1-[(4-fluorophenyl)-isocyanomethyl]sulfonyl-4-methylbenzene

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of pyruvaldehyde (40% w/w solution in water, 6.6 mL, 7.8 g, 0.058 mol) in DMSO (100 mL) at ambient temperature was added ethyl 4-aminopiperidinecarboxylate (10 g,, 0.058 mol). After 10 min, α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (8.4 g, 0.029 mol) and K2CO3 (8.0 g, 0.058 mol) were added. After stirring for 18 h, the solution was partition between EtOAc and 3N HCl and the organic phase was washed with 3N HCl. The combined aqueous layers were neutralized with solid K2CO3 and extracted twice with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give a brown oil which solidified upon standing. Flash chromatography eluting consecutively with 33%, 50% and 67% EtOAc in hexanes followed by trituration with ether afforded the title compound as a white solid; yield 3.5 g (23%). the solution was partition between EtOAc and 3N HCl the organic phase was washed with 3N HCl extracted twice with EtOAc The combined organics were washed with brine dried (MgSO4) concentrated in vacuo to give a brown oil which Flash chromatography eluting consecutively with 33%, 50% and 67% EtOAc in hexanes

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred suspension of α-(p-toluenesulfonyl)-4-fluorobenzylformamide produced in step (a) above, (100 g, 325 mmoles) in THF (650 mL, 6.5 volumes) was cooled to 0° C. and POCl3 (46 mL, 487 mmoles, 1.5 equiv.) was added. A 1° C. exotherm was observed. After 15 minutes at 0° C., the white slurry was cooled to −5° C. Triethylamine (166 g, 1.62 moles, 5 equiv.) was added dropwise to the slurry over 45 minutes at such a rate to keep the reaction temperature below 0° C. but above −5° C. Caution should be exercised at the beginning of the addition because the reaction has a tendency to exotherm quickly. After complete addition, the yellow slurry was stirred for 30 minutes at 0° C. The reaction slurry has a tendency to darken during the stirring period. The reaction was poured into a mixture of saturated aqueous sodium bicarbonate (1 L) and ethyl acetate (1 L), both pre-cooled to 0° C. The organic phase was subsequently washed with water followed by brine. The organic phase was concentrated under vacuum via rotary evaporation until about 10% of the initial volume remained. 1-Propanol (200 mL) was added and concentrated again under vacuum at 35° C. until about 10% of the initial volume remained. This process was repeated with fresh 1-propanol (200 mL). A fine, yellow precipitate was observed. The precipitate was cooled to 0° C. and the product was collected by suction filtration and rinsed with 1-propanol (50 mL). The off-white solid was dried to a constant weight at 40° C./<1 mm to give 65.7 g (227 mmoles) of desired product, affording a 70% yield. 1H NMR (300 MHz, CDCl3) δ 7.62 (2H, d, J=6.7 Hz), 7.46 (4H, m), 7.08 (2H, t, J=8.6 Hz), 5.62 (1H, s), 2.46 (3H, s). A 1° C. exotherm the white slurry was cooled to −5° C the reaction temperature below 0° C. but above −5° C Caution should be exercised at the beginning of the addition because the reaction After complete addition both pre-cooled to 0° C The organic phase was subsequently washed with water The organic phase was concentrated under vacuum via rotary evaporation until about 10% of the initial volume 1-Propanol (200 mL) was added concentrated again under vacuum at 35° C. until about 10% of the initial volume The precipitate was cooled to 0° C. the product was collected by suction filtration rinsed with 1-propanol (50 mL) The off-white solid was dried to a constant weight at 40° C./<1 mm

