Phenyl difluoroamidated aromatic compounds, their preparation methods and their applications

Abstract

The present invention discloses a phenyl difluoroamidated aromatic compound, a preparation method thereof and an application thereof. The structural formula of the phenyl difluoroamidated aromatic compound is: is any one of naphthyl, oxazole, benzodioxazole, indole or a derivative group thereof; Ar is any one of phenyl, fluorophenyl, morpholine, pyrrole and pyridine or a derivative group thereof; wherein, -R at different positions are respectively -H, -CH 3 , -CH 2 CH 3 , -OMe, -EtO and any one of. The present invention uses 2-bromo-2,2-difluoro-N-phenylacetamide as a difluoroamidation reagent source, 1,2-dimethoxybenzene as an aromatic substrate, triethylamine as a halogen atom transfer reagent, a mixed system of 1,4-epoxyhexane and water as a solvent, and ammonium persulfate as an oxidant to realize the difluoroamidation reaction of aromatic hydrocarbons initiated by α-amino carbon radicals. This method uses cheap and easily available raw materials, is simple to operate, has mild conditions, conforms to green chemistry and atom economy, and provides a new synthetic strategy for the direct difluoroamidation of aromatic hydrocarbons.

Description

Technical Field

[0001] The present invention relates to a fluoroamidated aromatic compound, a preparation method thereof and an application thereof, which are applied to the technical fields of pharmaceutical intermediate materials and bulk drugs. Background Art

[0002] On the basis of high efficiency and convenience, how to introduce fluorine-containing groups into compounds more environmentally friendly in green chemistry has attracted wide attention. In recent years, the reports on environmentally friendly fluoroalkylation methods have been increasing continuously. As a modification means, fluorine-containing groups have been applied in a large number of drugs, agrochemicals and functional materials. In particular, aryl difluoromethylidene (ArCF 2 ) has unique properties as an ether oxygen atom or a carbonyl group and a lipophilic hydrogen bond donor, and has become an ideal fluorine-containing building unit in the field of medicinal chemistry.

[0003] Under the background of the increasing environmental awareness today, green chemistry has become increasingly important in the field of organic synthesis. Seeking to introduce fluorine-containing groups into compounds in a more environmentally friendly way has become the common pursuit of scientific researchers. By improving the fluoroalkylation method, not only can the efficiency and selectivity of the fluorination reaction be improved, but also the impact on the environment can be reduced, contributing to sustainable development. In addition, it has been found that aryl difluoromethylidene (ArCF 2 ) as a fluorine-containing building unit with unique properties in medicinal chemistry provides an important cornerstone for the design and synthesis of new drugs. Amides play an important role in compounds in the medical field because they have stability and polarity and can interact with biological receptors and enzymes. However, in the complex human environment, drugs also need to resist rapid metabolic degradation. The carbon-fluorine (C-F) bond also has polarity and non-reactivity, but different from amides, they are almost irrelevant to biology and are difficult to be rapidly degraded by metabolic enzymes. Therefore, combining an amide group with a fluorine atom may be an effective drug research and development strategy. Therefore, constructing an effective aryl difluoroamide fragment plays an important role in the field of drug synthesis. Now many bioactive compounds contain aryl difluoroamide fragments, and introducing aryl difluoroamide fragments helps to improve the metabolic stability and other required properties of drug compounds. Therefore, exploring a convenient, inexpensive, environmentally friendly and easy-to-operate difluoroamidation method provides an effective way for the synthesis of fluorine-containing amide drugs. Summary of the Invention

[0004] In order to solve the problems of the existing technology, the purpose of the present invention is to overcome the deficiencies of the existing technology and provide a phenyl difluoroamidated aromatic compound, a preparation method thereof and an application thereof. Under the action of triethylamine and ammonium persulfate, the generation of phenyl difluoroamide radicals is promoted, which is beneficial to their participation in the reaction with aromatics. The present invention conducts the ethoxycarbonyl difluoromethylation reaction of the Csp 2 -H of aromatics and successfully constructs Csp2 -CF 2 Using 2-bromo-2,2-difluoro-N-phenylacetamide as the source of difluoroamidation reagent, 1,2-dimethoxybenzene as the aromatic hydrocarbon substrate, triethylamine as the halogen atom transfer reagent, a mixed system of 1,4-epoxyhexane and water as the solvent, and ammonium persulfate as the oxidant, the difluoroamidation reaction of aromatic hydrocarbons initiated by α-amino carbon radicals was successfully achieved by reacting at no less than 50 °C for at least 18 hours. This synthetic method uses inexpensive and readily available raw materials, is simple to operate, has mild conditions, conforms to green chemistry and atom economy, and provides a new synthetic strategy for the direct difluoroamidation of aromatic hydrocarbons.

[0005] A preferred synthetic route for phenyl difluoroamidated aromatic hydrocarbon compounds of the present invention is as follows:

[0006]

[0007] R = electron-donating group

[0008] To achieve the above object, the present invention adopts the following technical solutions:

[0009] A phenyl difluoroamidated aromatic hydrocarbon compound, the structural formula of the compound is: is any one of naphthyl, oxazole, benzodioxazole, indole or its derivative group; Ar is any one of phenyl, fluorophenyl, morpholine, pyrrole and pyridine or its derivative group; wherein, -R at different positions are respectively -H, -CH 3 , -CH 2 CH 3 , -OMe, -EtO and any one of.

[0010] Preferably, the present invention uses 2-bromo-2,2-difluoro-N-phenylacetamide as the difluoroamidation reagent source, 1,2-dimethoxybenzene as the aromatic hydrocarbon substrate, triethylamine as the halogen atom transfer reagent, a mixed system of 1,4-epoxyhexane and water as the solvent, and ammonium persulfate as the oxidant, and conducts the difluoroamidation reaction of aromatic hydrocarbons initiated by α-amino carbon radicals at no less than 50 °C for at least 18 hours to obtain phenyl difluoroamidated aromatic hydrocarbon compounds.

