Gem-difluorocyclopentane compound and synthetic method thereof

Abstract

The embodiment of the invention provides a gem-difluorocyclopentane compound and a synthesis method thereof, and belongs to the technical field of fluorine-containing cyclic compound synthesis. The invention provides a gem-difluorocyclopentane compound with a structural formula shown in the following formula: # imgabs0 #, in which Ar1 is selected from one of phenyl, 4-methylphenyl, 3, 5-dimethylphenyl, 4-chlorphenyl, 4-bromophenyl, 3, 5-bis (trifluoromethyl) phenyl, 2-methyl-4-methoxyphenyl and 2-naphthyl, and Ar2 is selected from one of phenyl, 4-methylphenyl, 3, 5-dimethylphenyl, 4-chlorphenyl, 4-bromophenyl, 3, 5-bis (trifluoromethyl) phenyl, 2-methyl-4-methoxyphenyl and 2-naphthyl; ar2 is selected from the group consisting of phenyl, 4-tert-butylphenyl, 4-methylphenyl, 4-phenylphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 4-chlorphenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 4-methoxycarbonylphenyl, 4-cyanophenyl, 2-methylphenyl, 2-fluorophenyl, 3, 5-dimethylphenyl, 1-naphthyl, 3-thienyl, 4-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 4-methoxycarbonylphenyl, 4-cyanophenyl, 2-methylphenyl, 2-fluorophenyl, 3, 5-dimethylphenyl, 1-naphthyl, 3-thienyl, 4-chlorophenyl, 4-chlorophenyl, 4-chlorophenyl, 4-chlorophenyl, 4-chlorophenyl the structural formula is one of 1, 3-benzothienyl and 2-benzofuranyl. The compound has higher lipophilicity, chemical stability and hydrogen bond forming ability, and can be widely applied to drug design.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of fluorine-containing cyclic compounds, and particularly relates to a geminal difluorocyclopentane compound and a synthesis method thereof. Background Art

[0002] The introduction of fluorine atoms or fluorine-containing functional groups into organic compounds can often change the physical, chemical properties and biological activity of the compounds. The synthesis of fluorine-containing organic molecules has a wide range of applications in new drug development and drug structure modification. With the increasing requirements for green chemistry and low-carbon chemistry, the development of a method for synthesizing fluorine-containing organic compounds with mild conditions, low cost and wide applicability has become an important goal in the field of organic synthesis. 2 ) is considered to be a bioisostere of ether, methylene, carbonyl, phosphinate and sulfonyl functional groups, which can improve the lipophilicity, binding affinity and hydrogen bond forming ability of the compound, and is widely used in drug design. Introducing difluoromethylene into cyclic hydrocarbons to obtain geminal difluorocyclic hydrocarbon compounds is an effective means in drug design, but geminal difluorocyclic hydrocarbons are difficult to obtain directly from cyclic hydrocarbons by fluorination. Therefore, the development of synthetic methods for geminal difluorocyclic hydrocarbons is an important challenge in the field of medicinal chemistry.

[0003] At present, the synthesis methods of geminal difluorocyclic hydrocarbon compounds mainly include the following:

[0004] 1. Geminal difluorocyclopropane compounds were obtained by cyclization of olefins with a series of difluorocarbene reagents (Beilstein J. Org. Chem. 2021, 17, 245-272.), as shown below.

[0005]

[0006] The reaction of olefins and difluorocarbene reagents to produce geminal difluorocyclopropanes can quickly prepare geminal difluorocyclic hydrocarbon compounds, and the preparation method is relatively simple. However, it is only applicable to the synthesis of geminal difluorocyclopropane compounds and cannot be applied to the synthesis of other geminal difluorocyclic hydrocarbons.

[0007] 2. Cyclic ketone raw materials are reacted with diethylaminosulfur trifluoride (DAST) or morpholine sulfur trifluoride (Morph-DAST) to prepare geminal difluorocyclic hydrocarbon compounds (ChemMedChem 2022, 17, e202200365.), as shown below.

[0008]

[0009] This route can be used to synthesize various geminal difluorocyclic hydrocarbons, but its disadvantages are: the use of highly toxic fluorinated reagents is not conducive to simplifying the process operation; the cyclic ketone raw materials are not easy to obtain, and the cyclic ketone raw materials with the same structure need to be prepared in advance.

[0010] 3. Another method is to prepare gem-difluorocyclopentene or gem-difluorocyclopentane compounds by cyclization of easily synthesized gem-difluorocyclopropene or gem-difluorocyclopropane with olefins. As shown in the following reaction formula (1), gem-difluorocyclopropene and olefins are first added under palladium catalysis to generate alkenyl gem-difluorocyclopropane, which is then cyclized at high temperature to obtain gem-difluorocyclopentene (J.Am.Chem.Soc.2022,144,20875-20883.); in the following reaction formula (2), gem-difluorocyclopentane is prepared by cycloaddition reaction of gem-difluorocyclopropane and olefin catalyzed by transition metal rhodium (Angew.Chem.Int.Ed.2023,62,e202307129.).

[0011]

[0012] In this method, although a series of gem-difluorocyclopentane or gem-difluorocyclopentene compounds can be prepared by the cyclization reaction of gem-difluorocyclopropane or gem-difluorocyclopropene with olefins, it generally requires the use of noble metal catalysts and ligands, and the reaction conditions are relatively complex, which is not conducive to industrial synthesis.

[0013] In summary, it is of great significance to study and develop a new synthesis method of geminal difluorocyclopentane compounds to solve the problems of high cost of raw materials and reagents, narrow reaction application range, and complex operation in the synthesis of geminal difluorocyclic hydrocarbons. Summary of the invention

[0014] In view of this, the technical problem to be solved by the present invention is to provide a geminal difluorocyclopentane compound and a synthesis method thereof. The synthesis method has readily available raw materials, simple operation, mild reaction conditions and high product yield.

[0015] The technical solution adopted by the present invention is as follows:

[0016] In a first aspect of the present invention, there is provided a geminal difluorocyclopentane compound having a structural formula as shown below:

[0017]

[0018] Among them, Ar 1 One selected from phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-chlorophenyl, 4-bromophenyl, 3,5-ditrifluoromethylphenyl, 2-methyl-4-methoxyphenyl and 2-naphthyl; Ar 2 One selected from phenyl, 4-tert-butylphenyl, 4-methylphenyl, 4-phenylphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 4-methoxycarbonylphenyl, 4-cyanophenyl, 2-methylphenyl, 2-fluorophenyl, 3,5-dimethylphenyl, 1-naphthyl, 3-thienyl, 3-benzothienyl and 2-benzofuranyl.

[0019] In the second aspect of the present invention, a method for synthesizing the above-mentioned geminal difluorocyclopentane compound is provided, wherein the method is:

[0020] N-arylcyclopropylamine and 1,1-difluoro-2-arylethene are used as raw materials, and the geminal difluorocyclopentane compound is synthesized by using an iridium photocatalyst under the irradiation of blue light.

