Reaction Steps
This compound was prepared according to the procedure described for the synthesis of Example 231 substituting Example 235 in place of 231a. A solution of (S)-3-methyl-2-oxo-1-(3-(3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)benzylthio)phenyl)-6,9,12-trioxa-3-azapentadecan-15-oic acid (120 mg, 0.13 mmol, 1.00 equiv) in dichloromethane (5 mL), 2-(2-(piperazin-1-yl)ethoxy)ethanol (33.7 mg, 0.19 mmol, 1.50 equiv), N-(3-dimethylaminopropyl)-Ni−-ethylcarbodiimide hydrochloride (49.7 mg, 0.26 mmol, 2.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (30% CH3CN up to 42% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 20 mg product was obtained. This resulted in 20 mg (14%) of (S)-2-(2-(3-(15-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)-3-methyl-2,15-dioxo-6,9,12-trioxa-3-azapentadecyl)phenylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide as a yellow solid. LC-MS (ES, m/z): 1084 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 12.19 (s, 1H), 9.65 (s, 1H), 9.19 (d, J=8.4 Hz, 1H), 8.91 (d, J=15.1 Hz, 1H), 8.28 (d, J=12.9 Hz, 2H), 7.90 (s, 1H), 7.85 (d, J=4.8 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.44˜7.57 (m, 8H), 7.10˜7.22 (m, 8H), 7.01 (d, J=2.4 Hz, 1H), 5.25 (d, J=6.6 Hz, 1H), 4.34 (s, 1H), 4.05 (s, 1H), 3.50˜3.80 (m, 8H), 3.30˜3.40 (m, 8H), 1.95 (s, 2H), 1.80 (s, 2H), 1.90˜2.10 (m, 2H), 1.50˜1.80 (m, 8H).
