2-phenyl aryl amide derivative and preparation method thereof

Abstract

The invention provides a 2-phenyl aryl amide derivative and a preparation method thereof, in an inert atmosphere, tetrahydrofuran, 2-methyltetrahydrofuran, normal hexane, 1, 4-dioxane or methyl tert-butyl ether are used as reaction solvents, a 2-phenoxy benzamide derivative and an aryl Grignard reagent are used as raw materials, the raw materials are stirred at 25-100 DEG C for a reaction, and the 2-phenyl aryl amide derivative is obtained. And after the reaction is completed, separating and purifying a product to obtain the 2-phenyl aryl amide derivative. The method has the advantages of low cost, mild reaction conditions, high selectivity, high yield, low product separation and purification difficulty and the like, and the use of harsh conditions and transition metal catalysts is avoided.

Description

Technical Field

[0001] The present invention belongs to the technical field of the synthesis of arylamide compounds, and particularly relates to a 2-phenylaryl amide derivative and a preparation method thereof. Background Art

[0002] As an important structural unit, biphenylamide compounds (BPAs) widely exist in natural products, drug molecules, bioactive substances and functional materials. Due to their unique rigid biphenyl skeleton and amide functional group, such compounds are often used as versatile building blocks in organic synthesis; therefore, developing efficient methods for constructing functionalized biphenylamides has important research value and application significance. The activation and arylation reaction of aryl C-O bonds provides an efficient and convenient approach for the synthesis of biphenyl derivatives. At present, researchers have developed a variety of transition metal catalysts, which can achieve the selective activation and arylation reaction of aryl C-O bonds in phenolic derivatives with aryl nucleophiles, thereby obtaining diverse functionalized biphenyl compounds. However, despite many progress, the research on the selective C-O bond activation and arylation reaction of amide-functionalized phenolic derivatives to synthesize biphenylamides is still significantly insufficient. Therefore, developing efficient strategies (especially methods without the participation of transition metals) to achieve this goal has important scientific significance and application value.

[0003] As an important method for constructing diverse C-C bonds, the Meyers reaction realizes excellent chemoselectivity and regioselectivity by activating the ortho-alkoxy group of aryl oxazoline and substituting it with nucleophiles such as aromatic Grignard reagents. After hydrolysis and amidation reactions of the obtained biphenyl oxazoline intermediate, the corresponding functionalized biphenylamide can be obtained. In principle, the Meyers-type reaction of arylamides is a step-economic and direct and effective method for synthesizing biphenylamides. However, such Meyers-type reactions have not been reported in the literature so far. The present invention provides for the first time an ortho-C-O bond arylation reaction of arylamides with aryl Grignard reagents under the condition of no transition metal catalyst. This method provides a new strategy for the efficient synthesis of structurally diverse biphenylamides, and has significant advantages such as high yield and wide substrate scope. Summary of the Invention

[0004] The object of the present invention is to provide a 2-phenylaryl amide derivative and a preparation method thereof. This method is a novel method for synthesizing carbon-carbon bonds by activating the ortho-carbon-oxygen bond of arylamides, and is a method for activating the ortho-carbon-oxygen bond of 2-phenoxyaryl amide compounds to synthesize 2-phenylaryl amide compounds.

[0005] To achieve the above object, the technical solution provided by the present invention is:

[0006] A preparation method of 2-phenylaryl amide derivatives, which is characterized in that:

[0007] Under an inert atmosphere, using tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, 1,4-dioxane or methyl tert-butyl ether as the reaction solvent, and using 2-phenoxybenzamide derivatives and aryl Grignard reagents as raw materials, stirring and reacting at 25-100 °C, and separating and purifying the product after the reaction is completed to obtain 2-phenylaryl amide derivatives;

[0008] The synthesis general formula is as follows:

[0009]

[0010] Among them, R and R 1 are both aliphatic groups or aromatic groups, and X is Br or Cl.