[0011] Preferably, the present invention prepares a mixed system of 1,4-epoxyhexane and water with a volume ratio of 1:3.

[0012] A method for preparing the phenyl difluoroamidated aromatic hydrocarbon compound of the present invention comprises the following steps. A mixed solution system is prepared according to the following ratio. Ammonium persulfate (3.00 mmol, 3.0 equivalents), aromatic hydrocarbon (4.00 mmol, 4.0 equivalents), 2-bromo-2,2-difluoro-N-phenylacetamide (1.00 mmol, 1.0 equivalent), and triethylamine (6.00 mmol, 6.0 equivalents) are added into a Schlenk tube equipped with a magnetic stir bar. Then, a mixed solution of 1,4-epoxyhexane and water with a volume of at least 10 mL is added under stirring to obtain a mixed solution system.

[0013] Then, nitrogen is added to the mixed solution system using a balloon. Then, the mixture is stirred at a temperature not lower than 50 °C for at least 18 hours. After the reaction is completed, the product mixture is cooled to a temperature, and then extracted with ethyl acetate and the extraction mixture. The organic phase of the extract is washed with saturated brine, and then the combined organic phases are dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure using a rotary evaporator to evaporate the solvent completely. Then, the crude product is separated and purified by column chromatography to obtain the phenyl difluoroamidated aromatic hydrocarbon compound.

[0014] Preferably, a mixed solution of 1,4-epoxyhexane and water is prepared according to a volume ratio of 1:3.

[0015] Preferably, during extraction, at least 5 mL of ethyl acetate is used to extract the mixture each time, and extraction is repeated at least 3 times.

[0016] Preferably, during washing, at least 5 mL of saturated brine is used to wash the organic phase each time, and washing is repeated at least 3 times.

[0017] Preferably, a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5-25:1 is used as the eluent for purification.

[0018] An application of the phenyl difluoroamidated aromatic hydrocarbon compound of the present invention uses the phenyl difluoroamidated aromatic hydrocarbon compound as a raw material for preparing a fluorine-containing amide drug or medicament.

[0019] Compared with the prior art, the present invention has the following obvious outstanding substantive features and remarkable advantages:

[0020] 1. Under the action of triethylamine and ammonium persulfate, the present invention promotes the generation of phenyl difluoroamide radicals, which is beneficial for their participation in the reaction with aromatic hydrocarbons.

[0021] 2. The raw materials used in the method of the present invention are cheap and easily available, the operation is simple, the conditions are mild, meeting the requirements of green chemistry and atom economy, and providing a new synthetic strategy for the direct difluoroamidation of aromatic hydrocarbons.

[0022] 3. The phenyl difluoroamidated aromatic compounds prepared by the present invention have excellent or outstanding yields, providing a variety of optional raw materials for the preparation of fluorinated amide drugs, effectively reducing the preparation cost of fluorinated amide drugs, and facilitating the improvement of production scale. Detailed Embodiments

[0023] The following are descriptions of the preferred cases of the present invention. It should be understood that the preferred cases described herein are only for illustrating and explaining the present invention and are not used to limit the present invention. For the public to have a full understanding of the present invention, specific details are described in detail in the preferred embodiments of the present invention.

[0024] The above scheme is further described below in conjunction with specific implementation examples. The preferred embodiments of the present invention are described in detail as follows:

[0025] Example 1:

[0026] Preparation process of 2-(3,4-dimethoxyphenyl)-2,2-difluoro-N-phenylacetamide.

[0027]

[0028] A 50-milliliter Schlenk tube containing ammonium persulfate (684 mg, 3.00 mmol, 3.0 equivalents), 2-bromo-2,2-difluoro-N-phenylacetamide (250 mg, 1.00 mmol, 1.0 equivalent) was evacuated and refilled with N 2 three times. After waiting for the nitrogen filling to be completed, then 1,2-dimethoxybenzene (554 mg, 4.00 mmol, 4.0 equivalents) was added. Finally, triethylamine (607 mg, 6.00 mmol, 6.0 equivalents) was added, and then 10 ml of a mixed solution of 1,4-dioxane and water (volume ratio 1:3) was added. The mixture was immediately transferred to a preheated aluminum block at 50 °C and stirred at this temperature for 18 hours. Subsequently, the mixture was extracted with ethyl acetate, and the organic phase of the extract was washed with saturated brine; when extracting, 5 ml of ethyl acetate was used to extract the mixture each time, and the extraction was repeated 3 times; when washing, 5 ml of saturated brine was used to wash the organic phase each time, and the washing was repeated 3 times. Then the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated using a vacuum distillation device to obtain a crude product. The crude product was purified by silica gel column chromatography (calculated by volume ratio, petroleum ether / ethyl acetate = 10:1) to obtain the compound 2-(3,4-dimethoxyphenyl)-2,2-difluoro-N-phenylacetamide with a yield of 78%. 1 HNMR(500MHz,CDCl 3)δ8.41(brs,1H),7.70 - 7.46(m,2H),7.34 - 7.28(m,2H),7.19(dd,J=8.3,2.1Hz,1H),7.19 - 7.11(m,2H),6.85(d,J=8.3Hz,1H),3.85(s,3H),3.84(s,3H).

[0029] 19 FNMR(471MHz,CDCl 3 )δ - 100.90(s,2F).

[0030] 13 CNMR(126MHz,CDCl 3 )δ162.3(t,J=31.7Hz),151.2,149.1,136.3,129.1,125.5,125.0(t,J=26.1Hz),120.4,118.5(t,J=6.6Hz),114.75(t,J=253.7Hz),110.76,108.6(t,J=5.5Hz),55.94,55.93.HRMS(ESI)calcdforC 16 H 15 F 2 NO 3 Na + [M + Na] + 330.09122,found330.09172.m.p.:80 - 84℃.

[0031] Example 2:

[0032] Preparation process of 2,2 - difluoro - 2 - (2 - methoxy - 5 - methylphenyl) - N - phenylacetamide.

