Preparation method of difluoromethyl-containing compound

Abstract

The invention discloses a preparation method of a difluoromethyl-containing compound, and belongs to the technical field of organic synthesis of medical intermediates. According to the invention, phosphoryl free radicals are generated under the assistance of a transition metal catalyst and alkali, the free radicals and an o-isocyano-alpha-trifluoromethyl styrene compound are subjected to free radical cascade cyclization, and then beta-fluorine negative ion elimination and 1, 3-hydrogen migration are carried out to synthesize the difluoromethyl-containing compound. A quinoline ring is synchronously and efficiently constructed in single conversion synthesis, and difluoromethyl and phosphoryl with biological activity are introduced. The method provided by the invention has the advantages of very wide substrate adaptability, high atom economy and simple and convenient reaction process operation, and is suitable for gram-scale synthesis.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediate modification and organic synthesis, and specifically relates to a method for preparing a difluoromethyl-containing compound. Background Art

[0002] Difluoromethyl (CF 2 H) is considered to be a metabolically stable bioisostere of thiol, hydroxyl and amino groups due to its strong lipophilic hydrogen-donating ability. It has excellent biological activity and is the key structure of important fluorinated drugs. It is widely present in many approved fluorinated drugs and candidate drug molecules entering clinical trials, such as: Targeting the PI3K / mTOR Pathway in Lymphoma with PQR309 and PQR620: Single Agent Activity and Synergism with the BCL2 Inhibitor Venetoclax discloses that PQR620 has in vitro and in vivo anti-lymphoma activity as a single agent; Discovery of AZD3839, a potent and selective BACE1 inhibitorclinical candidate for the treatment of Alzheimer disease discloses an effective human Beta-secretase 1 inhibitor AZD3839, which is a clinical candidate for the treatment of Alzheimer's disease; Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection discloses that voxilaprevir is an orally active direct-acting antiviral agent (DAA) for hepatitis C virus (HCV) infection, etc. In traditional methods, the introduction of difluoromethyl groups is mainly achieved through two approaches: (i) direct difluoromethylation using different difluoromethylating agents; (ii) using pre-functionalized building blocks containing difluoromethyl groups. However, unlike the more mature synthesis methods of geminal difluoroolefin compounds, the introduction of difluoromethyl groups, especially for quinoline compounds, has been less explored. Summary of the invention

[0003] In view of the above-mentioned shortcomings of the prior art, the present invention provides a method for preparing a difluoromethyl-containing compound.

[0004] To achieve the above object, the technical solution adopted by the present invention is:

[0005] A method for preparing a difluoromethyl-containing compound comprises the following steps: reacting a catalyst, a base, a phosphorus oxide compound, a solvent and an o-isocyano-α-trifluoromethylstyrene compound at 60° C. to 100° C. for 6 to 18 hours, removing the solvent by reduced pressure distillation, and performing column chromatography to obtain the difluoromethyl-containing compound;

[0006] The structural formula of the difluoromethyl-containing compound is:

[0007]

[0008] R 1 is one of hydrogen, methyl, fluorine, chlorine, bromine and trifluoromethyl; R 2 =R 3 When R 2 =R 3 is one of phenyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, biphenyl, naphthyl and thienyl; R 1 ≠R 2 When R 2 is phenyl, R 3 It is one of p-methylphenyl, p-chlorophenyl, biphenyl, 2-methylallyloxy, and pent-4-yn-1-oxy.

[0009] As a preferred embodiment of the present invention, the molar ratio of the catalyst, base, phosphorus oxide, solvent and o-isocyano-α-trifluoromethylstyrene compound is (0.03-0.2):(2-3):(1-3):(60-250):1.

[0010] As a preferred embodiment of the present invention, the structural formula of the o-isocyano-α-trifluoromethylstyrene compound is:

[0011] As a preferred embodiment of the present invention, the structural formula of the phosphorus oxide compound is:

[0012] As a preferred embodiment of the present invention, the catalyst is Cu(acac) 2 ,CuSO 4 ·5H 2 O, CuCl, CuBr 2 、Ag 2 O, AgF, AgOAc, AgOTf, AgBF 4 AgNO 3 、Ag 2 CO 3 、Ag 3 PO 4 One of them.

[0013] As a preferred embodiment of the present invention, the base is Cs 2 CO 3 , CsOH, K 2 CO 3 、Na 2 CO 3 , NaOH, K 3 PO 4 One of them.

[0014] As a preferred embodiment of the present invention, the solvent is one of tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

[0015] Compared with the prior art, the invention has the following beneficial effects: the invention generates a phosphoryl radical under the assistance of a transition metal catalyst and a base, and the radical undergoes a radical cascade cyclization with an o-isocyano-α-trifluoromethylstyrene compound, and then undergoes β-fluorine anion elimination and 1,3-hydrogen migration to synthesize a difluoromethyl compound, which can be used as a pharmaceutical intermediate. The method of the invention has very wide substrate adaptability, high atom economy, and a simple reaction process, and is suitable for gram-scale synthesis. DETAILED DESCRIPTION

[0016] 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.

[0017] Example 1: Synthesis of diphenyl (4-difluoromethylquinolin-2-yl) phosphine oxide (3a)

[0018] Under argon atmosphere, 0.006 mmol of Cu(acac) 2 , 0.4mmol Cs 2 CO 3 , 0.3 mmol of diphenylphosphine oxide (2a), 12 mmol of 1,4-dioxane, 0.2 mmol of 1-isocyano-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1a), followed by stirring and reacting at 90°C for 12 hours, and then concentrating the reaction product under reduced pressure to obtain a crude product, and the crude product was separated and extracted by a silica gel (200-300 mesh) column, using petroleum ether as an eluent, and the eluent was collected and dried to obtain 39 mg of diphenyl (4-difluoromethylquinolin-2-yl) phosphine oxide (3a), with a yield of 52%;

[0019] The reaction equation is as follows:

[0020]

[0021] The NMR and high-resolution mass spectrometry data of diphenyl(4-difluoromethylquinolin-2-yl)phosphine oxide (3a) are as follows:

[0022] 1 H NMR(600MHz,Chloroform-d)δ8.53(d,J=3.9Hz,1H),8.22(d,J=8.5Hz,1H),8.14(d,J=8.4Hz,1H),8.02–7.96(m,4H),7 .79(t,J=7.7Hz,1H),7.68(t,J=7.6Hz,1H),7.51(t,J=7.3Hz,2H),7.45(td,J=7.5,2.8Hz,4H),7.13(t,J=54.3Hz,1H). 13 C NMR (151MHz, Chloroform-d) δ 157.42 (d, J = 129.7Hz), 148.58 (d, J = 20.8Hz), 138.02 (td, J = 22.3, 8.8Hz), 132.22 (s), 132.14 (d, J = 4.1Hz), 131.47 ( s),131.19(s),130.52(s),129.52(s),128.46(d,J=12.2Hz),124.02(d,J =2.2Hz), 123.75(s), 120.55(dt,J=22.1,7.7Hz), 113.77(t,J=241.3Hz). 19 F NMR (565MHz, Chloroform-d) δ-113.60 (dd, J=54.3, 11.2Hz, 2F). 31 PNMR(243MHz,Chloroform-d)δ20.21.HRMS:calculated[M+H] + forC 22 H 17 F 2 NOP:380.1010,found:380.1012.

[0023] Example 2: Synthesis of diphenyl (6-methyl-4-difluoromethylquinolin-2-yl) phosphine oxide (3b)

[0024] Under argon atmosphere, 0.02 mmol of Ag 2 O, 0.4mmol Na 2 CO 3, 0.3 mmol of diphenylphosphine oxide (2a), 12 mmol of 1,4-dioxane, 0.2 mmol of 1-isocyano-4-methyl-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1b), followed by stirring and reacting at 80°C for 12 hours, and then concentrating the reaction product under reduced pressure to obtain a crude product, which was separated and extracted by a silica gel (200-300 mesh) column, using petroleum ether as an eluent, collecting the eluent, and drying to obtain 38 mg of diphenyl (6-methyl-4-trifluoromethylquinolin-2-yl) phosphine oxide (3b), with a yield of 48%; the reaction equation is as follows:

[0025]

[0026] The NMR and high-resolution mass spectrometry data of diphenyl (6-methyl-4-trifluoromethylquinolin-2-yl) phosphorus oxide (3b) are as follows:

[0027] 1 H NMR(600MHz,Chloroform-d)δ8.49(d,J=3.3Hz,1H),8.12(d,J=8.7Hz,1H),7.97(dd,J=11.4,7.9Hz,4H) ,7.91(s,1H),7.63(d,J=8.6Hz,1H),7.51(t,J=7.0Hz,2H),7.46–7.42(m,4H),7.11(s,1H),2.58(s,3H). 13 C NMR (151MHz, Chloroform-d) δ 156.07 (d, J = 130.9Hz), 147.42 (d, J = 20.9Hz), 140.17, 137.18 (td, J = 22.1, 8.8Hz), 132.88, 132.24 (d, J = 9.4Hz), 132.11 (d, J=2.6Hz),132.02(d,J=104.2Hz),130.91,128.47(d,J=12.2Hz),124.20(d,J =2.2Hz), 122.55, 120.71 (dt, J = 22.1, 7.5Hz), 113.96 (t, J = 241.1Hz), 22.31. 19 F NMR (565MHz, Chloroform-d) δ-113.53 (d, J = 54.2Hz, 2F). 31 P NMR(243MHz,Chloroform-d)δ20.33.HRMS:calculated[M+H] + for C 23 H 19 F 2NOP:394.1167,found:394.1166.

[0028] Example 3: Synthesis of diphenyl (6-fluoro-4-difluoromethylquinolin-2-yl) phosphine oxide (3c) In an argon atmosphere, 0.02 mmol of AgF, 0.4 mmol of K 2 CO 3 , 0.3 mmol of diphenylphosphine oxide (2a), 12 mmol of acetonitrile, 0.2 mmol of 1-isocyano-4-fluoro-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1c), followed by stirring and reacting at 70°C for 12 hours, the reaction product was concentrated under reduced pressure to obtain a crude product, the crude product was separated and extracted by a silica gel (200-300 mesh) column, petroleum ether was used as an eluent, the eluent was collected and dried to obtain 48 mg of diphenyl (6-fluoro-4-difluoromethylquinolin-2-yl) phosphine oxide (3c), the yield was 60%, and the reaction equation was as follows:

[0029]

[0030] The NMR data of diphenyl (6-fluoro-4-difluoromethylquinolin-2-yl) phosphorus oxide (3c) compound are as follows:

[0031] 1 H NMR(600MHz,Chloroform-d)δ8.53(d,J=3.3Hz,1H),8.23(dd,J=9.1,5.7Hz,1H),7.96(dd,J=11.7,7.8Hz,4H ),7.78(d,J=9.2Hz,1H),7.59–7.53(m,1H),7.51(t,J=7.2Hz,2H),7.48–7.41(m,4H),7.05(t,J=54.1Hz,1H). 13C NMR(151MHz,Chloroform-d)δ161.94(d,J=253.5Hz),156.76(dd,J=129.7,2.9Hz),145.84(d ,J=20.9Hz),137.66(ddq,J=22.4,14.7,7.6Hz),133.84(d,J=9.6Hz),132.20(d,J=2.6Hz),1 32.12(d,J=9.5Hz),131.59(d,J=104.6Hz),128.48(d,J=12.3Hz),124.99(d,J=10.6Hz),121 .44(dt,J=15.2,7.4Hz), 121.13(d,J=26.0Hz), 113.81(t,J=241.4Hz), 107.87(d,J=23.9Hz). 19 F NMR(565MHz,Chloroform-d)δ-106.44–-106.52(m,1F),-113.60(dd,J=54.3,19.5Hz,2F). 31 PNMR(243MHz,Chloroform-d)δ20.38.HRMS:calculated[M+H] + forC 22 H 16 F 3 NOP:398.0916,found:398.0914.