[0011] Furthermore, the molar ratio of the 2-phenoxybenzamide derivative to the aryl Grignard reagent is 1:2 - 1:4;

[0012] The dosage ratio of the reaction solvent to the 2-phenoxybenzamide derivative is 5 - 10:1 (mL:mmol), that is, 5 - 10 mL of reaction solvent is required for each millimole of 2-phenoxybenzamide derivative;

[0013] The reaction time is 24 - 48 h; thin-layer chromatography is used for tracking during the reaction process.

[0014] Furthermore, the aryl Grignard reagent is aryl magnesium bromide or aryl magnesium chloride.

[0015] Furthermore, the reaction temperature is 60 - 100 °C.

[0016] Furthermore, when the molar ratio of the 2-phenoxybenzamide derivative to the aryl Grignard reagent is 1:4, the reaction temperature is 100 °C, and the reaction time is 48 h, the yield under this condition is as high as over 90%.

[0017] Furthermore, the specific operation of separation and purification is to first extract with ethyl acetate, then dry with anhydrous Na2SO4, filter, reduce the pressure, and finally purify by column chromatography to obtain 2-phenylaryl amide derivatives, that is, aryl amide derivatives with an aryl group at the ortho position.

[0018] Furthermore, when the 2-phenoxybenzamide derivative is a compound of formula I and the aryl Grignard reagent is phenylmagnesium bromide, the product is a compound of formula I'.

[0019]

[0020] Among them, R1 is 4-methoxy, 4-methyl, 5-trifluoromethyl, 5-methoxy, 5-methyl, 3-trifluoromethyl, 3-methyl, 3-methoxy, 3-fluoro-4-methyl or 3-fluoro-4-ethoxy.

[0021] Further, when the 2-phenoxybenzamide derivative is a compound of Formula II and the aryl Grignard reagent is phenylmagnesium bromide, the product is a compound of Formula II';

[0022]

[0023] Among them, R2 is ethyl, isopropyl, isohexyl, cyclohexyl, cyclopentyl, cycloheptyl, phenyl, benzyl or 1-naphthyl.

[0024] Further, when the 2-phenoxybenzamide derivative is a compound of Formula III and the aryl Grignard reagent is phenylmagnesium bromide, the product is a compound of Formula III';

[0025]

[0026] In the formula, R3 is benzyloxy, methoxy or ethoxy.

[0027] Further, when the 2-phenoxybenzamide derivative is a compound of Formula IV and the aryl Grignard reagent is arylmagnesium bromide, the product is a compound of Formula IV';

[0028]

[0029] Among them, R4 is 4-methoxy, 4-methyl, 3-methoxy, 3-methyl, 4-phenyl, 4-fluoro, 4-chloro or 3-fluoro.

[0030] Meanwhile, the present invention also provides 2-phenylaryl amide derivatives prepared by the above method.

[0031] The advantages of the present invention are:

[0032] 1. The present invention first introduces arylamides (2-phenoxybenzamide derivatives) into the Meyers-type reaction mechanism. Through the cross-coupling reaction with aryl Grignard reagents, efficient C-C bond formation is achieved, and the corresponding 2-phenylaryl amide derivatives are obtained. This innovative method significantly expands the reaction scope of arylamides, indicating that even under the influence of different substituents (electron-donating or electron-withdrawing), the reaction still exhibits excellent activity and selectivity. The research results further show that electron-donating groups such as methyl and methoxy groups significantly improve the reaction yield, while electron-withdrawing groups have a certain inhibitory effect on the reaction yield, providing reference and guidance for further optimizing the reaction conditions and mechanism research. In addition, this method demonstrates the potential to achieve high yields and high selectivity under mild conditions, opening up a new way for constructing arylamide derivatives with high pharmaceutical efficacy and complex structures. By promoting the application of arylamides in the field of organic synthesis, the present invention not only provides new strategies for drug research and development and materials science, but also provides a theoretical basis and practical foundation for the development of sustainable chemistry, demonstrating great academic value and industrial potential.

[0033] 2. Based on the nucleophilic aromatic substitution mechanism of Grignard reagents in the Meyers-type reaction mechanism, the present invention achieves the highly selective cleavage of the ortho carbon-oxygen bond of arylamides at high temperature, with advantages such as low cost, mild reaction conditions, high selectivity, high yield, and easy separation and purification of products, avoiding the use of harsh conditions and transition metal catalysts. The present invention is applicable to the activation of the ortho carbon-oxygen bond of benzamide derivatives with different nitrogen substituents and aryl substituents to construct carbon-carbon bonds.

