Triethylamine → HCID 59176533, compound

Temperature

0 °C

To a cold (0° C.) solution of Boc-Lys(Z)—OH (Bachem, 10.0 g, 26.3 mmol) in dimethylformamide (80 mL) was added hydroxybenzotriazole-hydrate (4.3 g, 31.6 mmol), triethylamine (7.3 mL, 52.6 mmol) and EDAC (6.1 g, 31.6 mmol). After stirring at 0° C. for 1 h, 2-aminomethylpyridine (3.0 mL, 28.9 mmol) was added to the mixture. The mixture was warmed to room temperature and stirred for an additional 17 h. The mixture was diluted with aqueous saturated NaHCO3 and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0% to 5% methanol/CHCl3) to afford the desired product 27: 1H NMR (d6-DMSO) δ 8.43 (d, J=4.0 Hz, 1H), 8.39 (t, J=5.6 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.34-7.19 (m, 8H), 6.94 (d, J=7.6 Hz, 1H), 4.96 (s, 2H), 4.31 (d, J=5.6 Hz, 2H), 3.90-3.83 (m, 1H), 2.95-2.90 (m, 2H), 1.60-1.25 (m, 6H), 1.35 (s, 9H); ESI+ MS: m/z (rel intensity) 471.2 (100, [M+H]+). Step b: Preparation of (S)-tert-butyl-5-amino-6-oxo-6-(pyridin-2-ylmethyl-amino)hexylcarbamate (28). To a solution of (S)-benzyl 6-((tert-butoxycarbonyl)-amino)-1-oxo-1-(pyridin-2-ylmethylamino)hexan-2-ylcarbamate, 27, (3.8 g, 8.2 mmol) in methanol (80 mL) was added palladium (10 wt % on carbon, 0.5 g). The mixture was stirred under a hydrogen atmosphere for 2 h. The mixture was filtered through Celite and washed with methanol. The resulting filtrate was concentrated in vacuo. The crude residue was used without further purification: ESI+ MS: m/z (rel intensity) 337.2 (100, [M+H]+). Steps c and d: Preparation of tert-butyl(S)-6-oxo-6-(pyridin-2-ylmethylamino)-5-(5,6,7,8-tetrahydroquinolin-8-ylamino)hexylcarbamate (29). To a solution of (S)-tert-butyl 5-amino-6-oxo-6-(pyridin-2-ylmethyl-amino)hexylcarbamate, 28, (2.16 g, 6.43 mmol) in ethanol (14 mL) was added 6,7-dihydroquinolin-8(5H)-one (0.90 g, 6.12 mmol). The mixture was heated in microwave reactor at 150° C. for 13 min. After cooling the reaction to room temp., NaBH4 (0.46 g, 12.24 mmol) was added to the mixture. The reaction mixture was stirred at room temp for 1 h. The mixture was diluted with aqueous saturated NaHCO3, extracted twice with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (5% to 25% methanol/CH2Cl2) to afford the desired product 29: 1H NMR (d6-DMSO) δ 8.44 (d, J=4.4 Hz, 1H), 8.40 (m, 1H), 8.32-8.31 (m, 1H), 7.66 (t, J=7.2 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.20 (t, J=4.8 Hz, 1H), 7.13 (dd, J=8.0, 4.2 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 4.32 (d, J=5.6 Hz, 2H), 3.95-3.89 (m, 1H), 3.62-3.57 (m, 1H), 2.69 (d, J=4.8 Hz, 2H), 2.61-2.56 (m, 2H), 1.99-1.95 (m, 1H), 1.89-1.83 (m, 1H), 1.63-1.28 (m, 8H), 1.35 (s, 9H); ESI+ MS: m/z (rel intensity) 468.3 (100, [M+H]+). Step e: Preparation of (2S)-6-amino-N-(pyridin-2-ylmethyl)-2-(5,6,7,8-tetrahydro-quinolin-8-ylamino)hexanamide tetrahydrochloride (AZ). To a solution of tert-butyl(S)-6-oxo-6-(pyridin-2-ylmethylamino)-5-(5,6,7,8-tetrahydroquinolin-8-ylamino)-hexylcarbamate, 29, (1.07 g, 2.29 mmol) in methanol (50 mL) was bubbled HCl gas (generated from H2SO4 and NaCl). The reaction mixture was stirred at room temp. for 20 minutes. The mixture was concentrated in vacuo to afford the desired product. The tetrahydrochloride salt was used without further purification: ESI+ MS: m/z (rel intensity) 368.2 (100, [M+H]+).

1. temperatureThe mixture was warmed to room temperature
2. stirringstirred for an additional 17 h
3. extractionextracted with ethyl acetate
4. dry with materialThe organic phase was dried (MgSO4)
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customThe crude residue was purified by silica gel chromatography (0% to 5% methanol/CHCl3)

ORD record

ord-57d81d07ca4f4612bf5cb8e2a6eca00b

Source dataset

uspto-grants-2012_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08338448B2