(2-bromo-4-fluorophenyl)hydrazine

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Commercially available 2-bromo-4-fluoroaniline 1 (2.36 ml, 20.75 mmol) was added to a stirring solution of concentrated hydrochloric acid (40 ml) that was cooled to −5° C. This solution was allowed to age while stirring for 10 minutes. An aqueous solution of NaNO2 was added over 15 minutes. SnCl2/HCl (10.40 g, 46.1 mmol, 10 ml HCl) was added over 15 minutes and aged for an additional 30 minutes to 1 hour. The mixture was filtered and washed with dichloromethane. The resulting solid was dissolved in 1.0M HCl and extracted 3 times with dichloromethane. The organic layer was vacuum dried overnight to give 3.53 g (83% yield). 1H NMR (400 MHz, CDCl3): δ 7.169 (dd, J=8 Hz, J=2.8 Hz 1H), δ 7.076 (dd, J=5.2 Hz, J=9.2 Hz, 1H), δ 6.982 (td, J=8.4 Hz, J=2 Hz 1H), δ 5.540 (bs, 1H), δ 3.590 (bs, 1H). aged for an additional 30 minutes to 1 hour The mixture was filtered washed with dichloromethane The resulting solid was dissolved in 1.0M HCl extracted 3 times with dichloromethane dried overnight to give 3.53 g (83% yield)

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

実験手順: 2-Bromo-4-fluoro-phenylhydrazine (20 g, 0.097 mol) was dissolved in ethanol and the solution cooled to 0° C. (ice-bath). Ethyl pyruvate (11.3 ml, 0.101 mol) was added dropwise and the solution stirred 15 h at room temperature. The solvent was evaporated under reduced pressure, and the residue stirred with hexane. The mixture of hydrazones that formed upon cooling in an ice-bath was filtered and dried under vacuum. Yield 24.4 g, 82%. The hydrazone mixture (22 g, 0.073 mol) was dissolved in Eaton's reagent (230 ml) and the mixture heated 3 h at 50° C. The mixture was cooled to room temperature, diluted with dichloromethane and added to saturated aqueous sodium hydrogen carbonate. The phases were separated and the aqueous phase extracted twice with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated. The residue was taken up in diethyl ether, and hexane added whereupon part of the product precipitated. This was filtered and the mother liquor purified by column chromatography on silica gel (5:1 toluene/hexane eluant) to afford the product as a light yellow solid (14.1 g, 68%). Mp: 125° C., EI MS: 285.0 (M+) The solvent was evaporated under reduced pressure the residue stirred with hexane The mixture of hydrazones that formed upon cooling in an ice-bath was filtered dried under vacuum the mixture heated 3 h at 50° C The mixture was cooled to room temperature The phases were separated the aqueous phase extracted twice with dichloromethane The combined organic phases were washed with water dried over magnesium sulfate evaporated hexane added whereupon part of the product precipitated This was filtered the mother liquor purified by column chromatography on silica gel (5:1 toluene/hexane eluant)

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

実験手順: 2-Bromo-4-fluoro-phenylhydrazine (20 g, 0.097 mol) was dissolved in ethanol and the solution cooled to 0° C. (ice-bath). Ethyl pyruvate (11.3 ml, 0.101 mol) was added dropwise and the solution stirred 15 h at room temperature. The solvent was evaporated under reduced pressure, and the residue stirred with hexane. The mixture of hydrazones that formed upon cooling in an ice-bath was filtered and dried under vacuum. Yield 24.4 g, 82%. The hydrazone mixture (22 g, 0.073 mol) was dissolved in Eaton's reagent (230 ml) and the mixture heated 3 h at 50° C. The mixture was cooled to room temperature, diluted with dichloromethane and added to saturated aqueous sodium hydrogen carbonate. The phases were separated and the aqueous phase extracted twice with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated. The residue was taken up in diethyl ether, and hexane added whereupon part of the product precipitated. This was filtered and the mother liquor purified by column chromatography on silica gel (5:1 toluene/hexane eluant) to afford the product as a light yellow solid (14.1 g, 68%). Mp: 125° C., EI MS: 285.0 (M+) The solvent was evaporated under reduced pressure the residue stirred with hexane The mixture of hydrazones that formed upon cooling in an ice-bath was filtered dried under vacuum the mixture heated 3 h at 50° C The mixture was cooled to room temperature The phases were separated the aqueous phase extracted twice with dichloromethane The combined organic phases were washed with water dried over magnesium sulfate evaporated hexane added whereupon part of the product precipitated This was filtered the mother liquor purified by column chromatography on silica gel (5:1 toluene/hexane eluant)