[0034] 3. There has never been a report on the activation of the ortho carbon-oxygen bond of 2-phenoxybenzamide derivatives to construct a carbon-carbon bond reaction. The present invention uses 2-phenoxybenzamide derivatives and arylmagnesium bromide as raw materials to synthesize 2-phenylaryl amide derivatives that play an important role in pharmaceutical chemistry, material chemistry, and organic synthetic chemistry at 25 - 100 °C (the yield at 60 - 100 °C is higher than that below 60 °C, especially at 100 °C, the yield is the highest). This method has simple and easily available raw materials, simple operation, considerable yields, and good application prospects. Detailed implementation mode

[0035] The following further describes the content of the present invention in detail with reference to examples:

[0036] The present invention provides a method for preparing 2-phenylaryl amide derivatives: under an inert atmosphere, using tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, 1,4-dioxane or methyl tert-butyl ether as the reaction solvent, using 2-phenoxybenzamide derivatives and aryl Grignard reagents as raw materials, stirring and reacting at 25-100 °C. After the reaction is completed, the reaction product is poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate in portions, then dried over anhydrous Na2SO4, filtered, and the solvent is removed under reduced pressure. The target product is obtained by purification through flash silica gel column chromatography.

[0037] Example 1

[0038] 2-Phenyl-N-methylbenzamide

[0039]

[0040] The reaction equation is as follows:

[0041]

[0042] Prepare multiple samples. Under an argon atmosphere, add (0.2 mmol) 2-phenoxy-N-methylbenzamide to 1 mL of tetrahydrofuran, and slowly dropwise add 0.8 mL of a 1 mol / L tetrahydrofuran solution of phenylmagnesium bromide at room temperature. Stir and react at 25 °C, 60 °C, 70 °C, 80 °C, 90 °C, and 100 °C for 48 hours respectively. Subsequently, quench, wash, and separate to obtain the product. The yields are as follows:

[0043] Table 1

[0044]

[0045]

[0046] As can be seen from Table 1, 2-phenyl-N-methylbenzamide can be formed without the participation of transition metals between 25-100 °C, but the product yield is higher at 100 °C, indicating the influence of temperature on the yield.

[0047] The specific operations of the above quenching, washing, and separation are as follows: add 5 mL of saturated ammonium chloride aqueous solution to quench the reaction, use ethyl acetate (10 mL each time, 3 times), combine the extraction solutions, add anhydrous sodium sulfate for drying, and separate the product by column chromatography using petroleum ether:ethyl acetate = 8:1 as the eluent to obtain the product.

[0048] Similarly, this example also investigated the influence of different equivalents on the product yield:

[0049] Prepare multiple samples. Under an argon atmosphere, add (0.2 mmol) 2-phenoxy-N-methylbenzamide to 1 mL of tetrahydrofuran. At room temperature, slowly dropwise add the tetrahydrofuran solutions of 1.2 equivalents, 2 equivalents, 3 equivalents, 3.5 equivalents, and 4 equivalents of phenylmagnesium bromide respectively, and stir and react at 100 °C for 48 hours. Subsequently, quench, wash, and separate to obtain the products. The yields are as follows:

[0050] Table 2

[0051]

[0052] As can be seen from Table 2, no product is formed at 1.2 equivalents (i.e., no reaction occurs). At 2 - 4 equivalents, the reaction can proceed normally, and the product yield is the highest at 4 equivalents.

[0053] The spectral data and mass spectral data of the obtained product are as follows:

[0054] 1 H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.40–7.34 (m, 7H), 5.32 (s, 1H), 2.64 (d, J = 4.9 Hz, 3H);

[0055] 13 C NMR (125 MHz, CDCl3) δ 170.2, 140.1, 139.3, 135.7, 130.0, 123.0, 128.7, 128.5, 128.5, 127.6, 127.5, 26.5.

[0056] HRMS (ESI + ): calcd for C 14 H 14 NO[M + H] + 212.10754, found 212.10852.

