A kind of alpha-chlorodifluoromethylstyrene derivative and preparation method thereof

Abstract

The present invention discloses an α-chlorodifluoromethylstyrene derivative and a preparation method thereof. The preparation method of the α-chlorodifluoromethylstyrene derivative of the present invention comprises the following steps: adding 3,3-difluoroallylhydrazine derivatives and chloride salts to a solvent to react to obtain an α-chlorodifluoromethylstyrene derivative; the structural formula of the α-chlorodifluoromethylstyrene derivative is as shown in formula (I). The present invention adopts 3,3-difluoroallylhydrazine derivatives as raw materials, and obtains α-chlorodifluoromethylstyrene derivatives by chloride-mediated dehydrazine chlorination reaction. The above preparation method has a wide range of substrate applications, simple process operation, mild conditions, and successfully prepares α-chlorodifluoromethylstyrene derivatives containing chloro-substituted geminal difluoromethylene structural units and double bond structural units, providing a new method for its use as a drug modification synthesis process.

Description

Technical Field

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

[0002] In recent years, the importance of fluorinated compounds in agrochemicals, pharmaceuticals, and materials science has triggered an explosion of research efforts to develop new and efficient methods to introduce fluorinated functional groups into organic molecules. The difluoromethylene group is generally considered to be a bioisostere of oxygen or carbonyl groups, which can lead to an increase in dipole moment, increased acidity of adjacent groups, and conformational changes. The introduction of fluorinated substituents can significantly affect the pKa, lipophilicity, cellular permeability, and / or metabolic stability of bioactive molecules, often leading to significant improvements in their pharmacological and / or pharmacokinetic properties. α-Chlorodifluoromethylstyrene is an important synthetic intermediate and has been widely used because of its unique convertibility, which provides opportunities for the synthesis of a variety of fluorinated molecules.

[0003] Although science has made considerable progress in the fluorination, trifluoromethylation and difluoromethylation of organic substrates, the synthetic strategies of α-chlorodifluoromethylstyrene derivatives have been explored very little so far. Although there are a few reports on the preparation of α-chlorodifluoromethyl derivatives, the use of expensive fluorination reagents, as well as harsh, strong base and ultra-low temperature conditions, severely limits their wide synthetic applications. Therefore, it is crucial to explore a method for synthesizing a new type of α-chlorodifluoromethylstyrene derivative using cheap raw materials and mild process conditions, which is of great significance both in the biomedical field and in the field of organic synthesis. Summary of the invention

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

[0005] To achieve the above object, the technical scheme adopted by the present invention is as follows: a method for preparing an α-chlorodifluoromethylstyrene derivative, comprising the following steps: adding a 3,3-difluoroallylhydrazine derivative and a chloride salt to a solvent to react to obtain an α-chlorodifluoromethylstyrene derivative; the structural formula of the α-chlorodifluoromethylstyrene derivative is shown in formula (I):

[0006]

[0007] In formula (I), n is a substituted group R on the benzene ring. 1 The number of substitutions, n is a natural number from 1 to 5; when n = 2 to 5, it means that multiple hydrogens on the benzene ring are replaced by multiple substituents R 1 Substitution, the substituents at different substitution positions are the same or different groups; R1 It is one of phenyl, methyl, tert-butyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, acetyl, benzodiazolyl, naphthyl and thienyl.

[0008] The invention adopts 3,3-difluoroallylhydrazine derivatives as raw materials, and obtains alpha-chlorodifluoromethylstyrene derivatives through a chloride salt-mediated dehydrazine chlorination reaction. The preparation method has a wide substrate application range and is simple to operate. The alpha-chlorodifluoromethylstyrene derivatives containing chloro geminal difluoromethylene structural units and double bond structural units are successfully prepared, and a new method is provided for the drug modification synthesis process.

[0009] As a preferred embodiment of the present invention, the structural formula of the 3,3-difluoroallylhydrazine derivative is shown in formula (II):

[0010]

[0011] In formula (II), n is a substituted group R on the benzene ring. 1 The number of substitutions, n is a natural number from 1 to 5; when n = 2 to 5, it means that multiple hydrogens on the benzene ring are replaced by multiple substituents R 1 Substitution, the substituents at different substitution positions are the same or different groups; R 1 It is one of phenyl, methyl, tert-butyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, acetyl, benzodiazolyl, naphthyl and thienyl.

[0012] As a preferred embodiment of the present invention, the chloride salt is one of lithium chloride, zinc chloride, ferric chloride, cuprous chloride, cupric chloride, nickel chloride, potassium chloride and sodium chloride.

[0013] As a preferred embodiment of the present invention, the solvent is one of methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, toluene, 1,2-dichloroethane and dimethyl sulfoxide.