[0021] In some embodiments, the synthesis method is: using N-arylcyclopropylamine and 1,1-difluoro-2-arylethene as raw materials, and using an iridium photocatalyst to catalyze the synthesis of the gem-difluorocyclopentane compound under blue light irradiation.

[0022] In some embodiments, the aryl group in the N-arylcyclopropylamine is one of phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-chlorophenyl, 4-bromophenyl, 3,5-ditrifluoromethylphenyl, 2-methyl-4-methoxyphenyl and 2-naphthyl.

[0023] In some embodiments, the aromatic group in the 1,1-difluoro-2-arylethylene is one of phenyl, 4-tert-butylphenyl, 4-methylphenyl, 4-phenylphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 4-methoxycarbonylphenyl, 4-cyanophenyl, 2-methylphenyl, 2-fluorophenyl, 3,5-dimethylphenyl, 1-naphthyl, 3-thienyl, 3-benzothienyl and 2-benzofuranyl.

[0024] In some embodiments, the iridium photocatalyst is bis[2-(4,6-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium(hexafluorophosphate) salt (Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 ), bis[2-(4,6-difluorophenyl)-5-trifluoromethylpyridine](2-2'-bipyridine)iridium(hexafluorophosphate) salt (Ir[dF(CF 3 )ppy] 2 (bpy)PF 6 ), bis(2-phenylpyridine)(2-2'-bipyridine)iridium(hexafluorophosphate) salt (Ir(ppy) 2 (bpy)PF 6 ), bis[2-(4,6-difluorophenyl)-5-trifluoromethylpyridine](2-2'-bipyridine)iridium(hexafluorophosphate) salt (Ir[dF(CF 3 )ppy] 2 (bpy)PF 6), bis[2-(4,6-difluorophenyl)pyridine][2-2'-bi(4-tert-butylpyridine)]iridium(hexafluorophosphate) salt (Ir(dFppy) 2 (dtbbpy)PF 6 ), bis[2-(4-methylphenyl)-4-methylpyridinium][2-2'-bi(4-tert-butylpyridinium)]iridium(hexafluorophosphate) salt (Ir[Me(Me)ppy] 2 (dtbbpy)PF 6 ), bis[2-(4-fluorophenyl)-5-methylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium(hexafluorophosphate) salt (Ir[F(Me)ppy] 2 (dtbbpy)PF 6 ), tris[2-(4-trifluoromethylphenyl)pyridine]iridium (Ir(p-CF 3 ppy) 3 ), tris[2-(4-fluorophenyl)pyridinium(Ir(p-Fppy) 3 ), bis(2-phenylpyridine)(pyridine-2-carboxylate)iridium(Ir(ppy) 2 (pic)), bis[2-(4,6-difluorophenyl)pyridine](pyridine-2-carboxylate)iridium(Ir(dFppy) 2 (pic)), bis[2-(4,6-difluorophenyl)-5-trifluoromethylpyridine](pyridine-2-carboxylate)iridium (Ir[dF(CF 3 )ppy] 2 (pic)), bis(2-phenylpyridine)(4-trifluoromethylpyridine-2-carboxylate)iridium(Ir(ppy) 2 [(4-CF 3 )pic]), bis(2-phenylpyridine)(5-methoxypyridine-2-carboxylate)iridium(Ir(ppy) 2 [(5-OMe)pic]), bis(2-phenylpyridine)(6-methylpyridine-2-carboxylate)iridium (Ir(ppy) 2 [(6-Me)pic]), bis(2-phenylpyridine)(5-fluoropyridine-2-carboxylate)iridium (Ir(ppy) 2 [(5-F)pic]), bis(2-phenylpyridine)(5-chloropyridine-2-carboxylate)iridium(Ir(ppy) 2 [(5-Cl)pic]), bis(2-phenylpyridine)(4,5-difluoropyridine-2-carboxylate)iridium(Ir(ppy) 2 [(4,5-dF)pic]), bis[2-(4,6-difluorophenyl)pyridine](5-fluoropyridine-2-carboxylate)iridium (Ir(dFppy) 2[(5-F)pic]), bis[2-(4,6-difluorophenyl)pyridine](4-trifluoromethylpyridine-2-carboxylate)iridium (Ir(dFppy) 2 [(4-CF 3 )pic]), bis[2-(4,6-difluorophenyl)pyridine](5-methoxypyridine-2-carboxylate)iridium(Ir(dFppy) 2 [(5-OMe)pic]) and bis[2-(4,6-difluorophenyl)pyridine](5-chloropyridine-2-carboxylate)iridium (Ir(dFppy) 2 [(5-Cl)pic]).

[0025] In some embodiments, the synthetic route of the synthetic method is as follows:

[0026]

[0027] In some embodiments, the synthesis method is specifically:

[0028] N-arylcyclopropylamine 1 and 1,1-difluoro-2-arylethene 2 are mixed in a solvent, and an iridium photocatalyst is added to obtain a mixed solution;

[0029] The mixed solution was reacted at room temperature under continuous irradiation of blue light to obtain gem-difluorocyclopentane compound 3.

[0030] In some embodiments, the solvent is a mixture of any one or more of dichloromethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methanol, ethanol, isopropanol and ethylene glycol, more preferably methanol.

[0031] In some embodiments, in the above synthesis method, the molar ratio of N-arylcyclopropylamine, 1,1-difluoro-2-arylethene and iridium photocatalyst is 1:(1-10):(0.005-0.05), and more preferably 1:6:0.02.

[0032] In some embodiments, in the above synthesis method, the concentration of N-arylcyclopropylamine in the mixed solution is 0.05-0.3 mol / L, more preferably 0.1 mol / L.

[0033] In some embodiments, the blue light irradiation is specifically continuous irradiation using a blue light lamp, the wavelength of the blue light lamp is 410-480nm, more preferably 450-465nm, and the power of the blue light lamp is 3-30W, more preferably 10-20W.

[0034] In some embodiments, in the above synthesis method, the reaction time is 12 to 30 hours.

[0035] The post-processing operation of the present invention is simple. After the reaction of synthesizing the gem-difluorocyclopentane compound is completed, the gem-difluorocyclopentane compound is purified.

[0036] In some specific embodiments of the present invention, the purification operation steps are as follows: the reaction solution is transferred from the reaction tube to a round-bottom flask, the solvent is evaporated under reduced pressure, and the crude product is separated by silica gel column chromatography to obtain a high-purity geminal difluorocyclopentane compound, and the unreacted 1,1-difluoro-2-arylethene raw material can be recovered at the same time. The geminal difluorocyclopentane compound obtained by separation contains cis and trans isomers, and the ratio of the two isomers is determined by gas chromatography-mass spectrometry. 300-400 mesh silica gel is used in the column chromatography separation operation, and the eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:10.

[0037] A geminal difluorocyclopentane compound and a synthesis method thereof according to an embodiment of the present invention have at least one of the following advantages:

[0038] (1) The embodiments of the present invention provide a novel geminal difluorocyclopentane compound, which has higher lipophilicity, chemical stability and ability to form hydrogen bonds, and can be widely used in drug design.