[0033]

[0034] A 50 - mL Schlenk tube containing ammonium persulfate (684 mg, 3.00 mmol, 3.0 equiv), 2 - bromo - 2,2 - difluoro - N - phenylacetamide (250 mg, 1.00 mmol, 1.0 equiv) was evacuated and refilled with N 2Three times. After waiting for the nitrogen filling to be completed, then add 1-methoxy-4-methylbenzene (488 mg, 4.00 mmol, 4.0 eq), and finally add triethylamine (607 mg, 6.00 mmol, 6.0 eq). Then add 10 mL of a mixed solution of 1,4-epoxyhexane and water (volume ratio 1:3). Immediately transfer the mixture to a preheated aluminum block at 50 °C and stir at this temperature for 18 hours. Subsequently, use ethyl acetate to extract the mixture, and wash the organic phase of the extract with saturated brine; when performing extraction, use 5 mL of ethyl acetate to extract the mixture each time, and extract 3 times repeatedly; when performing washing, use 5 mL of saturated brine to wash the organic phase each time, and wash 3 times repeatedly. Combine the organic phases and dry them with anhydrous sodium sulfate. After filtration, use a reduced-pressure distillation device to concentrate the organic phase to obtain a crude product. The crude product is purified by silica gel column chromatography (calculated by volume ratio, petroleum ether / ethyl acetate = 5:1) to obtain the compound 2,2-difluoro-2-(2-methoxy-5-methylphenyl)-N-phenylacetamide, with a yield of 35%.

[0035] 1 HNMR(500MHz,CDCl 3 )δ8.02(brs,1H),7.62-7.56(m,2H),7.42-7.35(m,2H),7.23-7.18(m,2H),7.16(d,J=8.2Hz,1H),6.92(dd,J=8.2,2.8Hz,1H),3.82(s,3H),2.38(t,J=1.9Hz,3H). 19 FNMR(471MHz,CDCl 3 )δ-100.23(s,2F).

[0036] 13 CNMR(126MHz,CDCl 3 )δ161.6(t,J=30.6Hz),157.7,136.1,133.1,131.6(t,J=23.1Hz),129.3,128.2(t,J=3.1Hz),125.6,120.1,116.3,115.6(t,J=254.1Hz),112.4(t,J=9.4Hz),55.5,19.0.HRMS(ESI)calcdforC 16 H 15 F 2 NO 2 Na + [M+Na] + 314.09883,found330.09895.m.p.:73-78℃.

[0037] Example 3:

[0038] Preparation process of 2-(2-ethoxynaphthalen-1-yl)-2,2-difluoro-N-phenylacetamide.

[0039]

[0040] A 50 mL Schlenk tube containing ammonium persulfate (684 mg, 3.00 mmol, 3.0 equiv), 2-bromo-2,2-difluoro-N-phenylacetamide (250 mg, 1.00 mmol, 1.0 equiv) was evacuated and refilled with N 2 three times. After waiting for the nitrogen filling to be completed, then 2-ethoxynaphthalene (688.88 mg, 4.00 mmol, 4.0 equiv) was added. Finally, triethylamine (607 mg, 6.00 mmol, 6.0 equiv) was added. Then, 10 mL of a mixed solution of 1,4-epoxyhexane and water (volume ratio 1:3) was added. The mixture was immediately transferred to a preheated aluminum block at 50 °C and stirred at this temperature for 18 hours. Subsequently, the mixture was extracted with ethyl acetate, and the organic phase of the extract was washed with saturated brine; when extracting, 5 mL of ethyl acetate was used to extract the mixture each time, and the extraction was repeated 3 times; when washing, 5 mL of saturated brine was used to wash the organic phase each time, and the washing was repeated 3 times. After combining the organic phases, they were dried over anhydrous sodium sulfate, filtered, and then concentrated using a rotary evaporator under reduced pressure to obtain a crude product. The crude product was further purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1 by volume ratio) to obtain the compound 2-(2-ethoxynaphthalen-1-yl)-2,2-difluoro-N-phenylacetamide with a yield of 44%.

[0041] 1 HNMR (500 MHz, CDCl 3 ) δ 8.53 (d, J = 8.9 Hz, 1H), 8.27 (brs, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.4 Hz, 2H), 7.56 (ddd, J = 8.5, 6.9, 1.3 Hz, 1H), 7.44 - 7.35 (m, 3H), 7.24 (d, J = 9.1 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 4.15 (d, J = 7.0 Hz, 2H), 1.23 (t, J = 7.0 Hz, 3H).

[0042] 19 FNMR (471 MHz, CDCl 3 ) δ -93.26 (s, 2F).

[0043] 13CNMR(126MHz,CDCl 3 )δppm162.8(t,J=29.1Hz),155.7(t,J=6.4Hz),137.1,134.0,132.1,129.6,129.2,128.7,127.9(t,J=1.6Hz),124.8,124.5(t,J=9.5Hz),124.2,116.9(t,J=253.1Hz),115.0,114.1,113.6(t,J=23.9Hz),65.8,14.6.HRMS(ESI)calcdforC 20 H 17 F 2 NO 2 Na + [M+Na] + 364.10927,found364.10941.m.p.:154 - 159℃.

[0044] Example 4:

[0045] Preparation process of 2,2 - difluoro - 2-(4 - methoxynaphthalen - 1 - yl)-N - phenylacetamide.

