tert-butyl N-(2,6-difluorophenyl)carbamate

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:

Conditions: temp:57.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of Compound 5 (100.82 g, 0.33 mol, 1.0 equiv.), Compound 7 (101.05 g, 0.44 mol, 1.30 eq), and cesium carbonate (177.12 g, 0.54 mol, 1.60 eq) was suspended in DMSO (250 mL, 2.5 volumes) and stirred vigorously at 55-60° C. for 48 hours (completeness of reaction determined by HPLC). The mixture was cooled to 20-30° C. and the base was quenched by careful and slow addition of a 1 N HCl (aq) solution (540 mL, 1.60 eq), keeping the internal temperature of the reaction mixture below 30° C. Upon cooling, a precipitate formed and was filtered and washed with water (2×250 mL, 2×2.5 volumes). The precipitate was then suspended in absolute ethanol (1000 mL, 10 volumes) and heated to reflux. The reflux was maintained for 30-60 minutes, and water (200 mL, 2 volumes) was added to the mixture. The resulting mixture was then heated again to reflux, and reflux was maintained for 30 minutes, at which point the suspension was cooled to 10° C. The resulting solids were then filtered and washed with water (2×250 mL, 2×2.5 volumes), followed by absolute ethanol (250 mL, 2.5 volumes), and then transferred to a vacuum oven and dried at 50-60° C. The title Compound, 8, was obtained as a white crystalline solid. (1H NMR, 500 MHz; CDCl3) δ 8.28 (d, 1H), 8.12 (d, 1H), 7.19 (q, 1H), 6.96 (t, 2H), 6.81 (t, 1H), 6.74 (t, 1H), 4.25 (q, 2H), 1.50 (s, 9H), 1.20 (t, 3H). (completeness of reaction determined by HPLC) The mixture was cooled to 20-30° C. the base was quenched by careful and the internal temperature of the reaction mixture below 30° C Upon cooling a precipitate formed was filtered washed with water (2×250 mL, 2×2.5 volumes) heated to reflux The reflux was maintained for 30-60 minutes water (200 mL, 2 volumes) was added to the mixture The resulting mixture was then heated again to reflux reflux was maintained for 30 minutes, at which point the suspension was cooled to 10° C The resulting solids were then filtered washed with water (2×250 mL, 2×2.5 volumes) dried at 50-60° C

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen purged flask was charged palladium acetate (13.2 g, 59 mmoles, 0.04 eq), racemic BINAP (36.6 g, 59 mmoles, 0.04 eq), followed by 1.9 L toluene. The heterogeneous slurry was heated to 50° C. under nitrogen for 2 hours, cooled to 30° C., then the pyridyl chloride 41 (386.4 g, 1.45 moles, 1.0 eq) and Boc-2,6-difluoroaniline 42 (386.4 g, 1.69 moles, 1.2 eq), and K3PO4 (872 g, 4.1 moles, 2.8 eq) were added all at once followed by a 1.9 L toluene rinse. The heterogeneous reaction mixture was heated to 100° C. overnight and monitored by HPLC. When the reaction showed complete conversion to 43 by HPLC [Tret 41=17 min, Tret 43=20.5 min, Tret 44=17.6 min, monitored at 229 nm] (usually between 18-20 hours) the reaction was cooled to room temperature and the contents diluted with 1.94 L EtOAc. To this was added 1×1.94 L of 6N HCl, and both layers were filtered through celite. The celite wet cake was rinsed with 2×1.9 L EtOAc. The layers were separated and the organic layer washed with 1×1.9 L of brine, dried (MgSO4), filtered and concentrated to a brown, viscous oil. To remove the Boc-protecting group, the oil was dissolved in 1.94 L of methylene chloride and 388 mL TFA was added. The reaction was stirred overnight to facilitate Boc removal. The volatiles were removed in vacuo, EtOAc (1.9 L) and sufficient quantity of 1 or 6 N NaOH was added until the pH was 2-7. Then a sufficient quantity of 5% NaHCO3 was added to bring the pH to 8-9. The organic layer was separated and washed with 1×5% NaHCO3, dried (MgSO4), filtered an concentrated to a brown oil/liquid. The crude oil/liquid was azeodried twice with a sufficient quantity of toluene. At times the free base precipitated out resulting in a slurry. The residue was dissolved in 500 mL toluene and 1.6 L 1N HCl/ether solution was added, which resulted in the solids crashing out. Heat was applied until the homogenized/solids broke up. If necessary, 200 mL of EtOAc can be added to facilitate the break up. After cooling, the solid 44 was isolated by vacuum filtration. cooled to 30° C. rinse The heterogeneous reaction mixture was heated to 100° C. overnight by HPLC [Tret 41=17 min, Tret 43=20.5 min, Tret 44=17.6 min, monitored at 229 nm] usually between 18-20 hours was cooled to room temperature the contents diluted with 1.94 L EtOAc To this was added 1×1.94 L of 6N HCl both layers were filtered through celite The celite wet cake was rinsed with 2×1.9 L EtOAc The layers were separated the organic layer washed with 1×1.9 L of brine dried (MgSO4) filtered concentrated to a brown, viscous oil To remove the Boc- the oil was dissolved in 1.94 L of methylene chloride 388 mL TFA was added Boc removal The volatiles were removed in vacuo, EtOAc (1.9 L) and sufficient quantity of 1 or 6 N NaOH was added until the pH was 2-7 Then a sufficient quantity of 5% NaHCO3 was added The organic layer was separated washed with 1×5% NaHCO3 dried (MgSO4) filtered an concentrated to a brown oil/liquid At times the free base precipitated out resulting in a slurry which resulted in the solids Heat After cooling

