Synthesis method of 2, 2-diaryl acetonitrile compound

[0020] Example

[0021] 1. Based on hydrazine, N, N-dimethylaminopropones, trifluoromethanesulfonic acid aluminum is catalyst (reaction formula 1)

[0022]

[0023] In the pressure sealing tube, indole (100 mg, 0.85 mmol), N, N-dimethylaminoproponitrile (112 mg, 1.02 mmol), three were sequentially added in 1,2-dichloroethane solvent (2 mL). Fluoromethanesulfonate (81.06 mg, 0.17 mmol), at an argon atmosphere, a mixture was continuously stirred at 120 ° C for 8 hours, and the reaction was completed. The reaction tube was washed with acetone, and the resulting organic compound system was evaporated to dry and purified by column chromatography to give a pure desired product (103.06 mg, 89%).

[0024] The product detection data is as follows:

[0025] 1 H NMR (600MHz, DMSO-D 6 Δ11.17 (S, 2H), 7.59 (D, J = 7.8 Hz, 2H), 7.43-7.41 (m, 4H), 7.00 (T, J = 7.8 Hz, 2H), 7.00 (T, J = 7.8 Hz, 2H), 6.08 (S, 1H); 13 C NMR (150MHz, DMSO-D 6 ) δ136.54, 125.20, 123.69, 121.52, 12.68, 118.87, 118.49, 111.84, 109.43, 25.29; HRMS (ESI) Calcd for C18H13N3 [M + NA] + : 294.1002Found 294.1013; MP 170.9-178.3 ° C.

[0026] 2. Trifluoromethanesulfonate is a catalyst (reaction formula 2) with 4-methylindole, N, N-dimethylaminoproponitrile.

[0027]

[0028] In the pressure sealing tube, 4-methylindole (100 mg, 0.76 mmol), N, N-dimethylaminoproponitrile (1), N, N-dimethylaminoproponitrile (N), N, N-dimethylaminoproponitrile (N, N, N-dimethylaminoproponitrile) were sequentially added in the pressure sealing tube: tetrahydrofuran = 2: 1. 94 mg, 0.91 mmol), aluminum (72.36 mg, 0.15 mmol) of trifluoromethane (72.36 mg, 0.15 mmol), and the mixture was continuously stirred at 120 ° C for 8 hours under the argon atmosphere, and the reaction was completed. The reaction tube was washed with acetone, and the resulting organic compound system was evaporated to dry and purified by column chromatography on a rotary evaporator to give a pure desired product as a white solid (92.43 mg, 81%).

[0029] The product detection data is as follows:

[0030] 1 H NMR (400MHz, ACETONE-D 6 Δ10.32 (S, 2H), 7.31 (D, J = 8.0Hz, 2H), 7.01 - 7.095 (m, 2H), 7.05 (T, J = 8 Hz, 2H), 6.46 (D, J = 6.8 Hz 2H), 6.36 (S, 1H), 2.66 (s, 6h); 13 C NMR (100MHz, ACETONE-D 6 ) δ138.63, 130.60, 125.37, 125.11, 123.15, 122.55, 122.03, 113.34, 110.74, 30.67, 20.14; HRMS (ESI) Calcd for C 20 Hide 17 N 3 [M + h] + : 300.1495Found 300.1497; MP246.2-250.1 ° C.

[0031] 3. Trifluprifothalesulfonate is a catalyst (reactive 3) with 5-methylindole, N, N-dimethylaminoproponitrile.

[0032]

[0033]5-methylindole (10 mg, 0.076 mmol), N, N-dimethylaminoproponitrile (9.1 mg, "in 1,4-dioxane solvent (1 mL) was sequentially added in the pressure sealing tube (1 mL). 0.091 mmol), trifluoromethanesulfonate (5.45 mg, 0.015 mmol), under an argon atmosphere, a mixture was continuously stirred at 90 ° C for 12 hours, and the reaction was completed. The reaction tube was washed with acetone, and the resulting organic compound system was evaporated to dry and purified by column chromatography to give a white solid (7.65 mg, 67%).

[0034] The product detection data is as follows:

[0035] 1 H NMR (400MHz, ACETONE-D 6 Δ10.20 (S, 2H), 7.45 (S, 2H), 7.33 (D, J = 7.6Hz, 4H), 6.98 (D, J = 8.4 Hz, 2H), 5.86 (S, 1H), 2.37 ( s, 6h); 13 C NMR (100MHz, ACETONE-D 6 ) δ136.43, 128.99, 126.96, 124.66, 124.47, 121.20, 119.28, 112.40, 110.67, 26.65, 21.71; HRMS (ESI) Calcd for C 20 Hide 17 N 3 [M + na] + : 322.1315Found 322.1329; MP 205.1-210.1 ° C.

[0036] 4. Trifluoromethanesulfonate copper is catalyst (reactive formula 4) with 6-methylindole, N, N-diethyl aminopropones.

[0037]

[0038] In thick walls, in 1,2-dichloroethane: acetonitrile: toluene = 1: 1: 3 solvent (50 mL), 6-methylindole (5 g, 38.12 mmol), N, N, N-diethyl aminoproponitrile (7.84 g, 54.17 mmol), trifluoromethanesulfonate (2.76 g, 7.62 mmol), under an argon atmosphere, heat reflow in 100 ° C, continuously stirring reaction 18 Hour, the reaction was completed. The reaction bottle was washed with acetone, and the resulting organic compound was evaporated to dry and purified by column chromatography on a rotary evaporator to give a pure desired product as a white solid (3.994 g, 70%).