[0057] Example 2

[0058] 2-Phenyl-4-methoxy-N-methylbenzamide

[0059]

[0060] Under an argon atmosphere, (0.2 mmol) 2-phenoxy-4-methoxy-N-methylbenzamide was added to 1 mL of tetrahydrofuran. At room temperature, 0.8 mL of a 1 mol / L solution of phenylmagnesium bromide in tetrahydrofuran was slowly added dropwise. The reaction was stirred at 100 °C for 48 hours. The reaction was quenched by adding 5 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (10 mL each time, 3 times). The combined extracts were dried over anhydrous sodium sulfate and separated by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to obtain the product with a yield of 96%.

[0061] The spectral data and mass spectral data of the obtained product are as follows:

[0062] 1 H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 8.6 Hz, 1H), 7.44–7.34 (m, 5H), 6.91 (dd, J = 8.6, 2.5 Hz, 1H), 6.83 (d, J = 2.5 Hz, 1H), 5.16 (s, 1H), 3.84 (s, 3H), 2.63 (d, J = 4.9 Hz, 3H);

[0063] 13 C NMR (125 MHz, CDCl3) δ 169.7, 160.7, 141.3, 140.3, 131.0, 128.6, 127.9, 115.4, 113.0, 55.4, 26.6.

[0064] HRMS (ESI + ): calcd for C 15 H 16 NO2 [M+H] + 242.11810, found 242.11135.

[0065] Example 3

[0066] 2-Phenyl-4-methyl-N-methylbenzamide

[0067]

[0068] Under an argon atmosphere, (0.2 mmol) 2-phenoxy-4-methyl-N-methylbenzamide was added to 1 mL of tetrahydrofuran. At room temperature, 0.8 mL of a 1 mol / L solution of phenylmagnesium bromide in tetrahydrofuran was slowly added dropwise. The reaction was stirred at 100 °C for 48 hours. The reaction was quenched by adding 5 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (10 mL each time, 3 times). The combined extracts were dried over anhydrous sodium sulfate and separated by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to obtain the product with a yield of 92%.

[0069] The spectral data and mass spectrometry data of the obtained product are as follows:

[0070] 1 H NMR(500MHz,CDCl3)δ7.69(d,J=8.6Hz,1H),7.44–7.34(m,5H),6.91(dd,J=8.6,2.5Hz,1H),6.83(d,J=2.5Hz,1H),5.16(s,1H),3.84(s,3H),2.63(d,J=4.9Hz,3H);

[0071] 13 C NMR(125MHz,CDCl3)δ165.3,157.4,152.3,141.3,129.6,128.4,125.9,123.0122.7,115.6,115.1,56.2,26.7.

[0072] HRMS(ESI + ):calcd for C 15 H 16 NO[M+H] + 226.12319,found 226.12587.

[0073] Example 4

[0074] 2-Phenyl-3-methoxy-N-methylbenzamide

[0075]

[0076] Under an argon atmosphere,(0.2 mmol)2-phenoxy-3-methoxy-N-methylbenzamide was added to 1 mL of tetrahydrofuran. A solution of 0.8 mL of 1 mol / L phenylmagnesium bromide in tetrahydrofuran was slowly added dropwise at room temperature. The reaction was stirred at 100 °C for 48 hours. The reaction was quenched by adding 5 mL of saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate(10 mL each time,3 times). The combined extracts were dried over anhydrous sodium sulfate. The product was separated by column chromatography using petroleum ether:ethyl acetate = 6:1 as the eluent, and the product was obtained with a yield of 95%.

[0077] The spectral data and mass spectrometry data of the obtained product are as follows:

[0078] 11H NMR (500 MHz, CDCl3) δ 7.97 (s, 1H), 7.72 (dd, J = 8.0, 1.3 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.44 (ddd, J = 16.8, 7.1, 4.5 Hz, 5H), 5.23 (s, 1H), 2.70 (d, J = 4.9 Hz, 3H);

[0079] 13 13C NMR (125 MHz, CDCl3) δ 168.8, 142.8, 138.7, 136.3, 130.7, 128.7, 128.4, 126.5, 125.8, 125.7, 125.7, 124.8, 122.6, 26.5.