[0014] As a preferred embodiment of the present invention, the molar ratio of the 3,3-difluoroallylhydrazine derivative, the chloride salt and the solvent is 3,3-difluoroallylhydrazine derivative: chloride salt: solvent = 1: (1-4): (10-100).

[0015] As a preferred embodiment of the present invention, the reaction temperature is 50-90° C. and the reaction time is 2-5 hours.

[0016] As a preferred embodiment of the present invention, the method for preparing α-chlorodifluoromethylstyrene derivatives also includes the following steps: after the reaction of 3,3-difluoroallylhydrazine derivatives and chloride salts in a solvent is completed, the reaction solution is subjected to reduced pressure distillation to obtain a crude product, and then column chromatography is performed to obtain an α-chlorodifluoromethylstyrene derivative.

[0017] As a preferred embodiment of the present invention, the temperature of the reduced pressure distillation is 30-40° C.; the eluent for column chromatography is a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 or petroleum ether.

[0018] The present invention also claims to protect the α-chlorodifluoromethylstyrene derivative prepared by the method for preparing the α-chlorodifluoromethylstyrene derivative.

[0019] The α-chlorodifluoromethylstyrene derivative prepared by the preparation method of the present invention contains both chloro geminal difluoromethylene structural units and double bond structural units, and can be used as a potential pharmaceutical lead compound or a synthetic intermediate for active pharmaceutical molecules, thus providing an opportunity for the synthesis of synthetic macromolecular drugs.

[0020] Compared with the prior art, the present invention has the following beneficial effects: the present invention uses 3,3-difluoroallylhydrazine derivatives as raw materials, and successfully prepares α-chlorodifluoromethylstyrene derivatives with high yield, novel structure, difficult to synthesize by existing methods, and containing chloro-substituted geminal difluoromethylene and double bond structural units through a chloride-mediated dehydrazine chlorination reaction, thereby providing a new method for its use as a drug modification synthesis process. The preparation method has a wide range of substrate application, simple process operation, mild preparation conditions, high product yield, and high purity. DETAILED DESCRIPTION

[0021] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0022] Example 1

[0023] The synthesis of 4-(3-chloro-3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl described in this embodiment comprises the following steps:

[0024] 0.4 mmol of tert-butyl 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 1.2 mmol of cuprous chloride and 40 mmol of acetonitrile were added to a reactor in a molar ratio of tert-butyl 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylate: cuprous chloride: acetonitrile = 1:3:100, and the mixture was reacted at 85°C for 2 hours; the solvent was removed by reduced pressure distillation at 40°C to obtain a crude product, and then column chromatography was performed using petroleum ether as an eluent, and the silica gel for the column chromatography was 300 meshes, to obtain 75 mg of 4-(3-chloro-3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl, with a yield of 71%.

[0025] The reaction equation is as follows:

[0026]

[0027] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (600MHz, CDCl3) δ7.74–7.65(m,4H),7.62(d,J=7.8Hz,2H),7.52(t,J=7.8Hz,2H),7.44(m,1H),6.00(s,1H),5.73(d,J=1.2Hz,1H). 13 C NMR (151MHz, CDCl3) δ143.71 (t, J = 23.8Hz), 141.87, 140.36, 133.38, 129.00, 128.58, 127.81, 127.24, 127.22, 125.93 (t, J = 291.2Hz), 119.06 (t, J = 7.0Hz). 19 F NMR(471MHz, CDCl3)δ-50.83(s,2F).HRMS(ESI):mass found:287.0411,calculated mass for C 15 H 11 ClF2Na + [M+Na + ]:287.0410.

[0028] Example 2

[0029] The synthesis of 1-(3-chloro-3,3-difluoroprop-1-en-2-yl)-4-methylbenzene described in this embodiment comprises the following steps:

[0030] 0.4 mmol of tert-butyl 1-(3,3-difluoro-2-(p-tolyl)allyl)hydrazine-1-carboxylate, 1.2 mmol of copper chloride and 40 mmol of methanol were added to a reactor in a molar ratio of tert-butyl 1-(3,3-difluoro-2-(p-tolyl)allyl)hydrazine-1-carboxylate: lithium chloride: methanol = 1:3:100, and the mixture was reacted at 75°C for 3 hours; the solvent was removed by reduced pressure distillation at 40°C to obtain a crude product, which was then subjected to column chromatography using petroleum ether as an eluent, and the silica gel for the column chromatography was 300 mesh, to obtain 45 mg of 1-(3-chloro-3,3-difluoroprop-1-en-2-yl)-4-methylbenzene, with a yield of 56%.