[0039] The product detection data is as follows:

[0040] 1 H NMR (400MHz, ACETONE-D 6 Δ10.13 (S, 2H), 7.52 (D, J = 8.4 Hz, 2H), 7.31 (D, J = 2.4 Hz, 2H), 7.25 (S, 2H), 6.88 (D, J = 8.4 Hz, 2H), 5.87 (S, 1H), 2.40 (S, 6H); 13 C NMR (100MHz, ACETONE-D 6 Δ138.45, 132.30, 124.62, 123.83, 121.89, 121.18, 119.40, 112.46, 111.04, 26.79, 21.79; HRMS (ESI) Calcd for c 20 Hide 17 N 3 [M + na] + : 322.1315Found 322.1328; MP174.4-186.7 ° C.

[0041] 5. Trifluoromethanesulfonate is a catalyst (reactive formula 5) with 7-methylindole, N, N-diethyl aminoproponitrile.

[0042]

[0043] In the pressure sealing tube, 7-methylindole (100 mg, 0.76 mmol), N, N-diethyl aminoproponitrile (125 mg, 0.91 mmol) were sequentially added in the dimethyl sulfone solvent (2 mL). Silver (19.60 mg, 0.08 mmol) of trifluoromethane (19.60 mg, 0.08 mmol), at an argon atmosphere, a mixture was continuously stirred at 80 ° C for 10 hours, and the reaction was completed. EtOAc EtOAc (EtOAc) EtOAc m Pu film was purified by evaporation of the obtained organic phase and evaporated on a rotary evaporator after drying with anhydrous sodium sulfate. The product was required for a white solid (96.99 mg, 85%).

[0044] The product detection data is as follows:

[0045] 1 H NMR (400MHz, ACETONE-D 6 Δ10.32 (S, 2H), 7.48-7.45 (M, 2H), 7.37 (D, J = 2.8 Hz, 2H), 6.96-6.92 (M, 4H), 5.91 (S, 1H), 2.49 (S, 6h); 13 C NMR (100MHz, ACETONE-D 6 ) δ137.49, 126.38, 124.19, 123.39, 121.89, 121.11, 121, 117.43, 111.70, 26.88, 16.94; HRMS (ESI) Calcd for c 20 Hide 17 N 3 [M + h] + : 300.1495Found 300.1495; MP 204.1-221.4 ° C.

[0046] 6. Triflufluoromethanesulfonate copper is catalyst (reaction formula 6) with 5-methoxyride, N-methyl-N-phenyl aminopropones.

[0047]

[0048] In the pressure-resistant seal tube, 5-methoxy hydrane (100 mg, 0.68 mmol), N, N-dimethylformamide: dimethyl sulfoxide = 1: 4, 5-methoxycralatin (100 mg, 0.68 mmol), N - Methyl-N-phenyl aminoproponitrile (140 mg, 0.82 mmol), trifluoromethanesulfonate (49.19 mg, 0.14 mmol), sustained to stir in 120 ° C under argon atmosphere 18 Hour, the reaction was completed. EtOAc EtOAc (EtOAc) EtOAc m Pu film was purified by evaporation of the obtained organic phase and evaporated on a rotary evaporator after drying with anhydrous sodium sulfate. The product is required for a white solid (94.56 mg, 84%).

[0049] The product detection data is as follows:

[0050] 1 H NMR (400MHz, DMSO-D 6 Δ10.99 (S, 2H), 7.34 (D, J = 2.4 Hz, 2H), 7.30 (D, J = 8.8 Hz, 2H), 7.05 (D, J = 2.4 Hz, 2H), 6.77 (DD, J = 2.8, 9.2 Hz, 2H), 5.98 (S, 1H), 3.70 (S, 6H); 13 CNMR (100MHz, DMSO-D 6 ) δ153.17, 131.61, 125.63, 124.31, 120.71, 112.54, 111.44, 109.10, 100.58, 55.35, 25.06; HRMS (ESI) Calcd for c 20 Hide 17 N 3 O 2 [M + na] + : 354.1213found 354.1228; MP 118.5-123.0 ° C.

[0051] 7. Take 4-chloronne, N-methyl-N- (4-methylphenyl) aminoproponitrile as raw material, trifluoromethanesulfonic acid is catalyst (reaction formula 7)

[0052]

[0053] 4-chloropathy (100 mg, 0.66 mmol), N-methyl-N- (4-methylphenyl) was sequentially added in the N, N-dimethylformamide solvent (2 mL). Aminoproponitrile (147 mg, 0.79 mmol), trifluoromethane (20.28 mg, 0.03 mmol), at an argon atmosphere, a mixture was continuously stirred in 100 ° C for 18 hours, and the reaction was completed. EtOAc EtOAc (EtOAc) EtOAc m Pu film was purified by evaporation of the obtained organic phase and evaporated on a rotary evaporator after drying with anhydrous sodium sulfate. The product is required for a white solid (88.65 mg, 79%).

[0054] The product detection data is as follows:

[0055] 1 H NMR (400MHz, ACETONE-D 6 Δ10.68 (S, 2H), 7.46 (D, J = 8.0 Hz, 2H), 7.29 (D, J = 2.8 Hz, 2H), 7.08 (T, J = 7.6 Hz, 2H), 7.08 (D, J = 7.2Hz), 6.87 (S, 1H); 13 C NMR (100MHz, ACETONE-D 6 ) δ139.57, 126.95, 125.95, 123.74, 123.11, 121.71, 121.21, 112.52, 111.95, 27.78; HRMS (ESI) Calcd for c 18 Hide 11 CL 2 N 3 [M + na] + : 362.0222 Found 362.0235; MP 230.0-235.8 ° C.