[0039] (2) The raw materials for the synthesis method of the geminal difluorocyclopentane compound provided by the present invention are derived from cheap and readily available chemical reagents such as aryl bromide, 1-aminocyclopropane, aryl formaldehyde, sodium difluorochloroacetate, etc.; the synthesis technical conditions are simple, and in addition to the two reaction raw materials, only a photocatalyst needs to be added and continuous blue light irradiation is required; the reaction cost is low, the amount of photocatalyst used is small, and there is no need to use a large amount of expensive precious metal catalysts and ligands, and the use of strong acids, strong bases, unstable or difficult to obtain additives is avoided; the reaction operation is simple, no anhydrous and oxygen-free reaction conditions are required, and it is carried out at room temperature; the reaction by-products are small, the yield is high, and the range of geminal difluorocyclopentane compounds that can be synthesized is wide, which is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] These and / or other aspects and advantages of the present invention will become apparent and readily understood from the following description of the preferred embodiments in conjunction with the accompanying drawings, in which:

[0041] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of cis-3-(N-phenylamino)-2-(4-tert-butylphenyl)-1,1-difluorocyclopentane (cis-3a) prepared in Example 1;

[0042] Figure 2 The carbon NMR spectrum of cis-3-(N-phenylamino)-2-(4-tert-butylphenyl)-1,1-difluorocyclopentane (cis-3a) prepared in Example 1;

[0043] Figure 3 The NMR fluorine spectrum of cis-3-(N-phenylamino)-2-(4-tert-butylphenyl)-1,1-difluorocyclopentane (cis-3a) prepared in Example 1;

[0044] Figure 4 The H NMR spectrum of trans-3-(N-phenylamino)-2-(4-tert-butylphenyl)-1,1-difluorocyclopentane (trans-3a) prepared in Example 1;

[0045] Figure 5 The carbon NMR spectrum of trans-3-(N-phenylamino)-2-(4-tert-butylphenyl)-1,1-difluorocyclopentane (trans-3a) prepared in Example 1;

[0046] Figure 6 The NMR fluorine spectrum of trans-3-(N-phenylamino)-2-(4-tert-butylphenyl)-1,1-difluorocyclopentane (trans-3a) prepared in Example 1;

[0047] Figure 7 The hydrogen nuclear magnetic resonance spectrum of cis-3-(N-phenylamino)-2-(4-methylphenyl)-1,1-difluorocyclopentane (cis-3b) prepared in Example 2;

[0048] Figure 8 The carbon NMR spectrum of cis-3-(N-phenylamino)-2-(4-methylphenyl)-1,1-difluorocyclopentane (cis-3b) prepared in Example 2;

[0049] Fig. 9 The NMR fluorine spectrum of cis-3-(N-phenylamino)-2-(4-methylphenyl)-1,1-difluorocyclopentane (cis-3b) prepared in Example 2;

[0050] Fig.10 This is the H NMR spectrum of trans-3-(N-phenylamino)-2-(4-methylphenyl)-1,1-difluorocyclopentane (trans-3b) prepared in Example 2;

[0051] Fig.11 The carbon NMR spectrum of trans-3-(N-phenylamino)-2-(4-methylphenyl)-1,1-difluorocyclopentane (trans-3b) prepared in Example 2;

[0052] Fig.12 This is the NMR fluorine spectrum of trans-3-(N-phenylamino)-2-(4-methylphenyl)-1,1-difluorocyclopentane (trans-3b) prepared in Example 2. DETAILED DESCRIPTION

[0053] The technical solution of the present invention is further specifically described below by examples and in conjunction with the accompanying drawings. In the specification, the same or similar reference numerals indicate the same or similar components. The following description of the embodiments of the present invention with reference to the accompanying drawings is intended to explain the overall inventive concept of the present invention and should not be construed as a limitation of the present invention.

[0054] In order to further illustrate the present invention, the synthesis method of gem-difluorocyclopentane provided by the present invention is described in detail below with reference to examples.

[0055] In the synthesis steps of the geminal difluorocyclopentane compounds in the following embodiments of the present invention, N-arylcyclopropylamine is synthesized using aryl bromide and 1-aminocyclopropane as raw materials by a known synthesis method (J.Org.Chem.2024,89,57-67). 1,1-difluoro-2-arylethylene is synthesized using aryl formaldehyde and sodium difluorochloroacetate as raw materials by a known synthesis method (Angew.Chem.Int.Ed.2019,58,4690-4694).

[0056] Embodiment 1

[0057] Preparation of 3-(N-phenylamino)-2-(4-tert-butylphenyl)-1,1-difluorocyclopentane (3a)

[0058] Add 2.6 mg (0.004 mmol) of bis[2-(4,6-difluorophenyl)pyridine](pyridine-2-carboxylic acid)iridium complex, 26.6 mg (0.2 mmol) of N-phenylcyclopropylamine, 235.2 mg (1.2 mmol) of 2-(4-tert-butylphenyl)-1,1-difluoroethylene and 2 mL of methanol to a 10 mL dry Schlenk tube, tighten the Schlenk stopcock, and stir at room temperature for 24 h under blue light. After the reaction is completed, transfer the reaction solution to a round-bottom flask, evaporate the solvent under reduced pressure, and separate the crude product by column chromatography (the chromatographic column is filled with 300-400 mesh silica gel, and the eluent is a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:10), respectively, to obtain 56.5 mg of white solid products cis-3a and trans-3a, with a yield of 86% (cis:trans=32:68). 186.2 mg of 2-(4-tert-butylphenyl)-1,1-difluoroethylene was recovered.

[0059] The structure and NMR spectrum data of compound 3a are as follows:

[0060]

[0061] See also Figure 1 , 1H NMR (400 MHz, CDCl 3 )δ7.35(d,J=8.2Hz,2H),7.27–7.19(m,2H),7.16(t,J=7.8Hz,2H),6.71(t,J=7.4Hz,1H),6.52(d,J=8.0Hz,2H),4.40–4.27(m,1H),3.77–3.64(m,2H),2.57–2.33(m,2H),2.33–2.19(m,1H),2.08–1.96(m,1H),1.32(s,9H). Figure 2 , 13 C NMR (101 MHz, CDCl 3 )δ150.2,146.7,131.3(dd,J=255.2,250.4Hz),129.3(t,J=2.4Hz),129.2,129.1,125.4,117.5,113.1,54.4(d,J=5.4Hz),54.2(dd,J=23.9,21.5Hz),34.4,33.9(t,J=25.1Hz),31.2,28.1(t,J=4.0Hz).See Figure 3 , 19 F NMR (376 MHz, CDCl 3 )δ-87.47(d,J=232.3Hz),-94.35(d,J=232.4Hz).