[0046]

[0047] A 50 - mL Schlenk tube containing ammonium persulfate (684 mg, 3.00 mmol, 3.0 equiv), 2 - bromo - 2,2 - difluoro - N - phenylacetamide (250 mg, 1.00 mmol, 1.0 equiv) was evacuated and refilled with N 2 three times. After waiting for the nitrogen filling to be completed, then 1 - methoxynaphthalene (632.82 mg, 4.00 mmol, 4.0 equiv) was added. Finally, triethylamine (607 mg, 6.00 mmol, 6.0 equiv) was added. Then, 10 mL of a mixed solution of 1,4 - epoxyhexane and water (volume ratio 1:3) was added. The mixture was immediately transferred to a pre - heated aluminum block at 50 °C and stirred at this temperature for 18 hours. Subsequently, the mixture was extracted with ethyl acetate, and the organic phase of the extract was washed with saturated brine; when extracting, 5 mL of ethyl acetate was used to extract the mixture each time, and the extraction was repeated 3 times; when washing, 5 mL of saturated brine was used to wash the organic phase each time, and the washing was repeated 3 times. After combining the organic phases, they were dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated using a rotary evaporator to obtain a crude product. The crude product was further purified by silica gel column chromatography (calculated by volume ratio, petroleum ether / ethyl acetate = 20:1) to obtain the compound 2,2 - difluoro - 2-(4 - methoxynaphthalen - 1 - yl)-N - phenylacetamide with a yield of 66%.

[0048] 1 HNMR(500MHz,CDCl 3 )δ8.36(ddd,J=8.3,1.6,0.7Hz,1H),8.22 - 8.18(m,1H),8.09(brs,1H),7.80(d,J=8.2Hz,1H),7.66 - 7.48(m,4H),7.43 - 7.31(m,2H),7.22 - 7.14(m,1H),6.80(d,J=8.2Hz,1H),4.03(s,3H).

[0049] 19 FNMR(471MHz,CDCl 3 )δ - 96.85(s,2F).

[0050] 13 CNMR(125MHz,CDCl 3 )δ162.1(t,J=31.1Hz),158.1,136.2,130.7,129.2,127.9,126.4(t,J=9.2Hz),126.1,125.8,125.5,124.2(t,J=3.1Hz),122.8,120.2,120.1(t,J=23.8Hz),116.6(t,J=252.5Hz),102.1,55.7.HRMS(ESI)calcdforC 19 H 15 F 2 NO 2 Na + [M + Na] + 350.09912,found350.09953.m.p.:143 - 149℃.

[0051] Example 5:

[0052] Preparation process of 2-(2-(dimethylamino)phenyl)-2,2-difluoro-N-phenylacetamide.

[0053]

[0054] A 50 - mL Schlenk tube containing ammonium persulfate (684 mg, 3.00 mmol, 3.0 equiv), 2 - bromo - 2,2 - difluoro - N - phenylacetamide (250 mg, 1.00 mmol, 1.0 equiv) was evacuated and refilled with N 2Three times. After waiting for the nitrogen filling to be completed, then add N,N-dimethylaniline (484.72 mg, 4.00 mmol, 4.0 eq), and finally add triethylamine (607 mg, 6.00 mmol, 6.0 eq). Then add 10 mL of a mixed solution of 1,4-epoxyhexane and water (volume ratio 1:3). Immediately transfer the mixture to a preheated aluminum block at 50 °C and stir at this temperature for 18 hours. Subsequently, use ethyl acetate to extract the mixture, and wash the organic phase of the extract with saturated brine; when performing extraction, use 5 mL of ethyl acetate to extract the mixture each time, and extract repeatedly 3 times; when performing washing, use 5 mL of saturated brine to wash the organic phase each time, and wash repeatedly 3 times. Combine the organic phases and dry over anhydrous sodium sulfate. After filtration, use a rotary evaporator to concentrate the organic phase to obtain a crude product. The crude product is further purified by silica gel column chromatography (calculated by volume ratio, petroleum ether / ethyl acetate = 8:1) to obtain the compound 2-(2-(dimethylamino)phenyl)-2,2-difluoro-N-phenylacetamide, with a yield of 43%.

[0055] 1 HNMR(500MHz,CDCl 3 )δ8.75(brs,1H),7.75(dd,J=8.0,1.4Hz,1H),7.64-7.57(m,2H),7.51(t,J=8.2Hz,1H),7.39(dd,J=8.0,1.4Hz,1H),7.38-7.34(m,2H),7.31(t,J=7.5Hz,1H),7.15(t,J=7.5,1H),2.61(s,6H).

[0056] 19 FNMR(471MHz,CDCl 3 )δ-99.5(s,2F).

[0057] 13 CNMR(126MHz,CDCl 3 )δ162.5(t,J=29.7Hz),152.7(t,J=4.7Hz),137.2,132.2(t,J=1.8Hz),130.9(t,J=23.6Hz),129.2,127.1(t,J=7.6Hz),126.0,124.7,123.5,119.8,114.6(t,J=252.2Hz),46.1.HRMS(ESI)calcdforC 16 H 16 F 2 N 2 ONa + [M+Na] +313.10752, found 313.10775. Example 6:

[0058] Preparation process of 2-(benzo[1,3]dioxazol-5-yl)-2,2-difluoro-N-phenylacetamide.

[0059]

[0060] A 50 mL Schlenk tube containing ammonium persulfate (684 mg, 3.00 mmol, 3.0 eq), 2-bromo-2,2-difluoro-N-phenylacetamide (250 mg, 1.00 mmol, 1.0 eq) was evacuated and refilled with N 2 three times. After waiting for the nitrogen filling to be completed, then benzodioxole (484.48 mg, 4.00 mmol, 4.0 eq) was added, and finally triethylamine (607 mg, 6.00 mmol, 6.0 eq) was added. Then 10 mL of a mixed solution of 1,4-epoxyhexane and water (volume ratio 1:3) was added. The mixture was immediately transferred to a preheated aluminum block at 50 °C and stirred at this temperature for 18 hours. Subsequently, the mixture was extracted with ethyl acetate, and the organic phase of the extract was washed with saturated brine; when extracting, 5 mL of ethyl acetate was used to extract the mixture each time, and the extraction was repeated 3 times; when washing, 5 mL of saturated brine was used to wash the organic phase each time, and the washing was repeated 3 times. After combining the organic phases, they were dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated using a vacuum distillation apparatus to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1 by volume ratio) to obtain the compound 2-(benzo[1,3]dioxazol-5-yl)-2,2-difluoro-N-phenylacetamide with a yield of 65%. 1 HNMR(500MHz,CDCl 3 )δ8.04(brs,1H),7.57(d,J=8.0Hz,2H),7.36(m,2H),7.23 - 7.16(m,2H),7.14(d,J=1.6Hz,1H),6.86(d,J=8.0Hz,1H),6.02(s,2H).