[0056] 8. Triflufluoromethanesulfonate is a catalyst (reaction formula 8) with 5-chloronidine, 2- (piperidin-1-yl) propenyndomin.

[0057]

[0058] In the pressure-resistant seal tube, 5-chloronne (100 mg, 0.66 mmol) in the solvent (4 mL) of tetrahydrofuran: acetonitrile: acetonitrile: acetonitrile: acetonitrile: nitrin = 1: 1: 1: 1 ), 2- (piperidin-1-yl) proprialonitrile (118 mg, 0.79 mmol), trifluoromethanesulfonate (42.50 mg, 0.13 mmol), continuous mixture in 70 ° C under argon atmosphere The mixture was stirred for 18 hours and the reaction was completed. The reaction tube was washed with acetone, and the resulting organic compound system was evaporated to dry and purified by column chromatography to give a pure desired product as a white solid (89.77 mg, 80%).

[0059] The product detection data is as follows:

[0060] 1 H NMR (400MHz, CDCL 3Δ8.31 (S, 2H), 7.50 (D, J = 2.0 Hz, 2H), 7.24 (D, J = 8.4 Hz, 2H), 7.14-7.10 (m, 4H), 5.48 (S, 1H); 13 C NMR (100MHz, CDCL 3 ) δ134.88, 126.18, 125.76, 124.62, 123.10, 119.52, 118.02, 112.77, 109.13, 26.05; HRMS (ESI) Calcd for c 18 Hide 11 CL 2 N 3 [M + na] + : 362.0222 Found 362.0238; MP 163.0-175.4 ° C.

[0061] 9. Tienesulfonic acid tin as a catalyst (reactive 9) with 6-chloronidine, 2- (5-methylpiperidine-1-yl) propenyndomoine

[0062]

[0063] In the pressure sealing tube, 6-chloronne (200 mg, 1.32 mmol), 2- (5-methylpiperidine-1-yl) propenneston (258 mg, 1.58) were sequentially added in the dichloromethane solvent (6 mL). Mmol), tin tin (108.12 mg, 0.26 mmol), at an argon atmosphere, a mixture was continuously stirred at 60 ° C for 14 hours, and the reaction was completed. The reaction tube was washed with acetone, and the resulting organic compound system was evaporated to dry and purified by column chromatography to give a pure desired product as a white solid (184.03 mg, 82%).

[0064] The product detection data is as follows:

[0065] 1 H NMR (400MHz, DMSO-D 6 Δ11.33 (S, 2H), 7.52 (D, J = 8.8 Hz, 2H), 7.46 (D, J = 2.0 Hz, 4H), 7.02 (DD, J = 2.0, 8.4 Hz, 2H), 6.11 ( s, 1h); 13 C NMR (100MHz, DMSO-D 6 Δ136.97, 126.47, 125.01, 123.94, 125.01.57, 119.40, 111.57, 109.55, 25.05; HRMS (ESI) Calcdfor C 18 Hide 11 CL 2 N 3 [M + na] + : 362.0222 Found 362.0236; MP 175.6-178.2 ° C.

[0066] 10. Triflufluoromethanesulfonic acid is a catalyst (reactive 10) with 7-chloronne, 2- (morpholine-1-yl) propenyndomin.

[0067]

[0068] In the pressure sealing tube, 7-chloronne (100 mg, 0.66 mmol), 2- (morpholine-1-yl) propennitrile (119 mg) were sequentially added in the solvent (2 ml) of toluene: diethyl ether = 3: 1. 0.79 mmol), trifluoromethanesulfonic acid (77.76 mg, 0.16 mmol), under an argon atmosphere, a mixture was continuously stirred at 60 ° C for 12 hours, and the reaction was completed. The reaction tube was washed with acetone, and the resulting organic compound system was evaporated to dry and purified by column chromatography to give a pure desired product (94.26 mg, 84%).

[0069] The product detection data is as follows:

[0070] 1 H NMR (400MHz, ACETONE-D 6 Δ10.37 (S, 2H), 7.61 (D, J = 8.0 Hz, 2H), 7.57 (D, J = 2.8 Hz, 2H), 7.22 (D, J = 7.6 Hz, 2H), 7.04 (T, J = 8.0Hz, 2H), 6.04 (S, 1H); 13 C NMR (100MHz, ACETONE-D 6 ) δ134.84, 128.23, 125.75, 122.44, 121.28, 12.50, 118.61, 117.54, 112.10, 26.70; HRMS (ESI) Calcd for c 18 Hide 11 CL 2 N 3 [M + na] + : 362.0222 Found 362.0237; MP 161.2-168.8 ° C.

[0071] 11. Triflufluoromethanesulfonic acid is a catalyst (reactive 11) with 5-fluorone, 2- (2,6-dimethyl-morphine-4-yl).

[0072]

[0073] In the pressure seal tube, 5-fluorone (50 mg, 0.37 mmol) was sequentially added in N, N-dimethylformamide: dichloromethane: ethanol solvent (1.5 mL), 2- (2, 6-) Methyl - morpholine-4-yl) malononitrile (100 mg, 0.56 mmol), trifluoromethanesulfonic acid 钪 (36.42 mg, 0.08 mmol), at an argon atmosphere, a mixture is continuously stirred in 80 ° C 12 Hour, the reaction was completed. The reaction tube was washed with acetone, and the resulting organic compound system was evaporated to dry and purified by column chromatography to give a pure desired product as a red solid (50.60 mg, 89%).