[0062]

[0063] See also Figure 4 , 1 H NMR (400 MHz, CDCl 3 )δ7.37(d,J=8.3Hz,2H),7.24(d,J=8.2Hz,2H),7.15(t,J=7.9Hz,2H),6.72(t,J=7.3Hz,1H),6.57(d,J=7.9Hz,2H),4.17(d,J=7.5 Hz,1H),3.76(s,1H),3.36–3.20(m,1H),2.59(ddt,J=16.8,7.8,4.7Hz,1H),2.50–2.24(m,2H),1.78–1.64(m,1H),1.31(s,9H).See Figure 5 , 13 C NMR (101 MHz, CDCl 3)δ150.7,147.1,130.3(d,J=1.6Hz),129.3,128.8,128.3(dd,J=253.2,251.0Hz),125.5,117.9,113.4,57.9(t,J=23.0Hz),55.9(d,J=7.4Hz),34.5,33.5(t,J=25.0Hz),31.3,29.0(dd,J=4.4,3.0Hz).See Figure 6 , 19 F NMR (376 MHz, CDCl 3 )δ-95.5(d,J=228.2Hz),-97.3(d,J=228.2Hz).

[0064] Embodiment 2

[0065] Preparation of 3-(N-phenylamino)-2-(4-methylphenyl)-1,1-difluorocyclopentane (3b)

[0066] Add 2.6 mg (0.004 mmol) of bis[2-(4,6-difluorophenyl)pyridine](pyridine-2-carboxylic acid)iridium complex, 26.6 mg (0.2 mmol) of N-phenylcyclopropylamine, 184.8 mg (1.2 mmol) of 2-(4-methylphenyl)-1,1-difluoroethylene and 2 mL of methanol to a 10 mL dry Schlenk tube, tighten the Schlenk stopcock, and stir at room temperature for 24 h under blue light. After the reaction is completed, transfer the reaction solution to a round-bottom flask, evaporate the solvent under reduced pressure, and separate the crude product by column chromatography (the column is filled with 300-400 mesh silica gel, and the eluent is a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:10), respectively, to obtain a total of 39.1 mg of colorless oily liquid products cis-3b and trans-3b, with a yield of 68% (cis:trans=47:53). 150.9 mg of 2-(4-methylphenyl)-1,1-difluoroethylene was recovered.

[0067] The structure and NMR spectrum data of compound 3b are as follows:

[0068]

[0069] See also Figure 7 , 1 H NMR (400 MHz, CDCl 3)δ7.21–7.08 (m, 6H), 6.70 (t, J=7.3Hz, 1H), 6.55–6.47 (m, 2H), 4.37–4.29 (m, 1H), 3.77–3.64 (m, 2H), 2.55–2.35 (m, 2H), 2.33 (s, 3H), 2.32–2.21 (m, 1H), 2.05–1.93 (m, 1H). See Figure 8 , 13 C NMR (101 MHz, CDCl 3 )δ146.7,137.1,131.2(dd,J=255.7,250.0Hz),129.4,129.3(d,J=2.5Hz),129.2,129.2,117.6,113.2,54.41(d,J=5.3Hz),54.38(dd,J=24.0,21.5Hz),33.8(t,J=25.2Hz),28.3(t,J=4.0Hz),21.0.See Fig. 9 , 19 F NMR (376 MHz, CDCl 3 )δ-87.2(d,J=232.8Hz),-95.0(d,J=232.9Hz).

[0070]

[0071] See also Fig.10 , 1 H NMR (400 MHz, CDCl 3 )δ7.17(p,J=8.3Hz,6H),6.71(t,J=7.3Hz,1H),6.56(d,J=7.9Hz,2H),4.16(q,J=8.3Hz,1H) ,3.74(s,1H),3.35–3.18(m,1H),2.65–2.53(m,1H),2.50–2.23(m,5H),1.77–1.64(m,1H).See Fig.11 , 13 C NMR (101 MHz, CDCl 3 )δ147.1,137.6,130.4(d,J=1.6Hz),129.30,129.27,129.0,128.2(dd,J=253.6,252.2Hz),117.9,113.4,58.1(t,J=23.1Hz),56.0(d,J=7.2Hz),33.5(dd,J=25.2,24.3Hz),29.0(dd,J=4.7,2.9Hz),21.1.See Fig.12 ,19 F NMR (376 MHz, CDCl 3 )δ-95.4(d,J=228.6Hz),-97.3(d,J=228.4Hz).

[0072] Embodiment 3

[0073] Preparation of 3-(N-phenylamino)-2-(4-phenylphenyl)-1,1-difluorocyclopentane (3c)

[0074] Add 2.6 mg (0.004 mmol) of bis[2-(4,6-difluorophenyl)pyridine](pyridine-2-carboxylic acid)iridium complex, 26.6 mg (0.2 mmol) of N-phenylcyclopropylamine, 259.2 mg (1.2 mmol) of 2-(4-phenylphenyl)-1,1-difluoroethylene and 2 mL of methanol to a 10 mL dry Schlenk tube, tighten the Schlenk stopcock, and place under blue light and stir at room temperature for 24 h. After the reaction is completed, the reaction solution is transferred to a round-bottom flask, the solvent is evaporated under reduced pressure, and the crude product is separated by column chromatography (the chromatographic column is filled with 300-400 mesh silica gel, and the eluent is a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:10), and white solid products cis-3c and trans-3c are obtained, respectively, with a total of 48.9 mg, and a yield of 70% (cis:trans=40:60). 209.5 mg of 2-(4-phenylphenyl)-1,1-difluoroethylene was recovered.

[0075] The structure and NMR spectrum data of compound 3c are as follows:

[0076]

[0077] 1 H NMR (400 MHz, CDCl 3 )δ7.57(dd,J=13.1,7.8Hz,4H),7.44(t,J=7.6Hz,2H),7.40–7.31(m,3H),7.16(t,J=7.8Hz,2H),6.71(t,J=7.3Hz,1H),6.54(d,J=8.0Hz,2H ),4.40(p,J=7.4,6.7Hz,1H),3.79(td,J=14.2,6.9Hz,1H),3.67(d,J=7.7Hz,1H),2.61–2.37(m,2H),2.37–2.24(m,1H),2.11–1.97(m,1H). 13 C NMR (101 MHz, CDCl 3)δ146.6,140.5,140.2,131.2(dd,J=256.4,251.9Hz),131.5(d,J=2.0Hz),129.9,129.3,128.8,127.4,127. 1,127.0,117.7,113.2,54.5(d,J=5.4Hz),54.4(dd,J=23.7,21.6Hz),33.9(t,J=25.2Hz),28.3(t,J=3.9Hz). 19 F NMR (376 MHz, CDCl 3 )δ-87.3(d,J=233.0Hz),-94.5(d,J=233.0Hz).

[0078]

[0079] 1 H NMR (400 MHz, CDCl 3 )δ7.59(d,J=8.1Hz,4H),7.49–7.31(m,5H),7.17(dd,J=8.5,7.4Hz,2H),6.74(t,J=7.3Hz,1H),6.60(d,J=7.7Hz,2H),4.25(q,J= 8.1Hz,1H),3.78(d,J=9.2Hz,1H),3.35(ddd,J=18.2,13.2,10.5Hz,1H),2.69–2.27(m,3H),1.76(ddt,J=13.1,10.3,8.2Hz,1H). 13 C NMR (101 MHz, CDCl 3 )δ147.0,140.8,140.7,132.6(d,J=1.7Hz),129.5,129.3,128.7,128.3(dd,J=253.0,251.4Hz),127.3,127. 1,118.1,113.5,58.3(t,J=22.9Hz),56.3(d,J=7.2Hz),33.6(dd,J=25.4,24.5Hz),29.1(dd,J=4.5,2.9Hz). 19 F NMR (376 MHz, CDCl 3 )δ-95.0(d,J=228.8Hz),-97.1(d,J=228.8Hz).