[0031] The reaction equation is as follows:

[0032]

[0033] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (600MHz, CDCl3) δ7.39(d,J=7.8Hz,2H),7.21(d,J=7.8Hz,2H),5.89(s,1H),5.60(t,J=1.8Hz,1H),2.39(s,3H). 13 C NMR (151MHz, CDCl3) δ 143.97 (t, J = 23.6Hz), 139.05, 131.69, 129.26, 128.08, 126.03 (t, J = 291.2Hz), 118.56 (t, J = 7.0Hz), 21.36. 19 F NMR(471MHz, CDCl3)δ-51.06(s,2F).HRMS(ESI):mass found:225.0252,calculated mass for C 10 H9ClF2Na + [M+Na + ]:225.0253.

[0034] Example 3

[0035] The synthesis of 1-(tert-butyl)-4-(3-chloro-3,3-difluoroprop-1-en-2-yl)benzene described in this embodiment comprises the following steps:

[0036] 0.4 mmol 1-(2-(4-(tert-butyl)phenyl)-3,3-difluoroallyl)hydrazine-1-carboxylic acid tert-butyl ester: copper chloride: tetrahydrofuran are added to a reactor in a molar ratio of 1-(2-(4-(tert-butyl)phenyl)-3,3-difluoroallyl)hydrazine-1-carboxylic acid tert-butyl ester: copper chloride: tetrahydrofuran = 1:3:100, and the mixture is reacted at 65° C. for 4 hours; the solvent is removed by reduced pressure distillation at 40° C. to obtain a crude product, which is then subjected to column chromatography using petroleum ether as an eluent, and the silica gel for the column chromatography is 300 mesh, to obtain 69 mg 1-(tert-butyl)-4-(3-chloro-3,3-difluoroprop-1-en-2-yl)benzene, with a yield of 70%.

[0037] The reaction equation is as follows:

[0038]

[0039] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (600MHz, CDCl3) δ7.44(d,J=9.0Hz,2H),7.43–7.40(m,2H),5.89(s,1H),5.63(t,J=1.8Hz,1H),1.36(s,9H). 13 C NMR (151MHz, CDCl3) δ152.14, 143.90 (t, J = 23.7Hz), 131.54, 127.83, 126.03 (t, J = 291.2Hz), 125.51, 118.56 (t, J = 7.0Hz), 34.78, 31.37. 19 F NMR(471MHz,CDCl3)δ-50.91(s,2F).HRMS(ESI):mass found:245.0903,calculated mass forC 13 H 15 ClF2H + [M+H + ]:245.0903.

[0040] Example 4

[0041] The synthesis of 1-(3-chloro-3,3-difluoroprop-1-en-2-yl)-3-methylbenzene described in this embodiment comprises the following steps:

[0042] 0.4 mmol of tert-butyl 1-(3,3-difluoro-2-(m-tolyl)allyl)hydrazine-1-carboxylate, 1.2 mmol of ferric chloride and 40 mmol of 1,4-dioxane were added to a reactor in a molar ratio of 1-(3,3-difluoro-2-(m-tolyl)allyl)hydrazine-1-carboxylate: ferric chloride: 1,4-dioxane = 1:3:100, and the mixture was reacted at 90° C. for 2 hours; the solvent was removed by reduced pressure distillation at 40° C. to obtain a crude product, which was then subjected to column chromatography using petroleum ether as an eluent, and the silica gel for the column chromatography was 300 mesh, to obtain 41 mg of 1-(3-chloro-3,3-difluoroprop-1-en-2-yl)-3-methylbenzene, with a yield of 51%.

[0043] The reaction equation is as follows:

[0044]

[0045] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (500MHz, CDCl3) δ7.30(d,J=4.5Hz,3H),7.23(d,J=4.5Hz,1H),5.92(s,1H),5.61(s,1H),2.41(s,3H). 13 C NMR (126MHz, CDCl3) δ144.37 (t, J = 23.7Hz), 138.23, 134.63, 129.81, 128.98, 128. 43,126.03(t,J=291.1Hz), 125.38,119.04(dd,J=6.9,5.6Hz), 21.57(d,J=1.5Hz). 19 F NMR(471MHz,CDCl3)δ-50.94(s,2F).HRMS(ESI):mass found:225.0255,calculatedmass for C 10 H9ClF2Na + [M+Na + ]:225.0253.

[0046] Example 5

[0047] The synthesis of 1-(3-chloro-3,3-difluoroprop-1-en-2-yl)-4-methoxybenzene described in this embodiment comprises the following steps:

[0048] 0.4 mmol of tert-butyl 1-(3,3-difluoro-2-(4-methoxyphenyl)allyl)hydrazine-1-carboxylate, 1.2 mmol of zinc chloride and 40 mmol of toluene were added to a reactor in a molar ratio of tert-butyl 1-(3,3-difluoro-2-(4-methoxyphenyl)allyl)hydrazine-1-carboxylate: zinc chloride: toluene = 1:3:100, and the mixture was reacted at 65°C for 5 hours; the solvent was removed by distillation under reduced pressure at 40°C to obtain a crude product, which was then subjected to column chromatography using a petroleum ether / ethyl acetate 10:1 (volume ratio) eluent, and the silica gel for the column chromatography was 300 mesh, to obtain 53 mg of 1-(3-chloro-3,3-difluoroprop-1-en-2-yl)-4-methoxybenzene, with a yield of 60%.