[0074] The product detection data is as follows:

[0075] 1 H NMR (400MHz, ACETONE-D 6 Δ10.51 (S, 2H), 7.57 (D, J = 2.0 Hz, 2H), 7.46 (Q, J = 4.4 Hz, 2H), 7.28 (DD, J = 2.0, 9.9 Hz, 2H), 6.96- 9.91 (m, 2H), 5.96 (S, 1H); 13 C NMR (100MHz, DMSO-D 6 Δ156.76 (D, J = 230.9 Hz), 133.28, 125.89, 125.36 (D, J = 10.1 Hz), 120.42, 113.10 (D, J = 9.7 Hz), 109.91 (D, J = 25.9 Hz), 103.18 (D, J = 23.7Hz), 25.12; HRMS (ESI) Calcd for C 18 Hide 11 Fly 2 N 3 [M + na] + : 330.0813 Found 330.0826; MP 179.7-188.5 ° C.

[0076] 12. Take 5-bromonin, N-methyl-N- (4-chlorophenyl) aminoproponitrile as raw material, copper fluorinated copper is a catalyst (reactive 12)

[0077]

[0078] In the hexafluoropropyl alcohol solvent (2.5 mL), 5-bromo-N- (4-chlorophenyl) aminoproponitrile is sequentially added in the hexafluoropropyl alcohol solvent (2.5 mL). (210 mg, 1.02 mmol), copper fluoride (10.30 mg, 0.10 mmol), under an argon atmosphere, a mixture was continuously stirred at 60 ° C for 18 hours, and the reaction was completed. The reaction tube was washed with acetone, and the resulting organic compound system was evaporated to dry and purified by column chromatography on a rotary evaporator to give a pure desired product as a white solid (83.18 mg, 76%).

[0079] The product detection data is as follows:

[0080] 1 H NMR (400MHz, ACETONE-D 6 Δ10.54 (S, 2H), 7.84 (D, J = 0.8 Hz, 2H), 7.54 (D, J = 2.4 Hz, 2H), 7.43 (D, J = 8.8 Hz, 2H), 7.27 (DD, J = 1.6, 8.4 Hz, 2H), 6.00 (S, 1H); 13 C NMR (100MHz, DMSO-D 6 ) δ135.27, 126.87, 125.49, 124.18, 12.61, 12.33, 114.05, 111.59, 108.89, 24.79; HRMS (ESI) Calcd for c 18 Hide 11 Br 2 N 3 [M + h] + : 429.9372 Found 429.9371; MP219.6-223.7 ° C.

[0081] 13. Take 5-methyl-N- (4-fluorophenyl) aminoproponitrile as a raw material, aluminum trifluoromethanesulfonic acid is a catalyst (reaction formula 13)

[0082]

[0083] In the pressure-resistant seal tube, 5-methyl hydrazine (300 mg, 1.71 mmol), N-methyl-N-N-N-N-N-N-N-N-N-N-Dioxane (4 mL) was sequentially added in the pressure-resistant sealing tube: ethanol = 3: 1. - (4-fluorophenyl) aminoproponitrile (483 mg, 2.55 mmol), trifluoromethanesulfonic acid (162.66 mg, 0.33 mmol), under an argon atmosphere, mixture is continuously stirred in 80 ° C for 8 hours The reaction is completed. The obtained organic compound system was purified to dry and evaporated on a rotary evaporator with anhydrous sodium sulfate using diethyl ether and mixed with anhydrous sodium sulfate. The product was red solid (86.24 mg, 26%).

[0084] The product detection data is as follows:

[0085] 1 H NMR (400MHz, DMSO-D 6 Δ11.61 (S, 2H), 8.31 (S, 2H), 7.78 (DD, J = 1.2, 8.4 Hz, 2H), 7.53-7.48 (M, 4H), 6.37 (S, 1H), 3.82 (S 6h); 13 C NMR (100MHz, DMSO-D 6 δ167.07, 139.27, 125.92, 124.83, 122.71, 121.20, 12.62, 12.50, 112.08, 110.70, 51.80, 24.86; HRMS (ESI) Calcd for C 22 Hide 17 N 3 O 4 [M + h] + : 388.1292 Found 388.1292; MP 255.6-266.9 ° C.

[0086] 14. Take 5-trifluoromethylindole, N-methyl-N-benzyl aminopropones as raw materials, aluminum trifluoromethanesulfonic acid is catalyst (reaction formula 14)

[0087]

[0088] 5-trifluoromethylindole (100 mg, 0.54 mmol), N-methyl-N-benzyl aminoproponitrile (100 mg, 0.54 mmol) were sequentially added in the trichloromethane solvent (3 mL). ), Trifluoromethanesulfonate (54.22 mg, 0.11 mmol), under an argon atmosphere, a mixture was continuously stirred at 70 ° C for 18 hours, and the reaction was completed. The reaction tube was washed with acetone, and the resulting organic compound system was purified to dry and purified by column chromatography on a rotary evaporator to give a pure desired product as a white solid (70.40 mg, 64%).

[0089] The product detection data is as follows:

[0090] 1 H NMR (400MHz, ACETONE-D 6 δ 10.84 (S, 2H), 8.06 (S, 2H), 7.73-7.64 (m, 4H), 7.47 (DD, J = 1.6, 8.8 Hz, 2H), 6.26 (S, 1H); 13 C NMR (100MHz, ACETONE-D 6 δ 139.63, 126.55 (Q, J = 269.1 Hz), 127.89, 127.13, 122.25 (Q, J = 31.4 Hz), 120.65, 119.56 (Q, J = 3.2Hz), 117.32 (Q, J = 4.2 Hz), 113.67, 112.14, 26.37; HRMS (ESI) Calcd for C 20 Hide 11 Fly 6 N 3 [M + h] + : 408.0930Found 408.0945; MP 275.1-286.6 ° C.

