1,2,3,4-Tetrahydroquinoline → HCID 59467900, compound

Participants

Reaction Steps

To a solution of Boc Gly-OH (80) (4.0 g, 22.83 mmol) in dry CH2Cl2 (50 mL) at 0° C. under N2 was added HATU (8.70 g, 22.9 mmol). After stirring for 15 min at r.t., 1,2,3,4-tetrahydroquinoline (2.9 mL, 23.0 mmol), and DIPEA (12 mL, 68.8 mmol) were added. The reaction was stirred for 36 h at room temperature. The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with saturated NaHCO3, 5% HCl, water, and saturated NaCl. Dried over MgSO4, and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (10-50% EtOAc in hexanes) to afford 81 as a solid (5.76 g, 87%). 2-Amino-1-(3,4-dihydroquinolin-1(2H)-yl)ethanone, TFA salt (82): Compound 81 (2.8 g, 9.66 mmol) was dissolved in 20 mL of TFA/CH2Cl2 (1:3) at 0° C. under N2 After stirring for 1 h, the solvents were removed under reduced pressure. 5 mL of CH2Cl2/hexanes were added and removed again under reduced pressure to afford 82 (3.0 g). This crude material was used in the next step with out further purification. 2-(Benzo[d]thiazol-2-ylamino)-1-(3,4-dihydroquinolin-1(2H)-yl)ethanone (83): To a 0° C. solution of 2-chlorobenzothiazole (1.20 mL, 9.66 mmol) in 1-butanol (25 mL) was added compound 82 (2.94 g, 9.66 mmol)) followed by dropwise addition of Et3N (4.5 mL, 32 mmol). The reaction was heated to reflux for 24 h under N2. The solvent was removed under reduced pressure and the product was purified by column chromatography (20-50% EtOAc in hexanes) to afford 83 as a white foam (2.58 g, 82%); MS m/z: 324 (M+H)+. Anal. Calcd. For, C18H17N3OS: C, 66.85; H, 5.30; N, 12.99; S, 9.91. Found: C, 67.01; H, 5.42; N, 12.78; S, 9.85. Benzo[d]thiazol-2-yl(2-(3,4-dihydroquinolin-1(2H)-yl)-2-oxoethyl)cyanamide (84): To a suspension of compound 83 (340 g, 1.05 mmol) in dry CH3CN (10 mL) were added cyanogen bromide (5M in CH3CN) (0.42 mL, 2.1 mmol) and K2CO3 (580 g, 4.2 mmol). The reaction was heated to reflux for 4 h under N2. 0.84 mL (4.2 mmol) of cyanogen bromide was added and the reflux was continued for 12 h. The reaction mixture was diluted with EtOAc (50 mL). The solids were filtered off, filtrate was concentrated, and the yellow residue was purified by column chromatography (20% EtOAc in hexanes) to afford 84 as an off-white solid (80 mg, 28%). MS m/z: 349 (M+H)+. Anal. Calcd. For, C19H16N4OS.0.6H2O: C, 63.53; H, 4.83; N, 15.60; S, 8.92. Found: C, 63.24; H, 4.67; N, 15.25; S, 8.76.

Provenance & Evidence