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of pyruvaldehyde (40% w/w solution in water, 6.6 mL, 7.8 g, 0.058 mol) in DMSO (100 mL) at ambient temperature was added ethyl 4-aminopiperidinecarboxylate (10 g, 0.058 mol). After 10 min, α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (8.4 g, 0.029 mol) and K2CO3 (8.0 g, 0.058 mol) were added. After stirring for 18 h, the solution was partition between EtOAc and 3 N HCl and the organic phase was washed with 3N HCl. The combined aqueous layers were neutralized with solid K2CO3 and extracted twice with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give a brown oil which solidified upon standing. Flash chromatography eluting consecutively with 33%, 50% and 67% EtOAc in hexanes followed by trituration with ether afforded the title compound as a white solid; yield 3.5 g (23%). the solution was partition between EtOAc and 3 N HCl the organic phase was washed with 3N HCl extracted twice with EtOAc The combined organics were washed with brine dried (MgSO4) concentrated in vacuo to give a brown oil which Flash chromatography eluting consecutively with 33%, 50% and 67% EtOAc in hexanes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Beginning with 1-isobutyl-2-amino-6-(methyliminomethyl)-1H-benzimidazole (142 mg, 0.52 mmol), α-(p-toluenesulfonyl)-4-fluorobenzylisocyanide (302 mg, 1.05 mmol), methanol (2.5 ml), and methylamine (1.3 ml, 2M in tetrahydrofuran), 1-(isobutyl)-2-amino-6-(1-methyl-4 (4-fluorophenyl)-1H-imidazol-5-yl)-1H-benzimidazole may be prepared essentially as described in EXAMPLE 72. Treatment with 1 equivalent of methanesulfonic acid provides the title compound (114 mg). may be prepared essentially

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Beginning with 1-isobutyl-2-amino-6-(methyliminomethyl)-1H-benzimidazole (142 mg, 0.52 mmol), α-(p-toluenesulfonyl)-4-fluorobenzylisocyanide (302 mg, 1.05 mmol), methanol (2.5 ml), and methylamine (1.3 ml, 2M in tetrahydrofuran), 1-(isobutyl)-2-amino-6-(1-methyl-4 (4-fluorophenyl)-1H-imidazol-5-yl)-1H-benzimidazole may be prepared essentially as described in EXAMPLE 72. Treatment with 1 equivalent of methanesulfonic acid provides the title compound (114 mg). may be prepared essentially

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred suspension of α-(p-toluenesulfonyl)-4-fluorobenzylformamide produced in step (a) above, (100 g, 325 mmoles) in THF (650 mL, 6.5 volumes) was cooled to 0° C. and POCl3 (46 mL, 487 mmoles, 1.5 equiv.) was added. A 1° C. exotherm was observed. After 15 minutes at 0° C., the white slurry was cooled to -5° C. Triethylamine (166 g, 1.62 moles, 5 equiv.) was added dropwise to the slurry over 45 minutes at such a rate to keep the reaction temperature below 0° C. but above -5° C. Caution should be exercised at the beginning of the addition because the reaction has a tendency to exotherm quickly. After complete addition, the yellow slurry was stirred for 30 minutes at 0° C. The reaction slurry has a tendency to darken during the stirring period. The reaction was poured into a mixture of saturated aqueous sodium bicarbonate (1 L) and ethyl acetate (1 L), both pre-cooled to 0° C. The organic phase was subsequently washed with water followed by brine. The organic phase was concentrated under vacuum via rotary evaporation until about 10% of the initial volume remained. 1-Propanol (200 mL) was added and concentrated again under vacuum at 35° C. until about 10% of the initial volume remained. This process was repeated with fresh 1-propanol (200 mL). A fine, yellow precipitate was observed. The precipitate was cooled to 0° C. and the product was collected by suction filtration and rinsed with 1-propanol (50 mL). The off-white solid was dried to a constant weight at 40° C./<1 mm to give 65.7 g (227 mmoles) of desired product, affording a 70% yield. 1H NMR (300 MHz, CDCl3) δ7.62 (2H, d, J=6.7 Hz), 7.46 (4H, m), 7.08 (2H, t, J=8.6 Hz), 5.62 (1 H, s), 2.46 (3H, s). A 1° C. exotherm the white slurry was cooled to -5° C the reaction temperature below 0° C. but above -5° C Caution should be exercised at the beginning of the addition because the reaction After complete addition both pre-cooled to 0° C The organic phase was subsequently washed with water The organic phase was concentrated under vacuum via rotary evaporation until about 10% of the initial volume 1-Propanol (200 mL) was added concentrated again under vacuum at 35° C. until about 10% of the initial volume The precipitate was cooled to 0° C. the product was collected by suction filtration rinsed with 1-propanol (50 mL) The off-white solid was dried to a constant weight at 40° C./<1 mm