[0091] 15. N-methylindole, N-methyl-N- (4-chlorobenzyl) aminoproponitrile as raw material, alumina is a catalyst (reaction formula 15)

[0092]

[0093] In thick walls, in 1,4-dioxane: dimethyl sulfoxide: tetrahydrofuran: acetonitrile: Trichloromethane = 1: 1: 1: 1: 1 Solvent (10 mL) sequentially added n - Methyl hydrazine (1 g, 7.6 mmol), N-methyl-N- (4-chlorobenzyl) aminoproponitrile (2.01 g, 9.1 mmol), alumina (151 mg, 1.5 mmol), in argon Under the atmosphere, the mixture was heated in 80 ° C, and the reaction was stirred for 13 hours, and the reaction was completed. The obtained organic compound system was purified to dry and purified to dry and purified by column chromatography on a rotary evaporator with a saturated brine-extract system (15 ml / 5 times). For the white solid (958.52 mg, 84%).

[0094] The product detection data is as follows:

[0095] 1 H NMR (400MHz, DMSO-D 6 ) Δ7.62 (d, j = 7.6 Hz, 2H), 7.42 (t, j = 8.4 Hz, 4H), 7.19 (T, J = 8.0 Hz, 2H), 7.05 (T, J = 8.0 Hz, 2H) 6.10 (S, 1H), 3.75 (S, 6H); 13 C NMR (100MHz, DMSO-D 6 ) δ136.94, 127.90, 125.49, 121.68, 12.65, 119.08, 118.70, 110.08, 108.60, 32.41, 24.93; HRMS (ESI) Calcd for C 20 Hide 17 N 3 [M + na] + : 322.1315 Found 322.1326; MP 65.7-77.6 ° C.

[0096] 16. Raw material in 5-bromo-N-methylindole, N, N-dimethylaminopropones, alumina as catalyst (reaction formulation 16)

[0097]

[0098] 5-bromine-N-methylindole (100 mg, 0.48 mmol), N, N-dimethylaminoproponitrile (78 mg) were sequentially added in the diamel sulfone solvent (2 mL). 0.71 mmol), alumina (10 mg, 0.10 mmol), at an argon atmosphere, a mixture was continuously stirred at 120 ° C for 5 hours, and the reaction was completed. EtOAc EtOAc (EtOAc) EtOAc m Pu film was purified by evaporation of the obtained organic phase and evaporated on a rotary evaporator after drying with anhydrous sodium sulfate. The product is required for a white solid (83.79 mg, 77%).

[0099] The product detection data is as follows:

[0100] 1 H NMR (400MHz, ACETONE-D 6 Δ7.78 (S, 2H), 7.40 (T, J = 3.6 Hz, 4H), 7.31 (DD, J = 2.0, 8.8 Hz, 2H), 5.99 (S, 1H), 3.84 (S, 6H); 13 C NMR (100MHz, ACETONE-D 6 δ 136.48, 128.00, 126.09, 125.53, 121.81, 12.57, 114.49, 113.12, 110.15, 30.67, 26.35;

[0101] HRMS (ESI) Calcd for C 20 Hide 15 Br 2 N 3 [M + na] + : 479.9504Found 479.9522; MP 177.7-181.7 ° C.

[0102] 17. Catalyst (reaction formula 17) is catalyst (reaction formula 17) with 2-methyl hydrazine, N, N-dibutylpropylonitrile.

[0103]

[0104] 2-methylindole (10 mg, 0.076 mmol), N, N-dibutylamine (19.16 mg, 0.099 mmol), oxidation were sequentially added in the n-heptane solvent (1 mL). Aluminum (1.55 mg, 0.0152 mmol), under an argon atmosphere, a mixture was continuously stirred at 80 ° C for 12 hours, and the reaction was completed. The obtained organic compound system was purified to dry and purified by column chromatography on a rotary evaporator using diethyl ether and a saturated brine-extracted system (3 ml / 5 times), and the obtained organic compound system was evaporated to dry and purified by column chromatography to give pure desired product. It is a white solid (8.22 mg, 72%).

[0105] The product detection data is as follows:

[0106] 1 H NMR (400MHz, ACETONE-D 6 Δ10.17 (S, 2H), 7.63 (D, J = 7.6 Hz, 2H), 7.33 (D, J = 8.0 Hz, 2H), 7.05 (TD, J = 0.8, 7.2 Hz, 2H), 6.97 ( TD, J = 0.8, 7.6 Hz, 2H), 5.95 (S, 1H), 2.45 (S, 6H); 13 C NMR (100MHz, ACETONE-D 6 Δ136.29, 133.60, 128.17, 121.75, 121.23, 119.99, 118.92, 111.57, 106.04, 25.13, 12.09; HRMS (ESI) Calcd for C 20 Hide 17 N 3 [M + na] + : 322.1315Found 322.1327; MP 231.2-236.6 ° C.

[0107] 18. Catalyst (reaction formula 18) is catalyst (reaction formula 18) with 2-methyl-5-methylindole, N, N-dipropyl aminoproponitrile.

