ethyl 3,3,3-trifluoro-2-oxopropanoate

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

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

Conditions: temp:63.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 2-amino-5-fluorophenylcarbamate (30.5 g), toluene (300 mL), triethylamine (34.1 g) and ethyl 3,3,3-trifluoro-2-oxopropanoate (69.5 g) were charged into a reactor and warmed to 63° C. for 14 h, then cooled to ambient temperature. A 5% aq. NaOH solution (390 mL) was added, stirred, settled, and then the lower layer was separated. The organic layer extracted with another charge of 5% aq. NaOH solution (130 mL). To the combined aq. NaOH layers was charged 2-methyl-THF (390 mL) and concentrated HCl (77.9 g), keeping the temperature below 25° C. The layers were mixed, settled and separated. The acidic aq. layer was separated, and the organic layer was extracted with water (260 mL). The layers were separated and the organic layer was filtered to remove insoluble material. The product was isolated by switching the solvent to toluene by distillation (a total of 1.1 L toluene used). The final slurry was briefly warmed to 80° C. and then cooled −10° C. and filtered. The cake was washed with toluene (128 mL), then dried under vacuum at 60° C. To the crude solid was added ethanol (350 mL) and warmed to reflux to dissolve the solids. The solution was cooled to room temperature and concentrated to approximately 270 mL total volume by distillation. Water (250 g) was then added over 30 min. The slurry was filtered and washed with cold (1:1) ethanol: water (2×60 mL). The solid was dried under vacuum at 60° C. (26.1 g, 83% yield). cooled to ambient temperature the lower layer was separated The organic layer extracted with another charge of 5% aq. NaOH solution (130 mL) To the combined aq. NaOH layers was charged 2-methyl-THF (390 mL) and concentrated HCl (77.9 g) the temperature below 25° C The layers were mixed separated The acidic aq. layer was separated the organic layer was extracted with water (260 mL) The layers were separated the organic layer was filtered to remove insoluble material The product was isolated by distillation (a total of 1.1 L toluene The final slurry was briefly warmed to 80° C. cooled −10° C. filtered The cake was washed with toluene (128 mL) dried under vacuum at 60° C To the crude solid was added ethanol (350 mL) warmed to reflux to dissolve the solids The solution was cooled to room temperature concentrated to approximately 270 mL total volume by distillation Water (250 g) was then added over 30 min The slurry was filtered washed with cold (1:1) ethanol The solid was dried under vacuum at 60° C. (26.1 g, 83% yield)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ACE sealable tube was added 3-fluorobenzene-1,2-diamine (475.99 mg, 3.77 mmol), ethanol (5 ml) and ethyl trifluoropyruvate (0.500 ml, 3.77 mmol) at rt. The tube was sealed and placed in an oil bath at 90° C. The mixture was stirred at 90° C. for 3 hr, cooled to rt and the LC/MS showed starting diamines and three new peaks. More ethyl trifluoropyruvaate (0.2 ml) was added and the mixture was stirred at 90° C. overnight. The reaction mixture was cooled to rt and LC/MS showed no diamines, and two of the three new peaks remained. The reaction mixture was concentrated to give a dark solid, diluted with dichloromethane/dimethylformamide (3/1, 60 ml) and washed with HCl (1 N, 2×20 ml) and an aquious solution of sodium thiosulfate (0.1 M, 2×20 ml). The combined aq. layers were back-extracted with dichloromethane/dimethylformamide (3/1, 2×20 ml). The combined organic layers were washed with water and concentrated to give a dark solid (1.72 g). The solid was dissolved in acetone and silica gel (46 g) was added. The mixture was dried in vacuo, loaded on a silica gel column and purified by flash chromatography (CH3CN/CHCl3=1/8, 1/6 then 1/4) to give the title compound 112a (474.9 mg, 2.046 mmol, 54.2% yield). The tube was sealed placed in an oil bath at 90° C cooled to rt More ethyl trifluoropyruvaate (0.2 ml) was added the mixture was stirred at 90° C. overnight The reaction mixture was cooled to rt The reaction mixture was concentrated to give a dark solid washed with HCl (1 N, 2×20 ml) The combined aq. layers were back-extracted with dichloromethane/dimethylformamide (3/1, 2×20 ml) The combined organic layers were washed with water concentrated