[0080] Embodiment 4

[0081] Preparation of 3-(N-phenylamino)-2-(4-methoxyphenyl)-1,1-difluorocyclopentane (3d)

[0082] Add 2.6 mg (0.004 mmol) of bis[2-(4,6-difluorophenyl)pyridine](pyridine-2-carboxylic acid)iridium complex, 26.6 mg (0.2 mmol) of N-phenylcyclopropylamine, 204 mg (1.2 mmol) of 2-(4-methoxyphenyl)-1,1-difluoroethylene and 2 mL of methanol to a 10 mL dry Schlenk tube, tighten the Schlenk stopcock, and place under blue light and stir at room temperature for 24 h. After the reaction is completed, the reaction solution is transferred to a round-bottom flask, the solvent is evaporated under reduced pressure, and the crude product is separated by column chromatography (the chromatographic column is filled with 300-400 mesh silica gel, and the eluent is a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:10), respectively, to obtain colorless oily liquid products cis-3d and trans-3d, a total of 45.4 mg, with a yield of 75% (cis:trans=40:60). 171.2 mg of 2-(4-methoxyphenyl)-1,1-difluoroethylene was recovered.

[0083] The 3D structure and NMR spectrum data of the compound are as follows:

[0084]

[0085] 1 H NMR (400 MHz, CDCl 3 )δ7.20(d,J=8.5Hz,2H),7.14(t,J=7.8Hz,2H),6.86(d,J=8.7Hz,2H),6.69(t,J=7.3Hz,1H),6.50(d,J=7.9Hz, 2H),4.37–4.25(m,1H),3.79(s,3H),3.74–3.56(m,2H),2.56–2.21(m,3H),1.98(ddt,J=16.7,11.0,5.8Hz,1H). 13 C NMR (101 MHz, CDCl 3 )δ158.8,146.7,131.2(dd,J=255.2,250.3Hz),130.6,129.2,124.4(d,J=2.1Hz),117.6,113.9,1 13.1, 55.2, 54.4 (d, J = 5.5Hz), 54.0 (dd, J = 23.9, 21.4Hz), 33.8 (t, J = 25.2Hz), 28.3 (t, J = 3.9Hz). 19 F NMR (376 MHz, CDCl 3 )δ-87.8(d,J=232.3Hz),-95.1(d,J=232.3Hz).

[0086]

[0087] 1 H NMR (400 MHz, CDCl 3 )δ7.24(d,J=8.6Hz,2H),7.16(t,J=7.8Hz,2H),6.90(d,J=8.6Hz,2H),6.72(t,J=7.3Hz,1H),6.57(d,J=8.1Hz,2H),4.13(q,J=7.9Hz,1H),3 .80(s,3H),3.73(brs,1H),3.24(ddd,J=18.5,13.0,10.7Hz,1H),2.58(ddt,J=16.9,8.7,4.5Hz,1H),2.49–2.22(m,2H),1.78–1.65(m,1H). 13 C NMR (101 MHz, CDCl 3 )δ159.2,147.1,130.2,129.3,128.2(dd,J=253.5,251.8Hz),125.4(d,J=1.7Hz),117.9,114.0,113 .4,57.7(t,J=23.0Hz),56.1(d,J=7.3Hz),55.2,33.4(dd,J=25.5,24.4Hz),29.0(dd,J=4.7,2.9Hz). 19 F NMR (376 MHz, CDCl 3 )δ-95.8(d,J=228.3Hz),-97.4(d,J=228.3Hz).

[0088] Embodiment 5

[0089] Preparation of 3-(N-phenylamino)-2-(4-methylthiophenyl)-1,1-difluorocyclopentane (3e)

[0090] Add 2.6 mg (0.004 mmol) of bis[2-(4,6-difluorophenyl)pyridine](pyridine-2-carboxylic acid)iridium complex, 26.6 mg (0.2 mmol) of N-phenylcyclopropylamine, 223.2 mg (1.2 mmol) of 2-(4-methylthiophenyl)-1,1-difluoroethylene and 2 mL of methanol to a 10 mL dry Schlenk tube, tighten the Schlenk stopcock, and place under blue light and stir at room temperature for 24 h. After the reaction is completed, the reaction solution is transferred to a round-bottom flask, the solvent is evaporated under reduced pressure, and the crude product is separated by column chromatography (the chromatographic column is filled with 300-400 mesh silica gel, and the eluent is a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:10), respectively, to obtain colorless oily liquid products cis-3e and trans-3e, a total of 49.7 mg, with a yield of 78% (cis:trans=56:44). 178.5 mg of 2-(4-methylthiophenyl)-1,1-difluoroethylene was recovered.

[0091] The structure and NMR spectrum data of compound 3e are as follows:

[0092]

[0093] 1 H NMR (400 MHz, CDCl 3 )δ7.23–7.18(m,4H),7.18–7.10(m,2H),6.70(t,J=7.3Hz,1H),6.50(d,J=7.8Hz,2H),4.38–4.29(m,1 H),3.75–3.64(m,1H),3.60(d,J=6.5Hz,1H),2.55–2.33(m,5H),2.33–2.22(m,1H),2.05–1.92(m,1H). 13 C NMR (101 MHz, CDCl 3 )δ146.6,137.7,131.1(dd,J=255.3,250.8Hz),130.0,129.3,129.2(d,J=2.4Hz),126.5,117.7,1 13.2, 54.5 (d, J = 4.7Hz), 54.2 (dd, J = 23.9, 21.2Hz), 33.8 (t, J = 25.1Hz), 28.3 (t, J = 3.9Hz), 15.7. 19 F NMR (376 MHz, CDCl 3 )δ-87.6(d,J=233.1Hz),-94.8(d,J=232.9Hz).

[0094]

[0095] 1 H NMR (400 MHz, CDCl 3 )δ7.23(s,4H),7.15(t,J=7.9Hz,2H),6.72(t,J=7.3Hz,1H),6.55(d,J=7.8Hz,2H),4.14(q,J=8.1Hz,1H),3.71 (brs,1H),3.33–3.17(m,1H),2.65–2.53(m,1H),2.47(s,3H),2.46–2.21(m,2H),1.71(dq,J=13.1,8.4Hz,1H). 13 C NMR (101 MHz, CDCl 3 )δ147.0,138.2,130.3(d,J=1.8Hz),129.6,129.3,128.1(dd,J=253.1,251.4Hz),126.7,118.1,113 .4,58.1(t,J=22.9Hz),56.2(d,J=7.3Hz),33.5(dd,J=25.3,24.3Hz),29.1(dd,J=4.5,3.0Hz),15.7. 19 F NMR (376 MHz, CDCl 3 )δ-95.3(d,J=228.6Hz),-97.3(d,J=228.7Hz).