[0080] HRMS (ESI + ): calcd for C 15 H 16 NO2 [M + H] + 242.11810, found 242.11074.

[0081] Example 5

[0082] 2-Phenyl-5-methoxy-N-methylbenzamide

[0083]

[0084] Under an argon atmosphere, (0.2 mmol) 2-phenoxy-4-methoxy-N-methylbenzamide was added to 1 mL of tetrahydrofuran, and 0.8 mL of a 1 mol / L solution of phenylmagnesium bromide in tetrahydrofuran was slowly added dropwise at room temperature. The mixture was stirred at 100 °C for 48 hours, and the reaction was quenched by adding 5 mL of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (10 mL each time, 3 times), and the combined extracts were dried over anhydrous sodium sulfate. The product was separated by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent, and the product was obtained with a yield of 83%.

[0085] The spectral data and mass spectral data of the obtained product are as follows:

[0086] 1 1H NMR (500 MHz, CDCl3) δ 7.42–7.28 (m, 6H), 7.25 (d, J = 2.7 Hz, 1H), 7.02 (dd, J = 8.5, 2.8 Hz, 1H), 5.16 (s, 1H), 3.87 (s, 3H), 2.67 (d, J = 5.0 Hz, 3H);

[0087] 1313C NMR (125 MHz, CDCl3) δ 170.0, 159.0, 139.9, 136.6, 131.8, 131.4, 128.7, 128.6, 127.4, 116.9, 113.2, 55.5, 26.7.

[0088] HRMS (ESI + ): calcd for C 15 H 16 NO2 [M + H] + 242.11810, found 242.11175.

[0089] Example 6

[0090] 2-Phenyl-5-methyl-N-methylbenzamide

[0091]

[0092] Under an argon atmosphere, (0.2 mmol) 2-phenoxy-4-methyl-N-methylbenzamide was added to 1 mL of tetrahydrofuran, and 0.8 mL of a 1 mol / L solution of phenylmagnesium bromide in tetrahydrofuran was slowly added dropwise at room temperature. The reaction mixture was stirred at 100 °C for 48 hours, quenched with 5 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (10 mL each time, 3 times), the combined extracts were dried over anhydrous sodium sulfate, and the product was separated by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent, giving the product in a yield of 71%.

[0093] The spectral data and mass spectrum data of the obtained product were as follows:

[0094] 1 1H NMR (500 MHz, CDCl3) δ 7.43 (s, 1H), 7.34–7.30 (m, 4H), 7.29–7.25 (m, 1H), 7.20 (dd, J = 4.8, 1.8 Hz, 2H), 5.11 (s, 1H), 2.59 (d, J = 5.0 Hz, 3H), 2.33 (s, 3H);

[0095] 13 13C NMR (125 MHz, CDCl3) δ 170.4, 140.1, 137.5, 136.4, 135.5, 130.9, 130.1, 129.4, 128.6, 128.5, 127.5, 26.6, 21.0.

[0096] HRMS (ESI + ): calcd for C 15 H 16 NO [M + H]+ 226.12319, found 226.12254.

[0097] Example 7

[0098] 2-Phenyl-N-isopropylbenzamide

[0099]

[0100] Under an argon atmosphere, (0.2 mmol) 2-Phenoxy-N-isopropylbenzamide was added to 1 mL of tetrahydrofuran. A solution of 0.8 mL of 1 mol / L phenylmagnesium bromide in tetrahydrofuran was slowly added dropwise at room temperature. The mixture was stirred at 100 °C for 48 hours. The reaction was quenched by adding 5 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (10 mL each time, 3 times). The combined extracts were dried over anhydrous sodium sulfate and separated by column chromatography using petroleum ether:ethyl acetate = 10:1 as the eluent to obtain the product with a yield of 41%.