[0108]

[0109] In thick walls, 2-methyl-5-methylindole (1 g, 6.89 mmol), N-methyl-5-methylindole (1 g, 6.89 mmol), N-methyl, 6.89 mmol, N, 1: 1: 1: 1: 4, 1,2-dichloroethane: Tetrahydrofuran = 1: 4. N-dipropyl aminoproponitrile (1.37 g, 8.26 mmol), aluminum chloride (183.7 mg, 1.378 mmol), under the surrounding argon atmosphere, heat reflow in 100 ° C, continuously stirred for 6 hours, The reaction was completed. The reaction tube was washed with acetone, and the resulting organic compound system was evaporated to dryness and purified by column chromatography to give a pure desired product as a white solid (7444.11 mg, 66%).

[0110] The product detection data is as follows:

[0111] 1 H NMR (400MHz, ACETONE-D 6 Δ9.97 (S, 2H), 7.42 (S, 2H), 7.16 (D, J = 8.4 Hz, 2H), 6.85 (DD, J = 1.2, 8.4 Hz, 2H), 5.83 (S, 1H), 2.37 (S, 6H), 2.30 (s, 6h); 13 C NMR (100 MHz, ACETONE-D 6 ) δ134.63, 133.55, 128.65, 128.49, 123.26, 121.31, 118.76, 111.26, 105.62, 25.12, 21.85, 12.15; HRMS (ESI) Calcd for C 22 Hide 21 N 3 [M + na] + : 350.1682 Found 350.1643; MP231.2-236.4 ° C.

[0112] 19. Take 2-methyl-5-fluorone, N-ethyl-N-phenyl aminopropones, aluminum chloride as catalyst (reaction formulation 19)

[0113]

[0114]In the pressure-resistant seal tube, 2-methyl-5-fluorone is sequentially added in the solvent (2 mL) of tetrahydrofuran: tetrahydrofuran: tetrahydrofuran: ethanol: dichloromethane = 1: 1: 1: 1. (100 mg, 0.67 mmol), N-ethyl-N-phenyl aminoproponitrile (137 mg, 0.74 mmol), aluminum chloride (17.87 mg, 0.13 mmol), a mixture is continuously stirred at 70 ° C under an argon atmosphere 9 hours, the reaction was completed. The reaction tube was washed with acetone, and the obtained organic compound system was evaporated to dry and purified by column chromatography on a rotary evaporator to give a pure desired product as a yellow solid (89.93 mg, 80%).

[0115] The product detection data is as follows:

[0116] 1 H NMR (400MHz, ACETONE-D 6 Δ10.34 (S, 2H), 7.35 (Q, J = 4.4 Hz, 2H), 7.27 (DD, J = 2.8, 10.4 Hz, 2H), 6.87 (DT, J = 2.4, 9.2 Hz, 2H), 5.94 (S, 1H), 2.47 (S, 6H); 13 C NMR (100MHz, ACETONE-D 6 Δ158.45 (D, J = 230.7 Hz), 136.12, 132.85, 128.32 (D, J = 10.1 Hz), 120.89, 112.61 (D, J = 9.6 Hz), 109.68 (D, J = 26 Hz), 105.87 ( D, J = 4.5 Hz), 103.69 (D, J = 24.4 Hz), 25.09, 12.17; HRMS (ESI) Calcd for C 20 Hide 15 Fly 2 N 3 [M + na] + : 358.1126found 358.1140; MP181.4-199.0 ° C.

[0117] 20. Take 2-phenyl hydrazine, N-butyl-N-phenyl aminopropones as raw materials, palladium bisphenylphosphine dichloride is a catalyst (reaction formulation 20)

[0118]

[0119] 2-phenyl hydrazine (150 mg, 0.78 mmol), N-butyl-N-phenyl aminoproponitrile (248 mg, 1.16 mmol), double three in the acetonitrile solvent (4 ml) Pallanyl phosphine (27.37 mg, 0.039 mmol), at a surrounding of an argon, and the mixture was continuously stirred at 90 ° C for 18 hours, and the reaction was completed. The reaction tube was washed with acetone, and the resulting organic compound system was evaporated to dry and purified by column chromatography to give a pure desired product as a yellow solid (98.62 mg, 60%).

[0120] The product detection data is as follows:

[0121] 1 H NMR (400MHz, ACETONE-D 6 Δ10.67 (S, 2H), 7.93 (D, J = 8.0 Hz, 2H), 7.53-7.50 (M, 6H), 7.35-7.27 (M, 6H), 7.21 (T, J = 7.2 Hz, 2H ), 7.07 (t, j = 7.6 Hz, 2H), 6.06 (S, 1H); 13 CNMR (100MHz, ACETONE-D 6 ) δ137.32, 137.14, 132.74, 129.45, 129.28, 128.96, 128.05, 122.98, 121.46, 12.72, 12.61, 112.40, 107.14, 27.07; HRMS (ESI) Calcd for c 30 Hide 21 N 3 [M + na] + : 446.1628Found 446.1640; MP 101.0-129.9 ° C.

[0122] 21. Triflufluoromethanesulfonate is a catalyst (reactive 21) with 3-methylindole, N, N-dimethylaminoproponitrile.

[0123]

[0124] 3-methylindole (10 g, 76.23 mmol), N, N-dimethylaminoproponitrile (10 g, 76.23 mmol), N, N-dimethylaminoproponitrile (10 g, 76.23 mmol), N, N-dimethylaminoproponiton (N, N, N, N, N, N, N, N, N, N, N, N, N, N) were sequentially added in the 1,4-dioxane solvent (100 mL). 12.48 g, 114.35 mmol), zinc trifmenesulfonate (1.386 g, 3.81 mmol), under an argon atmosphere, the mixture was heated in 80 ° C, and the reaction was stirred for 3 hours, and the reaction was completed. EtOAc EtOAc m PETE was purified by hydraulous sodium sulfate with anhydrous sodium sulfate using diethyl ether and mixed with anhydrous sodium sulfate. For yellow solid (7.99 g, 70%).