[0032] Example 4: Synthesis of diphenyl (6-chloro-4-difluoromethylquinolin-2-yl) phosphine oxide (3d)

[0033] Under argon atmosphere, 0.02 mmol of AgOTf, 0.4 mmol of K 3 PO 4 , 0.3 mmol of diphenylphosphine oxide (2a), 12 mmol of 1,4-dioxane, 0.2 mmol of 1-isocyano-4-chloro-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1d), followed by stirring and reacting at 60°C for 12 hours, the reaction product was concentrated under reduced pressure to obtain a crude product, the crude product was separated and extracted by a silica gel (200-300 mesh) column, petroleum ether was used as an eluent, the eluent was collected and dried to obtain 52 mg of diphenyl (6-chloro-4-difluoromethylquinolin-2-yl) phosphine oxide (3d), the yield was 63%, and the reaction equation was as follows:

[0034]

[0035] The NMR and high-resolution mass spectrometry data of diphenyl(6-chloro-4-difluoromethylquinolin-2-yl)phosphine oxide (3d) are as follows:

[0036] 1 H NMR(600MHz,Chloroform-d)δ8.53(d,J=3.4Hz,1H),8.24(s,1H),8.13(d,J=8.9Hz,1H),7.96(dd,J=11 .6,7.9Hz,4H),7.66(d,J=8.9Hz,1H),7.54(t,J=7.2Hz,2H),7.50–7.44(m,4H),7.09(t,J=54.1Hz,1H). 13 C NMR (151MHz, Chloroform-d) δ 159.13 (d, J = 127.8Hz), 149.04 (d, J = 21.0Hz), 138.32 (td, J = 22.5, 8.7Hz), 136.76, 132.33 (d, J = 2.7Hz), 132.22 (d, J = 9. 5Hz),131.53(d,J=104.7Hz),130.51,130.01,128.59(d,J=12.3Hz),125.3 9,122.46(d,J=1.9Hz), 121.01(dt,J=21.6,7.6Hz), 113.86(t,J=241.5Hz). 19 F NMR(471MHz,Chloroform-d)δ-112.82(s,2F). 31 PNMR(203MHz,Chloroform-d)δ20.12.HRMS:calculated[M+H] + for C 22 H 16 CIF 2 NOP:414.0621,found:414.0624.

[0037] Example 5: Synthesis of diphenyl (6-bromo-4-difluoromethylquinolin-2-yl) phosphine oxide (3e)

[0038] In an argon atmosphere, 0.02 mmol of CuCl, 0.4 mmol of NaOH, 0.3 mmol of diphenylphosphine oxide (2a), 12 mmol of toluene, and 0.2 mmol of 1-isocyano-4-bromo-2-3,3,3-trifluoropropyl-1-en-2-yl)benzene (1e) were added to a 10 mL thick-walled test tube in sequence, and then stirred at 100° C. for 12 hours, and the reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200-300 mesh) column, using petroleum ether as an eluent, and the eluent was collected and dried to obtain 55 mg of diphenyl (6-bromo-4-difluoromethylquinolin-2-yl) phosphine oxide (3e), with a yield of 60%. The reaction equation is as follows:

[0039]

[0040] The NMR and high-resolution mass spectrometry data of diphenyl(6-bromo-4-difluoromethylquinolin-2-yl)phosphine oxide (3e) are as follows:

[0041] 1 H NMR(600MHz,Chloroform-d)δ8.53(d,J=4.1Hz,1H),8.33(s,1H),8.08(d,J=9.0Hz,1H),7.95(dd,J=12.0,7.6H z,4H),7.86(dd,J=9.1,2.1Hz,1H),7.53(t,J=7.4Hz,2H),7.46(td,J=7.7,3.0Hz,4H),7.07(t,J=54.1Hz,1H). 13 CNMR(126MHz,Chloroform-d)δ158.39(d,J=128.5Hz),147.31(d,J=20.9Hz),137.37(td,J=22.6,8.7Hz),134.31,132.76,132.28(d,J=3.1Hz),132.28 (d,J=9.1Hz),131.80(d,J=104.7Hz),128.59(d,J=12.3Hz),126.45,125.1 4(d,J=2.3Hz),124.37,121.68(dt,J=21.8,7.7Hz),113.80(t,J=241.7Hz). 19 F NMR(471MHz,Chloroform-d)δ-113.12(s,2F). 31 P NMR(203MHz,Chloroform-d)δ20.39.HRMS:calculated[M+H] + for C 22 H16 F 2 NOP:458.0115,found:458.0119.

[0042] Example 6: Synthesis of diphenyl (6-trifluoromethyl-4-difluoromethylquinolin-2-yl) phosphine oxide (3f)

[0043] Under argon atmosphere, 0.02 mmol of AgNO 3 , 0.4mmol Cs 2 CO 3 , 0.6 mmol of diphenylphosphine oxide (2a), 12 mmol of N,N-dimethylformamide, 0.2 mmol of 1-isocyano-4-trifluoromethyl-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1f), followed by stirring and reacting at 60°C for 12 hours, and then concentrating the reaction product under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200-300 mesh) column, using petroleum ether as an eluent, and the eluent was collected and dried to obtain 65 mg of diphenyl (6-trifluoromethyl-4-difluoromethylquinolin-2-yl) phosphine oxide (3f), with a yield of 73%. The reaction equation is as follows:

[0044]

[0045] The NMR and high-resolution mass spectrometry data of diphenyl (6-trifluoromethyl-4-difluoromethylquinolin-2-yl) phosphorus oxide (3f) are as follows:

[0046] 1 H NMR(600MHz,Chloroform-d)δ8.63(d,J=3.9Hz,1H),8.50(s,1H),8.37(d,J=8.9Hz,1H),7.97(dd ,J=12.5,7.5Hz,5H),7.55(t,J=7.5Hz,2H),7.48(td,J=7.7,3.1Hz,4H),7.15(t,J=53.9Hz,1H). 13C NMR(151MHz,Chloroform-d)δ160.62(d,J=126.5Hz),149.40(d,J=20.6Hz),139.23(td ,J=22.6,8.5Hz),132.52,132.45(d,J=2.6Hz),132.24(d,J=9.5Hz),131.26(d,J=104.9 Hz),131.03(q,J=33.19),128.65(d,J=12.3Hz),126.36(d,J=2.7Hz),123.58(q,J=272 .9Hz), 123.18 (d, J = 2.3Hz), 122.14, 121.94 (dt, J = 21.6, 7.6Hz) 113.72 (t, J = 241.9Hz). 19 F NMR(565MHz,Chloroform-d)δ-62.72(s,3F),-112.65(d,J=54.0Hz,2F). 31 P NMR(243MHz,Chloroform-d)δ20.36.HRMS:calculated[M+H] + for C 23 H 16 F 5 NOP:448.0884,found:448.0889.