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen purged flask was charged palladium acetate (13.2 g, 59 mmoles, 0.04 eq), racemic BINAP (36.6 g, 59 mmoles, 0.04 eq), followed by 1.9 L toluene. The heterogeneous slurry was heated to 50° C. under nitrogen for 2 hours, cooled to 30° C., then the pyridyl chloride 41 (386.4 g, 1.45 moles, 1.0 eq) and Boc-2,6-difluoroaniline 42 (386.4 g, 1.69 moles, 1.2 eq), and K3PO4 (872 g, 4.1 moles, 2.8 eq) were added all at once followed by a 1.9 L toluene rinse. The heterogeneous reaction mixture was heated to 100° C. overnight and monitored by HPLC. When the reaction showed complete conversion to 43 by HPLC [Tret 41=17 min, Tret 43=20.5 min, Tret 44=17.6 min, monitored at 229 nm] (usually between 18-20 hours) the reaction was cooled to room temperature and the contents diluted with 1.94 L EtOAc. To this was added 1×1.94 L of 6N HCl, and both layers were filtered through celite. The celite wet cake was rinsed with 2×1.9 L EtOAc. The layers were separated and the organic layer washed with 1×1.9 L of brine, dried (MgSO4), filtered and concentrated to a brown, viscous oil. To remove the Boc-protecting group, the oil was dissolved in 1.94 L of methylene chloride and 388 mL TFA was added. The reaction was stirred overnight to facilitate Boc removal. The volatiles were removed in vacuo, EtOAc (1.9 L) and sufficient quantity of 1 or 6 N NaOH was added until the pH was 2-7. Then a sufficient quantity of 5% NaHCO3 was added to bring the pH to 8-9. The organic layer was separated and washed with 1×5% NaHCO3, dried (MgSO4), filtered an concentrated to a brown oil/liquid. The crude oil/liquid was azeodried twice with a sufficient quantity of toluene. At times the free base precipitated out resulting in a slurry. The residue was dissolved in 500 mL toluene and 1.6 L 1N HCl/ether solution was added, which resulted in the solids crashing out. Heat was applied until the homogenized/solids broke up. If necessary, 200 mL of EtOAc can be added to facilitate the break up. After cooling, the solid 44 was isolated by vacuum filtration. cooled to 30° C. rinse The heterogeneous reaction mixture was heated to 100° C. overnight by HPLC [Tret 41=17 min, Tret 43=20.5 min, Tret 44=17.6 min, monitored at 229 nm] usually between 18-20 hours was cooled to room temperature the contents diluted with 1.94 L EtOAc To this was added 1×1.94 L of 6N HCl both layers were filtered through celite The celite wet cake was rinsed with 2×1.9 L EtOAc The layers were separated the organic layer washed with 1×1.9 L of brine dried (MgSO4) filtered concentrated to a brown, viscous oil To remove the Boc- the oil was dissolved in 1.94 L of methylene chloride 388 mL TFA was added Boc removal The volatiles were removed in vacuo, EtOAc (1.9 L) and sufficient quantity of 1 or 6 N NaOH was added until the pH was 2-7 Then a sufficient quantity of 5% NaHCO3 was added The organic layer was separated washed with 1×5% NaHCO3 dried (MgSO4) filtered an concentrated to a brown oil/liquid At times the free base precipitated out resulting in a slurry which resulted in the solids Heat After cooling

