Indole compound as well as preparation method, pharmaceutical composition and application thereof
A technology of compound and medicinal salt, applied in the field of new indole compounds
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Embodiment 1
[0288] 4-((3-Chloro-4-fluorophenyl)amino)-1H-indole-2-carboxylic acid
[0289]
[0290] a) 4-((3-chloro-4-fluorophenyl)amino)-1H-indole-2-carboxylic acid ethyl ester
[0291] Dissolve methyl 4-bromoindole-2-carboxylate (170mg, 0.67mmol) in toluene (10mL) and add Pd successively 2 (dba) 3 (61mg, 0.067mmol), Davephos (53mg, 0.13mmol) and K 3 PO 4 (426mg, 2.01mmol, 2mLH 2 O), after stirring evenly, 3-chloro-4-fluoroaniline (292mg, 2.01mmol) was added, under the protection of argon, the reaction was refluxed for 4h, and the raw materials disappeared. Cool to room temperature, concentrate, add EA (30 mL) to dissolve the residue, wash with saturated brine (20 mL×3), wash with water (20 mL×2), and perform column chromatography (P / E=10:1) to obtain 250 mg of off-white solid, The eluate was washed and filtered to obtain 155 mg of white powdery solid with a yield of 73% and a melting point of 168-170°C.
[0292] 1 H-NMR (400MHz, Acetone-d 6 )δ (ppm): 10.93 (brs, 1H), 7.68 (s,...
Embodiment 2
[0297] 4-((3-Chloro-4-fluorophenyl)amino)-7-fluoro-1H-indole-2-carboxylic acid
[0298]
[0299] a) Ethyl 2-azido-3-(2-bromo-5-fluorophenyl)acrylate
[0300] Sodium metal (2.27g, 98.5mmol) was dissolved in absolute ethanol (70mL) and cooled to -15°C. 2-Bromo-5-fluorobenzaldehyde (5.0g, 24.6mmol) and ethyl azidoacetate (12.8g, 98.5mmol) were dissolved in absolute ethanol (20mL), added dropwise to the above solution, 0°C After reacting overnight, the starting material disappeared. Pour the reaction solution into NH 4 Cl aqueous solution (100 mL), extracted with EA (50 mL×3), and column chromatography (P / E=100:1) gave 3.271 g of white solid, yield 42.3%.
[0301] 1 H-NMR (400MHz, CDCl 3 )δ (ppm): 7.94 (dd, J 1 =10.0Hz,J 2 =2.8Hz,1H), 7.56(dd,J 1 =8.8Hz,J 2 =5.6Hz,1H),7.19(s,1H),6.92(dt,J 1 =8.0Hz,J 2 =2.8Hz, 1H), 4.40(q, J=7.2Hz, 2H), 1.42(t, J=7.2Hz, 3H).
[0302] b) ethyl 4-bromo-7-fluoro-1H-indole-2-carboxylate
[0303] Dissolve ethyl 2-azido-3-(2-bromo-5-fluor...
Embodiment 3
[0312] 4-((3-Chloro-4-fluorophenyl)amino)-7-chloro-1H-indole-2-carboxylic acid
[0313]
[0314] a) Ethyl 2-azido-3-(2-bromo-5-chlorophenyl)acrylate
[0315] Sodium metal (12.58mg, 0.55mol) was dissolved in absolute ethanol (100mL) and cooled to -15°C. 2-Bromo-5-chlorobenzaldehyde (80g, 0.36mol), ethyl azidoacetate (70.6g, 0.55mol), ethyl trifluoroacetate (85.4mol, 0.55mol) were added to the reaction solution,- React at 15°C for 2 hours, raise to 0°C and react overnight, the starting material disappears. Pour the reaction solution into saturated NH 4 In the aqueous Cl solution, a solid was precipitated, filtered and dried, and the filter cake column chromatography (P / E=50:1) gave 60.75 g of a white solid, with a yield of 50.4%.
[0316] 1 H-NMR (400MHz, CDCl 3 )δ (ppm): 8.13 (s, 1H), 7.53 (d, J = 8.4Hz, 1H), 7.15 (s, 2H), 4.40 (q, J = 7.2Hz, 2H), 1.42 (t, J = 7.2Hz, 3H).
[0317] b) ethyl 4-bromo-7-chloro-1H-indole-2-carboxylate
[0318] Dissolve ethyl 2-azido-3-(2-...
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