[0047] Example 7: Synthesis of (4-difluoromethylquinolin-2-yl)di-p-tolylphosphine oxide (4a) In an argon atmosphere, 0.02 mmol of AgOAc, 0.4 mmol of K 3 PO 4 , 0.2 mmol of di-p-tolylphosphine oxide (2b), 12 mmol of dimethyl sulfoxide, 0.2 mmol of 1-isocyano-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1a), followed by stirring and reacting at 90°C for 12 hours, the reaction product was concentrated under reduced pressure to obtain a crude product, the crude product was separated and extracted by a silica gel (200-300 mesh) column, petroleum ether was used as an eluent, the eluent was collected and dried to obtain 41 mg of (4-difluoromethylquinolin-2-yl) di-p-tolylphosphine oxide (4a), with a yield of 50%, and the reaction equation is as follows:

[0048]

[0049] The NMR and high-resolution mass spectrometry data of (4-difluoromethylquinolin-2-yl)di-p-tolylphosphine oxide (4a) are as follows:

[0050] 1H NMR(600MHz,Chloroform-d)δ8.51(d,J=3.5Hz,1H),8.23(d,J=8.5Hz,1H),8.16(d,J=8.3Hz,1H),7.85(dd,J=11.6 ,8.1Hz,4H),7.80(t,J=7.6Hz,1H),7.70(t,J=7.6Hz,1H),7.31–7.24(m,4H),7.12(t,J=54.2Hz,1H),2.37(s,6H). 13 C NMR (151MHz, Chloroform-d) δ 157.94 (d, J = 129.4Hz), 148.64 (d, J = 20.7Hz), 142.65 (d, J = 2.7Hz), 137.92 (td, J = 22.3, 8.7Hz), 132.26 (d, J = 9.8Hz), 131.2 5,130.43,129.42,129.24(d,J=12.6Hz),128.67(d,J=106.9Hz),124.00(d,J =2.5Hz), 123.79, 120.60 (dt, J = 22.1, 7.6Hz), 113.93 (t, J = 241.2Hz), 21.71. 19 FNMR(565MHz,Chloroform-d)δ-113.37(dd,J=54.3,10.7Hz,2F). 31 PNMR(243MHz,Chloroform-d)δ21.06.HRMS:calculated[M+H] + forC 24 H 21 F 2 NOP:408.1323,found:408.1328.

[0051] Example 8: Synthesis of bis(4-fluorophenyl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4b)

[0052] Under argon atmosphere, 0.02 mmol of AgBF 4 , 0.4mmol Cs 2 CO 3, 0.3 mmol of bis(4-fluorophenyl)phosphine oxide (2c), 12 mmol of acetonitrile, 0.2 mmol of 1-isocyano-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1a), followed by stirring and reacting at 70°C for 12 hours, the reaction product was concentrated under reduced pressure to obtain a crude product, the crude product was separated and extracted by a silica gel (200-300 mesh) column, petroleum ether was used as an eluent, the eluent was collected and dried to obtain 66 mg of bis(4-fluorophenyl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4b), with a yield of 80%, and the reaction equation is as follows:

[0053]

[0054] The NMR and high-resolution mass spectrometry data of bis(4-fluorophenyl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4b) are as follows:

[0055] 1 H NMR(600MHz,Chloroform-d)δ8.53(d,J=4.2Hz,1H),8.23(d,J=8.6Hz,1H),8.18(d,J=8.5H z,1H),8.06–7.95(m,4H),7.83(t,J=7.8Hz,1H),7.73(t,J=7.8Hz,1H),7.25–7.03(m,5H). 13 C NMR(151MHz,Chloroform-d)δ165.30(dd,J=254.0,3.2Hz),157.00(d,J=132.0Hz),148 .60(d,J=21.1Hz),138.35(td,J=22.3,9.0Hz),134.72(dd,J=10.7,9.0Hz),130.94(d,J =54.2Hz),129.76,127.69(dd,J=107.9,3.4Hz),124.16(d,J=2.2Hz),123.85,120.41(d t,J=22.3,7.7Hz), 116.07(d,J=13.4Hz), 115.93(d,J=13.4Hz), 113.66(t,J=241.5Hz). 19 F NMR(565MHz,Chloroform-d)δ-106.11–-106.18(m,2F),-113.67(d,J=54.3Hz,2F). 31 P NMR(243MHz,Chloroform-d)δ18.75.HRMS:calculated[M+H] + for C 22 H15 F 4 NOP:416.0822,found:416.0824.

[0056] Example 9: Synthesis of bis(4-chlorophenyl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4c)

[0057] Under argon atmosphere, 0.02 mmol of CuBr 2 , 0.4mmol of Na 2 CO 3 , 0.3 mmol of bis(4-chlorophenyl)phosphine oxide (2d), 24 mmol of dimethyl sulfoxide, 0.2 mmol of 1-isocyano-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1a), followed by stirring and reacting at 80°C for 12 hours, the reaction product was concentrated under reduced pressure to obtain a crude product, the crude product was separated and extracted by a silica gel (200-300 mesh) column, petroleum ether was used as an eluent, the eluent was collected and dried to obtain 73 mg of bis(4-chlorophenyl) (4-difluoromethylquinolin-2-yl)phosphine oxide (4c), with a yield of 82%. The reaction equation is as follows:

[0058]

[0059] The NMR and high-resolution mass spectrometry data of bis(4-chlorophenyl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4c) are as follows:

[0060] 1 H NMR(600MHz,Chloroform-d)δ8.52(d,J=4.2Hz,1H),8.23(d,J=8.5Hz,1H),8.18(d,J=8.5Hz,1H),7.91(dd,J=11 .5,8.3Hz,4H),7.84(t,J=7.7Hz,1H),7.74(t,J=7.7Hz,1H),7.44(dd,J=8.5,2.5Hz,4H),7.15(t,J=54.2Hz,1H). 13C NMR(151MHz,Chloroform-d)δ156.59(d,J=132.2Hz),148.63(d,J=21.1Hz),139.08(d,J=3.4Hz),138.45(td,J=22.3,8.9Hz),133.57(d,J=10.3Hz),13 1.14,130.84,130.09(d,J=106.1Hz),129.87,128.99(d,J=12.9Hz),124.2 4(d,J=2.3Hz),123.88,120.44(dt,J=22.5,7.7Hz),113.62(t,J=241.4Hz). 19 F NMR (565MHz, Chloroform-d) δ-113.70 (d, J = 54.2Hz, 2F). 31 P NMR(243MHz,Chloroform-d)δ18.59.HRMS:calculated[M+H] + forC 22 H 15 Cl 2 F 2 NOP:448.0231,found:448.0232.

[0061] Example 10: Synthesis of bis(4-bromophenyl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4d)

[0062] Under argon atmosphere, 0.04 mmol of AgOAc, 0.4 mmol of K 2 CO 3 , 0.3 mmol of bis(4-bromophenyl)phosphine oxide (2e), 12 mmol of 1,4-dioxane, 0.2 mmol of 1-isocyano-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1a), followed by stirring and reacting at 100°C for 12 hours, the reaction product was concentrated under reduced pressure to obtain a crude product, the crude product was separated and extracted by a silica gel (200-300 mesh) column, petroleum ether was used as an eluent, the eluent was collected and dried to obtain 64 mg of bis(4-bromophenyl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4d), with a yield of 60%, and the reaction equation is as follows:

[0063]

[0064] The NMR and high-resolution mass spectrometry data of bis(4-bromophenyl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4d) are as follows:

[0065] 1 H NMR(600MHz,Chloroform-d)δ8.51(d,J=4.2Hz,1H),8.23(d,J=8.5Hz,1H),8.18(d,J=8.5Hz,1H),7.8 4(dd,J=11.9,8.1Hz,5H),7.74(t,J=7.7Hz,1H),7.61(dd,J=8.5,2.6Hz,4H),7.15(t,J=54.2Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ156.32(d,J=132.3Hz),148.48(d,J=21.2Hz),138.31(td,J=22.4,9.0Hz),133.52(d,J=10.1Hz),131.78(d,J=12.7Hz),1 31.01,130.72,130.41(d,J=105.6Hz),129.74,127.62(d,J=3.4Hz),124.1 0(d,J=2.5Hz),123.75,120.31(dt,J=22.4,7.6Hz),113.48(t,J=241.4Hz). 19 F NMR (565MHz, Chloroform-d) δ-113.71 (d, J = 53.9Hz, 2F). 31 P NMR(243MHz,Chloroform-d)δ18.85.HRMS:calculated[M+H] + for C 22 H 15 Br 2 F 2 NOP:535.9221,found:535.9222.

[0066] Example 11: Synthesis of bis([1,1'-biphenyl]-4-yl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4e)

[0067] Under argon atmosphere, 0.02 mmol of AgF, 0.4 mmol of Cs 2 CO 3, 0.3 mmol of bis([1,1'-biphenyl]-4-yl)phosphine oxide (2f), 12 mmol of acetonitrile, 0.2 mmol of 1-isocyano-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1a), followed by stirring and reacting at 80°C for 12 hours, and then concentrating the reaction product under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200-300 mesh) column, using petroleum ether as an eluent, and the eluent was collected and dried to obtain 74 mg of bis([1,1'-biphenyl]-4-yl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4e), with a yield of 70%. The reaction equation is as follows:

[0068]

[0069] The NMR and high-resolution mass spectrometry data of bis([1,1'-biphenyl]-4-yl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4e) are as follows:

[0070] 1 H NMR(600MHz,Chloroform-d)δ8.63(d,J=4.1Hz,1H),8.31(d,J=8.5Hz,1H),8.20(d,J=8.6Hz,1H),8.14(dd,J=11.7,8.1Hz,4H),7.83 (t,J=7.7Hz,1H),7.73(dd,J=8.4,2.6Hz,5H),7.60(d,J=7.9Hz,4H),7.45(t,J=7.6Hz,4H),7.37(t,J=7.4Hz,2H),7.28–7.07(m,1H). 13 C NMR(151MHz,Chloroform-d)δ157.38(d,J=130.2Hz),148.56(d,J=20.9Hz),144.81 (d,J=2.7Hz),139.82,138.01(td,J=22.3,8.8Hz),132.62(d,J=9.7Hz),131.12,13 0.46,130.31(d,J=105.7Hz),129.45,128.86,128.08,127.20,127.10(d,J=12.5Hz ), 123.99 (d, J = 2.5Hz), 123.73, 120.52 (dt, J = 21.9, 7.6Hz), 113.73 (t, J = 241.4Hz). 19 F NMR (565MHz, Chloroform-d) δ-113.35 (d, J = 54.3Hz, 2F). 31P NMR(243MHz,Chloroform-d)δ20.17.HRMS:calculated[M+H] + for C 34 H 25 F 2 NOP:532.1636,found:532.1638.

