5,6-二氟-2,3-二氢-1H-茚-2-胺

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To an acetic acid solution (100 mL) containing 5,6-difluoro-1H-indene-1,2(3H)-dione 2-oxime (3.97 g, 20.2 mmol) in a Parr bottle was added 8 mL of concentrated HCl followed by 10% Pd/C (1.07 g). The solution was hydrogenated at 50 psi for 24 hours on a Parr hydrogenator. The heterogeneous solution was filtered through a bed of Celite with the celite being rinsed thoroughly with chloroform. The solvent was then removed in vacuo and the residual dark oil dissolved in water. The aqueous solution was then made basic with solid K2CO3. The organics were extracted with chloroform three times followed by drying over MgSO4. The solvent was removed in vacuo and the residual amber oil purified by column chromatography (10% MeOH/CH2Cl2) yielding 1.06 g (6.26 mmol) of 5,6-difluoro-2,3-dihydro-1H-inden-2-amine as a brown oil. 1H NMR (400 MHz, CDCl3) delta 6.95 (t, 2H, J=8.9 Hz), 3.83 (m, 1H), 3.10 (dd, 2H, J=15.8, 6.8 Hz), 2.60 (dd, 2H, J=15.8 & 5.0 Hz) ppm; (M+1) 170.1, 0.68 min (LC/MS method A). The oil was dissolved in diethyl ether (˜5 mL) and 4.0 mL of a 4.0 M dioxane solution of HCl (16.0 mmol) was added. The resulting precipitate was triturated with diethyl ether and collected by vacuum filtration yielding 795 mg (3.87 mmol, 19% yield) of 5,6-difluoro-2,3-dihydro-1H-inden-2-amine hydrochloride as an off-white solid. The heterogeneous solution was filtered through a bed of Celite with the celite being rinsed thoroughly with chloroform The solvent was then removed in vacuo the residual dark oil dissolved in water The organics were extracted with chloroform three times by drying over MgSO4 The solvent was removed in vacuo the residual amber oil purified by column chromatography (10% MeOH/CH2Cl2)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (4.60 g, 27.4 mmol) in MeOH (90 mL) at 40° C. was added isoamyl nitrite (4.17 g, 35.6 mmol) followed by concentrated HCl (2.7 mL). Upon heating for 45 min the solution was cooled to room temperature and water was added. Precipitated solid was collected by filtration and rinsed thoroughly with water affording 3.97 g of a light orange solid. The solid was dissolved in HOAc (100 mL), conc HCl (8 mL) was added, followed by 10% Pd/C (1.07 g). The mixture was hydrogenated under 50 psi H2 for 24 hr using a Parr hydrogenation apparatus, and filtered through a bed of Celite (CHCl3 wash). The filtrate was concentrated in vacuo and the residue was dissolved in water. The aqueous solution was basified with solid K2CO3, extracted with CHCl3 (3×), combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/CH2Cl2) affording the title compound as a brown oil. 1H NMR (400 MHz, CDCl3) δ 6.95 (t, 2H, J=8.9 Hz), 3.83 (m, 1H), 3.10 (dd, 2H, J=15.8 & 6.8 Hz), 2.60 (dd, 2H, J=15.8 & 5.0 Hz); (M+H) 170, 0.68 min (LC/MS method A). Upon heating for 45 min the solution Precipitated solid was collected by filtration rinsed thoroughly with water affording 3.97 g of a light orange solid The solid was dissolved in HOAc (100 mL) conc HCl (8 mL) was added filtered through a bed of Celite (CHCl3 wash) The filtrate was concentrated in vacuo the residue was dissolved in water extracted with CHCl3 (3×) were dried over MgSO4 concentrated in vacuo The residue was purified by flash chromatography (MeOH/CH2Cl2)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 6,7-difluoro-3,3a,4,8b-tetrahydroindeno[2,1-d]oxazol-2-one (Preparation 80) (145 mg, 0.69 mmol) and 10% palladium on carbon (15 mg) in EtOH (10 mL) was stirred under H2 for 1 h. The reaction mixture was filtered through celite and the solvent removed in vacuo to give the title compound: δH (CDCl3) 2.66 (2H, dd), 3.15 (2H, dd), 3.86-3.94 (1H, m), 7.00 (2H, t). The reaction mixture was filtered through celite the solvent removed in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (4.60 g, 27.4 mmol) in MeOH (90 mL) at 40° C. was added isoamyl nitrite (4.17 g, 35.6 mmol) followed by concentrated HCl (2.7 mL). Upon heating for 45 min the solution was cooled to room temperature and water was added. Precipitated solid was collected by filtration and rinsed thoroughly with water affording 3.97 g of a light orange solid. The solid was dissolved in HOAc (100 mL), conc HCl (8 mL) was added, followed by 10% Pd/C (1.07 g). The mixture was hydrogenated