2-[tert-butyl(dimethyl)silyl]oxy-1-(4-chloro-3-fluorophenyl)ethanone

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

Procedure: n-BuLi (2.5N, 8.0 mL) was added at −78° C. to a mixture of methyltriphenylphosphonium bromide (5.6 g, 0.15 mol) in THF (50 mL). After being stirred for 0.5 hours, 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (3.9 g, 0.013 mol) was added to the reaction mixture. The mixture was then stirred for 2 hours at 25° C. After quenching with saturated NH4CL (100 mL), the reaction mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether to give tert-butyl (2-(4-chloro-3-fluorophenyl)allyloxy)dimethylsilane (1.6 g, 40% yield). The mixture was then stirred for 2 hours at 25° C After quenching with saturated NH4CL (100 mL) the reaction mixture was extracted with ethyl acetate (3×50 mL) The combined organic layers were dried concentrated The residue was purified by silica gel column chromatography eluting with petroleum ether

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

Procedure: n-BuLi (2.5N, 8.0 mL) was added at −78° C. to a mixture of methyltriphenylphosphonium bromide (5.6 g, 0.15 mol) in THF (50 mL). After being stirred for 0.5 hours, 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (3.9 g, 0.013 mol) was added to the reaction mixture. The mixture was then stirred for 2 hours at 25° C. After quenching with saturated NH4CL (100 mL), the reaction mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether to give tert-butyl (2-(4-chloro-3-fluorophenyl)allyloxy)dimethylsilane (1.6 g, 40% yield). The mixture was then stirred for 2 hours at 25° C After quenching with saturated NH4CL (100 mL) the reaction mixture was extracted with ethyl acetate (3×50 mL) The combined organic layers were dried concentrated The residue was purified by silica gel column chromatography eluting with petroleum ether

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

Procedure: n-BuLi (2.5N, 8.0 mL) was added at −78° C. to a mixture of methyltriphenylphosphonium bromide (5.6 g, 0.15 mol) in THF (50 mL). After being stirred for 0.5 hours, 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (3.9 g, 0.013 mol) was added to the reaction mixture. The mixture was then stirred for 2 hours at 25° C. After quenching with saturated NH4CL (100 mL), the reaction mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether to give tert-butyl (2-(4-chloro-3-fluorophenyl)allyloxy)dimethylsilane (1.6 g, 40% yield). The mixture was then stirred for 2 hours at 25° C After quenching with saturated NH4CL (100 mL) the reaction mixture was extracted with ethyl acetate (3×50 mL) The combined organic layers were dried concentrated The residue was purified by silica gel column chromatography eluting with petroleum ether

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

Procedure: To a solution of 1-(3,4-dichlorophenyl)-2-hydroxyethanone (11.86 g, 57.843 mmol, CASRN 113337-38-5), imidazole (5.91 g, 86.764 mmol), and DMAP (0.71 g, 5.7843 mmol) in DMF (100 mL) cooled to 0° C. was added slowly tert-butylchlorodimethylsilane (10.898 g, 72.304 mmol) and the reaction was stirred at RT for 18 h. Water was added and the mixture was extracted with ether. The organic layer was dried, filtered, and concentrated. The crude residue was purified by passage through a SiO2 plug eluting with an EtOAc/hexane gradient (10 to 50% EtOAc) to afford 12.15 g (82.0%) of 2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethanone (84). Conversion of 84 to (S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanamine (85) was carried out in accord with the procedure in steps 3 to 5 of example 10 except in step 3,2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (62) was replaced with 84. The title compound was prepared from 85 in accord with the procedure in steps 6 and 7 of example 10 except in step 6, 72 was used in place of 26 and 85 was used in place of 68 to afford 136 mg (56%) of I-16: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.42 (m, 2H), 7.18 (d, 1H), 5.32 (m, 1H), 4.95 (m, 1H), 4.81 (d, 1H), 4.38 (s, 2H), 4.10 (m, 1H), 3.92 (m, 1H), 3.83 (m, 1H), 3.75-3.60 (m, 2H), 2.67 (t, 2H), 2.55 (bs, 1H), 1.22 (d, 6H); LCMS (ACPI-pos) m/z 426.4 (M+H)+. to afford 136 mg (56%) of I-16

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

Procedure: To a solution of 60 (15.12 g, 64.79 mmol) and THF (50 mL) cooled to 0° C. was added dropwise (4-chloro-3-fluorophenyl)magnesium bromide (226.8 mL, 113.4 mmol) and the solution was stirred at 0° C. for 2 h. Saturated NH4Cl was added and the reaction was extracted with DCM. The organic layer was separated, dried, filtered and concentrated. The crude product was purified by passage through a SiO2 plug eluting with 5% EtOAc/hexane to afford 18.36 g (93.6%) of 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (62). the reaction was extracted with DCM The organic layer was separated dried filtered concentrated The crude product was purified by passage through a SiO2 plug eluting with 5% EtOAc/hexane

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

Procedure: To a solution of 60 (15.12 g, 64.79 mmol) and THF (50 mL) cooled to 0° C. was added dropwise (4-chloro-3-fluorophenyl)magnesium bromide (226.8 mL, 113.4 mmol) and the solution was stirred at 0° C. for 2 h. Saturated NH4Cl was added and the reaction was extracted with DCM. The organic layer was separated, dried, filtered and concentrated. The crude product was purified by passage through a SiO2 plug eluting with 5% EtOAc/hexane to afford 18.36 g (93.6%) of 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (62). the reaction was extracted with DCM The organic layer was separated dried filtered concentrated The crude product was purified by passage through a SiO2 plug eluting with 5% EtOAc/hexane

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

Procedure: To a solution of 60 (15.12 g, 64.79 mmol) and THF (50 mL) cooled to 0° C. was added dropwise (4-chloro-3-fluorophenyl)magnesium bromide (226.8 mL, 113.4 mmol) and the solution was stirred at 0° C. for 2 h. Saturated NH4Cl was added and the reaction was extracted with DCM. The organic layer was separated, dried, filtered and concentrated. The crude product was purified by passage through a SiO2 plug eluting with 5% EtOAc/hexane to afford 18.36 g (93.6%) of 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (62). the reaction was extracted with DCM The organic layer was separated dried filtered concentrated The crude product was purified by passage through a SiO2 plug eluting with 5% EtOAc/hexane

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

Procedure: n-BuLi (2.5N, 8.0 mL) was added at −78° C. to a mixture of methyltriphenylphosphonium bromide (5.6 g, 0.15 mol) in THF (50 mL). After being stirred for 0.5 hours, 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (3.9 g, 0.013 mol) was added to the reaction mixture. The mixture was then stirred for 2 hours at 25° C. After quenching with saturated NH4Cl (100 mL), the reaction mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether to give tert-butyl (2-(4-chloro-3-fluorophenyl)allyloxy)dimethylsilane (1.6 g, 40% yield). The mixture was then stirred for 2 hours at 25° C After quenching with saturated NH4Cl (100 mL) the reaction mixture was extracted with ethyl acetate (3×50 mL) The combined organic layers were dried concentrated The residue was purified by silica gel column chromatography eluting with petroleum ether