[0096] Embodiment 6

[0097] Preparation of 3-(N-phenylamino)-2-(4-chlorophenyl)-1,1-difluorocyclopentane (3f)

[0098] Add 2.6 mg (0.004 mmol) of bis(2-phenylpyridine)(5-fluoropyridine-2-carboxylic acid)iridium complex, 26.6 mg (0.2 mmol) of N-phenylcyclopropylamine, 208.8 mg (1.2 mmol) of 2-(4-chlorophenyl)-1,1-difluoroethylene and 2 mL of methanol to a 10 mL dry Schlenk tube, tighten the Schlenk stopcock, and place under blue light and stir at room temperature for 24 h. After the reaction is completed, the reaction solution is transferred to a round-bottom flask, the solvent is evaporated under reduced pressure, and the crude product is separated by column chromatography (the chromatography column is filled with 300-400 mesh silica gel, and the eluent is a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:10), and white solid products cis-3f and trans-3f are obtained, respectively, with a total of 51.0 mg, and a yield of 83% (cis:trans=53:47). 160.1 mg of 2-(4-chlorophenyl)-1,1-difluoroethylene was recovered.

[0099] The structure and NMR spectrum data of compound 3f are as follows:

[0100]

[0101] 1 H NMR (400 MHz, CDCl 3 )δ7.27(d,J=9.1Hz,2H),7.21(d,J=8.4Hz,2H),7.14(t,J=7.8Hz,2H),6.70(t,J=7.3Hz,1H),6.49(d,J=7.9Hz,2H) ,4.35(q,J=5.8Hz,1H),3.77–3.64(m,1H),3.58(brs,1H),2.54–2.33(m,2H),2.34–2.22(m,1H),2.05–1.92(m,1H). 13 CNMR (101MHz, CDCl 3 )δ146.4,133.3,131.0(d,J=1.6Hz),130.9,129.3,128.5,117.8,113.0,54.3( d,J=5.6Hz), 54.0(dd,J=23.6,21.3Hz), 33.7(t,J=25.0Hz), 28.3(t,J=4.0Hz). 19 F NMR (376 MHz, CDCl 3 )δ-88.2(d,J=233.2Hz),-94.5(d,J=233.2Hz).

[0102]

[0103] 1 H NMR (400 MHz, CDCl 3 )δ7.32(d,J=8.4Hz,2H),7.24(d,J=8.5Hz,2H),7.15(t,J=7.8Hz,2H),6.73(t,J=7.3Hz,1H),6.55(d,J=7.9Hz,2H),4.15(q,J=8. 5Hz,1H),3.68(s,1H),3.26(ddd,J=18.2,13.1,10.5Hz,1H),2.63–2.53(m,1H),2.51–2.21(m,2H),1.71(dq,J=13.1,8.4Hz,1H). 13 C NMR (101 MHz, CDCl 3)δ146.8,133.8,132.2(d,J=1.8Hz),130.5,129.3,128.8,128.0(dd,J=253.3,251.6Hz),118.2,1 13.4, 58.0 (t, J = 22.9Hz), 56.3 (d, J = 7.2Hz), 33.5 (dd, J = 25.3, 24.2Hz), 29.0 (dd, J = 4.6, 2.9Hz). 19 F NMR (376 MHz, CDCl 3 )δ-95.2(d,J=229.5Hz),-97.2(d,J=229.0Hz).

[0104] Embodiment 7

[0105] Preparation of 3-(N-phenylamino)-2-(4-bromophenyl)-1,1-difluorocyclopentane (3 g)

[0106] Add 2.6 mg (0.004 mmol) of bis(2-phenylpyridine)(5-fluoropyridine-2-carboxylic acid)iridium complex, 26.6 mg (0.2 mmol) of N-phenylcyclopropylamine, 262.8 mg (1.2 mmol) of 2-(4-bromophenyl)-1,1-difluoroethylene and 2 mL of methanol to a 10 mL dry Schlenk tube, tighten the Schlenk stopcock, and place under blue light and stir at room temperature for 24 h. After the reaction is completed, transfer the reaction solution to a round-bottom flask, evaporate the solvent under reduced pressure, and separate the crude product by column chromatography (the chromatographic column is filled with 300-400 mesh silica gel, and the eluent is a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:10), respectively, to obtain white solid products cis-3g and trans-3g, a total of 55.0 mg, with a yield of 78% (cis:trans=43:57). 194.9 mg of 2-(4-bromophenyl)-1,1-difluoroethylene was recovered.

[0107] The structure and NMR spectrum data of compound 3g are as follows:

[0108]

[0109] 1 H NMR (400 MHz, CDCl 3)δ7.43(d,J=8.4Hz,2H),7.19–7.11(m,4H),6.72(t,J=7.3Hz,1H),6.50(d,J=7.9Hz,2H),4.36(s,1H),3.69(td,J=15.4,14.5,6.7Hz,1H),3.59(s,1H),2.56–2.34(m,2H),2.34–2.22(m,1H),2.05–1.92(m,1H). 13 C NMR(101MHz,CDCl 3 )δ146.4,131.5(d,J=1.4Hz),131.5,131.2,130.9(dd,J=254.8,251.7Hz),129.3,121.5,117.9,113.1,54.4(d,J=5.8Hz),54.1(dd,J=23.7,21.3Hz),33.8(t,J=25.1Hz),28.3(t,J=3.9Hz). 19 F NMR(376MHz,CDCl 3 )δ-88.2(d,J=233.2Hz),-94.5(d,J=233.2Hz).

[0110]

[0111] 1 H NMR(400MHz,CDCl 3 )δ7.48(d,J=8.4Hz,2H),7.17(dd,J=15.5,8.1Hz,4H),6.73(t,J=7.3Hz,1H),6.55(d,J=8.0Hz,2H),4.15(q,J=8.2Hz,1H),3.69(s,1H),3.25(ddd,J=18.2,12.9,10.7Hz,1H),2.59(ddt,J=16.9,8.2,4.5Hz,1H),2.51–2.23(m,2H),1.78–1.65(m,1H). 13 C NMR(101MHz,CDCl 3 )δ146.8,132.6(d,J=1.8Hz),131.7,130.8,129.3,128.0(dd,J=254.3,252.4Hz),122.0,118.2,113.4,58.0(t,J=22.9Hz),56.1(d,J=7.2Hz),33.5(dd,J=25.3,24.4Hz),29.0(dd,J=4.6,2.8Hz). 19F NMR (376 MHz, CDCl 3 )δ-95.2(d,J=229.0Hz),-97.1(d,J=229.3Hz).