[0049] The reaction equation is as follows:

[0050]

[0051] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (600MHz, CDCl3) δ7.42(d,J=9.0Hz,2H),6.95–6.87(m,2H),5.85(s,1H),5.56(t,J=1.8Hz,1H),3.84(s,3H). 13 C NMR (151MHz, CDCl3) δ160.16, 143.53 (t, J = 23.6Hz), 129.47, 126.89, 126.09 (t, J = 291.1Hz), 117.97 (t, J = 7.0Hz), 113.90, 55.41. 19 F NMR(471MHz, CDCl3)δ-51.07(s,2F).HRMS(ESI):mass found:219.0383,calculated mass for C 10 H9ClF2OH + [M+H + ]:219.0383.

[0052] Example 6

[0053] The synthesis of 1-(3-chloro-3,3-difluoroprop-1-en-2-yl)-4-fluorobenzene described in this embodiment comprises the following steps:

[0054] 0.4 mmol of tert-butyl 1-(3,3-difluoro-2-(4-fluorophenyl)allyl)hydrazine-1-carboxylate, 1.2 mmol of potassium chloride and 40 mmol of 1,2-dichloroethane were added to a reactor in a molar ratio of tert-butyl 1-(3,3-difluoro-2-(4-fluorophenyl)allyl)hydrazine-1-carboxylate: potassium chloride: 1,2-dichloroethane = 1:3:100, and the mixture was reacted at 75°C for 3 hours; the solvent was removed by distillation under reduced pressure at 40°C to obtain a crude product, which was then subjected to column chromatography using petroleum ether as an eluent, and the silica gel for the column chromatography was 300 mesh, to obtain 37 mg of 1-(3-chloro-3,3-difluoroprop-1-en-2-yl)-4-fluorobenzene, with a yield of 45%.

[0055] The reaction equation is as follows:

[0056]

[0057] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR(600MHz, CDCl3) δ7.46(dd,J=8.4,5.4Hz,2H),7.16–7.01(m,2H),5.92(s,1H),5.59(d,J=1.2Hz,1H). 13 C NMR (126MHz, CDCl3) δ163.26 (d, J = 248.8Hz), 143.26 (t, J = 24.1Hz), 130.67 (d, J = 3.4Hz), 130.22(d,J=8.2Hz), 125.81(t,J=290.9Hz), 119.36(t,J=6.7Hz), 115.60(d,J=21.6Hz). 19 F NMR(471MHz, CDCl3)δ-51.53(s,2F),-112.50(dq,J=8.6,5.3Hz,1F).HRMS(ESI):mass found:207.0183,calculated mass for C9H6ClF3H + [M+H + ]:207.0183.

[0058] Example 7

[0059] The synthesis of 1-chloro-4-(3-chloro-3,3-difluoroprop-1-en-2-yl)benzene described in this embodiment specifically comprises the following steps:

[0060] 0.4 mmol of tert-butyl 1-(2-(4-chlorophenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 1.2 mmol of sodium chloride and 40 mmol of N,N-dimethylformamide were added to a reactor in a molar ratio of tert-butyl 1-(2-(4-chlorophenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate: sodium chloride: N,N-dimethylformamide = 1:3:100, and the mixture was reacted at 80°C for 4 hours; the solvent was removed by reduced pressure distillation at 40°C to obtain a crude product, which was then subjected to column chromatography using petroleum ether as an eluent. The silica gel for the column chromatography was 300 mesh, and 44 mg of 1-chloro-4-(3-chloro-3,3-difluoroprop-1-en-2-yl)benzene was obtained, with a yield of 49%.

[0061] The reaction equation is as follows:

[0062]

[0063] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (600MHz, CDCl3) δ7.41(d,J=9.0Hz,2H),7.39–7.34(m,2H),5.94(t,J=1.2Hz,1H),5.62(t,J=1.8Hz,1H). 13 C NMR (151MHz, CDCl3) δ 143.11 (t, J = 24.2Hz), 135.22, 132.97, 129.61, 128.82, 125.62 (t, J = 291.0Hz), 119.64 (t, J = 6.9Hz). 19 FNMR(471MHz,CDCl3)δ-51.39(s,2F).HRMS(ESI):mass found:244.9707,calculated mass for C9H6Cl2F2Na + [M+Na + ]:244.9707.

