of 1,4-dioxane were successively added to the reactor, and the reaction was carried out at 65 °C for 3 hours; the solvent was removed by distillation under reduced pressure at 35 °C to obtain the crude product, and then column chromatography was carried out using petroleum ether as the eluent. The silica gel for column chromatography was 200-300 mesh, and 31 mg of 1-(1-(3,3-difluoroprop-1-en-2-yl)-3-methylbenzene was obtained, with a yield of 44%.

[0047] The reaction equation is as follows:

[0048]

[0049] The characterization data of the 1H NMR, 13C NMR, and 19F NMR of the product are as follows: 1 H NMR(500MHz,CDCl3)δ7.34–7.27(m,3H),7.22–7.16(m,1H),6.41(t,J=55.5Hz,1H),5.73(t,J=1.5Hz,1H),5.67(t,J=2.0Hz,1H),2.40(s,3H). 13 C NMR(126MHz,CDCl3)δ142.23(t,J=20.0Hz),138.36,134.88,129.52,128.60,127.76,124.16,118.79(t,J=9.5Hz),115.55(t,J=239.4Hz),21.58(d,J=1.9Hz). 19 F NMR(471MHz,CDCl3)δ-113.19(s,2F).

[0050] Example 5

[0051] The synthesis of 1-(3,3-difluoroprop-1-en-2-yl)-4-methoxybenzene described in this example specifically includes the following steps:

[0052] According to the ratio of tert-butyl 1-(3,3-difluoro-2-(4-methoxyphenyl)allyl)hydrazine-1-carboxylate:nickel dichloride:cesium carbonate:toluene = 1:3:1:100, 0.4 mmol of tert-butyl 1-(3,3-difluoro-2-(4-methoxyphenyl)allyl)hydrazine-1-carboxylate, 1.2 mmol of nickel dichloride, 0.4 mmol of cesium carbonate, and 40 mmol of toluene were successively added to the reactor, and the reaction was carried out at 85 °C for 5 hours; the solvent was removed by distillation under reduced pressure at 40 °C to obtain the crude product, and then column chromatography was carried out with a petroleum ether / ethyl acetate mixed eluent with a volume ratio of 10:1. The silica gel for column chromatography was 200-300 mesh, and 38 mg of 1-(3,3-difluoroprop-1-en-2-yl)-4-methoxybenzene was obtained with a yield of 51%.

[0053] The reaction equation is as follows:

[0054]

[0055] The characterization data of the 1H NMR, 13C NMR, and 19F NMR of the product are as follows: 1 H NMR(600MHz,CDCl3)δ7.44(d,J=9.0Hz,2H),6.94–6.86(m,2H),6.37(t,J=55.4Hz,1H),5.66(t,J=1.8Hz,1H),5.57(t,J=2.0Hz,1H),3.83(s,3H). 13 C NMR(151MHz,CDCl3)δ160.00,141.33(t,J=20.0Hz),128.29,127.11,117.55(t,J=9.6Hz),115.92(t,J=239.4Hz),114.06,55.43. 19 F NMR(471MHz,CDCl3)δ-112.96(s,1F),-113.07(s,1F).

[0056] Example 6

[0057] The synthesis of 1-(3,3-difluoroprop-1-en-2-yl)-4-fluorobenzene described in this example specifically includes the following steps:

[0058] According to the ratio of tert-butyl 1-(3,3-difluoro-2-(4-fluorophenyl)allyl)hydrazine-1-carboxylate: copper(I) iodide: N,N-diisopropylethylamine: 1,2-dichloroethane = 1:3:1:100, 0.4 mmol of tert-butyl 1-(3,3-difluoro-2-(4-fluorophenyl)allyl)hydrazine-1-carboxylate, 1.2 mmol of copper(I) iodide, 0.4 mmol of N,N-diisopropylethylamine, and 40 mmol of 1,2-dichloroethane were successively added to the reactor and reacted at 80 °C for 2.5 hours; the solvent was removed by distillation under reduced pressure at 35 °C to obtain the crude product, and then column chromatography was carried out with petroleum ether as the eluent. The silica gel for column chromatography was 200-300 mesh, and 30 mg of 1-(3,3-difluoroprop-1-en-2-yl)-4-fluorobenzene was obtained with a yield of 43%.