[0112] Embodiment 8

[0113] Preparation of 3-(N-phenylamino)-2-(4-iodophenyl)-1,1-difluorocyclopentane (3h)

[0114] Add 2.6 mg (0.004 mmol) of bis(2-phenylpyridine)(5-fluoropyridine-2-carboxylic acid)iridium complex, 26.6 mg (0.2 mmol) of N-phenylcyclopropylamine, 319.2 mg (1.2 mmol) of 2-(4-iodophenyl)-1,1-difluoroethylene and 2 mL of methanol to a 10 mL dry Schlenk tube, tighten the Schlenk stopcock, and place under blue light and stir at room temperature for 24 hours. After the reaction is completed, the reaction solution is transferred to a round-bottom flask, the solvent is evaporated under reduced pressure, and the crude product is separated by column chromatography (the chromatography column is filled with 300-400 mesh silica gel, and the eluent is a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:10), and white solid products cis-3h and trans-3h are obtained, respectively, with a total of 55.8 mg, and a yield of 70% (cis:trans=60:40). 234.1 mg of 2-(4-iodophenyl)-1,1-difluoroethylene was recovered.

[0115] The structure and NMR spectrum data of compound 3h are as follows:

[0116]

[0117] 1 H NMR (400 MHz, CDCl 3 )δ7.63(d,J=8.4Hz,2H),7.15(t,J=7.9Hz,2H),7.03(d,J=8.2Hz,2H),6.71(t,J=7.3Hz,1H),6.50(d,J=7.9Hz,2H),4 .35(s,1H),3.67(td,J=14.4,13.7,6.8Hz,1H),3.57(s,1H),2.56–2.33(m,2H),2.33–2.20(m,1H),2.04–1.93(m,1H). 13 C NMR (101 MHz, CDCl 3)δ146.4,137.4,132.2(d,J=2.2Hz),131.5,130.9(dd,J=254.8,251.6Hz),129.3,117.9,113. 1, 93.1, 54.4 (d, J = 6.0Hz), 54.2 (dd, J = 23.7, 21.4Hz), 33.8 (t, J = 25.1Hz), 28.3 (t, J = 3.9Hz). 19 F NMR (376 MHz, CDCl 3 )δ-88.0(d,J=233.6Hz),-94.5(d,J=233.6Hz).

[0118]

[0119] 1 H NMR (400 MHz, CDCl 3 )δ7.68(d,J=8.4Hz,2H),7.20–7.11(m,2H),7.06(d,J=8.2Hz,2H),6.73(t,J=7.3Hz,1H),6.55(d,J=7.8Hz,2H),4.15(q,J =8.0Hz,1H),3.68(s,1H),3.23(ddd,J=18.1,13.0,10.6Hz,1H),2.64–2.51(m,1H),2.50–2.22(m,2H),1.78–1.65(m,1H). 13 C NMR (101 MHz, CDCl 3 )δ146.8,137.7,133.3(d,J=1.7Hz),131.0,129.3,127.9(dd,J=253.5,251.5Hz),118.2,113 .4,93.6,58.1(t,J=23.0Hz),56.0(d,J=7.1Hz),33.5(d,J=24.8Hz),29.0(dd,J=4.6,2.8Hz). 19 F NMR (376 MHz, CDCl 3 )δ-95.1(d,J=229.0Hz),-97.0(d,J=229.3Hz).

[0120] Embodiment 9

[0121] Preparation of 3-[N-(4-chlorophenyl)amino]-2-(4-tert-butylphenyl)-1,1-difluorocyclopentane (3i)

[0122] Add 2.6 mg (0.004 mmol) of bis(2-phenylpyridine)(5-fluoropyridine-2-carboxylic acid)iridium complex, 33.4 mg (0.2 mmol) of N-(4-chlorophenyl)cyclopropylamine, 235.2 mg (1.2 mmol) of 2-(4-tert-butylphenyl)-1,1-difluoroethylene and 2 mL of methanol to a 10 mL dry Schlenk tube, tighten the Schlenk stopcock, and stir at room temperature for 24 h under blue light. After the reaction, transfer the reaction solution to a round-bottom flask, evaporate the solvent under reduced pressure, and separate the crude product by column chromatography (the column is filled with 300-400 mesh silica gel, and the eluent is a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:10), respectively, to obtain 61.8 mg of white solid products cis-3i and trans-3i, with a yield of 85% (cis:trans=43:57). 199.9 mg of 2-(4-tert-butylphenyl)-1,1-difluoroethylene was recovered.

[0123] The structure and NMR spectrum data of compound 3i are as follows:

[0124]

[0125] 1 H NMR (400 MHz, CDCl 3 )δ7.33(d,J=8.4Hz,2H),7.18(d,J=8.1Hz,2H),7.07(d,J=8.8Hz,2H),6.41(d,J=8.8Hz,2H), 4.28(p,J=6.1Hz,1H),3.75–3.62(m,2H),2.57–2.20(m,3H),2.02–1.91(m,1H),1.31(s,9H). 13 C NMR (101 MHz, CDCl 3 )δ150.3,145.3,131.1(dd,J=255.1,250.6Hz),129.11(d,J=1.7Hz),129.07,129.0,125.4,122.1,11 4.2, 54.6 (d, J = 5.6Hz), 54.2 (dd, J = 23.9, 21.4Hz), 34.4, 33.8 (t, J = 25.3Hz), 31.2, 28.1 (t, J = 3.9Hz). 19 F NMR (376 MHz, CDCl 3 )δ-88.0(d,J=232.8Hz),-94.9(d,J=232.6Hz).

[0126]

[0127] 1 H NMR (400 MHz, CDCl 3 )δ7.41–7.35(m,2H),7.23(d,J=8.1Hz,2H),7.15–7.06(m,2H),6.52–6.44(m,2H),4.15(d,J=14.0Hz,1H),3.76(s ,1H),3.26(ddd,J=18.3,13.1,10.4Hz,1H),2.62–2.23(m,3H),1.70(ddt,J=13.1,10.2,8.2Hz,1H),1.32(s,9H). 13 C NMR (101 MHz, CDCl 3 )δ150.8,145.6,130.2(d,J=1.7Hz),129.0,128.7,128.2(t,J=253.1Hz),125.6,122.5,114.5, 58.0 (t, J = 23.1Hz), 56.2 (d, J = 7.3Hz), 34.5, 33.5 (t, J = 25.0Hz), 31.3, 28.8 (dd, J = 4.7, 2.8Hz). 19 F NMR (376 MHz, CDCl 3 )δ-95.4(d,J=228.6Hz),-97.4(d,J=228.4Hz).

[0128] In summary, the preparation method of the present invention has mild conditions and is easy to operate. In the synthesis reaction of the geminal difluorocyclopentane compound of the present invention, there are few side reactions, high yield, simple post-processing, low production cost, and the synthesis efficiency of the geminal difluorocyclopentane compound is greatly improved, which is conducive to large-scale industrial production.

[0129] A geminal difluorocyclopentane compound and a synthesis method thereof according to an embodiment of the present invention have at least one of the following advantages:

[0130] (1) The embodiments of the present invention provide a novel geminal difluorocyclopentane compound, which has higher lipophilicity, chemical stability and ability to form hydrogen bonds, and can be widely used in drug design.