[0064] Example 8

[0065] The synthesis of 1-bromo-4-(3-chloro-3,3-difluoroprop-1-en-2-yl)benzene described in this embodiment specifically comprises the following steps:

[0066] 0.4 mmol of tert-butyl 1-(2-(4-bromophenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 1.2 mmol of copper chloride and 40 mmol of dimethyl sulfoxide were added to a reactor in a molar ratio of tert-butyl 1-(2-(4-bromophenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate: copper chloride: dimethyl sulfoxide = 1:3:100, and the mixture was reacted at 85°C for 3.5 hours; the solvent was removed by reduced pressure distillation at 40°C to obtain a crude product, which was then subjected to column chromatography using petroleum ether as an eluent. The silica gel for the column chromatography was 300 mesh, and 49 mg of 1-bromo-4-(3-chloro-3,3-difluoroprop-1-en-2-yl)benzene was obtained, with a yield of 46%.

[0067] The reaction equation is as follows:

[0068]

[0069] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (600MHz, CDCl3) δ7.56–7.48(m,2H),7.35(d,J=8.4Hz,2H),5.94(s,1H),5.62(t,J=1.8Hz,1H). 13 CNMR (151MHz, CDCl3) δ143.16 (t, J = 24.2Hz), 133.44, 131.78, 129.88, 125.55 (t, J = 291.0Hz), 123.47, 119.66 (t, J = 6.9Hz). 19 F NMR(471MHz,CDCl3)δ-51.39(s,2F).HRMS(ESI):mass found:288.9202,calculated mass for C9H6BrClF2Na + [M+Na + ]:288.9202.

[0070] Example 9

[0071] The synthesis of 1-(3-chloro-3,3-difluoroprop-1-en-2-yl)-4-(trifluoromethyl)benzene described in this embodiment comprises the following steps:

[0072] 0.4 mmol of tert-butyl 1-(3,3-difluoro-2-(4-(trifluoromethyl)phenyl)allyl)hydrazine-1-carboxylate, 1.2 mmol of nickel chloride and 40 mmol of acetonitrile were added to a reactor in a molar ratio of tert-butyl 1-(3,3-difluoro-2-(4-(trifluoromethyl)phenyl)allyl)hydrazine-1-carboxylate: nickel chloride: acetonitrile = 1:3:100, and the mixture was reacted at 50° C. for 5 hours; the solvent was removed by reduced pressure distillation at 40° C. to obtain a crude product, which was then subjected to column chromatography using petroleum ether as an eluent, and the silica gel for the column chromatography was 300 mesh, to obtain 49 mg of 1-(3-chloro-3,3-difluoroprop-1-en-2-yl)-4-(trifluoromethyl)benzene, with a yield of 48%.

[0073] The reaction equation is as follows:

[0074]

[0075] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (600MHz, CDCl3) δ7.66 (d, J = 8.4Hz, 2H), 7.60 (d, J = 8.4Hz, 2H), 6.02 (s, 1H), 5.68 (t, J = 1.8Hz, 1H). 13 C NMR (151MHz, CDCl3) δ143.16 (t, J = 24.4Hz), 138.10, 131.16 (q, J = 32.7Hz), 128.73, 125 .58(q,J=3.7Hz), 125.45(t,J=290.9Hz), 124.04(q,J=272.2Hz), 120.67(t,J=6.8Hz). 19 F NMR(85MHz, CDCl3)δ-133.99(s,3F),-145.48(s,2F).HRMS(ESI):massfound:257.0151,calculated mass for C 10 H6ClF5H + [M+H + ]:257.0151.

[0076] Example 10

[0077] The synthesis of 1-(4-(3-chloro-3,3-difluoroprop-1-en-2-yl)phenyl)ethane-1-one described in this embodiment comprises the following steps:

[0078] 0.4 mmol of tert-butyl 1-(2-(4-acetylphenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 1.2 mmol of zinc chloride and 40 mmol of toluene were added to a reactor in a molar ratio of tert-butyl 1-(2-(4-acetylphenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate: zinc chloride: toluene = 1:3:100, and the mixture was reacted at 60°C for 4.5 hours; the solvent was removed by reduced pressure distillation at 40°C to obtain a crude product, which was then subjected to column chromatography using a petroleum ether / ethyl acetate 10:1 (volume ratio) eluent, and the silica gel for the column chromatography was 300 mesh, to obtain 65 mg of 1-(4-(3-chloro-3,3-difluoroprop-1-en-2-yl)phenyl)ethane-1-one, with a yield of 70%.