[0061] 19 FNMR(471MHz,CDCl 3 )δ - 100.60(s,2F).

[0062] 13 CNMR(126MHz,CDCl 3) δ 161.8 (t, J = 31.4 Hz), 149.9, 148.0, 136.0, 129.2, 126.2 (t, J = 26.0 Hz), 125.6, 120.1, 120.0 (t, J = 7.0 Hz), 114.6 (t, J = 253.5 Hz), 108.3, 106.3 (t, J = 6.2 Hz), 101.7. HRMS(ESI) calcd for C 15 H 11 F 2 NO 3 Na + [M + Na] + 314.05921, found 314.05937. m.p.: 112 - 115 °C. Example Seven:

[0063] Preparation process of 2,2 - difluoro - 2 - (1 - methyl - 1H - indol - 2 - yl) - N - phenylacetamide.

[0064]

[0065] A 50 - mL Schlenk tube containing ammonium persulfate (684 mg, 3.00 mmol, 3.0 equiv), 2 - bromo - 2,2 - difluoro - N - phenylacetamide (250 mg, 1.00 mmol, 1.0 equiv) was evacuated and refilled with N 2 three times. After waiting for the nitrogen filling to be completed, then 1 - methylindole (524.68 mg, 4.00 mmol, 4.0 equiv) was added. Finally, triethylamine (607 mg, 6.00 mmol, 6.0 equiv) was added. Then 10 mL of a mixed solution of 1,4 - epoxyhexane and water (volume ratio 1:3) was added. The mixture was immediately transferred to a pre - heated aluminum block at 50 °C and stirred at this temperature for 18 hours. Subsequently, the mixture was extracted with ethyl acetate, and the organic phase of the extract was washed with saturated brine; when extracting, 5 mL of ethyl acetate was used to extract the mixture each time, and the extraction was repeated 3 times; when washing, 5 mL of saturated brine was used to wash the organic phase each time, and the washing was repeated 3 times. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and then concentrated using a rotary evaporator to obtain a crude product. The crude product was further purified by silica gel column chromatography (calculated by volume ratio, petroleum ether / ethyl acetate = 25:1) to obtain the compound 2,2 - difluoro - 2 - (1 - methyl - 1H - indol - 2 - yl) - N - phenylacetamide with a yield of 42%.

[0066] 1 HNMR(500 MHz, CDCl 3)δ8.02(brs,1H),7.64(d,J=8.0Hz,1H),7.62 - 7.59(m,2H),7.43 - 7.37(m,3H),7.34(t,J=7.8Hz,1H),7.22(tt,J=7.1,1.1Hz,1H),7.16(ddd,J=7.8,7.1,1.1Hz,1H),6.88(m,1H),3.96(s,3H).

[0067] 19 FNMR(471MHz,CDCl 3 )δ - 97.53(s,2F).

[0068] 13 CNMR(126MHz,CDCl 3 )δ160.6(t,J=30.2Hz),139.0,135.9,129.3(t,J=29.8Hz),129.3,126.0,125.8,124.2,122.0,120.5,120.3,112.7(t,J=250.3Hz),109.8,105.2(t,J=6.5Hz),31.3(t,J=3.1Hz).HRMS(ESI)calcdforC 17 H 14 F 2 N 2 ONa + [M + Na] + 323.09925,found323.09954. Example VIII:

[0069] Preparation process of 2,2 - difluoro - 2 - (2 - methyl - 1H - indol - 4 - yl) - N - phenylacetamide.

[0070]

[0071] A 50 - mL Schlenk tube containing ammonium persulfate (684 mg, 3.00 mmol, 3.0 equiv), 2 - bromo - 2,2 - difluoro - N - phenylacetamide (250 mg, 1.00 mmol, 1.0 equiv) was evacuated and backfilled with N 2Three times. After waiting for the nitrogen filling to be completed, then add 2-methyl-1H-indole (524.71 mg, 4.00 mmol, 4.0 eq), and finally add triethylamine (607 mg, 6.00 mmol, 6.0 eq). Then add 10 mL of a mixed solution of 1,4-epoxyhexane and water (volume ratio 1:3). Immediately transfer the mixture to a preheated aluminum block at 50 °C and stir at this temperature for 18 hours. Subsequently, use ethyl acetate to extract the mixture, and wash the organic phase of the extract with saturated brine; when extracting, use 5 mL of ethyl acetate to extract the mixture each time, and extract 3 times repeatedly; when washing, use 5 mL of saturated brine to wash the organic phase each time, and wash 3 times repeatedly. Combine the organic phases and dry them with anhydrous sodium sulfate. After filtration, use a rotary evaporator to concentrate the organic phase to obtain a crude product. The crude product is further purified by silica gel column chromatography (calculated by volume ratio, petroleum ether / ethyl acetate = 20:1) to obtain the compound 2,2-difluoro-2-(3-methyl-1H-indol-7-yl)-N-phenylacetamide, with a yield of 36%.

[0072] 1 HNMR(500MHz,CDCl 3 )δ8.15(brs,1H),8.05(brs,1H),7.61-7.52(m,2H),7.41-7.30(m,4H),7.20-7.11(m,2H),6.55-6.50(m,1H),2.44(s,3H).

[0073] 19 FNMR(471MHz,CDCl 3 )δ-101.42(s,2F).

