1-(3-amino-4-fluorophenyl)ethanone

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: 4.9 g of 3'-amino-4'-fluoroacetophenone were diazotized in 25 ml of concentrated hydrochloric acid at 0° to 5° C with a solution of 2.3 g of NaNO2 in 5 ml of water and treated with a solution, prepared from 2.7 g of sodium bisulfite in 5 ml of water and 25 ml of concentrated hydrochloric acid and the oily 3'-chlorosulfonyl-4'-fluoroacetophenone was reacted with 20 ml of liquid ammonia to give the 4'-fluoro-3'-sulfamoylacetophenone, melting point: 135° C from glacial acetic acid. treated with a solution

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

Procedure: 39 g of 4'-fluoro-3'-nitroacetophenone, melting point: 44° C, were hydrogenated in 390 ml of methanol at 20 atm. and 40° C in the presence of Raney-Nickel to give the 3'-amino-4'-fluoro-acetophenone, melting point: 70° C).

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

Procedure: 39 g of 4'-fluoro-3'-nitroacetophenone, melting point: 44° C, were hydrogenated in 390 ml of methanol at 20 atm. and 40° C in the presence of Raney-Nickel to give the 3'-amino-4'-fluoro-acetophenone, melting point: 70° C).

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 solution of 1-(3-amino-4-fluorophenyl)-ethanone (3 g) in a mixture of MeOH (20 mL) and CH2Cl2 (20 mL) was added in portions NaBH4 (1520 mg) at 0° C. After stirring for 0.5 hours, the reaction mixture was quenched with saturated NH4Cl solution and most of the solvent was removed in vacuo. The residue was extracted with CH2Cl2, and the combined organic layer was washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography (33% ethyl acetate in hexane) to give 2.9 g of the title compound as an oil. the reaction mixture was quenched with saturated NH4Cl solution and most of the solvent was removed in vacuo The residue was extracted with CH2Cl2 the combined organic layer was washed with water dried over MgSO4 concentrated in vacuo The residue was purified by silica gel flash chromatography (33% ethyl acetate in hexane)

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

Procedure: A mixture of 1-(4-fluoro-3-nitrophenyl)-ethanone (4.94 g) and 5% Pt(S)/C (500 mg) in ethanol (50 mL) was hydrogenated at 50 psi for 3 hours. After filtration and concentration, the residue was purified by silica gel flash chromatography over silica gel (elution with 30% ethyl acetate in hexane) to give 3.3 g of the title compound as a solid. After filtration and concentration the residue was purified by silica gel flash chromatography over silica gel (elution with 30% ethyl acetate in hexane)

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

Procedure: To a stirred mixture of 3'-amino-4'-fluoroacetophenone (7.56 g, 49.4 mmol) in triethylene glycol (60 mL) was added 4.94 g of sodium hydroxide. Neat hydrazine hydrate (7.2 mL) was added to the mixture in one portion via a syringe. This addition resulted in a slight exotherm (temperature around 50°). The reaction flask (three neck, equipped with claisen adapter and receiving flask) was then equipped with a heating mantle and the reaction heated to 100° C. for 1 hour, then 150° C. At the higher temperature distillate began to collect in the receiving flask. After 1 hour at 150° C. the reaction mixture was then heated to 180° C., while still collecting distillate. After 45 minutes at 180° C. thin layer chromatography indicated the complete absence of starting material and the appearance of a single major product. The reaction mixture was cooled to room temperature with an ice bath and poured into 100 mL of water. The aqueous mixture was extracted three times with ether (125 mL). The combined organic extracts were washed once with water, once with brine and then dried over potassium carbonate. Concentration of the organic extracts in vacuo afforded 2-fluoro-5-ethylaniline (6.82 g) as an amber liquid. This material was further purified by column chromatography (silica gel, hexanes/ethyl acetate: 2/1) to give 7.11 grams of product as a viscous liquid. This addition resulted in a slight exotherm (temperature around 50°) The reaction flask (three neck, equipped with claisen adapter and receiving flask) was then equipped with a heating mantle 150° C to collect in the receiving flask After 1 hour at 150° C. the reaction mixture was then heated to 180° C. while still collecting distillate The reaction mixture was cooled to room temperature with an ice bath poured into 100 mL of water The aqueous mixture was extracted three times with ether (125 mL) The combined organic extracts were washed once with water, once with brine dried over potassium carbonate

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

Procedure: To a stirred mixture of 3'-nitro-4'-fluoroacetophenone (10.04 g, 55 mmol) in 72 mL of concentrated hydrochloric acid, was added tin (II) chloride dihydrate (37 grams), in portions. After approximately one third of the material had been added, a rapid rise in the internal reaction temperature (to 95° C.) was noted. The mixture was then heated to reflux for 10 minutes, this resulted in the dissolution of all solids to give a solution. The mixture was then cooled to room temperature and poured onto an ice/water mixture (150 g). The mixture was then further cooled in an ice bath while 50% sodium hydroxide was added until pH 12 was reached. The aqueous layer was extracted twice with ether (50 mL). The combined organic extracts were washed with brine and then dried over sodium sulfate. Removal of the drying agent and in vacuo concentration of the filtrate afforded a yellow-orange oil (8.73 g) which was recrystallized on standing. This material was of sufficient purity to be used directly in the next step (Part 3). After approximately one third of the material had been added in the internal reaction temperature (to 95° C.) The mixture was then heated to reflux for 10 minutes this resulted in the dissolution of all solids to give a solution was added until pH 12 The aqueous layer was extracted twice with ether (50 mL) The combined organic extracts were washed with brine dried over sodium sulfate Removal of the drying agent

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

Procedure: To a stirred mixture of 3'-amino-4'-fluoroacetophenone (7.56 g, 49.4 mmol) in triethylene glycol (60 mL) was added 4.94 g of sodium hydroxide. Neat hydrazine hydrate (7.2 mL) was added to the mixture in one portion via a syringe. This addition resulted in a slight exotherm (temperature around 50°). The reaction flask (three neck, equipped with claisen adapter and receiving flask) was then equipped with a heating mantle and the reaction heated to 100° C. for 1 hour, then 150° C. At the higher temperature distillate began to collect in the receiving flask. After 1 hour at 150° C. the reaction mixture was then heated to 180° C., while still collecting distillate. After 45 minutes at 180° C. thin layer chromatography indicated the complete absence of starting material and the appearance of a single major product. The reaction mixture was cooled to room temperature with an ice bath and poured into 100 mL of water. The aqueous mixture was extracted three times with ether (125 mL). The combined organic extracts were washed once with water, once with brine and then dried over potassium carbonate. Concentration of the organic extracts in vacuo afforded 2-fluoro-5-ethylaniline (6.82 g) as an amber liquid. This material was further purified by column chromatography (silica gel, hexanes/ethyl acetate: 2/1) to give 7.11 grams of product as a viscous liquid. This addition resulted in a slight exotherm (temperature around 50°) The reaction flask (three neck, equipped with claisen adapter and receiving flask) was then equipped with a heating mantle 150° C to collect in the receiving flask After 1 hour at 150° C. the reaction mixture was then heated to 180° C. while still collecting distillate The reaction mixture was cooled to room temperature with an ice bath poured into 100 mL of water The aqueous mixture was extracted three times with ether (125 mL) The combined organic extracts were washed once with water, once with brine dried over potassium carbonate