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

Procedure: To a pressure tube was added 1,2-diamino-4-fluorobenzene (5.0567 g, 40.1 mmol) and p-toluenesulfonic acid (7.63 g, 40.1 mmol) followed by dichloroethane (40.1 ml). The suspension was stirred for a few minutes and ethyl trifluoropyruvate (5.11 ml, 42.1 mmol) was added. The tube was capped and the suspension was stirred at 80° C. and the solid dissolved. The stiffing continued overnight and then the solution was cooled to rt, diluted with dichloromethane/dimethylformamide (4/1, 2×50 ml) and washed with NaHCO3 (1 N, 2×100 ml) and water (100 ml). The combined aq. layers was back-extracted with dichloromethane/dimethylformamide (4/1, 2×50 ml). The combined organic layer was dried (anh. Na2SO4), filtered, and concentrated to give a dark mixture of solid and oil. This residue was diluted with dichloromethane and hexane and concentrated to give a solid (7 g). The ratio of isomers (6-F/7-F) was 2/1 based on 1H NMR integration of the crude material. The solid was dissolved in acetone and silica gel (140 g) was added. The mixture was concentrated, and the solid mixture was loaded on a silica gel column. The column was eluted with ethyl acetate/hexane=1/6 to 1/3 and then the 6F-isomer was flushed out with ethyl acetate/hexane=2/1) to give the title compound 106a. The tube was capped the suspension was stirred at 80° C. the solid dissolved washed with NaHCO3 (1 N, 2×100 ml) and water (100 ml) The combined aq. layers was back-extracted with dichloromethane/dimethylformamide (4/1, 2×50 ml) The combined organic layer was dried (anh. Na2SO4) filtered concentrated to give a dark mixture of solid and oil concentrated

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

Procedure: A solution of ethyl trifluoropyruvate (124.84 g, 0.734 mol) in 2.0 L of THF was treated with methylallyl magnesium chloride (0.5 M in THF, 1.90 L, 0.954 mol) over 4 hours while the internal temperature was maintained below −60° C. The reaction mixture was allowed to reach room temperature overnight, concentrated in vacuo to remove THF, quenched with 1 L of saturated ammonium chloride solution, and extracted with three 1 L portions of diethyl ether. The combined organic phases were washed with 100 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Vacuum distillation at 60 mmHg afforded 100.1 g of 2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acid ethyl ester as a clear oil (b.p. 97° C.-103° C., 60% yield). was maintained below −60° C concentrated in vacuo to remove THF quenched with 1 L of saturated ammonium chloride solution extracted with three 1 L portions of diethyl ether The combined organic phases were washed with 100 mL of brine dried over magnesium sulfate filtered concentrated in vacuo Vacuum distillation at 60 mmHg

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

Procedure: To a chilled (−78° C.) solution of 5.2 mL (30.18 mmol) of 2-bromoallyltrimethylsilane and 5.3 g (31.16 mmol) of ethyl trifluoropyruvate in 75 mL of dichloromethane was added 30 mL (30 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane over a 10 minute period. The cold bath was then removed and the mixture was warmed to room temperature. After 3 hours, the mixture was cautiously added to 100 mL of saturated aqueous ammonium chloride and filtered through diatomaceous earth, washing with dichloromethane. The dichloromethane was separated and the aqueous layer was extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, 50 mL of brine, dried over magnesium sulfate, filtered, and concentrated to afford 6.7 g (76%) of 4-bromo-2-hydroxy-2-trifluoromethylpent-4-enoic acid ethyl ester as a yellow oil which was used without further purification. The cold bath was then removed the mixture was cautiously added to 100 mL of saturated aqueous ammonium chloride filtered through diatomaceous earth washing with dichloromethane The dichloromethane was separated the aqueous layer was extracted with three 50 mL portions of dichloromethane The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, 50 mL of brine dried over magnesium sulfate filtered concentrated

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

Procedure: 1.3 g of anhydrous zinc chloride and 13.2 g of granular manganese are heated to boiling in 100 ml of tetrahydrofuran and boiled with 0.2 ml of methallyl bromide for 30 minutes. Then, the solution of 25 g of methallyl bromide and 17 g of trifluoropyruvic acid ethyl ester in 80 ml of tetrahydrofuran is added in drops at boiling heat over 2 hours, and boiled for another hour. Then, while being cooled with ice, saturated ammonium chloride solution and 300 ml of ethyl acetate are added, stirred for 30 minutes at 0° C., and the separated ethyl acetate phase is washed with saturated ammonium chloride solution and three times with water. The solvent is dried (Na2SO4) and concentrated by evaporation, and the residue is distilled in a vacuum. 17.6 g of 2-hydroxy-4-methylene-2-trifluoromethyl-valeric acid ethyl ester, boiling point 48° C./1 hPa, is obtained. at boiling heat over 2 hours boiled for another hour are added the separated ethyl acetate phase is washed with saturated ammonium chloride solution and three times with water The solvent is dried (Na2SO4) concentrated by evaporation the residue is distilled in a vacuum

