3,3-dibromo-1,1,1-trifluoropropan-2-one

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

Procedure: To a solution of 22.5 g sodium acetate in 230 ml water was added 21.5 g 3,3-dibromo-1,1,1-trifluoropropanone at reflux and the mixture was refluxed for 10 min. The resulting solution was cooled to 0° C. in an acetone ice bath and added dropwise to a suspension of 19.5 g aminoacetamidine dihydrobromide in 250 ml methanol at −30° C. (dry ice acetone cooling) so that the temperature did not rise above −30° C. during the addition. To the resulting solution was added dropwise a solution of 12.285 g sodium hydroxide in 100 ml water. The mixture was then allowed to warm to room temperature (warm water bath) and then stirred at room temperature for 3 h. The dark reaction mixture was concentrated under aspirator vacuum to remove methanol and extracted with ethyl acetate (4 times). The phases were separated and the organic phase was washed with brine, treated with charcoal and dried with sodium sulfate and evaporated. To the concentrated yellow solution was added heptane and the mixture was seeded whereby crystallization was initiated. The mixture was stirred at room temperature to complete crystallization. The solid was collected by filtration to yield 8.81 g of the title compound as light yellow crystals. The aqueous layers were kept at room temperature for 72 h and then extracted (2 times) with ethyl acetate. The combined organic layers were treated with charcoal and sodium sulfate and evaporated. The residue was taken up in dichloromethane and heptane was added. The mixture was concentrated again until crystallization occurred. The solid was collected by filtration to yield another 2.06 g of the title compound as light yellow crystals. MS (M−H) at 162.1. at reflux the mixture was refluxed for 10 min did not rise above −30° C. during the addition to warm to room temperature The dark reaction mixture was concentrated under aspirator vacuum to remove methanol extracted with ethyl acetate (4 times) The phases were separated the organic phase was washed with brine treated with charcoal dried with sodium sulfate evaporated To the concentrated yellow solution was added heptane whereby crystallization The mixture was stirred at room temperature crystallization The solid was collected by filtration

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

Procedure: To a stirred solution of sodium acetate trihydrate (22.62 g, 166.2 mmol) in water (80 ml) was added 1,1-dibromo-3,3,3-trifluoroacetone (21.57 g, 79.9 mmol). The solution was heated at reflux under nitrogen for 30 min, then allowed to cool to room temperature before adding solid aminoguanidine bicarbonate (10.88 g, 79.9 mmol). The resulting pale yellow solution (pH 5) was stirred at room temperature for 3 h, then 4 N aqueous NaOH solution (40 ml, 160 mmol) was added causing a precipitate to appear. The mixture (pH 10) was stirred under nitrogen for a further 39 h. The solid was collected by filtration, washed with water and dried at 60° C. under vacuum to give 6.96 g of a mixture of two isomers in a 28:72 ratio. This was further purified by flash chromatography (silica gel, 30% EtOAc/isohexane), then recrystallised from ethanol to afford 3.53 g (27%) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.00 (2H, br s), 9.08 (1H, s). The solution was heated at reflux under nitrogen for 30 min The solid was collected by filtration washed with water dried at 60° C. under vacuum

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5.3 g (53.3 mmol) of sodium acetate mixed with about 100 ml of water was added under ice cooling 6.6 g (24.3 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone, and the mixture was stirred at 70° C. for 20 minutes. The reaction mixture was cooled to room temperature, to which a solution of 5.8 g (21.5 mmol) of 2-fluoro-4-chloro-5-isopropoxyphenylhydrazine dissolved in about 20 ml of diethyl ether was added, and the mixture was stirred at room temperature for 1 hour. The ether layer was separated and then concentrated. About 60 ml of tetrahydrofuran (hereinafter referred to as THF) was added to the residue, to which 8.3 g (23.0 mmol) of (carbethoxyethylidene)triphenylphosphorane was added, and the mixture was heated under reflux for 2 hours. The THF was distilled out under reduced pressure, and the residue was subjected to silica gel column chromatography, which afforded 3.8 g (10.5 mmol) of 2-[2-fluoro-4-chloro-5-isopropoxyphenyl]-4-methyl-5-trifluoromethylpyridazin-3-one. was added the mixture was stirred at room temperature for 1 hour The ether layer was separated concentrated was added the mixture was heated under reflux for 2 hours The THF was distilled out under reduced pressure