[0071] Example 12: Synthesis of bis(2-naphthyl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4f)

[0072] Under argon atmosphere, 0.02 mmol of Ag 2 CO 3 , 0.4mmol of CsOH, 0.3mmol of di(2-naphthyl)phosphine oxide (2g), 12mmol of toluene, 0.2mmol of 1-isocyano-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1a), then stirred and reacted at 90°C for 12 hours, the reaction product was concentrated under reduced pressure to obtain a crude product, the crude product was separated and extracted by a silica gel (200-300 mesh) column, petroleum ether was used as an eluent, the eluent was collected and dried to obtain 77mg of di(2-naphthyl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4f), the yield was 80%, and the reaction equation was as follows:

[0073]

[0074] The NMR and high-resolution mass spectrometry data of bis(2-naphthyl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4f) are as follows:

[0075] 1 H NMR(600MHz,Chloroform-d)δ8.70–8.56(m,3H),8.26(d,J=8.5Hz,1H),8.17(d,J=8.5Hz,1H),8.05(t,J=9.2Hz,2H),7.96–7.88(m,4H) ,7.85(d,J=8.2Hz,2H),7.83–7.78(m,1H),7.70(t,J=7.7Hz,1H),7.57(t,J=7.5Hz,2H),7.52(t,J=7.5Hz,2H),7.16(t,J=54.3Hz,1H). 13C NMR(151MHz,Chloroform-d)δ157.57(d,J=130.2Hz),148.75(d,J=20.9Hz),138.21(td,J=22 .3,8.8Hz),134.90(d,J=2.2Hz),134.32(d,J=9.0Hz),132.49(d,J=13.5Hz),131.32,130.62, 129.63,129.15,129.02(d,J=104.8Hz),128.44,128.36(d,J=12.0Hz),127.91,127.18(d,J= 10.3Hz), 126.98, 124.19 (d, J = 2.3Hz), 123.90, 120.84 (d, J = 22.3Hz), 113.91 (t, J = 241.5Hz). 19 F NMR (565MHz, Chloroform-d) δ-113.41 (d, J = 54.3Hz, 2F). 31 P NMR(243MHz,Chloroform-d)δ21.07.HRMS:calculated[M+H] + for C 30 H 21 F 2 NOP:480.1323,found:480.1320.

[0076] Example 13: Synthesis of bis(thiophene-2-yl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4 g)

[0077] Under argon atmosphere, 0.02 mmol of Ag 3 PO 4 , 0.4mmol Cs 2 CO 3 , 0.3 mmol of di(thiophen-2-yl)phosphine (2h), 12 mmol of N,N-dimethylformamide, 0.2 mmol of 1-isocyano-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1a), then stirred and reacted at 70°C for 12 hours, the reaction product was concentrated under reduced pressure to obtain a crude product, the crude product was separated and extracted by a silica gel (200-300 mesh) column, petroleum ether was used as an eluent, the eluent was collected and dried to obtain 39 mg of bis(thiophen-2-yl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4g), with a yield of 50%, and the reaction equation is as follows:

[0078]

[0079] The NMR and high-resolution mass spectrometry data of bis(thiophene-2-yl)(4-difluoromethylquinolin-2-yl)phosphine oxide (4g) are as follows:

[0080] 1 H NMR(600MHz,Chloroform-d)δ8.49(d,J=4.2Hz,1H),8.31(d,J=8.5Hz,1H),8.16(d ,J=8.5Hz,1H),7.84(dt,J=7.6,4.7Hz,3H),7.78–7.68(m,3H),7.25–7.03(m,3H). 13 C NMR(151MHz,Chloroform-d)δ156.96(d,J=145.9Hz),148.53(d,J=22.8Hz),138.32(td,J=22.2,9.4Hz),137.14(d,J=10.1Hz),134.85(d,J=4.8Hz),1 32.96,132.15,130.86(d,J=31.4Hz),129.75,128.17(d,J=14.9Hz),124.3 5(d,J=2.3Hz),123.78,119.47(dt,J=24.9,7.6Hz),113.55(t,J=241.1Hz). 19 F NMR (565MHz, Chloroform-d) δ-113.77 (d, J = 54.2Hz, 2F). 31 P NMR(243MHz,Chloroform-d)δ10.22.HRMS:calculated[M+H] + for C 18 H 13 F 2 NOPS 2 :392.0139,found:392.0135.

[0081] Example 14: Synthesis of (4-(difluoromethyl)quinolin-2-yl)(phenyl)(p-tolyl)phosphine oxide (4h)

[0082] Under argon atmosphere, 0.02 mmol of AgNO 3 , 0.4mmol K 2 CO 3, 0.3 mmol of phenyl (p-tolyl) phosphine oxide (2i), 48 mmol of 1,4-dioxane, 0.2 mmol of 1-isocyano-2-(3,3,3-trifluoropropyl-1-en-2-yl) benzene (1a), followed by stirring and reacting at 60°C for 12 hours, and then concentrating the reaction product under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200-300 mesh) column, using petroleum ether as an eluent, and the eluent was collected and dried to obtain 57 mg of (4-(difluoromethyl)quinolin-2-yl)(phenyl)(p-tolyl) phosphine oxide (4h), with a yield of 73%. The reaction equation is as follows:

[0083]

[0084] The NMR and high-resolution mass spectrometry data of 4-(difluoromethyl)quinolin-2-yl)(phenyl)(p-tolyl)phosphine oxide (4h) are as follows:

[0085] 1 H NMR(600MHz,Chloroform-d)δ8.52(d,J=4.1Hz,1H),8.23(d,J=8.3Hz,1H),8.16(d,J=8.6Hz,1H),7.97(dd,J=11.9,7.7Hz,2H),7.89– 7.77(m,3H),7.70(t,J=7.6Hz,1H),7.51(t,J=7.3Hz,1H),7.49–7.42(m,2H),7.37–7.24(m,2H),7.12(t,J=54.3Hz,1H),2.37(s,3H). 13 C NMR(151MHz,Chloroform-d)δ157.79(d,J=129.6Hz),148.69(d,J=20.8Hz),142.78(d,J=2.9Hz) ,138.02(td,J=22.3,8.7Hz),132.29(d,J=17.8Hz),132.29,132.18(d,J=104.5Hz),132.10(d,J =2.8Hz),131.31,130.51,129.51,129.31(d,J=12.7Hz),128.50(d,J=106.9Hz),128.48(d,J=12 .3Hz), 124.09 (d, J = 2.7Hz), 123.87, 120.69 (dt, J = 22.1, 7.7Hz), 113.96 (t, J = 241.3Hz), 21.76. 19 F NMR(471MHz,Chloroform-d)δ-113.32(s,2F). 31P NMR(203MHz,Chloroform-d)δ20.55.HRMS:calculated[M+H] + for C 23 H 19 F 2 NOP:394.1167,found:394.1170.