[0131] (2) The raw materials for the synthesis method of the geminal difluorocyclopentane compound provided by the present invention are derived from cheap and readily available chemical reagents such as aryl bromide, 1-aminocyclopropane, aryl formaldehyde, sodium difluorochloroacetate, etc.; the synthesis technical conditions are simple, and in addition to the two reaction raw materials, only a photocatalyst needs to be added and continuous blue light irradiation is required; the reaction cost is low, the amount of photocatalyst used is small, and there is no need to use a large amount of expensive precious metal catalysts and ligands, and the use of strong acids, strong bases, unstable or difficult to obtain additives is avoided; the reaction operation is simple, no anhydrous and oxygen-free reaction conditions are required, and it is carried out at room temperature; the reaction by-products are small, the yield is high, and the range of geminal difluorocyclopentane compounds that can be synthesized is wide, which is suitable for large-scale production.

[0132] Although some embodiments of the present general inventive concept have been shown and described, it will be appreciated by those skilled in the art that changes may be made to these embodiments without departing from the principles and spirit of the present general inventive concept, the scope of which is defined by the claims and their equivalents.

Claims

1. A geminal difluorocyclopentane compound having the structural formula shown below, in, Ar 1 One selected from phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-chlorophenyl, 4-bromophenyl, 3,5-ditrifluoromethylphenyl, 2-methyl-4-methoxyphenyl and 2-naphthyl; Ar 2 One selected from phenyl, 4-tert-butylphenyl, 4-methylphenyl, 4-phenylphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 4-methoxycarbonylphenyl, 4-cyanophenyl, 2-methylphenyl, 2-fluorophenyl, 3,5-dimethylphenyl, 1-naphthyl, 3-thienyl, 3-benzothienyl and 2-benzofuranyl.

2. A method for synthesizing the geminal difluorocyclopentane compound according to claim 1, characterized in that: The synthesis method is: N-arylcyclopropylamine and 1,1-difluoro-2-arylethene are used as raw materials, and the geminal difluorocyclopentane compound is synthesized by using an iridium photocatalyst under the irradiation of blue light.

3. The synthesis method according to claim 2, characterized in that The aryl group in the N-arylcyclopropylamine is one of phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-chlorophenyl, 4-bromophenyl, 3,5-ditrifluoromethylphenyl, 2-methyl-4-methoxyphenyl and 2-naphthyl.

4. The synthesis method according to claim 2, characterized in that The aromatic group in the 1,1-difluoro-2-arylethene is one of phenyl, 4-tert-butylphenyl, 4-methylphenyl, 4-phenylphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 4-methoxycarbonylphenyl, 4-cyanophenyl, 2-methylphenyl, 2-fluorophenyl, 3,5-dimethylphenyl, 1-naphthyl, 3-thienyl, 3-benzothienyl and 2-benzofuranyl.

5. The synthesis method according to claim 2, characterized in that The iridium photocatalyst is bis[2-(4,6-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium(hexafluorophosphate) salt (Ir[dF(CF3)ppy]2(dtbbpy)PF6), bis[2-(4,6-difluorophenyl)-5-trifluoromethylpyridine](2-2'-bipyridine)iridium(hexafluorophosphate) salt (Ir[dF(CF3)ppy]2(bpy)PF6), bis(2-phenylpyridine)(2-2'-bipyridine)iridium(hexafluorophosphate) salt (Ir(ppy)2(bpy)PF6), bis[2-(4,6-difluorophenyl)-5-trifluoromethylpyridine](2-2'-bipyridine)iridium(hexafluorophosphate) salt (Ir[dF(CF3)ppy]2(bpy)PF6), bis[2-(4,6-difluorophenyl)pyridine][2-2'-bi(4-tert-butylpyridine)]iridium(hexafluorophosphate) salt (Ir(dFppy)2(dtbbpy)PF6), bis[2-(4-methylphenyl)-4-methylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium(hexafluorophosphate) salt (Ir[Me(Me)ppy]2(dtbbpy)PF6), bis[2-(4-fluorophenyl)-5-methylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium(hexafluorophosphate) salt (Ir[F(Me)ppy]2(dtbbpy)PF6), tris[2-(4- trifluoromethylphenyl)pyridine]iridium (Ir(p-CF3ppy)3), tris[2-(4-fluorophenyl)pyridine]iridium (Ir(p-Fppy)3), bis(2-phenylpyridine)(pyridine-2-carboxylate)iridium (Ir(ppy)2(pic)), bis[2-(4,6-difluorophenyl)pyridine](pyridine-2-carboxylate)iridium (Ir(dFppy)2(pic)), bis[2-(4,6-difluorophenyl)-5-trifluoromethylpyridine](pyridine-2-carboxylate)iridium (Ir[dF(CF3)ppy]2(pic)), bis(2-phenylpyridine)(4-trifluoromethylpyridine-2-carboxylate)iridium (Ir(ppy)2[(4-CF3)pic ]), bis(2-phenylpyridine)(5-methoxypyridine-2-carboxylate)iridium complex (Ir(ppy)2[(5-OMe)pic]), bis(2-phenylpyridine)(6-methylpyridine-2-carboxylate)iridium complex (Ir(ppy)2[(6-Me)pic]), bis(2-phenylpyridine)(5-fluoropyridine-2-carboxylate)iridium complex (Ir(ppy)2[(5-F)pic]), bis(2-phenylpyridine)(5-chloropyridine-2-carboxylate)iridium complex (Ir(ppy)2[(5-Cl)pic]), bis(2-phenylpyridine)(4,5-difluoropyridine-2-carboxylate)iridium complex (Ir(ppy)2[(4,5-dF)pic]), bis[2-(4,6-difluorophenyl)pyridine](5-fluoropyridine-2-carboxylic acid)iridium complex (Ir(dFppy)2[(5-F)pic]), bis[2-(4,6-difluorophenyl)pyridine](4-trifluoromethylpyridine-2-carboxylic acid)iridium complex (Ir(dFppy)2[(4-CF3)pic]), bis[2-(4,6-difluorophenyl)pyridine](5-methoxypyridine-2-carboxylic acid)iridium complex (Ir(dFppy)2[(5-OMe)pic]) and bis[2-(4,6-difluorophenyl)pyridine](5-chloropyridine-2-carboxylic acid)iridium complex (Ir(dFppy)2[(5-Cl)pic]). , 6. The synthesis method according to claim 2, characterized in that The synthesis method is specifically: Mixing N-arylcyclopropylamine and 1,1-difluoro-2-arylethene in a solvent, adding an iridium photocatalyst, and obtaining a mixed solution; The mixed solution is reacted at room temperature under continuous blue light irradiation to obtain a gem-difluorocyclopentane compound; Wherein, the solvent is one or more of dichloromethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methanol, ethanol, isopropanol and ethylene glycol.

7. The synthesis method according to claim 2, characterized in that The molar ratio of the N-arylcyclopropylamine, 1,1-difluoro-2-arylethene and iridium photocatalyst is 1:(1-10):(0.005-0.05).

8. The synthesis method according to claim 7, characterized in that In the mixed solution, the concentration of N-arylcyclopropylamine is 0.05-0.3 mol / L.

9. The synthesis method according to any one of claims 2 to 8, characterized in that: The conditions of the blue light irradiation are: wavelength of 410-480nm, power of 3-30W.

10. The synthesis method according to claim 6, characterized in that: The reaction time is 12 to 30 hours.

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