[0101] The spectral data and mass spectrometry data of the obtained product are as follows:

[0102] 1 H NMR (500 MHz, CDCl3) δ 7.73 (dd, J = 7.6, 1.2 Hz, 1H), 7.46–7.39 (m, 7H), 7.33 (dd, J = 7.5, 1.1 Hz, 1H), 4.99 (s, 1H), 1.10 (s, 9H);

[0103] 13 C NMR (125 MHz, CDCl3) δ 168.3, 130.0, 129.8, 129.0, 128.9, 128.6, 127.7, 127.6, 51.3, 28.2.

[0104] HRMS (ESI + ): calcd for C 17 H 20 NO [M+H] + 254.15449, found 254.15724.

[0105] Example 8

[0106] 2-Phenyl-N-phenylbenzamide

[0107]

[0108] Under an argon atmosphere, (0.2 mmol) 2-phenoxy-N-phenylbenzamide was added to 1 mL of tetrahydrofuran, and 0.8 mL of a 1 mol / L solution of phenylmagnesium bromide in tetrahydrofuran was slowly added dropwise at room temperature. The reaction was stirred at 100 °C for 48 hours, and the reaction was quenched by adding 5 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (10 mL each time, 3 times), and the combined extracts were dried over anhydrous sodium sulfate. The product was separated by column chromatography using petroleum ether:ethyl acetate = 10:1 as the eluent, and the product was obtained with a yield of 89%.

[0109] The spectral data and mass spectrometry data of the obtained product are as follows:

[0110] 1 H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 7.1 Hz, 1H), 7.55 (td, J = 7.5, 1.1 Hz, 1H), 7.51–7.40 (m, 7H), 7.23 (t, J = 7.8 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.90 (s, 1H);

[0111] 13 C NMR (125 MHz, CDCl3) δ 167.1, 139.9, 139.5, 137.5, 135.2, 130.7, 130.3, 129.6, 129.0, 128.8, 128.8, 128.1, 127.9, 124.4, 119.9.

[0112] HRMS (ESI + ): calcd for C 19 H 16 NO [M+H] + 274.12319, found 274.12357.

[0113] Example 9

[0114] 4'-Methoxy-N-methyl-[1,1'-biphenyl]-2-carboxamide

[0115]

[0116] Under an argon atmosphere, (0.2 mmol) 2-phenoxy-N-methylbenzamide was added to 1 mL of tetrahydrofuran, and 0.8 mL of a 1 mol / L tetrahydrofuran solution of 4-methoxyphenylmagnesium bromide was slowly added dropwise at room temperature. The reaction was stirred at 100 °C for 48 hours. The reaction was quenched by adding 5 mL of saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (10 mL each time, 3 times), and the combined extracts were dried over anhydrous sodium sulfate. The product was separated by column chromatography using petroleum ether:ethyl acetate = 8:1 as the eluent, and the product was obtained with a yield of 95%.

[0117] The spectral data and mass spectral data of the obtained product are as follows:

[0118] 1 H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 8.6 Hz, 1H), 7.44–7.34 (m, 5H), 6.91 (dd, J = 8.6, 2.5 Hz, 1H), 6.83 (d, J = 2.5 Hz, 1H), 5.16 (s, 1H), 3.84 (s, 3H), 2.63 (d, J = 4.9 Hz, 3H);

[0119] 13 C NMR (125 MHz, CDCl3) δ 170.5, 159.3, 138.9, 135.5, 132.4, 130.1, 129.8, 128.8, 127.2, 114.0, 55.3, 26.7.

[0120] HRMS (ESI + ): calcd for C 15 H 16 NO2[M + H] + 242.11810, found 242.11795.

[0121] Example 10

[0122] N-Methyl-[1,1':4',1''-terphenyl]-2-carboxamide

[0123]

[0124] Under an argon atmosphere, (0.2 mmol) 2-phenoxy-N-methylbenzamide was added to 1 mL of tetrahydrofuran, and 0.8 mL of a 1 mol / L tetrahydrofuran solution of 4-phenyl-phenylmagnesium bromide was slowly added dropwise at room temperature. The reaction was stirred at 100 °C for 48 hours, and the reaction was quenched by adding 5 mL of saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (10 mL each time, 3 times), and the extraction solutions were combined, dried over anhydrous sodium sulfate, and separated by column chromatography using petroleum ether:ethyl acetate = 8:1 as the eluent to obtain the product with a yield of 91%.

