C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10][CH2:9]1)(C)(C)C.[H-].[Na+].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25](F)=[C:26]([Cl:29])[CH:27]=2)[CH:22]=[CH:21][N:20]=1.C([OH:38])C1C=CC=CC=1.Cl.[OH-].[Na+]>CC(N(C)C)=O.CO>[NH2:7][C@@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][C:26]=2[Cl:29])[C:19](=[O:38])[NH:20][CH:21]=[CH:22]3)[CH2:12][CH2:13]12.19 g (10.2 mmol) of cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester were dissolved in 20 ml of dimethyl acetamide. Under argon atmosphere, 814 mg (20.4 mmol) of sodium hydride (60%) were added and the mixture was stirred at room temperature. After 30 min, a solution of 2.0 g (9.26 mmol) of 1,7-dichloro-6-fluoro-isoquinoline (6) in 5 ml of dimethyl acetamide was added and stirring was continued at room temperature. After 1 h, 2.0 g (18.5 mmol) of benzyl alcohol and 740 mg (18.5 mmol) of sodium hydride (60%) were added. The reaction was stirred for 2 h at room temperature and 30 minutes at 80° C. to achieve complete conversion. The solvent was removed in vacuo and the residue was taken up in dichloromethane and washed twice with water. After drying over magnesium sulfate, the organic layer was evaporated, to furnish 4.44 g of the crude intermediate cis-[4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester. The intermediate was dissolved in methanol and treated with 2 N HCl at room temperature. After stirring for 2 d, the reaction mixture was adjusted to alkaline pH by addition of sodium hydroxide. The solvent was removed in vacuo and the residue was stirred in ethanol. Filtration and evaporation of the filtrate yielded a solid material, which was purified by preparative HPLC. The obtained trifluoroacetate was dissolved in 2 N HCl. Final lyophilization gave 433 mg of the title compound as hydrochloride. Rt=0.89 min (Method B). Detected mass: 293.2/295.2 (M+H+).
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