[0074] 13 CNMR(126MHz,CDCl 3 )δ162.2(t,J=31.8Hz),137.1,136.7,136.3,129.2,125.8(t,J=3.4Hz),125.4,122.7(t,J=25.6Hz),120.4,120.1,117.4(t,J=7.5Hz),116.1(t,J=253.1Hz),113.3,100.0(t,J=2.4Hz),13.8.HRMS(ESI)calcdforC 17 H 14 F 2 N 2 ONa + [M+Na] + 323.09975,found323.09984.

[0075] Example 9:

[0076] Preparation process of 2-(3,4-dimethoxyphenyl)-2,2-difluoro-N-(4-fluorophenyl)acetamide.

[0077]

[0078] A 50 mL Schlenk tube containing ammonium persulfate (684 mg, 3.00 mmol, 3.0 equiv), 2-bromo-2,2-difluoro-N-(4-fluorophenyl)acetamide (268.03 mg, 1.00 mmol, 1.0 equiv) was evacuated and refilled with N 2 three times. After waiting for the nitrogen filling to be completed, then 1,2-dimethoxybenzene (544.23 mg, 4.00 mmol, 4.0 equiv) was added. Finally, triethylamine (607 mg, 6.00 mmol, 6.0 equiv) was added, and then 10 mL of a mixed solution of 1,4-dioxane and water (volume ratio 1:3) was added. The mixture was immediately transferred to a preheated aluminum block at 50 °C and stirred at this temperature for 18 hours. Subsequently, the mixture was extracted with ethyl acetate, and the organic phase of the extract was washed with saturated brine; when extracting, 5 mL of ethyl acetate was used to extract the mixture each time, and the extraction was repeated 3 times; when washing, 5 mL of saturated brine was used to wash the organic phase each time, and the washing was repeated 3 times. After combining the organic phases, they were dried over anhydrous sodium sulfate, filtered, and then concentrated using a rotary evaporator to obtain a crude product. The crude product was further purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1 by volume ratio) to obtain the compound 2-(3,4-dimethoxyphenyl)-2,2-difluoro-N-(4-fluorophenyl)acetamide with a yield of 89%.

[0079] 1 HNMR(500MHz,CDCl 3 )δ8.24(brs,1H),7.56-7.50(m,2H),7.19(dd,J=8.8,1.8Hz,1H),7.16(d,J=1.8Hz,1H),7.07-6.97(m,2H),6.88(d,J=8.8Hz,1H),3.88(s,6H).

[0080] 19 FNMR(471MHz,CDCl 3 )δ-100.85(s,2F),-115.95--116.05(m,F).

[0081] 13 CNMR(126MHz,CDCl 3)δ162.1(t, J = 32.4 Hz), 161.0, 159.0, 151.2, 149.1, 132.1(d, J = 3.2 Hz), 124.8(t, J = 25.9 Hz), 122.1(d, J = 8.6 Hz), 118.5(t, J = 6.7 Hz), 115.9(d, J = 23.5 Hz), 114.8(t, J = 253.8 Hz), 110.7, 108.6(t, J = 5.5 Hz), 56.0, 55.9. HRMS(ESI) calcd for C 16 H 14 F 3 NO 3 Na + [M + Na] + 348.07926, found 348.07934. m.p.: 91 - 93 °C.

[0082] Example X:

[0083] Preparation process of 2-(3,4-dimethoxyphenyl)-2,2-difluoro-1-morpholinoethyl-1-one.

[0084]

[0085] A 50 mL Schlenk tube containing ammonium persulfate (684 mg, 3.00 mmol, 3.0 eq), 2-bromo-2,2-difluoro-1-morpholinoethanone (301.12 mg, 1.00 mmol, 1.0 eq) was evacuated and refilled with N 2 three times. After waiting for the nitrogen filling to be completed, then 1,2-dimethoxybenzene (544.23 mg, 4.00 mmol, 4.0 eq) was added, and finally triethylamine (607 mg, 6.00 mmol, 6.0 eq) was added. Then 10 mL of a mixed solution of 1,4-epoxyhexane and water (volume ratio 1:3) was added. The mixture was immediately transferred to a preheated aluminum block at 50 °C and stirred at this temperature for 18 hours. Subsequently, the mixture was extracted with ethyl acetate, and the organic phase of the extract was washed with saturated brine; during extraction, 5 mL of ethyl acetate was used to extract the mixture each time, and the extraction was repeated 3 times; during washing, 5 mL of saturated brine was used to wash the organic phase each time, and the washing was repeated 3 times. After combining the organic phases, they were dried over anhydrous sodium sulfate, filtered, and then concentrated using a rotary evaporator to obtain a crude product. The crude product was further purified by silica gel column chromatography (calculated by volume ratio, petroleum ether / ethyl acetate = 15:1) to obtain the compound 2-(3,4-dimethoxyphenyl)-2,2-difluoro-1-morpholinoethyl-1-one with a yield of 40%.

[0086] 1HNMR(500MHz,CDCl 3 )δ7.10 - 7.05(m,1H),7.01(d,J=2.1Hz,1H),6.89(d,J=8.4Hz,1H),3.90(s,3H),3.89(s,3H),3.69(s,4H),3.46(s,4H).

[0087] 19 FNMR(471MHz,CDCl 3 )δ - 92.85(s,2F).

[0088] 13 CNMR(126MHz,CDCl 3 )δ162.2(t,J=30.5Hz),151.0,149.3,125.6(t,J=25.3Hz),118.0(t,J=6.2Hz),115.5(t,J=249.7Hz),110.7,107.9(t,J=5.3Hz),66.6,66.3,56.0,55.0,46.7,43.4.HRMS(ESI)calcdforC 14 H 7 F 2 NO 4 Na + [M + Na] + 324.09952,found324.09987.

[0089] Example XI:

[0090] Preparation process of 2-(3,4 - dimethoxyphenyl)-2,2 - difluoro - 1-(pyrrolidin - 1 - yl)ethan - 1 - one.