[0079] The reaction equation is as follows:

[0080]

[0081] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (600MHz, CDCl3) δ8.02–7.92(m,2H),7.57(d,J=8.4Hz,2H),6.00(s,1H),5.70(t,J=1.8Hz,1H),2.62(s,3H). 13 C NMR (151MHz, CDCl3) δ 197.63, 143.28 (t, J = 24.3Hz), 138.98, 137.25, 128.53, 128.44, 125.45 (t, J = 291.1Hz), 120.47 (t, J = 6.9Hz), 26.82. 19 F NMR(471MHz,CDCl3)δ-51.12(s,2F).HRMS(ESI):mass found:231.0383,calculated mass forC 11 H9ClF2OH + [M+H + ]:231.0383.

[0082] Embodiment 11

[0083] The synthesis of 4-(3-chloro-3,3-difluoroprop-1-en-2-yl)benzonitrile described in this embodiment specifically comprises the following steps:

[0084] 0.4 mmol of tert-butyl 1-(2-(4-cyanophenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate, 1.2 mmol of copper chloride and 40 mmol of acetonitrile were added to a reactor in a molar ratio of tert-butyl 1-(2-(4-cyanophenyl)-3,3-difluoroallyl)hydrazine-1-carboxylate: copper chloride: acetonitrile = 1:3:100, and the mixture was reacted at 55° C. for 2.5 hours. The solvent was removed by reduced pressure distillation at 40° C. to obtain a crude product, which was then subjected to column chromatography using a petroleum ether / ethyl acetate 10:1 (volume ratio) eluent, and the silica gel for the column chromatography was 300 mesh, to obtain 40 mg of 4-(3-chloro-3,3-difluoroprop-1-en-2-yl)benzonitrile, with a yield of 47%.

[0085] The reaction equation is as follows:

[0086]

[0087] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (600MHz, CDCl3) δ7.78–7.63(m,2H),7.59(d,J=8.4Hz,2H),6.04(s,1H),5.71(t,J=1.2Hz,1H). 13 CNMR (151MHz, CDCl3) δ 142.74 (t, J = 24.6Hz), 138.91, 132.37, 128.94, 125.15 (t, J = 291.0Hz), 121.25 (t, J = 6.8Hz), 118.43, 112.94. 19 F NMR(85MHz,CDCl3)δ-145.72(s,2F).HRMS(ESI):mass found:214.0230,calculated mass for C 10 H6ClF2NH + [M+H + ]:214.0230.

[0088] Example 12

[0089] The synthesis of 5-(3-chloro-3,3-difluoroprop-1-en-2-yl)benzo[d][1,3]dioxane described in this embodiment specifically comprises the following steps:

[0090] 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 ferric chloride and 40 mmol of 1,4-dioxane were added to a reactor in a molar ratio of tert-butyl 1-(2-(benzo[d][1,3]dioxol-5-yl)-3,3-difluoroallyl)hydrazine-1-carboxylate: ferric chloride: 1,4-dioxane = 1:3:100, and the mixture was reacted at 80°C for 3 hours; the solvent was removed by distillation under reduced pressure at 40°C to obtain a crude product, which was then subjected to column chromatography using a petroleum ether / ethyl acetate 10:1 (volume ratio) eluent, and the silica gel for the column chromatography was 300 mesh, to obtain 47 mg of 5-(3-chloro-3,3-difluoroprop-1-en-2-yl)benzo[d][1,3]dioxane, with a yield of 50%.

[0091] The reaction equation is as follows:

[0092]

[0093] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (600MHz, CDCl3) δ7.02–6.90(m,2H),6.87–6.76(m,1H),6.00(s,2H),5.85(s,1H),5.55(t,J=1.8Hz,1H). 13 C NMR (126MHz, CDCl3) δ148.30, 147.76, 143.65 (t, J = 23.8Hz), 128.40, 125.94 (t, J = 291.1Hz), 122.39, 118.67 (t, J = 6.9Hz), 108.73, 108.36, 101.51. 19 F NMR(471MHz,CDCl3)δ-51.16(s,2F).HRMS(ESI):mass found:254.9996,calculated mass forC 10 H7ClF2O2Na + [M+Na + ]:254.9995.

[0094] Example 13

[0095] The synthesis of 2-(3-chloro-3,3-difluoroprop-1-en-2-yl)naphthalene described in this embodiment specifically comprises the following steps:

[0096] 0.4 mmol of tert-butyl 1-(3,3-difluoro-2-(naphthalene-2-yl)allyl)hydrazine-1-carboxylate, 1.2 mmol of copper chloride and 40 mmol of ethanol were added to a reactor in a molar ratio of tert-butyl 1-(3,3-difluoro-2-(naphthalene-2-yl)allyl)hydrazine-1-carboxylate: copper chloride: ethanol = 1:3:100, and the mixture was reacted at 75°C for 5 hours; the solvent was removed by reduced pressure distillation at 40°C to obtain a crude product, which was then subjected to column chromatography using petroleum ether as an eluent, and the silica gel for the column chromatography was 300 mesh, to obtain 62 mg of 2-(3-chloro-3,3-difluoroprop-1-en-2-yl)naphthalene 2m, with a yield of 65%.