[0059] The reaction equation is as follows:

[0060]

[0061] The characterization data of the proton nuclear magnetic resonance, carbon nuclear magnetic resonance, and fluorine nuclear magnetic resonance spectra of the product are as follows: 1 H NMR(600MHz,CDCl3)δ7.47(dd,J=8.4,5.4Hz,2H),7.12–7.01(m,2H),6.37(t,J=55.2Hz,1H),5.69(t,J=1.8Hz,1H),5.65(t,J=2.4Hz). 13 C NMR(126MHz,CDCl3)δ163.11(d,J=248.2Hz),141.18(t,J=20.4Hz),130.79(d,J=3.3Hz),129.02(d,J=8.2Hz),119.35(td,J=9.5,1.0Hz),115.75(t,J=240.0Hz),115.67(d,J=21.5Hz). 19 FNMR(471MHz,CDCl3)δ-112.93(t,J=1.9Hz,1F),-113.05(s,1F),-113.08(dt,J=8.6,5.3Hz,1F).

[0062] Example 7

[0063] The synthesis of 1-chloro-4-(3,3-difluoroprop-1-en-2-yl)benzene described in this example specifically includes the following steps:

[0064] According to the ratio of tert-butyl 1-(2-(4-chlorophenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate: anhydrous ferric trichloride: N,N-diisopropylethylamine: methanol = 1:3:1:100, 0.4 mmol of tert-butyl 1-(2-(4-chlorophenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 1.2 mmol of anhydrous ferric trichloride, 0.4 mmol of N,N-diisopropylethylamine, and 40 mmol of methanol were successively added to the reactor, and the reaction was carried out at 65 °C for 3 hours; the solvent was removed by distillation under reduced pressure at 35 °C to obtain the crude product, and then column chromatography was carried out with petroleum ether eluent. The silica gel for column chromatography was 200-300 mesh, and 36 mg of 1-chloro-4-(3,3-difluoroprop-1-en-2-yl)benzene was obtained with a yield of 47%.

[0065] The reaction equation is as follows:

[0066]

[0067] The characterization data of the 1H NMR, 13C NMR, and 19F NMR of the product are as follows: 1 H NMR(600MHz,CDCl3)δ7.42(d,J=9.0Hz,2H),7.38–7.33(m,2H),6.37(t,J=55.2Hz,1H),5.73(t,J=2.0Hz,1H),5.67(t,J=2.4Hz,1H). 13 C NMR(151MHz,CDCl3)δ141.05(t,J=20.4Hz),134.83,133.08,128.91,128.48,119.83(t,J=9.5Hz),115.60(t,J=239.5Hz). 19 F NMR(471MHz,CDCl3)δ-112.94(s,1F),-113.06(s,1F).

[0068] Example 8

[0069] The synthesis of 1-bromo-4-(3,3-difluoroprop-1-en-2-yl)benzene described in this example specifically includes the following steps:

[0070] According to the ratio of tert-butyl 1-(2-(4-bromophenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate:nickel dichloride:N,N-diisopropylethylamine:N,N-dimethylformamide = 1:3:1:100, 0.4 mmol of tert-butyl 1-(2-(4-bromophenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 1.2 mmol of anhydrous iron(III) chloride, 0.4 mmol of N,N-diisopropylethylamine, and 40 mmol of N,N-dimethylformamide were successively added to the reactor, and the reaction was carried out at 85 °C for 2.5 hours; the solvent was removed by distillation under reduced pressure at 35 °C to obtain the crude product, and then column chromatography was carried out with petroleum ether eluent. The silica gel for column chromatography was 200-300 mesh, and 37 mg of 1-bromo-4-(3,3-difluoroprop-1-en-2-yl)benzene was obtained with a yield of 40%.

[0071] The reaction equation is as follows:

[0072]

[0073] The characterization data of the product by 1H NMR, 13C NMR, and 19F NMR are as follows: 1 H NMR(600MHz,CDCl3)δ7.55–7.47(m,2H),7.36(d,J=8.6Hz,2H),6.34(t,J=55.2Hz,1H),5.74(t,J=2.0Hz,1H),5.68(t,J=2.4Hz,1H). 13 C NMR(151MHz,CDCl3)δ141.11(t,J=20.4Hz),133.55,131.87,128.77,123.07,119.89(t,J=9.5Hz),115.54(t,J=239.5Hz). 19 F NMR(471MHz,CDCl3)δ-112.94(s,1F),-113.06(s,1F).

