Reaction Steps
trans-4-{(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-[3-(4-chloro-phenyl)-acryloyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester. The ester (1.26 g, 87%) was prepared as in Example 20 using trans-3-(4-chloro-phenyl)-acrylic acid in place of trans-3-thiophen-3-yl-acrylic acid and 4-(1-acetyl-2,3-dihydro-1H-indol-6-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (Example 41, Step A) in place of 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone. 1H NMR (500 MHz, CDCl3): 8.02 (s, 1H), 7.56 (d, J=15.5 Hz, 1H), 7.21-7.17 (m, 5H), 6.73-6.71 (m, 1H), 6.10 (d, J=15.5 Hz, 1H), 4.84-4.79 (m, 1H), 4.17-4.12 (m, 4H), 3.29-3.24 (m, 2H), 2.80 (br s, 2H), 2.23 (s, 3H), 1.90-1.77 (m, 2H), 1.51-1.27 (m, 11H). MS: exact mass calculated for C29H34ClN3O4, 523.22; m/z found, 546.2 [M+Na]+, 548.2 [M+Na]+. Step B. trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-(4-chloro-phenyl)-N-piperidin-4-yl-acrylamide. The intermediate from Step A (1.22 g, 2.32 mmol) was dissolved in CH2Cl2 (10 mL) and was treated with TFA (10 mL). The mixture was stirred for 30 min at rt and then was concentrated in vacuo. The residue was dissolved in CH2Cl2 and treated with Dowex 550A resin. After stirring for several hours, the mixture was filtered and concentrated in vacuo to give 966 mg (98%) of the desired compound, which was taken on to the next step without further purification. Step C. The title compound (54 mg, 61%) was prepared from the intermediate from Step B (70.0 mg, 0.165 mmol) as in Example 43, using 1,2-dichloroethane as the solvent. 1H NMR (500 MHz, CDCl3): 8.04 (s, 1H), 7.57 (d, J=15.5 Hz, 1H), 7.30-7.16 (m, 5H), 6.75 (br s, 1H), 6.14 (d, J=15.5 Hz, 1H), 4.75 (br s, 1H), 4.17-4.14 (m, 2H) 3.53-3.27 (m, 4H), 2.92 (br s, 2H), 2.28-2.23 (m, 4H), 2.07-2.04 (m, 2H), 1.66-1.43 (m, 9H), 1.29-1.11 (m, 5H), 0.89-0.86 (m, 2H). MS: exact mass calculated for C32H40ClN3O2, 533.28; m/z found, 534.2 [M+H]+, 556.3 [M+Na]+.