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Commercially available 2-bromo-4-fluoroaniline 1 (2.36 ml, 20.75 mmol) was added to a stirring solution of concentrated hydrochloric acid (40 ml) that was cooled to −5° C. This solution was allowed to age while stirring for 10 minutes. An aqueous solution of NaNO2 was added over 15 minutes. SnCl2/HCl (10.40 g, 46.1 mmol, 10 ml HCl) was added over 15 minutes and aged for an additional 30 minutes to 1 hour. The mixture was filtered and washed with dichloromethane. The resulting solid was dissolved in 1.0M HCl and extracted 3 times with dichloromethane. The organic layer was vacuum dried overnight to give 3.53 g (83% yield). 1H NMR (400 MHz, CDCl3): 7.169 (dd, J=8 Hz, J=2.8 Hz 1H), δ 7.076 (dd, J=5.2 Hz, J=9.2 Hz, 1H), 6.982 (td, J=8.4 Hz, J=2 Hz 1H), 5.540 (bs, 1H), δ 3.590 (bs, 1H). aged for an additional 30 minutes to 1 hour The mixture was filtered washed with dichloromethane The resulting solid was dissolved in 1.0M HCl extracted 3 times with dichloromethane dried overnight to give 3.53 g (83% yield)

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Commercially available 2-bromo-4-fluoroaniline 1 (2.36 ml, 20.75 mmol) was added to a stirring solution of concentrated hydrochloric acid (40 ml) that was cooled to −5° C. This solution was allowed to age while stirring for 10 minutes. An aqueous solution of NaNO2 was added over 15 minutes. SnCl2/HCl (10.40 g, 46.1 mmol, 10 ml HCl) was added over 15 minutes and aged for an additional 30 minutes to 1 hour. The mixture was filtered and washed with dichloromethane. The resulting solid was dissolved in 1.0M HCl and extracted 3 times with dichloromethane. The organic layer was vacuum dried overnight to give 3.53 g (83% yield). 1H NMR (400 MHz, CDCl3): δ 7.169 (dd, J=8 Hz, J=2.8 Hz 1H), δ 7.076 (dd, J=5.2 Hz, J=9.2 Hz, 1H), δ 6.982 (td, J=8.4 Hz, J=2 Hz 1H), δ 5.540 (bs, 1H), δ 3.590 (bs, 1H). aged for an additional 30 minutes to 1 hour The mixture was filtered washed with dichloromethane The resulting solid was dissolved in 1.0M HCl extracted 3 times with dichloromethane dried overnight to give 3.53 g (83% yield)