[0074] Example 9

[0075] The synthesis of 1-(3,3-difluoroprop-1-en-2-yl)-4-(trifluoromethyl)benzene described in this example specifically includes the following steps:

[0076] According to the ratio of tert-butyl 1-(3,3-difluoro-2-(4-(trifluoromethyl)phenyl)allyl)hydrazine-1-carboxylate: cuprous chloride: 1,8-diazabicyclo[5.4.0]undec-7-ene: acetonitrile = 1:3:1:100, 0.4 mmol of tert-butyl 1-(3,3-difluoro-2-(4-(trifluoromethyl)phenyl)allyl)hydrazine-1-carboxylate, 1.2 mmol of cuprous chloride, 0.4 mmol of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 40 mmol of acetonitrile were successively added to the reactor, and the reaction was carried out at 75 °C for 4 hours; the solvent was removed by distillation under reduced pressure at 35 °C to obtain the crude product, and then column chromatography was carried out with petroleum ether eluent. The silica gel for column chromatography was 200-300 mesh, and 40 mg of 1-(3,3-difluoroprop-1-en-2-yl)-4-(trifluoromethyl)benzene was obtained, with a yield of 45%.

[0077] The reaction equation is as follows:

[0078]

[0079] The characterization data of the 1H NMR, 13C NMR, and 19F NMR of the product are as follows: 1 H NMR(600MHz,CDCl3)δ7.64(d,J=8.4Hz,2H),7.60(d,J=8.4Hz,2H),6.40(t,J=55.2Hz,1H),5.81(t,J=1.8Hz,1H),5.77(t,J=2.4Hz). 13 C NMR(151MHz,CDCl3)δ141.14(t,J=20.6Hz),138.19,130.77(q,J=32.6Hz),127.59,125.66(q,J=3.7Hz),124.11(q,J=272.1Hz),121.27(t,J=9.5Hz),115.48(t,J=239.6Hz). 19 F NMR(85MHz,CDCl3)δ-83.15(s,1F),-83.80(s,1F),-133.68(s,3F).

[0080] Example 10

[0081] The synthesis of 1-(4-(3,3-difluoroprop-1-en-2-yl)phenyl)ethan-1-one described in this example specifically includes the following steps:

[0082] According to the ratio of tert-butyl 1-(2-(4-acetylphenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate: anhydrous ferric chloride: cesium carbonate: 1,2-dichloroethane = 1:3:1:100, 0.4 mmol of tert-butyl 1-(2-(4-acetylphenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 1.2 mmol of anhydrous ferric chloride, 0.4 mmol of cesium carbonate, and 40 mmol of 1,2-dichloroethane were successively added to the reactor and reacted at 85 °C for 3 hours; the solvent was removed by distillation under reduced pressure at 40 °C to obtain the crude product, and then column chromatography was carried out with a petroleum ether / ethyl acetate 10:1 (volume ratio) eluent. The silica gel for column chromatography was 200-300 mesh, and 49 mg of 1-(4-(3,3-difluoroprop-1-en-2-yl)phenyl)ethan-1-one was obtained with a yield of 62%.

[0083] The reaction equation is as follows:

[0084]

[0085] The characterization data of the product by 1H NMR, 13C NMR, 19F NMR, and high-resolution mass spectrometry are as follows: 1 1H NMR(600MHz,CDCl3)δ7.97–7.93(m,2H),7.57(d,J=8.4Hz,2H),6.41(t,J=55.0Hz,1H),5.83(t,J=1.8Hz,1H),5.76(t,J=2.4Hz,1H),2.60(s,3H). 13 13C NMR(151MHz,CDCl3)δ197.69,141.18,139.13,136.96,128.67,127.26,121.06(t,J=9.5Hz),115.39(t,J=239.7Hz),26.77. 19 19F NMR(471MHz,CDCl3)δ-112.98(s,1F),-113.09(s,1F).HRMS(ESI):mass found:219.0594,calculated mass for C 11 H 10 F2ONa + [M+Na + :219.0592.

[0086] Example 11

[0087] The synthesis of 4-(3,3-difluoroprop-1-en-2-yl)benzonitrile described in this example specifically includes the following steps:

[0088] According to the ratio of tert-butyl 1-(2-(4-cyanophenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate:nickel chloride:N,N-diisopropylethylamine:toluene = 1:3:1:100, 0.4 mmol of tert-butyl 1-(2-(4-cyanophenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 1.2 mmol of nickel chloride, 0.4 mmol of N,N-diisopropylethylamine, and 40 mmol of toluene were successively added to the reactor, and the reaction was carried out at 65 °C for 3.5 hours; the solvent was removed by distillation under reduced pressure at 40 °C to obtain the crude product, and then column chromatography was carried out with a petroleum ether / ethyl acetate mixed eluent with a volume ratio of 10:1. The silica gel for column chromatography was 200-300 mesh, and 43 mg of 4-(3,3-difluoroprop-1-en-2-yl)benzonitrile was obtained with a yield of 60%.