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

Procedure: 1.3 g of anhydrous zinc chloride and 13.2 g of granular manganese are heated to boiling in 100 ml of tetrahydrofuran and boiled with 0.2 ml of methallyl bromide for 30 minutes. Then, the solution of 25 g of methallyl bromide and 17 g of trifluoropyruvic acid ethyl ester in 80 ml of tetrahydrofuran is added in drops at boiling heat over 2 hours, and boiled for another hour. Then, while being cooled with ice, saturated ammonium chloride solution and 300 ml of ethyl acetate are added, stirred for 30 minutes at 0° C., and the separated ethyl acetate phase is washed with saturated ammonium chloride solution and three times with water. The solvent is dried (Na2SO4) and concentrated by evaporation, and the residue is distilled in a vacuum. 17.6 g of 2-hydroxy-4-methylene-2-trifluoromethyl-valeric acid ethyl ester, boiling point 48° C./1 hPa, is obtained. at boiling heat over 2 hours boiled for another hour are added the separated ethyl acetate phase is washed with saturated ammonium chloride solution and three times with water The solvent is dried (Na2SO4) concentrated by evaporation the residue is distilled in a vacuum

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

Procedure: To tert-butyl 4-(2,3-diaminopyridin-4-yloxy)naphthalen-1-ylcarbamate (1.00 g, 2.73 mmol) dissolved in 20 mL of anhydrous ethanol under argon and at reflux was added the ethyl trifluoropyruvate (697 mg, 0.50 mL, 4.10 mmol). The reaction mixture was stirred at reflux for 3 hours. After cooling at RT, a precipitate was formed, filtered off and rinsed with Et2O. tert-butyl 4-(3-oxo-2-(trifluoromethyl)-3,4-dihydropyrido[2,3-b]pyrazin-8-yloxy)naphthalen-1-ylcarbamate was obtained as a white solid (116 mg, 0.246 mmol, 9%). The filtrate was evaporated under vacuum. The residue was chromatographied (eluent: CH2Cl2/EtOAc: 4/1 towards 0/1) to afford the second isomer as a slightly yellow solid (540 mg, 1.14 mmol, 42%). at reflux at reflux for 3 hours a precipitate was formed filtered off rinsed with Et2O

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

Procedure: To a chilled (−78° C.) solution of 5.2 mL (30.18 mmol) of 2-bromoallyltrimethylsilane and 5.3 g (31.16 mmol) of ethyl trifluoropyruvate in 75 mL of dichloromethane was added 30 mL (30 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane over a 10 minute period. The cold bath was then removed and the mixture was warmed to room temperature. After 3 hours, the mixture was cautiously added to 100 mL of saturated aqueous ammonium chloride and filtered through diatomaceous earth washing with dichloromethane. The dichloromethane was separated and the aqueous layer was extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, 50 mL of brine, dried over magnesium sulfate, filtered, and concentrated to afford 6.7 g (76%) of 4-bromo-2-hydroxy-2-trifluoromethylpent-4-enoic acid ethyl ester as a yellow oil which was used without further purification. The cold bath was then removed the mixture was cautiously added to 100 mL of saturated aqueous ammonium chloride filtered through diatomaceous earth washing with dichloromethane The dichloromethane was separated the aqueous layer was extracted with three 50 mL portions of dichloromethane The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, 50 mL of brine dried over magnesium sulfate filtered concentrated

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

Procedure: To a chilled (−78° C.) solution of 5.2 mL (30.18 mmol) of 2-bromoallyltrimethylsilane and 5.3 g (31.16 mmol) of ethyl trifluoropyruvate in 75 mL of dichloromethane was added 30 mL (30 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane over a 10 minute period. The cold bath was then removed and the mixture was warmed to room temperature. After 3 hours, the mixture was cautiously added to 100 mL of saturated aqueous ammonium chloride and filtered through diatomaceous earth washing with dichloromethane. The dichloromethane was separated and the aqueous layer was extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, 50 mL of brine, dried over magnesium sulfate, filtered, and concentrated to afford 6.7 g (76%) of 4-bromo-2-hydroxy-2-trifluoromethylpent-4-enoic acid ethyl ester as a yellow oil which was used without further purification. The cold bath was then removed the mixture was cautiously added to 100 mL of saturated aqueous ammonium chloride filtered through diatomaceous earth washing with dichloromethane The dichloromethane was separated the aqueous layer was extracted with three 50 mL portions of dichloromethane The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, 50 mL of brine dried over magnesium sulfate filtered concentrated