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

Procedure: To an ice bath-cooled solution of 5,6-diaminopyrimidin-4-ol (18 g, 143 mmol) in 3M sodium hydroxide (180 mL, 540 mmol), was added 3,3-dibromo-1,1,1-trifluoropropan-2-one (25.2 g, 93 mmol). The reaction was stirred for 3 days at ambient temperature. The solids were filtered, dissolved in 60% sulfuric acid (140 mL), and stirred at 135° C. for 8 h. The reaction was cooled, poured over ice and allowed to sit for 16 hours. The solution was neutralized to pH 8 with conc. ammonium hydroxide and extracted with ethyl acetate (5×100 mL), dried over sodium sulfate, filtered and concentrated. The solid residue was recrystallized from benzene/hexane to afford 5-(trifluoromethyl)pyrazin-2-amine (2.28 g, 14 mmol, 15% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.32 (1 H, s), 7.99 (1 H, d, J=1.26 Hz), 5.02 (2 H, br. s.). MS (LC/MS) R.T.=1.56; [M+H]+=164.03. The solids were filtered dissolved in 60% sulfuric acid (140 mL) stirred at 135° C. for 8 h The reaction was cooled poured over ice to sit for 16 hours extracted with ethyl acetate (5×100 mL) dried over sodium sulfate filtered concentrated The solid residue was recrystallized from benzene/hexane

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

Procedure: To an ice bath-cooled solution of 5,6-diaminopyrimidin-4-ol (18 g, 143 mmol) in 3M sodium hydroxide (180 mL, 540 mmol), was added 3,3-dibromo-1,1,1-trifluoropropan-2-one (25.2 g, 93 mmol). The reaction was stirred for 3 days at ambient temperature. The solids were filtered, dissolved in 60% sulfuric acid (140 mL), and stirred at 135° C. for 8 h. The reaction was cooled, poured over ice and allowed to sit for 16 hours. The solution was neutralized to pH 8 with conc. ammonium hydroxide and extracted with ethyl acetate (5×100 mL), dried over sodium sulfate, filtered and concentrated. The solid residue was recrystallized from benzene/hexane to afford 5-(trifluoromethyl)pyrazin-2-amine (2.28 g, 14 mmol, 15% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.32 (1 H, s), 7.99 (1 H, d, J=1.26 Hz), 5.02 (2 H, br. s.). MS (LC/MS) R.T.=1.56; [M+H]+=164.03. The solids were filtered dissolved in 60% sulfuric acid (140 mL) stirred at 135° C. for 8 h The reaction was cooled poured over ice to sit for 16 hours extracted with ethyl acetate (5×100 mL) dried over sodium sulfate filtered concentrated The solid residue was recrystallized from benzene/hexane

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

Procedure: Then, 49.2 g of sodium acetate and 40.5 g of 1,1-dibromo-3,3,3-trifluoroacetone were dissolved in 400 ml of water, and the solution was heated at 80° to 90° C. for 40 minutes. The solution was cooled to 0° C., to which 75 g of the crude 2-fluoro-4-chloro-5-hydroxyphenylhydrazine hydrochloride crystals obtained above was added, and the mixture was stirred at room temperature for 70 minutes. The precipitated crystals were collected by filtration and dried under reduced pressure, which afforded 35.4 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-hydroxyphenylhydrazone). the solution was heated at 80° to 90° C. for 40 minutes obtained above was added The precipitated crystals were collected by filtration dried under reduced pressure, which

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First, 7.4 g (90.2 mmol) of sodium acetate and 8.0 g (28.2 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone were mixed with 70 ml of water, and the mixture was stirred at 80° C. for 30 minutes and then cooled, to which 7.0 g of ethyl 2-chloro-5-hydrazinocinnamate was added at 10° C. or lower, and the mixture was stirred for 3 hours. The precipitated crystals were collected by filtration and dried, which afforded 9.6 g (27.5 mmol) of ethyl 2-chloro-5-(3,3,3-trifluoro-2-oxopropylidenehydrazino)cinnamate. was added at 10° C. lower, and the mixture was stirred for 3 hours The precipitated crystals were collected by filtration dried

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First, 50 g (0.61 mol) of sodium acetate and 41 g (0.14 mol) of 1,1-dibromo-3,3,3-trifluoroacetone were mixed with 500 ml of water, and the mixture was stirred at 80° C. for 30 minutes and then cooled to 0° C. Then, 45 g (0.14 mol) of 4-bromo-2-fluoro-5-isopropoxyphenylhydrazine hydrochloride was added at 10° C. or lower, and the mixture was stirred at 10° C. or lower for 3 hours. The precipitated crystals were collected by filtration and dried, which afforded 35 g (94.3 mmol) of 3,3,3-trifluoro-2-oxopropanal 1-(4-bromo-2-fluoro-5-isopropoxyphenylhydrazone). cooled to 0° C lower, and the mixture was stirred at 10° C. or lower for 3 hours The precipitated crystals were collected by filtration dried