[0125] The spectral data and mass spectral data of the obtained product are as follows:

[0126] 1 H NMR (500 MHz, CDCl3) δ 7.67 (dt, J = 14.6, 8.0 Hz, 5H), 7.51–7.36 (m, 8H), 5.35 (d, J = 4.1 Hz, 1H), 2.71 (d, J = 4.9 Hz, 3H);

[0127] 13 C NMR (125 MHz, CDCl3) δ 170.3, 140.4, 140.3, 139.0, 138.8, 135.7, 130.1, 129.0, 128.8, 127.6, 127.5, 127.2, 127.0, 26.7.

[0128] HRMS (ESI + ): calcd for C 20 H 18 NO [M+H] + 288.13884, found 288.13876.

[0129] From the above examples, it can be seen that the present invention can not only successfully synthesize 2-phenylaryl amide derivatives without the participation of transition metals and has a considerable product yield, but also shows the wide range of substrates.

[0130] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the scope of the technology disclosed by the present invention can easily think of various equivalent modifications or substitutions, and these modifications or substitutions should be covered within the protection scope of the present invention.

Claims

1. A method for preparing a 2-phenylaryl amide derivative, characterized in that: Under an inert atmosphere, using tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, 1,4-dioxane or methyl tert-butyl ether as the reaction solvent, using a 2-phenoxybenzamide derivative and an aryl Grignard reagent as raw materials, stirring at 25-100 °C for reaction, and after the reaction is completed, separating and purifying the product to obtain a 2-phenylaryl amide derivative.

2. The preparation method according to claim 1, characterized in that: The molar ratio of the 2-phenoxybenzamide derivative to the aryl Grignard reagent is 1:2 - 1:4, The dosage ratio of the reaction solvent to the 2-phenoxybenzamide derivative is 5-10:1 (mL:mmol); The reaction time is 24-48 h; thin layer chromatography is used for tracking during the reaction process.

3. The preparation method according to claim 2, characterized in that: The aryl Grignard reagent is arylmagnesium bromide or arylmagnesium chloride.

4. The preparation method according to claim 3, characterized in that: The reaction temperature is 60-100 °C.

5. The preparation method according to any one of claims 1-4, characterized in that: The specific operation of separation and purification is to first extract with ethyl acetate, then dry with anhydrous Na2SO4, filter, reduce pressure, and finally purify by column chromatography to obtain a 2-phenylaryl amide derivative.

6. The preparation method according to claim 1, characterized in that: When the 2-phenoxybenzamide derivative is a compound of formula I and the aryl Grignard reagent is phenylmagnesium bromide, the product is a compound of formula I'; Among them, R1 is 4-methoxy, 4-methyl, 5-trifluoromethyl, 5-methoxy, 5-methyl, 3-trifluoromethyl, 3-methyl, 3-methoxy, 3-fluoro-4-methyl or 3-fluoro-4-ethoxy.

7. The preparation method according to claim 1, characterized in that: When the 2-phenoxybenzamide derivative is a compound of formula II and the aryl Grignard reagent is phenylmagnesium bromide, the product is a compound of formula II'; Among them, R2 is ethyl, isopropyl, isohexyl, cyclohexyl, cyclopentyl, cycloheptyl, phenyl, benzyl or 1-naphthyl.

8. The preparation method according to claim 1, characterized in that: When the 2-phenoxybenzamide derivative is a compound of formula III and the aryl Grignard reagent is phenylmagnesium bromide, the product is a compound of formula III'; In the formula, R3 is benzyloxy, methoxy or ethoxy.

9. The preparation method according to claim 1, characterized in that: When the 2-phenoxybenzamide derivative is a compound of formula IV and the aryl Grignard reagent is arylmagnesium bromide, the product is a compound of formula IV'; Among them, R4 is 4-methoxy, 4-methyl, 3-methoxy, 3-methyl, 4-phenyl, 4-fluoro, 4-chloro or 3-fluoro.

10. A 2-phenylaryl amide derivative, characterized in that, Prepared by using the preparation method according to any one of claims 1-9.

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