[0091]

[0092] A 50 - mL Schlenk tube containing ammonium persulfate (684 mg, 3.00 mmol, 3.0 equiv), 2 - bromo - 2,2 - difluoro - 1-(pyrrolidin - 1 - yl)ethan - 1 - one (285.34 mg, 1.00 mmol, 1.0 equiv) was evacuated and refilled with N 2Three times, after waiting for the nitrogen filling to be completed, then add 1,2-dimethoxybenzene (544.23 mg, 4.00 mmol, 4.0 eq), and finally add triethylamine (607 mg, 6.00 mmol, 6.0 eq). Then add 10 mL of a mixed solution of 1,4-epoxyhexane and water (volume ratio 1:3). Immediately transfer the mixture to a preheated aluminum block at 50 °C and stir at this temperature for 18 hours. Subsequently, use ethyl acetate to extract the mixture, and wash the organic phase of the extract with saturated brine; when performing extraction, use 5 mL of ethyl acetate to extract the mixture each time, and extract 3 times repeatedly; when performing washing, use 5 mL of saturated brine to wash the organic phase each time, and wash 3 times repeatedly. Combine the organic phases and dry them with anhydrous sodium sulfate. After filtration, use a reduced-pressure distillation device to concentrate the organic phase to obtain a crude product. The crude product is purified by silica gel column chromatography (calculated by volume ratio, petroleum ether / ethyl acetate = 15:1) to obtain compound 2-(3,4-dimethoxyphenyl)-2,2-difluoro-1-(pyrrolidin-1-yl)ethan-1-one, with a yield of 35%.

[0093] 1 HNMR(500MHz,CDCl 3 )δ7.14-7.09(m,1H),7.07(d,J=2.1Hz,1H),6.88(d,J=8.4Hz,1H),3.88(s,3H),3.88(s,3H),3.62-3.37(m,4H),1.97-1.72(m,4H).

[0094] 19 FNMR(471MHz,CDCl 3 )δ-96.91(s,2F).

[0095] 13 CNMR(126MHz,CDCl 3 )δ162.34(t,J=31.3Hz),150.91,149.16,125.65(t,J=26.5Hz),118.28(t,J=6.5Hz),115.40(t,J=250.00.3Hz),110.7,108.4(t,J=5.1Hz),56.0,55.9,47.4,46.8(t,J=4.9Hz),26.4,23.3.HRMS(ESI)calcdforC 14 H 17 F 2 NO 3 Na + [M+Na] + 308.10945,found308.10947.

[0096] Example 12:

[0097] Preparation process of 2-(3,4-dimethoxyphenyl)-2,2-difluoro-N-(pyridin-4-yl)acetamide.

[0098]

[0099] A 50 mL Schlenk tube containing ammonium persulfate (684 mg, 3.00 mmol, 3.0 eq), 2-bromo-2,2-difluoro-N-(pyridin-4-yl)acetamide (308.32 mg, 1.00 mmol, 1.0 eq) was evacuated and refilled with N 2 three times. After waiting for the nitrogen filling to be completed, then 1,2-dimethoxybenzene (544.23 mg, 4.00 mmol, 4.0 eq) was added. Finally, triethylamine (607 mg, 6.00 mmol, 6.0 eq) was added, and then 10 mL of a mixed solution of 1,4-dioxane and water (volume ratio 1:3) was added. The mixture was immediately transferred to a preheated aluminum block at 50 °C and stirred at this temperature for 18 hours. Subsequently, the mixture was extracted with ethyl acetate, and the organic phase of the extract was washed with saturated brine; when extracting, 5 mL of ethyl acetate was used to extract the mixture each time, and the extraction was repeated 3 times; when washing, 5 mL of saturated brine was used to wash the organic phase each time, and the washing was repeated 3 times. After combining the organic phases, they were dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated using a rotary evaporator to obtain a crude product. The crude product was further purified by silica gel column chromatography (calculated by volume ratio, petroleum ether / ethyl acetate = 5:1) to obtain the compound 2-(3,4-dimethoxyphenyl)-2,2-difluoro-N-(pyridin-4-yl)acetamide with a yield of 75%.

[0100] 1 HNMR(500MHz,CDCl 3 )δ9.16(brs,1H),8.66(dd,J=2.6,0.7Hz,1H),8.35(dd,J=4.8,1.5Hz,1H),8.18(ddd,J=8.4,2.6,1.5Hz,1H),7.27(dd,J=8.4,4.8Hz,1H),7.15(m,1H),7.12(d,J=2.1Hz,1H),6.85(d,J=8.4Hz,1H),3.85(s,3H),3.83(s,3H).

[0101] 19 FNMR(471MHz,CDCl 3 )δ-100.87(s,2F).

[0102] 13CNMR(126MHz,CDCl 3 )δ162.9(t,J=32.6Hz),151.3,149.1,146.0,141.5,133.6,128.0,124.5(t,J=25.9Hz),123.9,118.5(t,J=6.7Hz),114.7(t,J=253.9Hz),110.8,108.5(t,J=5.8Hz),56.0,55.9.HRMS(ESI)calcdforC 15 H 14 F 2 N 2 O 3 Na + [M+Na] + 331.08925,found331.08956.m.p.:130 - 137℃.

[0103] Example XIII:

[0104] Using the above Examples 1 - 12 of the present invention, the phenyl difluoroamidated aromatic compounds can be used to prepare fluorine - containing amide drugs or agents, to prepare benzoylaniline, as an aniline - type fungicide, an agent for controlling sheath blight of rice, having good efficacy, long control time, being able to improve the setting rate of crops and the yield of agricultural products, and being able to increase the rice yield by at least 5%. Flutolanil has strong systemic conduction and long - lasting efficacy, and has relatively good control effects on diseases such as sheath blight, smut, and damping - off caused by Deuteromycetes and Basidiomycetes, and the comprehensive disease - resistant rate is not less than 90%. Flutolanil can also inhibit the activity of mitochondrial respiratory chain complex II (succinate - ubiquinone oxidoreductase) in pathogenic fungi, so that electrons cannot be transferred from succinate to ubiquinone, resulting in the abnormal synthesis of ATP in the fungal cells, and ultimately leading to the death of the fungal cells due to energy shortage. Currently, most existing flutolanil is a single agent. By using the synergistic effect produced by mixing two active components, the control efficacy can be improved, the disease control spectrum can be expanded, the dosage of the active ingredient can be reduced, the drug use cost can be saved, the generation of pathogen resistance can be delayed, and environmental pollution can be reduced. This is an important means for the integrated control of agricultural diseases. In addition, using the above Examples 1 - 12 of the present invention, the phenyl difluoroamidated aromatic compounds can be used to prepare fluorine - containing amide drugs or agents, and can also be used to control other diseases caused by certain Basidiomycetes fungi and the sheath blight of rice caused by Rhizoctonia solani. The preparations can be micro - powder, powder, and wettable powder.

