2,2-difluoro-2-phenylethanamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 3-bromo-1-(ethoxycarbonylmethyl)-6-methylpyrazinone (750 mg, 2.75 mmol), as prepared in step 5 of Example 2, in toluene (30 mL) was added 2,2-difluoro-2-phenylethylamine (900 mg, 5.75 mmol), as prepared in the preceding step. The mixture was refluxed for two days under nitrogen. The solution was allowed to cool to room temperature, and ethyl acetate (50 mL) was added. The diluted reaction mixture was washed with 10% HCl (2×20 mL) and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 10% citric acid (50 mL), brine, and dried over Na2SO4. After evaporating the solvent, the solid was collected and washed with 15% ethyl acetate in hexane to give the title compound as an off-white solid (730 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 2H), 7.43 (m, 3H), 6.67 (s, 1H ), 6.14 (s(br), 1H), 4.70 (s, 2H), 4.24 (q, 2H, J=7.1 Hz), 4.09 (td, 2 H, J=14.3, 6.5 Hz), 2.11 (s, 3H), 1.29 (t, 3H, J=7.1 Hz). as prepared in the preceding step The mixture was refluxed for two days under nitrogen The diluted reaction mixture was washed with 10% HCl (2×20 mL) the aqueous layer was extracted with ethyl acetate (3×20 mL) The combined organic layers were washed with 10% citric acid (50 mL), brine dried over Na2SO4 After evaporating the solvent the solid was collected washed with 15% ethyl acetate in hexane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,2-Difluoro-2-phenylacetamide (2.4 g, 14 mmol), as prepared in the preceding step, was dissolved in tetrahydrofuran (30 mL) and cooled to 0° C. To this stirred solution was added 1.0 M borane in tetrahydrofuran (35 mL, 35 mmol) dropwise in 30 minutes, and the reaction mixture was refluxed for 16 hours. After cooling to room temperature, a solution of potassium carbonate (5 g) in water (20 mL) was added to the reaction mixture. The mixture was concentrated in vacuo to about 50 mL and extracted with dichloromethane (3×50 mL). The dichloromethane layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (1:1 ethyl acetate:hexane) to give the title compound as a pale yellow oil (900 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 7.45 (m, 5H), 3.18 (t, 2H, J=14.5 Hz), 1.60 (s(br), 2H). the reaction mixture was refluxed for 16 hours After cooling to room temperature The mixture was concentrated in vacuo to about 50 mL extracted with dichloromethane (3×50 mL) The dichloromethane layer was washed with brine dried over Na2SO4 concentrated in vacuo The residue was then purified by flash column chromatography (1:1 ethyl acetate:hexane)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,2-Difluoro-2-phenylacetamide (2.4 g, 14 mmol), as prepared in the preceding step, was dissolved in tetrahydrofuran (30 mL) and cooled to 0° C. To this stirred solution was added 1.0 M borane in tetrahydrofuran (35 mL, 35 mmol) dropwise in 30 minutes, and the reaction mixture was refluxed for 16 hours. After cooling to room temperature, a solution of potassium carbonate (5 g) in water (20 mL) was added to the reaction mixture. The mixture was concentrated in vacuo to about 50 mL and extracted with dichloromethane (3×50 mL). The dichloromethane layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (1:1 ethyl acetate:hexane) to give the title compound as a pale yellow oil (900 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 7.45 (m, 5H), 3.18 (t, 2H, J=14.5 Hz), 1.60 (s(br), 2H). the reaction mixture was refluxed for 16 hours After cooling to room temperature The mixture was concentrated in vacuo to about 50 mL extracted with dichloromethane (3×50 mL) The dichloromethane layer was washed with brine dried over Na2SO4 concentrated in vacuo The residue was then purified by flash column chromatography (1:1 ethyl acetate:hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (9 g, 21.1 mmol) with 4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamine isomer 2 (11.4 g, 42.3 mmol) in anhydrous toluene (270 mL). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 4:1 gradient) to obtain 7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine isomer 2 (9.5 g, 83%). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 4:1 gradient)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Use a method similar to the General Procedure 5-3 to react 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (541 mg, 1.274 mmol), palladium(II) acetate (57 mg, 0.225 mmol), tris(dibenzylideneacetone)dipalladium(0) (117 mg, 0.127 mmol), BINAP (0.506 g, 0.764 mmol), 2,2-difluoro-2-phenyl-ethylamine (400 mg, 2.547 mmol) and cesium carbonate (830 mg, 2.548 mmol) in degassed toluene (35 mL). Degas the mixture with vacuum/nitrogen purge and heat to 100° C. for 16 h. Cool the mixture to room temperature, dilute with EtOAc and filter over Celite®. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to obtain 7-chloro-6-(2,2-difluoro-2-phenyl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (335 mg, 61%). MS (ES+) m/z: 433 (M+H)+. Degas the mixture with vacuum/nitrogen purge Cool the mixture to room temperature dilute with EtOAc filter over Celite® Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve (2-azido-1,1-difluoro-ethyl)-benzene (475 mg, 2.59 mmol) in EtOAc (30 mL). Add 10% Pd/C and submit the mixture to hydrogenation under atmospheric pressure (balloon) for 1 h. Filter the catalyst through Celite® and concentrate the filtrate in vacuo to provide the title compound as an oil (400 mg, 98%) that was used without any further purification. for 1 h Filter the catalyst through Celite® concentrate the filtrate in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve (2-azido-1,1-difluoro-ethyl)-benzene (475 mg, 2.59 mmol) in EtOAc (30 mL). Add 10% Pd/C and submit the mixture to hydrogenation under atmospheric pressure (balloon) for 1 h. Filter the catalyst through Celite® and concentrate the filtrate in vacuo to provide the title compound as an oil (400 mg, 98%) that was used without any further purification. for 1 h Filter the catalyst through Celite® concentrate the filtrate in vacuo

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 507 mg (1.843mmol) of 7-4 in 10 ml of toluene was added 578 mg (3.68 mmol) of 7-6 via pipet. The reaction mixture was heated to 110° C. overnight. The solution was allowed to cool to room temperature and ethyl acetate was added. The diluted reaction mixture was washed with 10% hydrochloric acid. Three ethyl acetate extractions were performed on the aqueous layer. The organic layers were combined, dried (sodium sulfate), and concentrated in vacuo to give 745 mg of an off white solid. The solid was purified using a 40 mm column, 6 inches of silica gel and a 1:1 ethyl acetate/hexane solvent system to give 7-7 as a colorless solid: H1NMR CDCl3): δ 1.25 (t, 3H, 6.2 Hz), 2.1 (s, 3H), 4.0-4.1 (m, 2H), 4.25 (q, 2H, 7.1 Hz), 4.72 (s, 2H), 6.15 (s 1H), 6.68 (s, 1H) 7.4-7.6 (m, 3H), 7.6-7.8 (m, 2H). to cool to room temperature The diluted reaction mixture was washed with 10% hydrochloric acid Three ethyl acetate extractions dried (sodium sulfate) concentrated in vacuo to give 745 mg of an off white solid The solid was purified