[0097] The reaction equation is as follows:

[0098]

[0099] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (600MHz, CDCl3) δ8.00(s,1H),7.96–7.79(m,3H),7.60(d,J=8.4Hz,1H),7.55(dq,J=6.6,3.4Hz,2H),6.04(s,1H),5.76(s,1H). 13 C NMR (151MHz, CDCl3) δ144.10 (t, J = 23.8Hz), 133.32, 133.06, 131.89, 128.54, 128.23, 127.81, 127.76, 126.92, 126.69, 126.01 (t, J = 291.2Hz), 125.64, 119.54 (t, J = 7.0Hz). 19 F NMR(471MHz, CDCl3)δ-50.71(s,2F).HRMS(ESI):massfound:261.0253,calculated mass for C 13 H9ClF2Na + [M+Na + ]:261.0253.

[0100] Embodiment 14

[0101] The synthesis of 3-(3-chloro-3,3-difluoroprop-1-en-2-yl)thiophene described in this embodiment specifically comprises the following steps:

[0102] 0.4 mmol of tert-butyl 1-(3,3-difluoro-2-(thiophen-3-yl)allyl)hydrazine-1-carboxylate, 1.2 mmol of lithium chloride and 40 mmol of methanol were added to a reactor in a molar ratio of tert-butyl 1-(3,3-difluoro-2-(thiophen-3-yl)allyl)hydrazine-1-carboxylate: lithium chloride: methanol = 1:3:100, and the mixture was reacted at 70°C for 4 hours; the solvent was removed by reduced pressure distillation at 40°C to obtain a crude product, and then column chromatography was performed with petroleum ether as an eluent, and the silica gel for column chromatography was 300 mesh, to obtain 33 mg of 3-(3-chloro-3,3-difluoroprop-1-en-2-yl)thiophene, with a yield of 42%.

[0103] The reaction equation is as follows:

[0104]

[0105] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (500MHz, CDCl3) δ7.48 (d, J = 1.5 Hz, 1H), 7.33 (dd, J = 5.0, 3.0 Hz, 1H), 7.25 (m, 1H), 5.82 (s, 1H), 5.71 (s, 1H). 13 C NMR (126MHz, CDCl3) δ 139.01 (t, J = 24.7Hz), 134.19, 126.87, 125.96, 125.55 (t, J = 290.8Hz), 124.29 (t, J = 2.1Hz), 116.67 (t, J = 7.1Hz). 19 F NMR(471MHz,CDCl3)δ-52.08(s,2F).HRMS(ESI):mass found:194.9841,calculated mass forC7H5ClF2SH + [M+H + ]:194.9841.

[0106] Embodiment 15

[0107] The synthesis of 4-(3-chloro-3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl described in this embodiment comprises the following steps:

[0108] 0.4 mmol 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylic acid tert-butyl ester: cuprous chloride: acetonitrile are added to a reactor in a molar ratio of 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylic acid tert-butyl ester: cuprous chloride: acetonitrile = 1:1:50, and the mixture is reacted at 85°C for 2 hours; the solvent is removed by reduced pressure distillation at 40°C to obtain a crude product, and then column chromatography is performed using petroleum ether as an eluent, and the silica gel for the column chromatography is 300 meshes, to obtain 51 mg 4-(3-chloro-3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl, with a yield of 48%.

[0109] The reaction equation is as follows:

[0110]

[0111] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (600MHz, CDCl3) δ7.74–7.65(m,4H),7.62(d,J=7.8Hz,2H),7.52(t,J=7.8Hz,2H),7.44(m,1H),6.00(s,1H),5.73(d,J=1.2Hz,1H). 13 C NMR (151MHz, CDCl3) δ143.71 (t, J = 23.8Hz), 141.87, 140.36, 133.38, 129.00, 128.58, 127.81, 127.24, 127.22, 125.93 (t, J = 291.2Hz), 119.06 (t, J = 7.0Hz). 19 F NMR(471MHz, CDCl3)δ-50.83(s,2F).HRMS(ESI):mass found:287.0411,calculated mass for C 15 H 11 ClF2Na + [M+Na + ]:287.0410.

[0112] Example 16

[0113] The synthesis of 4-(3-chloro-3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl described in this embodiment comprises the following steps:

[0114] 0.4 mmol 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylic acid tert-butyl ester: cuprous chloride: acetonitrile are added to a reactor in a molar ratio of 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylic acid tert-butyl ester: cuprous chloride: acetonitrile = 1:4:10, and the mixture is reacted at 85°C for 2 hours; the solvent is removed by reduced pressure distillation at 40°C to obtain a crude product, and then column chromatography is performed using petroleum ether as an eluent, and the silica gel for the column chromatography is 300 meshes, to obtain 56 mg 4-(3-chloro-3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl, with a yield of 53%.