[0089] The reaction equation is as follows:

[0090]

[0091] The characterization data of the nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum of the product are as follows: 1 HNMR(600MHz,CDCl3)δ7.71–7.64(m,2H),7.59(d,J=8.4Hz,2H),6.40(t,J=54.6Hz,1H),5.84(t,J=2.0Hz,1H),5.80(t,J=2.4Hz). 13 C NMR(151MHz,CDCl3)δ140.74(t,J=20.9Hz),139.00,132.44,127.85,122.13(t,J=9.4Hz),116.95,118.89–111.77(m),113.77. 19 F NMR(471MHz,CDCl3)δ-112.80(s,2F).HRMS(ESI):mass found:202.0439,calculatedmass forC 10 H7F2NNa + [M+Na + :202.0439.

[0092] Example 12

[0093] The synthesis of 5-(3,3-difluoroprop-1-en-2-yl)benzo[d][1,3]oxazole described in this example specifically includes the following steps:

[0094] According to the ratio of tert-butyl 1-(2-(benzo[d][1,3]dioxol-5-yl)-3,3-difluoroallyl)hydrazine-1-carboxylate: copper(I) iodide: trifluoroacetic acid: 1,4-dioxane = 1:3:1:100, 0.4 mmol of tert-butyl 1-(2-(benzo[d][1,3]dioxol-5-yl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 1.2 mmol of copper(I) iodide, 0.4 mmol of trifluoroacetic acid, and 40 mmol of 1,4-dioxane were successively added to a reactor, and the reaction was carried out at 85 °C for 2.5 hours; the solvent was removed by distillation under reduced pressure at 40 °C to obtain the crude product, and then column chromatography was carried out with a petroleum ether / ethyl acetate 10:1 (volume ratio) eluent. The silica gel for column chromatography was 200-300 mesh, and 33 mg of 5-(3,3-difluoroprop-1-en-2-yl)benzo[d][1,3]dioxole was obtained, with a yield of 42%.

[0095] The reaction equation is as follows:

[0096]

[0097] The characterization data of the 1H NMR, 13C NMR, and 19F NMR of the product are as follows: 1 H NMR(600MHz,CDCl3)δ6.98(d,J=7.2Hz,2H),6.87–6.77(m,1H),6.34(t,J=55.2Hz,1H),5.98(s,2H),5.64(t,J=3.6Hz,1H),5.58(t,J=2.0Hz,1H). 13 C NMR(126MHz,CDCl3)δ148.10,148.00,141.55(t,J=20.1Hz),128.74,121.01,118.24(t,J=9.5Hz),115.71(t,J=239.5Hz),108.47,107.58,101.40. 19 F NMR(471MHz,CDCl3)δ-112.88(t,J=1.9Hz,1F),-112.99(t,J=1.8Hz,1F).

[0098] Example 13

[0099] The synthesis of 2-(3,3-difluoroprop-1-en-2-yl)naphthalene described in this example specifically includes the following steps:

[0100] According to the ratio of tert-butyl 1-(3,3-difluoro-2-(naphthalen-2-yl)allyl)hydrazine-1-carboxylate: cuprous chloride: N,N-diisopropylethylamine: N,N-dimethylformamide = 1:3:1:100, 0.4 mmol of tert-butyl 1-(3,3-difluoro-2-(naphthalen-2-yl)allyl)hydrazine-1-carboxylate, 1.2 mmol of cuprous chloride, 0.4 mmol of N,N-diisopropylethylamine, and 40 mmol of N,N-dimethylformamide were successively added to the reactor and reacted at 80 °C for 3 hours; the solvent was removed by distillation under reduced pressure at 40 °C to obtain the crude product, and then column chromatography was carried out with petroleum ether as the eluent. The silica gel for column chromatography was 200-300 mesh, and 43 mg of 2-(3,3-difluoroprop-1-en-2-yl)naphthalene was obtained with a yield of 52%.