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen purged flask was charged palladium acetate (13.2 g, 59 mmoles, 0.04 eq), racemic BINAP (36.6 g, 59 mmoles, 0.04 eq), followed by 1.9 L toluene. The heterogeneous slurry was heated to 50° C. under nitrogen for 2 hours, cooled to 30° C., then the pyridyl chloride 41 (386.4 g, 1.45 moles, 1.0 eq) and Boc-2,6-difluoroaniline 42 (386.4 g, 1.69 moles, 1.2 eq), and K3PO4 (872 g, 4.1 moles, 2.8 eq) were added all at once followed by a 1.9 L toluene rinse. The heterogeneous reaction mixture was heated to 100° C. overnight and monitored by HPLC. When the reaction showed complete conversion to 43 by HPLC [Tret 41=17 min, Tret 43=20.5 min, Tret 44=17.6 min, monitored at 229 nm] (usually between 18-20 hours) the reaction was cooled to room temperature and the contents diluted with 1.94 L EtOAc. To this was added 1×1.94 L of 6N HCl, and both layers were filtered through celite. The celite wet cake was rinsed with 2×1.9 L EtOAc. The layers were separated and the organic layer washed with 1×1.9 L of brine, dried (MgSO4), filtered and concentrated to a brown, viscous oil. To remove the Boc-protecting group, the oil was dissolved in 1.94 L of methylene chloride and 388 mL TFA was added. The reaction was stirred overnight to facilitate Boc removal. The volatiles were removed in vacuo, EtOAc (1.9 L) and sufficient quantity of 1 or 6 N NaOH was added until the pH was 2-7. Then a sufficient quantity of 5% NaHCO3 was added to bring the pH to 8-9. The organic layer was separated and washed with 1×5% NaHCO3, dried (MgSO4), filtered an concentrated to a brown oil/liquid. The crude oil/liquid was azeodried twice with a sufficient quantity of toluene. At times the free base precipitated out resulting in a slurry. The residue was dissolved in 500 mL toluene and 1.6 L 1N HCl/ether solution was added, which resulted in the solids crashing out. Heat was applied until the homogenized/solids broke up. If necessary, 200 mL of EtOAc can be added to facilitate the break up. After cooling, the solid 44 was isolated by vacuum filtration. cooled to 30° C. rinse The heterogeneous reaction mixture was heated to 100° C. overnight by HPLC [Tret 41=17 min, Tret 43=20.5 min, Tret 44=17.6 min, monitored at 229 nm] usually between 18-20 hours was cooled to room temperature the contents diluted with 1.94 L EtOAc To this was added 1×1.94 L of 6N HCl both layers were filtered through celite The celite wet cake was rinsed with 2×1.9 L EtOAc The layers were separated the organic layer washed with 1×1.9 L of brine dried (MgSO4) filtered concentrated to a brown, viscous oil To remove the Boc- the oil was dissolved in 1.94 L of methylene chloride 388 mL TFA was added Boc removal The volatiles were removed in vacuo, EtOAc (1.9 L) and sufficient quantity of 1 or 6 N NaOH was added until the pH was 2-7 Then a sufficient quantity of 5% NaHCO3 was added The organic layer was separated washed with 1×5% NaHCO3 dried (MgSO4) filtered an concentrated to a brown oil/liquid At times the free base precipitated out resulting in a slurry which resulted in the solids Heat After cooling