under 50 psi H2 for 24 hr using a Parr hydrogenation apparatus, and filtered through a bed of Celite (CHCl3 wash). The filtrate was concentrated in vacuo and the residue was dissolved in water. The aqueous solution was basified with solid K2CO3, extracted with CHCl3 (3×), combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/CH2Cl2) affording the title compound as a brown oil. 1H NMR (400 MHz, CDCl3) δ 6.95 (t, 2H, J=8.9 Hz), 3.83 (m, 1H), 3.10 (dd, 2H, J=15.8 & 6.8 Hz), 2.60 (dd, 2H, J=15.8 & 5.0 Hz); (M+H) 170, 0.68 min (LC/MS method A). Upon heating for 45 min the solution Precipitated solid was collected by filtration rinsed thoroughly with water affording 3.97 g of a light orange solid The solid was dissolved in HOAc (100 mL) conc HCl (8 mL) was added filtered through a bed of Celite (CHCl3 wash) The filtrate was concentrated in vacuo the residue was dissolved in water extracted with CHCl3 (3×) were dried over MgSO4 concentrated in vacuo The residue was purified by flash chromatography (MeOH/CH2Cl2)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To an acetic acid solution (100 mL) containing 5,6-difluoro-1H-indene-1,2(3H)-dione 2-oxime (3.97 g, 20.2 mmol) in a Parr bottle was added 8 mL of concentrated HCl followed by 10% Pd/C (1.07 g). The solution was hydrogenated at 50 psi for 24 hours on a Parr hydrogenator. The heterogeneous solution was filtered through a bed of Celite with the celite being rinsed thoroughly with chloroform. The solvent was then removed in vacuo and the residual dark oil dissolved in water. The aqueous solution was then made basic with solid K2CO3. The organics were extracted with chloroform three times followed by drying over MgSO4. The solvent was removed in vacuo and the residual amber oil purified by column chromatography (10% MeOH/CH2Cl2) yielding 1.06 g (6.26 mmol) of 5,6-difluoro-2,3-dihydro-1H-inden-2-amine as a brown oil. 1H NMR (400 MHz, CDCl3) delta 6.95 (t, 2H, J=8.9 Hz), 3.83 (m, 1H), 3.10 (dd, 2H, J=15.8, 6.8 Hz), 2.60 (dd, 2H, J=15.8 & 5.0 Hz) ppm; (M+1) 170.1, 0.68 min (LC/MS method A). The oil was dissolved in diethyl ether (˜5 mL) and 4.0 mL of a 4.0 M dioxane solution of HCl (16.0 mmol) was added. The resulting precipitate was triturated with diethyl ether and collected by vacuum filtration yielding 795 mg (3.87 mmol, 19% yield) of 5,6-difluoro-2,3-dihydro-1H-inden-2-amine hydrochloride as an off-white solid. The heterogeneous solution was filtered through a bed of Celite with the celite being rinsed thoroughly with chloroform The solvent was then removed in vacuo the residual dark oil dissolved in water The organics were extracted with chloroform three times by drying over MgSO4 The solvent was removed in vacuo the residual amber oil purified by column chromatography (10% MeOH/CH2Cl2)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (4.60 g, 27.4 mmol) in MeOH (90 mL) at 40° C. was added isoamyl nitrite (4.17 g, 35.6 mmol) followed by concentrated HCl (2.7 mL). Upon heating for 45 min the solution was cooled to room temperature and water was added. Precipitated solid was collected by filtration and rinsed thoroughly with water affording 3.97 g of a light orange solid. The solid was dissolved in HOAc (100 mL), conc HCl (8 mL) was added, followed by 10% Pd/C (1.07 g). The mixture was hydrogenated under 50 psi H2 for 24 hr using a Parr hydrogenation apparatus, and filtered through a bed of Celite (CHCl3 wash). The filtrate was concentrated in vacuo and the residue was dissolved in water. The aqueous solution was basified with solid K2CO3, extracted with CHCl3 (3×), combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/CH2Cl2) affording the title compound as a brown oil. 1H NMR (400 MHz, CDCl3) δ 6.95 (t, 2H, J=8.9 Hz), 3.83 (m, 1H), 3.10 (dd, 2H, J=15.8 & 6.8 Hz), 2.60 (dd, 2H, J=15.8 & 5.0 Hz); (M+H) 170, 0.68 min (LC/MS method A). Upon heating for 45 min the solution Precipitated solid was collected by filtration rinsed thoroughly with water affording 3.97 g of a light orange solid The solid was dissolved in HOAc (100 mL) conc HCl (8 mL) was added filtered through a bed of Celite (CHCl3 wash) The filtrate was concentrated in vacuo the residue was dissolved in water extracted with CHCl3 (3×) were dried over MgSO4 concentrated in vacuo The residue was purified by flash chromatography (MeOH/CH2Cl2)