[0101] The reaction equation is as follows:

[0102]

[0103] The characterization data of the proton nuclear magnetic resonance, carbon nuclear magnetic resonance, and fluorine nuclear magnetic resonance spectra of the product are as follows: 1 H NMR(600MHz,CDCl3)δ8.00(s,1H),7.94–7.82(m,3H),7.64(d,J=9.0Hz,1H),7.58–7.50(m,2H),6.55(t,J=55.2Hz,1H),5.90(s,1H),5.79(s,1H). 13 C NMR(151MHz,CDCl3)δ141.85(t,J=20.0Hz),133.26,133.25,131.98,128.54,128.40,127.72,126.70,126.60,126.33,124.64,119.40(t,J=9.5Hz),115.71(t,J=239.6Hz). 19 F NMR(471MHz,CDCl3)δ-112.85(s,1F),-112.96(s,1F).

[0104] Example 14

[0105] The synthesis of 3-(3,3-difluoroprop-1-en-2-yl)thiophene described in this example specifically includes the following steps:

[0106] According to the ratio of tert-butyl 1-(3,3-difluoro-2-(thiophen-3-yl)allyl)hydrazine-1-carboxylate: anhydrous ferric trichloride: 1,8-diazabicyclo[5.4.0]undec-7-ene: 1,2-dichloroethane = 1:3:1:100, 0.4 mmol of tert-butyl 1-(3,3-difluoro-2-(thiophen-3-yl)allyl)hydrazine-1-carboxylate, 1.2 mmol of anhydrous ferric trichloride, 0.4 mmol of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 40 mmol of 1,2-dichloroethane were successively added to a reactor and reacted at 85 °C for 4 hours; the solvent was removed by distillation under reduced pressure at 40 °C to obtain the crude product, and then column chromatography was carried out with petroleum ether as the eluent. The silica gel for column chromatography was 200-300 mesh, and 26 mg of 3-(3,3-difluoroprop-1-en-2-yl)thiophene was obtained with a yield of 41%.

[0107] The reaction equation is as follows:

[0108]

[0109] The characterization data of the product by 1H NMR, 13C NMR, 19F NMR, and high-resolution mass spectrometry are as follows: 1 1H NMR(500 MHz, CDCl3) δ 7.44(d, J = 1.5 Hz, 1H), 7.33(dd, J = 5.5, 3.0 Hz, 1H), 7.26(d, J = 5 Hz, 1H), 6.33(t, J = 55.0 Hz, 1H), 5.74(t, J = 1.5 Hz, 1H), 5.58(d, J = 2.0 Hz, 1H). 13 13C NMR(126 MHz, CDCl3) δ 137.03(t, J = 20.7 Hz), 135.05, 126.12, 126.05, 123.03, 117.16(t, J = 9.6 Hz), 115.66(t, J = 239.3 Hz). 19 19F NMR(471 MHz, CDCl3) δ -114.09(s, 2F). HRMS(ESI): mass found: 161.0231, calculated mass for C7H6F2SH + [M+H + : 161.0231.

[0110] Example 15

[0111] The preparation of 4-(3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl described in this example includes the following steps:

[0112] According to the molar ratio of tert-butyl 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylate: zinc dichloride: N,N-diisopropylethylamine: acetonitrile = 1:1:2:50, 0.4 mmol of tert-butyl 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 0.4 mmol of zinc dichloride, 0.8 mmol of N,N'-diisopropylethylamine, and 20 mmol of acetonitrile were successively added to the reactor, and the reaction was carried out at 60 °C for 2 hours; the solvent was removed by distillation under reduced pressure at 40 °C to obtain the crude product, and column chromatography was carried out using petroleum ether as the eluent. The silica gel for column chromatography was 200-300 mesh, and 46 mg of 4-(3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl was obtained with a yield of 50%.

[0113] The reaction equation is as follows:

[0114]

[0115] The characterization data of the 1H NMR, 13C NMR, and 19F NMR of the product are as follows: 1 H NMR(600MHz,CDCl3)δ7.64(ddd,J=24.2,6.6,2.0Hz,6H),7.49(dd,J=13.8,7.2Hz,2H),7.41(td,J=7.2,1.2Hz,1H),6.47(t,J=55.2Hz,1H),5.83(s,1H),5.72(s,1H). 13 C NMR(151MHz,CDCl3)δ141.57,141.54(t,J=20.1Hz),140.50,133.59,128.99,127.72,127.43,127.40,127.19,119.04(t,J=9.5Hz),115.70(t,J=239.6Hz). 19 F NMR(471MHz,CDCl3)δ-112.94(s,1F),-113.06(s,1F).