[0125] The product detection data is as follows:

[0126] 1 H NMR (400MHz, ACETONE-D 6 Δ10.15 (S, 2H), 7.54 (D, J = 7.6 Hz, 2H), 7.36 (D, J = 8.0 Hz, 2H), 7.16-7.05 (M, 4H), 6.23 (s, 1h), 2.38 (S, 6H); 13 C NMR (100MHz, ACETONE-D 6 ) δ137.15, 129.88, 126.63, 123.09, 126.63, 123.09, 12.06, 112.22, 109.86, 28.07, 8.60; HRMS (ESI) Calcd for c 20 Hide 17 N 3 [M + h] + : 300.1495Found 300.1501; MP 232.4-240.5 ° C.

[0127] 22. Trifluoromethanesulfonate is a catalyst (reactive 22) with pyrrole, 2- (piperidine-1-yl) propenpron, silver trifluoromethanesulfonate

[0128]

[0129] In thick walls, in N, N-dimethylformamide: dimethyl sulfoxide: tetrahydrofuran: 1,2-dichloroethane = 5: 1: 5: 9 solvent (40 mL) Pyrrole (12 g, 178.86 mmol), 2- (piperidin-1-yl) propennectile (2.67 g, 179.10 mmol), silver methanesulfonate (9.20 mg, 35.82 mmol), under argon atmosphere, The mixture was heated in 80 ° C, and the reaction was continued for 12 hours, the reaction was completed. EtOAc EtOAc m PETE was purified by hydraulous sodium sulfate with anhydrous sodium sulfate using diethyl ether and mixed with anhydrous sodium sulfate. For brown oily liquids (9.19 g, 62%).

[0130] The product detection data is as follows:

[0131] 1 H NMR (400MHz, ACETONE-D 6 Δ10.13 (S, 2H), 6.78 (D, J = 1.2 Hz, 2H), 6.11 (D, J = 1.2 Hz, 2H), 6.05 (D, J = 2.8 Hz, 2H), 5.59 (S, 1h); 13 C NMR (100MHz, CDCL 3 ) δ 122.79, 119.44, 117.71, 109.04, 108.32, 29.99; HRMS (ESI) Calcd for C 10 Hide 9 N 3 [M + h] + : 172.0869found172.0869.

[0132] 23. Triflufluoromethanesulfonic acid is catalyst (reactive 23) with N-methylpyrrole, 2- (3,5-dimethylpiperidine-1-yl).

[0133]

[0134] N-methylpyrrole (100 mg, 1.23 mmol), 2, 2 mg, 1.23 mmol), 2, 2-dichlorometholide: 1,2-dichloromethylformamide: 1,2-dichloromethalamide: 1,2-dichloromethane = 1: 1. (3,5-dimethylpiperidin-1-yl) propennitrile (437 mg, 2.47 mmol), trifluoromethanesulfonic acid 钪 (91 mg, 0.18 mmol), under an argon atmosphere, mixture in 100 ° C The mixture was continued for 6 hours and the reaction was completed. EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc Ethalm Sodium Sodium Sodium EtOAc For brown oily liquids (68.78 mg, 56%).

[0135] The product detection data is as follows:

[0136] 1 H NMR (400MHz, ACETONE-D 6 Δ6.72 (T, J = 2.4 Hz, 2H), 6.01-5.99 (m, 2H), 5.74 (S, 1H), 3.57 (S, 6H); 13 C NMR (100MHz, ACETONE-D 6 ) δ125.11, 124.90, 118.75, 109.76, 107.67, 34.18, 28.67; HRMS (ESI) Calcd for C 12 Hide 13 N 3 [M + h] + : 200.1182 Found 200.1182.

[0137] 24. Trifluoromethanesulfonic acid nickel is a catalyst (reaction formula 24) with 2-methylpyrrole, N, N-dimethylaminopropones.

[0138]

[0139] In thick walls, 2-methylpyrrole (1 g, 12.31 mmol), N, N-dimethylaminoproponitrile (2.69 g, 24.62 mmol), trifluoride were sequentially added in diethyl ether solvent (10 mL). Nickel (653 mg, 1.83 mmol) of mesylate (653 mmol) was heated in an argon atmosphere, and the mixture was heated in 60 ° C, and the reaction was continuously stirred for 18 hours, and the reaction was completed. The reaction tube was washed with acetone, and the resulting organic compound system was evaporated to dry and purified by column chromatography, which was purified by column chromatography to give a pure desired product (711.3 mg, 58%).

[0140] The product detection data is as follows:

[0141] 1 H NMR (400MHz, ACETONE-D 6Δ9.77 (S, 2H), 5.94 (S, 2H), 5.69 (S, 2H), 5.39 (S, 1H), 2.17 (S, 6H); 13 C NMR (100MHz, ACETONE-D 6 ) δ129.50, 124.00, 119.56, 108.10, 106.63, 12.16; HRMS (ESI) Calcd for C 12 Hide 13 N 3 [M + h] + : 200.1182Found 200.1182.

[0142] 25. Tienyl-3,5-dimethylpyrrole, N-methyl-N-phenyl aminoproponitrile, trifluoromethanesulfonate is catalyst (reaction formula 25)

[0143]

[0144] In the pressure sealing tube, 4-ethyl-3,5-dimethylpyrrole (100 mg, 0.82 mmol), N-methyl-N-phenyl aminoproponitrile was sequentially added in the acetonitrile solvent (2 mL). 277 mg, 1.62 mmol, trifluoromethanesulfonate (66.70 mg, 0.16 mmol), under an argon atmosphere, a mixture was continuously stirred at 120 ° C for 3 hours, and the reaction was completed. The reaction tube was washed with acetone, and the resulting organic compound system was evaporated to dry and purified by column chromatography to give a pure desired product (66.71 mg, 58%).

