Reaction Steps
4-(1-Acetyl-2,3-dihydro-1H-indol-6-ylamino)-piperidine-1-carboxylic acid tert-butyl ester. The desired ester (2.37 g, 68%) was prepared as in Example 39, using 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.9 g, 19 mmol), 1-acetyl-6-aminoindoline (1.7 g, 9.8 mmol), Na(OAc)3BH (6.2 g, 29 mmol) and AcOH (3 mL, 50 mmol) in 1,2-dichloroethane (50 mL). Step B. trans-4-[(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-(3-phenyl-acryloyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester. The title compound (2.26 g, 70%) was made from the product of Step A, as described in Example 2, Step C. 1H NMR (500 MHz, CDCl3): 8.04 (s, 1H), 7.64 (d, J=15.5 Hz, 1H), 7.36-7.21 (m, 5H), 7.19 (d, J=7.7 Hz, 1H), 6.74 (dd, J=8.4, 1.3 Hz, 1H), 6.15 (d, J=15.5 Hz, 1H), 4.90-4.80 (m, 1H), 4,21-3.98 (m, 4H), 3.33-3.21 (m, 2H), 2.90-2.75 (m, 2H), 2.24 (s, 3H), 1.96-1.72 (m, 2H), 1.49-1.31 (m, 2H), 1.40 (s, 9H). MS: exact mass calculated for C29H35N3O4, 489.26; m/z found, 512.3 [M+Na]+. Step C. trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-phenyl-N-piperidin-4-yl-acrylamide. The product from Step B (100 mg, 0.2 mmol) was dissolved in 2 mL of CH2Cl2 and then TFA (2 mL) was added. After stirring for 1 h, the reaction mixture was concentrated under reduced pressure to provide the desired product (80 mg, 69%). 1H NMR (500 MHz, CDCl3): 9.20-9.14 (m, 1H), 8.61-8.49 (m, 1H), 8.00 (s, 1H), 7.64 (d, J=15.5 Hz, 1H), 7.32-7.27 (m, 5H), 7.23 (d, J=7.8 Hz, 1H), 7.67 (d, J=6.7 Hz, 1H), 6.17 (d, J=15.5 Hz, 1H), 4.97-4.85 (m, 1H), 4.21-4.15 (m, 2H), 3.54-3.35 (m, 2H), 3.21-3.16 (m, 2H), 3.07-2.93 (m, 2H), 2.24 (s, 3H), 2.16-1.95 (m, 2H), 1.82-162 (m, 2H). MS: exact mass calculated for C24H27N3O2, 389.21; n/z found, 390.3 [M+H]+. Step D. To a solution of 4-phenyl-butyraldehyde (104 mg, 0.780 mmol) and the acrylamide from Step C (232 mg, 0.60 mmol) in CH2Cl2 (0.2 M) was added Na(OAc)3BH (160 mg, 0.78 mmol). The resulting mixture was allowed to stir overnight. The reaction was quenched by the addition of satd. aq. NaHCO3 and CH2Cl2. The layers were separated, and the organic portion was extracted with brine, dried with Na2SO4, and concentrated. Purification by silica gel chromatography (1 to 5% MeOH/CH2Cl2) provided 77 mg (25%) of the desired product. 1H NMR (500 MHz, CDCl3): 7.93 (d, J=1.8 Hz, 1H), 7.56 (d, J=15.4 Hz, 1H), 7.25-7.10 (m, 10H), 7.07 (dd, J=8.3, 1.5 Hz, 1H), 6.68 (dd, J=7.8, 2.0 Hz, 1H), 6.10 (d, J=15.6 Hz, 1H), 4.83-4.68 (m, 1H), 4.15-4.02 (m, 2H), 3.25-3.15 (m, 2H), 2.62-2.53 (m, 4H), 2.16 (s, 3H), 2.08-1.81 (m, 10H). MS: exact mass calculated for C33H37N3O2, 507.29; m/z found, 508.4 [M+H]+.
