Реакция #489704

Уравнение реакции

benzyl alcohol

sodium hydride

HCl

sodium hydroxide

sodium hydride

1,7-dichloro-6-fluoro-isoquinoline

1,7-Dichloro-6-fluoro-isoquinoline

cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester

→

title compound

Выход 16.0%

6-(cis-4-Amino-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one

Выход 16.0%

Растворители

methanol

dimethyl acetamide

dimethyl acetamide

Условия реакции

Обработка

1. 1
   workup.STIRRINGstirring
2. 2
   Другоеwas continued at room temperature
3. 3
   workup.WAITAfter 1 h
4. 4
   workup.STIRRINGThe reaction was stirred for 2 h at room temperature and 30 minutes at 80° C.
5. 5
   ДругоеThe solvent was removed in vacuo
6. 6
   Промывкаwashed twice with water
7. 7
   СушкаAfter drying over magnesium sulfate
8. 8
   Другоеthe organic layer was evaporated
9. 9
   Другоеto furnish 4.44 g of the crude intermediate cis-[4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester
10. 10
    workup.STIRRINGAfter stirring for 2 d
11. 11
    ДругоеThe solvent was removed in vacuo
12. 12
    workup.STIRRINGthe residue was stirred in ethanol
13. 13
    ФильтрацияFiltration and evaporation of the filtrate
14. 14
    Другоеyielded a solid material, which
15. 15
    Другоеwas purified by preparative HPLC
16. 16
    workup.DISSOLUTIONThe obtained trifluoroacetate was dissolved in 2 N HCl

Методика

2.19 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+).

Источник