[0145] The product detection data is as follows:

[0146] 1 H NMR (400MHz, ACETONE-D 6 Δ9.16 (S, 2H), 5.45 (S, 1H), 2.32 (DD, J = 7.2, 14.8 Hz, 4H), 2.00 (S, 6H), 1.00 (T, J) = 7.6Hz, 6H); 13 C NMR (100MHz, ACETONE-D 6 ) δ123.63, 121.38, 119.52, 118.25, 114.83, 27.02, 18.25, 16.17, 10.97, 9.23; HRMS (ESI) Calcd for C 18 Hide 25 N 3 [M + h] + : 284.2121found 284.2127.

[0147] 26. Based on phenylglycine ethyl ester, N-methyl-N-phenyl aminopropones as raw materials, aluminum chloride is a catalyst (reaction formula 26)

[0148]

[0149] In the pressure-resistant sealed tube, phenylglycine ethyl ester (100 mg, 0.56 mmol) was sequentially added in the solvent (2 ml) of acetonitrile: 1,2-dichloroethane = 1: 1: 2. N-methyl-N-phenyl aminoproponitrile (115 mg, 0.67 mmol), aluminum chloride (14.93 mg, 0.11 mmol), at an argon atmosphere, a mixture is continuously stirred at 120 ° C for 10 hours The reaction is completed. EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc Ethalm Sodium Sodium Sodium EtOAc EtOAc It is a white solid (63.99 mg, 58%).

[0150] The product detection data is as follows:

[0151] 1 H NMR (400MHz, CDCL 3 Δ7.11 (D, J = 8.4 Hz, 4H), 6.56 (D, J = 8.4 Hz, 4H), 4.94 (S, 1H), 4.37 (S, 2H), 4.24 (Q, J = 6.8 Hz, 4H), 3.87 (S, 4H), 1.29 (T, J = 8.0 Hz, 6H);

[0152] 13 C NMR (100MHz, CDCL 3 Δ170.82, 146.65, 128.62, 125.71, 12.50, 113.16, 61.36, 45.62, 40.94, 14.13; HRMS (ESI) Calcd for C 22 Hide 25 N 3 O 4 [M + h] + : 396.1918Found 396.1929; MP87.5-93.4 ° C.

[0153] 27. Phenylglycine methyl ester, 2-morpholino propylene diaphonitrile as raw material, copper fluorinated copper is a catalyst (reaction formula 27)

[0154]

[0155] The phenylglycine (100 mg, 0.61 mmol), 2-morpholinocedronitrile (137 mg, 0.91 mmol) was added in dichloromethane: diethyl ether = 3: 1. Copper fluoride (12.22 mg, 0.12 mmol), at an argon atmosphere, a mixture was continuously stirred at 60 ° C for 10 hours, and the reaction was completed. The reaction tube was washed with acetone, and the resulting organic compound system was evaporated to dry and purified by column chromatography to give a pure desired product as a white solid (67.84 mg, 61%).

[0156] The product detection data is as follows:

[0157] 1 H NMR (400MHz, CDCL 3 Δ7.12 (D, J = 8.4 Hz, 4H), 6.56 (D, J = 8.4 Hz, 4H), 4.94 (S, 1H), 4.16 (S, 2H), 3.89 (S, 4H), 3.77 ( s, 6h); 13 C NMR (100MHz, CDCL 3 ) δ 171.35, 146.59, 128.64, 125.83, 12.45, 113.21, 52.23, 45.46, 40.94; HRMS (ESI) Calcd for C 20 Hide 21 N 3 O 4 [M + h] + : 368.1605found 368.1620; MP 132.7-140.8 ° C.

[0158] 28. Trifluoromethanesulfonic acid aluminum is a catalyst (reactive 28) with N, N-N-phenylglycine ethyl ester, N, N-dimethylaminopropones.

[0159]

[0160] N-methyl-N-phenylglycine (100 mg, 0.52 mmol), N, N-methyl-N-phenylglycine, N, N-methyl-N-phenylglycine, N, N-methyl-N-phenylglycine, N, N-methyl-N-phenylglycine, N, N-methyl-N-phenylglycine, N, N-methyl-N-phenylglycine, N, N-methyl-N-phenylglycine (100 ml), N-dimethylaminoproponitrile (68 mg, 0.62 mmol), trifluoromethanesulfonate (49.08 mg, 0.10 mmol), under an argon atmosphere, a mixture is continuously stirred at 80 ° C for 12 hours, and the reaction is completed . The reaction tube was washed with acetone, and the resulting organic compound system was evaporated to dry and purified by column chromatography to give a white solid (63.55 mg, 58%).

[0161] The product detection data is as follows:

[0162] 1 H NMR (400MHz, ACETONE-D 6 Δ7.22-7.18 (m, 4H), 6.73-6.69 (m, 4H), 5.23 (S, 1H), 4.04 (S, 6H), 1.20 (T, J = 7.2Hz, 6H); 13 C NMR (100MHz, ACETONE-D 6 δ171.07, 149.60, 129.06, 126.07, 121.60, 113.15, 61.10, 54.23, 40.85, 39.55, 14.58; HRMS (ESI) Calcd for c 24 Hide 29 N 3 O 4 [M + h] + : 424.2231 Found 424.2240.