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Commercially available 2-bromo-4-fluoroaniline 1 (2.36 ml, 20.75 mmol) was added to a stirring solution of concentrated hydrochloric acid (40 ml) that was cooled to −5° C. This solution was allowed to age while stirring for 10 minutes. An aqueous solution of NaNO2 was added over 15 minutes. SnCl2/HCl (10.40 g, 46.1 mmol, 10 ml HCl) was added over 15 minutes and aged for an additional 30 minutes to 1 hour. The mixture was filtered and washed with dichloromethane. The resulting solid was dissolved in 1.0M HCl and extracted 3 times with dichloromethane. The organic layer was vacuum dried overnight to give 3.53 g (83% yield). 1H NMR (400 MHz, CDCl3): 7.169 (dd, J=8 Hz, J=2.8 Hz 1H), δ 7.076 (dd, J=5.2 Hz, J=9.2 Hz, 1H), 6.982 (td, J=8.4 Hz, J=2 Hz 1H), δ 5.540 (bs, 1H), δ 3.590 (bs, 1H). aged for an additional 30 minutes to 1 hour The mixture was filtered washed with dichloromethane The resulting solid was dissolved in 1.0M HCl extracted 3 times with dichloromethane dried overnight to give 3.53 g (83% yield)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Commercially available 2-bromo-4-fluoroaniline 1 (2.36 ml, 20.75 mmol) was added to a stirring solution of concentrated hydrochloric acid (40 ml) that was cooled to −5° C. This solution was allowed to age while stirring for 10 minutes. An aqueous solution of NaNO2 was added over 15 minutes. SnCl2/HCl (10.40 g, 46.1 mmol, 10 ml HCl) was added over 15 minutes and aged for an additional 30 minutes to 1 hour. The mixture was filtered and washed with dichloromethane. The resulting solid was dissolved in 1.0M HCl and extracted 3 times with dichloromethane. The organic layer was vacuum dried overnight to give 3.53 g (83% yield). 1H NMR (400 MHz, CDCl3): 7.169 (dd, J=8 Hz, J=2.8 Hz 1H), δ 7.076 (dd, J=5.2 Hz, J=9.2 Hz, 1H), 6.982 (td, J=8.4 Hz, J=2 Hz 1H), δ 5.540 (bs, 1H), δ 3.590 (bs, 1H). aged for an additional 30 minutes to 1 hour The mixture was filtered washed with dichloromethane The resulting solid was dissolved in 1.0M HCl extracted 3 times with dichloromethane dried overnight to give 3.53 g (83% yield)

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

実験手順: Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (2-bromo-4-fluoro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=496.9 (M+H)+

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Commercially available 2-bromo-4-fluoroaniline 1 (2.36 ml, 20.75 mmol) was added to a stirring solution of concentrated hydrochloric acid (40 ml) that was cooled to −5° C. This solution was allowed to age while stirring for 10 minutes. An aqueous solution of NaNO2 was added over 15 minutes. SnCl2/HCl (10.40 g, 46.1 mmol, 10 ml HCl) was added over 15 minutes and aged for an additional 30 minutes to 1 hour. The mixture was filtered and washed with dichloromethane. The resulting solid was dissolved in 1.0M HCl and extracted 3 times with dichloromethane. The organic layer was vacuum dried overnight to give 3.53 g (83% yield). 1H NMR (400 MHz, CDCl3): δ7.169 (dd, J=8 Hz, J=2.8 Hz 1H), δ7.076 (dd, J=5.2 Hz, J=9.2 Hz, 1H), δ6982 (td, J=8.4 Hz, J=2 Hz 1H), δ5.540 (bs, 1H), δ3.590 (bs, 1H). aged for an additional 30 minutes to 1 hour The mixture was filtered washed with dichloromethane The resulting solid was dissolved in 1.0M HCl extracted 3 times with dichloromethane dried overnight to give 3.53 g (83% yield)

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Commercially available 2-bromo-4-fluoroaniline 1 (2.36 ml, 20.75 mmol) was added to a stirring solution of concentrated hydrochloric acid (40 ml) that was cooled to −5° C. This solution was allowed to age while stirring for 10 minutes. An aqueous solution of NaNO2 was added over 15 minutes. SnCl2/HCl (10.40 g, 46.1 mmol, 10 ml HCl) was added over 15 minutes and aged for an additional 30 minutes to 1 hour. The mixture was filtered and washed with dichloromethane. The resulting solid was dissolved in 11.0M HCl and extracted 3 times with dichloromethane. The organic layer was vacuum dried overnight to give 3.53 g (83% yield). 1H NMR (400 MHz, CDCl3): 7.169 (dd, J=8 Hz, J=2.8 Hz 1H), δ 7.076 (dd, J=5.2 Hz, J=9.2 Hz, 1H), 6.982 (td, J=8.4 Hz, J=2 Hz 1H), 5.540 (bs, 1H), δ 3.590 (bs, 1H). aged for an additional 30 minutes to 1 hour The mixture was filtered washed with dichloromethane The resulting solid was dissolved in 11.0M HCl extracted 3 times with dichloromethane dried overnight to give 3.53 g (83% yield)