Conditions: temp:57.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of Compound 5 (100.82 g, 0.33 mol, 1.0 equiv.), Compound 7 (101.05 g, 0.44 mol, 1.30 eq), and cesium carbonate (177.12 g, 0.54 mol, 1.60 eq) was suspended in DMSO (250 mL, 2.5 volumes) and stirred vigorously at 55-60° C. for 48 hours (completeness of reaction determined by HPLC). The mixture was cooled to 20-30° C. and the base was quenched by careful and slow addition of a 1 N HCl (aq) solution (540 mL, 1.60 eq), keeping the internal temperature of the reaction mixture below 30° C. Upon cooling, a precipitate formed and was filtered and washed with water (2×250 mL, 2×2.5 volumes). The precipitate was then suspended in absolute ethanol (1000 mL, 10 volumes) and heated to reflux. The reflux was maintained for 30-60 minutes, and water (200 mL, 2 volumes) was added to the mixture. The resulting mixture was then heated again to reflux, and reflux was maintained for 30 minutes, at which point the suspension was cooled to 10° C. The resulting solids were then filtered and washed with water (2×250 mL, 2×2.5 volumes), followed by absolute ethanol (250 mL, 2.5 volumes), and then transferred to a vacuum oven and dried at 50-60° C. The title Compound, 8, was obtained as a white crystalline solid. (1H NMR, 500 MHz; CDCl3) δ 8.28 (d, 1H), 8.12 (d, 1H), 7.19 (q, 1H), 6.96 (t, 2H), 6.81 (t, 1H), 6.74 (t, 1H), 4.25 (q, 2H), 1.50 (s, 9H), 1.20 (t, 3H). (completeness of reaction determined by HPLC) The mixture was cooled to 20-30° C. the base was quenched by careful and the internal temperature of the reaction mixture below 30° C Upon cooling a precipitate formed was filtered washed with water (2×250 mL, 2×2.5 volumes) heated to reflux The reflux was maintained for 30-60 minutes water (200 mL, 2 volumes) was added to the mixture The resulting mixture was then heated again to reflux reflux was maintained for 30 minutes, at which point the suspension was cooled to 10° C The resulting solids were then filtered washed with water (2×250 mL, 2×2.5 volumes) dried at 50-60° C

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen purged flask was charged palladium acetate (13.2 g, 59 mmoles, 0.04 eq), racemic BINAP (36.6 g, 59 mmoles, 0.04 eq), followed by 1.9 L toluene. The heterogeneous slurry was heated to 50° C. under nitrogen for 2 hours, cooled to 30° C., then the pyridyl chloride 41 (386.4 g, 1.45 moles, 1.0 eq) and Boc-2,6-difluoroaniline 42 (386.4 g, 1.69 moles, 1.2 eq), and K3PO4 (872 g, 4.1 moles, 2.8 eq) were added all at once followed by a 1.9 L toluene rinse. The heterogeneous reaction mixture was heated to 100° C. overnight and monitored by HPLC. When the reaction showed complete conversion to 43 by HPLC [Tret 41=17 min, Tret 43=20.5 min, Tret 44=17.6 min, monitored at 229 nm] (usually between 18–20 hours) the reaction was cooled to room temperature and the contents diluted with 1.94 L EtOAc. To this was added 1×1.94 L of 6N HCl, and both layers were filtered through celite. The celite wet cake was rinsed with 2×1.9 L EtOAc. The layers were separated and the organic layer washed with 1×1.9 L of brine, dried (MgSO4), filtered and concentrated to a brown, viscous oil. To remove the Boc-protecting group, the oil was dissolved in 1.94 L of methylene chloride and 388 mL TFA was added. The reaction was stirred overnight to facilitate Boc removal. The volatiles were removed in vacuo, EtOAc (1.9 L) and sufficient quantity of 1 or 6N NaOH was added until the pH was 2–7. Then a sufficient quantity of 5% NaHCO3 was added to bring the pH to 8–9. The organic layer was separated and washed with 1×5% NaHCO3, dried (MgSO4), filtered an concentrated to a brown oil/liquid. The crude oil/liquid was azeodried twice with a sufficient quantity of toluene. At times the free base precipitated out resulting in a slurry. The residue was dissolved in 500 mL toluene and 1.6 L 1N HCl/ether solution was added, which resulted in the solids crashing out. Heat was applied until the homogenized/solids broke up. If necessary, 200 mL of EtOAc can be added to facilitate the break up. After cooling, the solid 44 was isolated by vacuum filtration. cooled to 30° C. rinse The heterogeneous reaction mixture was heated to 100° C. overnight by HPLC [Tret 41=17 min, Tret 43=20.5 min, Tret 44=17.6 min, monitored at 229 nm] usually between 18–20 hours was cooled to room temperature the contents diluted with 1.94 L EtOAc To this was added 1×1.94 L of 6N HCl both layers were filtered through celite The celite wet cake was rinsed with 2×1.9 L EtOAc The layers were separated the organic layer washed with 1×1.9 L of brine dried (MgSO4) filtered concentrated to a brown, viscous oil To remove the Boc- the oil was dissolved in 1.94 L of methylene chloride 388 mL TFA was added Boc removal The volatiles were removed in vacuo, EtOAc (1.9 L) and sufficient quantity of 1 or 6N NaOH was added until the pH was 2–7 Then a sufficient quantity of 5% NaHCO3 was added The organic layer was separated washed with 1×5% NaHCO3 dried (MgSO4) filtered an concentrated to a brown oil/liquid At times the free base precipitated out resulting in a slurry which resulted in the solids Heat After cooling

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