[0115] The reaction equation is as follows:

[0116]

[0117] The characterization data of the product's hydrogen nuclear magnetic resonance spectrum, carbon spectrum, fluorine spectrum, and high-resolution mass spectrum are as follows: 1 HNMR (600MHz, CDCl3) δ7.74–7.65(m,4H),7.62(d,J=7.8Hz,2H),7.52(t,J=7.8Hz,2H),7.44(m,1H),6.00(s,1H),5.73(d,J=1.2Hz,1H). 13 C NMR (151MHz, CDCl3) δ143.71 (t, J = 23.8Hz), 141.87, 140.36, 133.38, 129.00, 128.58, 127.81, 127.24, 127.22, 125.93 (t, J = 291.2Hz), 119.06 (t, J = 7.0Hz). 19 F NMR(471MHz, CDCl3)δ-50.83(s,2F).HRMS(ESI):mass found:287.0411,calculated mass for C 15 H 11 ClF2Na + [M+Na + ]:287.0410.

[0118] Comparative Example 1

[0119] The preparation of 4-(3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl described in this embodiment comprises the following steps:

[0120] 0.4 mmol 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylic acid tert-butyl ester: zinc dichloride: N,N-diisopropylethylamine: 2-methyltetrahydrofuran in a molar ratio of 1:3:1:100, 0.4 mmol 1-(2-([1,1'-biphenyl]-4-yl)-3,3-difluoroallyl)hydrazine-1-carboxylic acid tert-butyl ester, 1.2 mmol zinc dichloride, 0.4 mmol N,N'-diisopropylethylamine, 40 mmol tetrahydrofuran were added to a reactor in sequence, and the mixture was reacted at 60° C. for 2 hours; the solvent was removed by distillation under reduced pressure at 40° C. to obtain a crude product, and then column chromatography was performed using petroleum ether as an eluent, and the silica gel for column chromatography was 200-300 meshes to obtain 32 mg 4-(3,3-difluoroprop-1-en-2-yl)-1,1'-biphenyl, yield 30%.

[0121] The above embodiments are only used to illustrate the technical solution 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 skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing an α-chlorodifluoromethylstyrene derivative, characterized in that: The method comprises the following steps: adding a 3,3-difluoroallylhydrazine derivative and a chloride salt into a solvent to react and obtain an α-chlorodifluoromethylstyrene derivative; the structural formula of the α-chlorodifluoromethylstyrene derivative is shown in formula (I): In formula (I), n is a substituted group R on the benzene ring. 1 The number of substitutions, n is a natural number from 1 to 5; when n = 2 to 5, it means that multiple hydrogens on the benzene ring are replaced by multiple substituents R 1 Substitution, 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, benzodiazolyl, naphthyl, and thienyl; The structural formula of the 3,3-difluoroallylhydrazine derivative is shown in formula (II):

2. The method for preparing the α-chlorodifluoromethylstyrene derivative according to claim 1, characterized in that: The chloride salt is one of lithium chloride, zinc chloride, ferric chloride, cuprous chloride, cupric chloride, nickel chloride, potassium chloride and sodium chloride.

3. The method for preparing the α-chlorodifluoromethylstyrene derivative according to claim 1, characterized in that: The solvent is one of methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, toluene, 1,2-dichloroethane and dimethyl sulfoxide.

4. The method for preparing the α-chlorodifluoromethylstyrene derivative according to claim 1, characterized in that: The molar ratio of the 3,3-difluoroallylhydrazine derivative, the chloride salt and the solvent is 3,3-difluoroallylhydrazine derivative: chloride salt: solvent = 1: (1-4): (10-100).

5. The method for preparing the α-chlorodifluoromethylstyrene derivative according to claim 1, characterized in that: The reaction temperature is 50-90° C. and the reaction time is 2-5 hours.

6. The method for preparing the α-chlorodifluoromethylstyrene derivative according to claim 1, characterized in that: The method also includes the following steps: after the reaction of the 3,3-difluoroallylhydrazine derivative and the chloride salt in a solvent is completed, the reaction solution is subjected to reduced pressure distillation to obtain a crude product, and then column chromatography is performed to obtain an α-difluoromethylstyrene derivative.

7. The method for preparing the α-chlorodifluoromethylstyrene derivative according to claim 6, characterized in that: The temperature of the reduced pressure distillation is 30-40° C.; the eluent of the column chromatography is a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 or petroleum ether.

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