[0105] The preparation method of the phenyl difluoroamidated aromatic compounds in the above Examples 1 - 12 of the present invention realizes the ethoxycarbonyl difluoromethylation reaction of the Csp 2 -H of aromatic hydrocarbons, and successfully constructs the Csp 2 -CF 2Key. Using 2-bromo-2,2-difluoro-N-phenylacetamide as the difluoroamidation reagent source, 1,2-dimethoxybenzene as the aromatic hydrocarbon substrate, triethylamine as the halogen atom transfer reagent, a mixed system of 1,4-epoxyhexane and water as the solvent, and ammonium persulfate as the oxidant, the difluoroamidation reaction of aromatic hydrocarbons initiated by α-amino carbon radicals is carried out at a temperature not lower than 50 °C for at least 18 hours to obtain phenyl difluoroamidated aromatic compounds. The raw materials used in this synthesis method are cheap and easily available, the operation is simple, and the conditions are mild, meeting the requirements of green chemistry and atom economy, providing a new synthetic strategy for the direct difluoroamidation of aromatic hydrocarbons. Using the phenyl difluoroamidated aromatic compounds in Examples 1 to 12 as raw materials for the preparation of fluorine-containing amide drugs provides rich raw material resources, effectively reduces the preparation cost of fluorine-containing amide drugs, and is conducive to realizing the improvement of production scale.

[0106] The above describes the embodiments of the present invention, but the present invention is not limited to the above embodiments. Various changes can be made according to the purpose of the invention of the present invention. Any changes, modifications, substitutions, combinations or simplifications made based on the spirit and principle of the technical solution of the present invention shall be equivalent replacement methods. As long as they meet the invention purpose of the present invention and do not deviate from the technical principle and inventive concept of the present invention, they all belong to the protection scope of the present invention.

Claims

1. A method for preparing phenyl difluoroamidated aromatic compounds, characterized in that, Using 2-bromo-2,2-difluoro- N -phenylacetamide as the difluoroamidation reagent source, 1,2-dimethoxybenzene as the aromatic hydrocarbon substrate, triethylamine as the halogen atom transfer reagent, a mixed system of 1,4-epoxyhexane and water as the solvent, and ammonium persulfate as the oxidant, the difluoroamidation reaction of aromatic hydrocarbons initiated by α-amino carbon radicals is carried out at a temperature not lower than 50 °C for at least 18 hours to obtain phenyl difluoroamidated aromatic compounds, and the structural formula of the phenyl difluoroamidated aromatic compounds is: , wherein Ar in 3 is any one of naphthyl, oxazole, benzodioxazole, and indole, and -R at different positions are respectively -H, -CH 2 CH 3 , -OMe, -OEt, and -N(CH 3 ) 2 any one of them; Ar in NH-Ar is phenyl or fluorophenyl.

2. The method for preparing phenyl difluoroamidated aromatic compounds according to claim 1, characterized in that: Ar in it is any one of naphthyl and indole, and -R at different positions is respectively -H, -OMe and -N(CH 3 ) 2 any one of them; Ar in NH-Ar is phenyl.

3. The method for preparing phenyl difluoroamidated aromatic compounds according to claim 1, characterized in that: A mixed system of 1,4 - epoxyhexane and water is prepared at a volume ratio of 1:

3.

4. The method for preparing phenyl difluoroamidated aromatic compounds according to claim 1, characterized in that, It has the following steps. A mixed solution system is prepared according to the following ratio. 3.00 mmol of ammonium persulfate, 4.00 mmol of aromatic hydrocarbon, 1.00 mmol of 2 - bromo - 2,2 - difluoro - N - phenylacetamide, and 6.00 mmol of triethylamine are added to a Schlenk tube equipped with a magnetic stir bar. Then, at least 10 mL of a mixed solution of 1,4 - epoxyhexane and water is added under stirring to obtain a mixed solution system; Then, nitrogen is added to the mixed solution system using a balloon; then, it is stirred at a temperature not lower than 50 °C for at least 18 hours; after the reaction ends, the product mixture is cooled to a temperature, and then ethyl acetate is used to extract the mixture, and the organic phase of the extract is washed with saturated brine. Then, the combined organic phases are dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure using a rotary evaporator to evaporate the solvent, and then the crude product is separated and purified by column chromatography to obtain phenyl difluoroamidated aromatic compounds.

5. The method for preparing phenyl difluoroamidated aromatic compounds according to claim 4, characterized in that: A mixed solution of 1,4 - epoxyhexane and water is prepared at a volume ratio of 1:

3.

6. The method for preparing phenyl difluoroamidated aromatic compounds according to claim 4, characterized in that: When performing extraction, at least 5 mL of ethyl acetate is used to extract the mixture each time, and extraction is repeated at least 3 times.

7. The method for preparing phenyl difluoroamidated aromatic compounds according to claim 4, characterized in that: When performing washing, at least 5 mL of saturated brine is used to wash the organic phase each time, and washing is repeated at least 3 times.

8. The method for preparing phenyl difluoroamidated aromatic compounds according to claim 4, characterized in that: A mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5 - 25:1 is used as the developing agent for purification.

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