Reaction Steps
This compound was prepared according to the procedure described for the synthesis of (S)—N1-(4-(diethylamino)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)-N3-methyl-N3-(17-methyl-1-morpholino-4-oxo-8,11,14-trioxa-3,5,17-triazanonadecan-19-yl)isophthalamide Example 223 substituting 2,2′-azanediyldiethanol in place of 2-morpholinoethanamine. Into a 100-mL round-bottom flask, was placed a solution of (S)-4-nitrophenyl 1-(3-(4-(diethylamino)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)phenyl)-2,5-dimethyl-1-oxo-8,11,14-trioxa-2,5-diazahexadecan-16-ylcarbamate (150 mg, 0.15 mmol, 1.00 equiv) in acetonitrile (10 mL), 2,2′-azanediyldiethanol (20 mg, 0.19 mmol, 1.24 equiv), 4-dimethylaminopyridine (28 mg, 0.23 mmol, 1.49 equiv). The resulting solution was stirred for 4 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 20 mL of dichloromethane. The resulting mixture was washed with 2×30 mL of NH4Cl (aq). The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (1#-PreP-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, CH3CN and water with 0.05% TFA (22% CH3CN to 38% in 6 min, up to 100% in 1 min, down to 22% in 0.7 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 11.7 mg (6%) of (S)—N1-(4-(diethylamino)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)-N3-(1-hydroxy-3-(2-hydroxyethyl)-17-methyl-4-oxo-8,11,14-trioxa-3,5,17-triazanonadecan-19-yl)-N3-methylisophthalamide as yellow oil. LC-MS (ES, m/z): 939 [M+H]+ H-NMR (300 MHz, CD3OD, ppm) 8.96˜8.94 (d, J=5.1 Hz, 1H), 8.74˜8.72 (m, 1H), 8.39 (s, 1H), 8.17˜8.12 (m, 2H), 7.89˜7.87 (m, 2H), 7.78˜7.73 (m, 2H), 7.61˜7.56 (m, 1H), 7.25 (s, 1H), 7.18˜7.16 (m, 3H), 5.41˜5.37 (m, 1H), 4.05˜3.92 (m, 4H), 3.80˜3.39 (m, 26H), 3.13˜3.10 (m, 6H), 2.94˜2.9 (m, 3H), 2.19˜1.86 (m, 4H), 1.26˜1.22 (m, 6H).
