Hydrochloric Acid → (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-(tetrahydro-2H-pyran-4-ylcarbamoyl)isoquinolin-3-yl)ethylcarbamate

Participants

Reaction Steps

To a solution of (S)-3-(1-(((9H-fluoren-9-yl)methoxy)carbonylamino)ethyl)-8-chloroisoquinoline-1-carboxylic acid (349) (25.5 g, 54.0 mmol, 1.0 eq) and DMF (1.5 mL, 19.3 mmol, 0.35 eq) in CH2Cl2 (200 mL), oxalyl chloride (30 mL, 177.7 mmol, 3.29 eq) was added dropwise slowly. The resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 (100 mL). This solution was added dropwise to a solution of tetrahydro-2H-pyran-4-amine (15 mL, 133 mmol, 2.46 eq) and Et3N (30 mL, 210.9 mmol, 3.90 eq) in CH2Cl2 (200 mL) at 0° C. The mixture was warmed to RT and stirred for 30 min. 5% Hydrochloric acid aqueous solution was added to the reaction mixture until the pH=1˜2. The mixture was poured into water (400 mL), extracted with CH2Cl2 (150 mL×2). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5-10% MeOH-DCM) to afford (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-(tetrahydro-2H-pyran-4-ylcarbamoyl)isoquinolin-3-yl)ethylcarbamate (351).

Provenance & Evidence