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred suspension of α-(p-toluenesulfonyl)-4-fluorobenzylformamide produced in step (a) above, (100 g, 325 mmoles) in THF (650 mL, 6.5 volumes) was cooled to 0° C. and POCl3 (46 mL, 487 mmoles, 1.5 equiv.) was added. A 1° C. exotherm was observed. After 15 minutes at 0° C., the white slurry was cooled to -5° C. Triethylamine (166 g, 1.62 moles, 5 equiv.) was added dropwise to the slurry over 45 minutes at such a rate to keep the reaction temperature below 0° C. but above -5° C. Caution should be exercised at the beginning of the addition because the reaction has a tendency to exotherm quickly. After complete addition, the yellow slurry was stirred for 30 minutes at 0° C. The reaction slurry has a tendency to darken during the stirring period. The reaction was poured into a mixture of saturated aqueous sodium bicarbonate (1 L) and ethyl acetate (1 L), both-pre-cooled to 0° C. The organic phase was subsequently washed with water followed by brine. The organic phase was concentrated under vacuum via rotary evaporation until about 10% of the initial volume remained. 1-Propanol (200 mL) was added and concentrated again under vacuum at 35° C. until about 10% of the initial volume remained. This process was repeated with fresh 1-propanol (200 mL). A fine, yellow precipitate was observed. The precipitate was cooled to 0° C. and the product was collected by suction filtration and rinsed with 1-propanol (50 mL). The off-white solid was dried to a constant weight at 40° C./<1 mm to give 65.7 g (227 mmoles) of desired product, affording a 70% yield. 1H NMR (300 MHz, CDCl3) δ7.62 (2H, d, J=6.7 Hz), 7.46 (4H, m), 7.08 (2H, t, J=8.6 Hz), 5.62 (1H, s), 2.46 (3H, s). A 1° C. exotherm the white slurry was cooled to -5° C the reaction temperature below 0° C. but above -5° C Caution should be exercised at the beginning of the addition because the reaction After complete addition both-pre-cooled to 0° C The organic phase was subsequently washed with water The organic phase was concentrated under vacuum via rotary evaporation until about 10% of the initial volume 1-Propanol (200 mL) was added concentrated again under vacuum at 35° C. until about 10% of the initial volume The precipitate was cooled to 0° C. the product was collected by suction filtration rinsed with 1-propanol (50 mL) The off-white solid was dried to a constant weight at 40° C./<1 mm