[0086] Example 15: Synthesis of (4-chlorophenyl)(4-(difluoromethyl)quinolin-2-yl)(phenyl)phosphine oxide (4i)

[0087] Under argon atmosphere, 0.02 mmol of Ag 2 O, 0.4 mmol Cs 2 CO 3 , 0.3 mmol of (4-chlorophenyl)(phenyl)phosphine oxide (2j), 12 mmol of toluene, 0.2 mmol of 1-isocyano-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1a), followed by stirring and reacting at 70°C for 12 hours, the reaction product was concentrated under reduced pressure to obtain a crude product, the crude product was separated and extracted by a silica gel (200-300 mesh) column, petroleum ether was used as an eluent, the eluent was collected and dried to obtain 62 mg of (4-chlorophenyl)(4-(difluoromethyl)quinolin-2-yl)(phenyl)phosphine oxide (4i), with a yield of 75%, and the reaction equation is as follows:

[0088]

[0089] The NMR data of (4-chlorophenyl)(4-(difluoromethyl)quinolin-2-yl)(phenyl)phosphine oxide (4i) are as follows:

[0090] 1 H NMR(600MHz,Chloroform-d)δ8.53(d,J=4.2Hz,1H),8.23(d,J=8.5Hz,1H),8.17(d,J=8.5Hz,1H),7.95(dd,J=11.2,8.5 Hz,4H),7.82(t,J=7.7Hz,1H),7.72(t,J=7.7Hz,1H),7.53(t,J=7.4Hz,1H),7.50–7.39(m,4H),7.14(t,J=54.2Hz,1H). 13C NMR(151MHz,Chloroform-d)δ157.04(d,J=130.9Hz),148.65(d,J=21.0Hz),138.85(d,J=3.4H z),138.27(td,J=22.3,8.8Hz),133.73(d,J=10.2Hz),132.39(d,J=2.7Hz),132.11(d,J=9.5H z),131.94,131.22,130.71,130.40(d,J=105.4Hz),129.73,128.86(d,J=12.8Hz),128.65(d, J=12.3Hz), 124.17 (d, J=2.3Hz), 123.87, 120.56 (dt, J=22.3, 7.7Hz), 113.76 (t, J=241.2Hz). 19 F NMR (565MHz, Chloroform-d) δ-113.60 (dd, J=54.3, 5.3Hz, 2F). 31 PNMR(243MHz,Chloroform-d)δ19.45.HRMS:calculated[M+H] + forC 22 H 16 CIF 2 NOP:414.0621,found:414.0622.

[0091] Example 16: Synthesis of [1,1'-biphenyl]-4-yl(4-(difluoromethyl)quinolin-2-yl)(phenyl)phosphine oxide (4j)

[0092] Under argon atmosphere, 0.02 mmol of AgF, 0.4 mmol of Cs 2 CO 3 , 0.3 mmol of [1,1'-biphenyl]-4-yl (phenyl) phosphine oxide (2k), 12 mmol of 1,4-dioxane, 0.2 mmol of 1-isocyano-2-(3,3,3-trifluoropropyl-1-en-2-yl) benzene (1a), then stirred and reacted at 90°C for 12 hours, the reaction product was concentrated under reduced pressure to obtain a crude product, the crude product was separated and extracted by a silica gel (200-300 mesh) column, petroleum ether was used as an eluent, the eluent was collected and dried to obtain 67 mg of [1,1'-biphenyl]-4-yl (4-(difluoromethyl) quinolin-2-yl) (phenyl) phosphine oxide (4j), the yield was 74%, and the reaction equation was as follows:

[0093]

[0094] The NMR data of [1,1'-biphenyl]-4-yl(4-(difluoromethyl)quinolin-2-yl)(phenyl)phosphine oxide (4j) are as follows:

[0095] 1 H NMR(600MHz,Chloroform-d)δ8.57(d,J=4.1Hz,1H),8.27(d,J=8.5Hz,1H),8.19(d,J=8.5Hz,1H),8.10–8.01(m,4H),7.83(t,J=7.7H z,1H),7.76–7.66(m,3H),7.63–7.52(m,3H),7.52–7.47(m,2H),7.44(t,J=7.6Hz,2H),7.37(t,J=7.4Hz,1H),7.15(t,J=54.3Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ157.52(d,J=129.9Hz),148.69(d,J=20.8Hz),144.92(d,J=2.8H z),139.98,138.12(td,J=22.3,8.8Hz),132.78(d,J=9.8Hz),132.25(d,J=9.4Hz),131.61,131 .28,130.75,130.59,130.05,129.58,129.01,128.56(d,J=12.2Hz),128.23,127.35,127.21(d , J=12.6Hz), 124.12 (d, J=2.8Hz), 123.86, 120.66 (dt, J=21.9, 7.7Hz), 113.88 (t, J=241.4Hz). 19 F NMR (565MHz, Chloroform-d) δ-113.43 (dd, J=53.4, 7.1Hz, 2F). 31 PNMR(243MHz,Chloroform-d)δ20.23.HRMS:calculated[M+H] + for C 28 H 21 F 2 NOP:456.1323,found:456.1320.

[0096] Example 17: Synthesis of 2-methylallyl (4-(difluoromethyl)quinolin-2-yl)(phenyl)phosphite (4k)

[0097] Under argon atmosphere, 0.02 mmol of AgOAc, 0.4 mmol of Na 2 CO 3 , 0.3 mmol of 2-methylallylphenyl phosphite (2l), 12 mmol of 1,4-dioxane, 0.2 mmol of 1-isocyano-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1a), followed by stirring and reacting at 80°C for 12 hours, the reaction product was concentrated under reduced pressure to obtain a crude product, the crude product was separated and extracted by a silica gel (200-300 mesh) column, petroleum ether was used as an eluent, the eluent was collected and dried to obtain 43 mg of 2-methylallyl (4-(difluoromethyl)quinolin-2-yl)(phenyl) phosphite (4k), with a yield of 57%, and the reaction equation is as follows:

[0098]

[0099] The NMR and high-resolution mass spectrometry data of 2-methylallyl (4-(difluoromethyl)quinolin-2-yl)(phenyl) hypophosphite (4k) are as follows:

[0100] 1 H NMR (600MHz, Chloroform-d) δ8.31(d,J=4.1Hz,1H),8.27(d,J=8.5Hz,1H),8.13(d,J=8.5Hz,1H),8.07(dd,J=12.1,7.4Hz,2H),7.81(t,J=7.7Hz,1H),7. 71(t,J=7.7Hz,1H),7.58–7.53(m,1H),7.48(td,J=7.6,3.6Hz,2H),7.14(t, J=54.3Hz,1H),5.07(s,1H),4.92(s,1H),4.54(d,J=7.1Hz,2H),1.80(s,3H). 13C NMR(151MHz,Chloroform-d)δ155.41(d,J=166.4Hz),148.69(d,J=22.4Hz),140.11(d,J=6 .9Hz), 137.84 (td, J=22.0, 9.7Hz), 132.71 (d, J=2.7Hz), 132.42 (d, J=9.9Hz), 131.31, 130. 42,129.56,129.32(d,J=139.8Hz),128.43(d,J=13.3Hz),124.16(d,J=2.5Hz),123.43,12 0.31(dt,J=25.3,7.7Hz),113.54,113.43(td,J=241.2,1.8Hz),68.78(d,J=6.1Hz),19.15. 19 F NMR (565MHz, Chloroform-d) δ-113.75 (dd, J=307.0, 54.3Hz, 1F), -114.39 (dd, J=307.2, 54.4Hz, 1F). 31 P NMR(243MHz,Chloroform-d)δ25.11.HRMS:calculated[M+H] + forC 20 H 19 F 2 NO 2 P:374.1116,found:374.1118.

[0101] Example 18: Synthesis of pent-4-yn-1-yl (4-(difluoromethyl)quinolin-2-yl)(phenyl)phosphinate (41)

[0102] Under argon atmosphere, 0.02 mmol of AgOTf, 0.4 mmol of NaOH, 0.3 mmol of pent-4-yn-1-phenyl phosphite (2m), 12 mmol of 1,4-dioxane, and 0.2 mmol of 1-isocyano-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene (1a) were added to a 10 mL thick-walled test tube in sequence. The mixture was stirred and reacted at 100° C. for 12 hours. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200-300 mesh) column, using petroleum ether as an eluent. The eluent was collected and dried to obtain 49 mg of pent-4-yn-1-yl (4-(difluoromethyl)quinolin-2-yl) (phenyl) phosphite (4l) with a yield of 64%. The reaction equation is as follows:

[0103]

[0104] The NMR and high resolution mass spectrometry data of pent-4-yn-1-yl (4-(difluoromethyl)quinolin-2-yl) (phenyl) hypophosphite (4l) are as follows:

[0105] 1 H NMR(600MHz,Chloroform-d)δ8.30(d,J=4.2Hz,1H),8.27(d,J=8.6Hz,1H),8.11(d, J=8.5Hz,1H),8.05(dd,J=12.3,7.5Hz,2H),7.81(t,J=7.7Hz,1H),7.70(t,J=7.7Hz, 1H),7.54(t,J=7.4Hz,1H),7.47(td,J=7.6,3.7Hz,2H),7.13(t,J=54.3Hz,1H),4.31 –4.15(m,2H),2.39(td,J=7.0,2.7Hz,2H),2.00–1.93(m,2H),1.86(t,J=2.7Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ155.45(d,J=165.7Hz),148.85(d,J=22.3Hz),138.01(td,J= 22.1,9.8Hz),132.86(d,J=2.7Hz),132.52(d,J=9.9Hz),131.45,130.57,129.71,129.50( d,J=140.3Hz),128.58(d,J=13.3Hz),124.30(d,J=2.5Hz),123.57,120.55(dt,J=25.2,7. 7Hz), 113.59 (t, J = 241.2Hz), 83.03, 69.16, 64.38 (d, J = 6.3Hz), 29.49 (d, J = 6.7Hz), 14.99. 19 F NMR(471MHz,Chloroform-d)δ-113.27–-114.81(m,2F). 31 PNMR(203MHz,Chloroform-d)δ24.99.HRMS:calculated[M+H] + for C 21 H 19 F 2 NO 2 P:386.1116,found:386.1116.

[0106] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection 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 a difluoromethyl-containing compound, comprising the following steps: reacting a catalyst, a base, a phosphorus oxide, a solvent and an o-isocyano-α-trifluoromethylstyrene compound at 60°C to 100°C for 6 to 18 hours, removing the solvent by reduced pressure distillation, and performing column chromatography to obtain a difluoromethyl-containing compound; The structural formula of the difluoromethyl-containing compound is: R 1 is one of hydrogen, methyl, fluorine, chlorine, bromine and trifluoromethyl; R 2 =R 3 When R 2 =R 3 is one of phenyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, biphenyl, naphthyl and thienyl; R 1 ≠R 2 When R 2 is phenyl, R 3 It is one of p-methylphenyl, p-chlorophenyl, biphenyl, 2-methylallyloxy, and pent-4-yn-1-oxy.

2. The method for preparing the difluoromethyl compound according to claim 1, characterized in that: The molar ratio of the catalyst, the base, the phosphorus oxide compound, the solvent and the o-isocyano-α-trifluoromethylstyrene compound is (0.05-0.2):(2-3):(1-3):(60-250):

1.

3. The method for preparing a difluoromethyl compound according to claim 1, characterized in that: The structural formula of the o-isocyano-α-trifluoromethylstyrene compound is:

4. The method for preparing a difluoromethyl compound according to claim 1, wherein: The structural formula of the phosphorus oxide compound is:

5. The method for preparing a difluoromethyl compound according to claim 1, wherein: The catalyst is one of Cu(acac)2, CuSO4·5H2O, CuCl, CuBr2, Ag2O, AgF, AgOAc, AgOTf, AgBF4, AgNO3, Ag2CO3, and Ag3PO4.

6. The method for preparing a difluoromethyl compound according to claim 1, characterized in that: The base is one of Cs2CO3, CsOH, K2CO3, Na2CO3, NaOH, and K3PO4.

7. The method for preparing a difluoromethyl-containing compound according to claim 1, characterized in that: The solvent is one of tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

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