[0116] Example 16

[0117] The preparation of 4-(3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl described in this example includes the following steps:

[0118] According to the molar ratio of tert-butyl 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylate: zinc dichloride: N,N-diisopropylethylamine: acetonitrile = 1:4:0.5:10, 0.4 mmol of tert-butyl 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 1.6 mmol of zinc dichloride, 0.2 mmol of N,N'-diisopropylethylamine, and 4 mmol of acetonitrile were successively added to the reactor, and the reaction was carried out at 60 °C for 2 hours; the solvent was removed by distillation under reduced pressure at 40 °C to obtain the crude product, and then column chromatography was carried out using petroleum ether as the eluent. The silica gel for column chromatography was 200-300 mesh, and 48 mg of 4-(3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl was obtained with a yield of 52%.

[0119] The reaction equation is as follows:

[0120]

[0121] The characterization data of the 1H NMR, 13C NMR, and 19F NMR of the product are as follows: 1 H NMR(600MHz,CDCl3)δ7.64(ddd,J=24.2,6.6,2.0Hz,6H),7.49(dd,J=13.8,7.2Hz,2H),7.41(td,J=7.2,1.2Hz,1H),6.47(t,J=55.2Hz,1H),5.83(s,1H),5.72(s,1H). 13 C NMR(151MHz,CDCl3)δ141.57,141.54(t,J=20.1Hz),140.50,133.59,128.99,127.72,127.43,127.40,127.19,119.04(t,J=9.5Hz),115.70(t,J=239.6Hz). 19 F NMR(471MHz,CDCl3)δ-112.94(s,1F),-113.06(s,1F).

[0122] Comparative Example 1

[0123] The preparation of 4-(3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl described in this example includes the following steps:

[0124] According to the ratio of tert-butyl 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylate: zinc dichloride: N,N-diisopropylethylamine: tetrahydrofuran = 1:3:1:100, 0.4 mmol of tert-butyl 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 1.2 mmol of zinc dichloride, 0.4 mmol of N,N'-diisopropylethylamine, and 40 mmol of tetrahydrofuran were successively added to the reactor and reacted at 60 °C for 2 hours; the solvent was removed by distillation under reduced pressure at 40 °C to obtain the crude product, and then column chromatography was carried out using petroleum ether as the eluent. The silica gel for column chromatography was 200-300 mesh, and 19 mg of 4-(3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl was obtained with a yield of 21%.

[0125] The above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A method for preparing an α-difluoromethylstyrene derivative, characterized in that, It includes the following steps: (1) Add 3,3-difluoroallyl hydrazine, transition metal salt and additive into a solvent for reaction to obtain a reaction solution; (2) Carry out vacuum distillation on the reaction solution to obtain a crude product, and then carry out column chromatography to obtain an α-difluoromethylstyrene derivative; The solvent is one of methanol, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, toluene, 1,2-dichloroethane; The structural formula of the 3,3-difluoroallyl hydrazine is as shown in formula (Ⅱ): ； The transition metal salt is one of ZnCl2, CuCl2, CuI, FeCl3, CuCl, NiCl2; The additive is one of cesium carbonate, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, trifluoroacetic acid; The structure of the α-difluoromethylstyrene derivative is as shown in formula (I): ； In formulas (I) and (II), n represents the number of H atoms on the benzene ring substituted by substituent R 1 The number of substitutions, and n is a natural number from 1 to 5; when n = 2 to 5, it means that multiple hydrogens on the benzene ring are substituted by multiple substituents R 1 The substituents at different substitution positions are the same or different groups; R 1 is one of phenyl, methyl, tert-butyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, acetyl, benzodiazole, naphthalene, and thiophene.

2. The preparation method of the α-difluoromethylstyrene derivative according to claim 1, characterized in that, The molar ratio of the 3,3-difluoroallyl hydrazine, transition metal, additive and solvent is 3,3-difluoroallyl hydrazine: transition metal salt: additive: solvent = 1: (1 - 4): (0.5 - 2): (10 - 100).

3. The preparation method of the α-difluoromethylstyrene derivative according to claim 1, characterized in that, The reaction temperature is 60 - 85 °C, and the reaction time is 2 - 5 hours.

4. The preparation method of the α-difluoromethylstyrene derivative according to claim 1, characterized in that, The temperature of the vacuum distillation is 35 - 40 °C; the eluent for column chromatography is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 10:1 or petroleum ether.

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