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of pyruvaldehyde (40% w/w solution in water, 6.6 mL, 7.8 g, 0.058 mol) in DMSO (100 mL) at ambient temperature was added ethyl 4-aminopiperidinecarboxylate (10 g,, 0.058 mol). After 10 min, α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (8.4 g, 0.029 mol) and K2CO3 (8.0 g, 0.058 mol) were added. After stirring for 18 h, the solution was partition between EtOAc and 3N HCl and the organic phase was washed with 3N HCl. The combined aqueous layers were neutralized with solid K2CO3 and extracted twice with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give a brown oil which solidified upon standing. Flash chromatography eluting consecutively with 33%, 50% and 67% EtOAc in hexanes followed by trituration with ether afforded the title compound as a white solid; yield 3.5 g (23%). the solution was partition between EtOAc and 3N HCl the organic phase was washed with 3N HCl extracted twice with EtOAc The combined organics were washed with brine dried (MgSO4) concentrated in vacuo to give a brown oil which Flash chromatography eluting consecutively with 33%, 50% and 67% EtOAc in hexanes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of pyruvaldehyde (40% w/w solution in water, 6.6 mL, 7.8 g, 0.058 mol) in DMSO (100 mL) at ambient temperature was added ethyl 4-aminopiperidinecarboxylate (10 g,, 0.058 mol). After 10 min, α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (8.4 g, 0.029 mol) and K2CO3 (8.0 g, 0.058 mol) were added. After stirring for 18 h, the solution was partition between EtOAc and 3N HCl and the organic phase was washed with 3N HCl. The combined aqueous layers were neutralized with solid K2CO3 and extracted twice with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give a brown oil which solidified upon standing. Flash chromatography eluting consecutively with 33%, 50% and 67% EtOAc in hexanes followed by trituration with ether afforded the title compound as a white solid; yield 3.5 g (23%). the solution was partition between EtOAc and 3N HCl the organic phase was washed with 3N HCl extracted twice with EtOAc The combined organics were washed with brine dried (MgSO4) concentrated in vacuo to give a brown oil which Flash chromatography eluting consecutively with 33%, 50% and 67% EtOAc in hexanes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of pyruvaldehyde (40% w/w solution in water, 6.6 mL, 7.8 g, 0.058 mol) in DMSO (100 mL) at ambient temperature was added ethyl 4-aminopiperidinecarboxylate (10 g, 0.058 mol). After 10 min, α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (8.4 g, 0.029 mol) and K2CO3 (8.0 g, 0.058 mol) were added. After stirring for 18 h, the solution was partition between EtOAc and 3 N HCl and the organic phase was washed with 3N HCl. The combined aqueous layers were neutralized with solid K2CO3 and extracted twice with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give a brown oil which solidified upon standing. Flash chromatography eluting consecutively with 33%, 50% and 67% EtOAc in hexanes followed by trituration with ether afforded the title compound as a white solid; yield 3.5 g (23%). the solution was partition between EtOAc and 3 N HCl the organic phase was washed with 3N HCl extracted twice with EtOAc The combined organics were washed with brine dried (MgSO4) concentrated in vacuo to give a brown oil which Flash chromatography eluting consecutively with 33%, 50% and 67% EtOAc in hexanes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of pyruvaldehyde (40% w/w solution in water, 6.6 mL, 7.8 g, 0.058 mol) in DMSO (100 mL) at ambient temperature was added ethyl 4-aminopiperidinecarboxylate (10 g, 0.058 mol). After 10 min, α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (8.4 g, 0.029 mol) and K2CO3 (8.0 g, 0.058 mol) were added. After stirring for 18 h, the solution was partition between EtOAc and 3 N HCl and the organic phase was washed with 3N HCl. The combined aqueous layers were neutralized with solid K2CO3 and extracted twice with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give a brown oil which solidified upon standing. Flash chromatography eluting consecutively with 33%, 50% and 67% EtOAc in hexanes followed by trituration with ether afforded the title compound as a white solid; yield 3.5 g (23%). the solution was partition between EtOAc and 3 N HCl the organic phase was washed with 3N HCl extracted twice with EtOAc The combined organics were washed with brine dried (MgSO4) concentrated in vacuo to give a brown oil which Flash chromatography eluting consecutively with 33%, 50% and 67% EtOAc in hexanes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Beginning with 1-isobutyl-2-amino-6-(methyliminomethyl)-1H-benzimidazole (142 mg, 0.52 mmol), α-(p-toluenesulfonyl)-4-fluorobenzylisocyanide (302 mg, 1.05 mmol), methanol (2.5 ml), and methylamine (1.3 ml, 2M in tetrahydrofuran), 1-(isobutyl)-2-amino-6-(1-methyl-4 (4-fluorophenyl)-1H-imidazol-5-yl)-1H-benzimidazole may be prepared essentially as described in EXAMPLE 72. Treatment with 1 equivalent of methanesulfonic acid provides the title compound (114 mg). may be prepared essentially