ethyl 4,4-difluoro-3-oxobutanoate

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Process step c): 778.1 g (5.25 mol) of triethyl orthoformate were charged in a stirred vessel, the pressure within the vessel was slowly reduced to 170 mbar and the triethyl orthoformate was heated to 92° C. 134.3 g (0.35 mol-100% conversion in process steps a) and b) assumed) of ethyl 4,4-difluoroacetoacetate (in the form of a suspension coming from process step b)) were added at 92° C. to 95° C. within 4 hours. Thereafter, the reaction mixture was stirred at 95° C. for further 30 minutes. During the entire reaction time low boiling compounds were continuously removed by distillation under reduced pressure. Afterwards, the triethyl orthoformate was distilled by lowering the pressure accordingly. The resulting concentrated product suspension was cooled down to room temperature and 70.2 g of xylenes were added. The resulting suspension (178 g) comprised 40.0% (w/w) of the desired product (GC analysis, quantification with internal standard). This corresponds to an overall yield over the two synthetic steps of 91.6%, based on ethyl difluoroacetate used. were added at 92° C. to 95° C. within 4 hours During the entire reaction time low boiling compounds were continuously removed by distillation under reduced pressure Afterwards, the triethyl orthoformate was distilled The resulting concentrated product suspension was cooled down to room temperature 70.2 g of xylenes were added This corresponds to an overall yield over the two synthetic steps of 91.6%

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Process step c): 778.1 g (5.25 mol) of triethyl orthoformate were charged in a stirred vessel, the pressure within the vessel was slowly reduced to 310 mbar and the triethyl orthoformate was heated to 104° C. 121.1 g (0.175 mol-100% conversion in process steps a) and b) assumed) of ethyl 4,4-difluoroacetoacetate (in the form of a suspension coming from process step b)) were added at 103° C. to 104° C. within 2 hours. Thereafter, the reaction mixture was stirred at 105° C. for further 30 minutes. During the entire reaction time low boiling compounds were removed by distillation under reduced pressure. Afterwards, the suspension was cooled down to room temperature. The resulting suspension (761 g) comprised 4.36% (w/w) of the desired product (GC analysis, quantification with internal standard). This corresponds to an overall yield over the two synthetic steps of 85.4%, based on ethyl difluoroacetate used. were added at 103° C. to 104° C. within 2 hours During the entire reaction time low boiling compounds were removed by distillation under reduced pressure Afterwards, the suspension was cooled down to room temperature This corresponds to an overall yield over the two synthetic steps of 85.4%

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

Procedure: Process step c): 185.3 g (1.25 mol) of triethyl orthoformate were initially charged in a stirred vessel, the pressure in the vessel was reduced to 500 mbar and the triethyl orthoformate was heated to 100° C. 177.5 g (0.25 mol-100% conversion in process steps a) and b) assumed) of ethyl 4,4-difluoroacetoacetate (in the form of a suspension coming from process step b)) were added at 98° C. to 105° C. within 2 hours. Thereafter, the reaction mixture was stirred at 100° C. for further 3.5 hours. Within this post reaction time the pressure was further reduced to 300 mbar. During the whole reaction time low boiling compounds were removed by distillation under reduced pressure. The resulting suspension (191 g) comprised 16.7% (w/w) of the desired product (GC analysis, quantification with internal standard). The yield, based on ethyl difluoroacetate used, was 57.3%. were added at 98° C. to 105° C. within 2 hours Within this post reaction time the pressure During the whole reaction time low boiling compounds were removed by distillation under reduced pressure

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add acetic anhydride (166 kg, 1625 mol) to a mixture of ethyl 4,4-difluoroacetoacetate (33 kg, 199 mol) and triethyl orthoformate (60 kg, 407 mol) maintained at 90-100° C. Stir the mixture at 90-100° C. for 8.5 hours and remove ethyl acetate using a Dean-Stark apparatus. Concentrate the reaction mixture to give the title compound (37.8 kg, 86% yield, 97% GC purity). 1H NMR (500 MHz, CDCl3,) δ 7.88 (d, J=6 Hz, 1H), 6.3 (m, 1H), 4.3 (m, 4H), 1.4 (m, 3H), 1.32 (m, 3H). remove ethyl acetate using a Dean-Stark apparatus Concentrate the reaction mixture

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add acetic anhydride (166 kg, 1625 mol) to a mixture of ethyl 4,4-difluoroacetoacetate (33 kg, 199 mol) and triethyl orthoformate (60 kg, 407 mol) maintained at 90-100° C. Stir the mixture at 90-100° C. for 8.5 hours and remove ethyl acetate using a Dean-Stark apparatus. Concentrate the reaction mixture to give the title compound (37.8 kg, 86% yield, 97% GC purity). 1H NMR (500 MHz, CDCl3,) δ 7.88 (d, J=6 Hz, 1H), 6.3 (m, 1H), 4.3 (m, 4H), 1.4 (m, 3H), 1.32 (m, 3H). remove ethyl acetate using a Dean-Stark apparatus Concentrate the reaction mixture

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add sodium metal (7 kg, 300 mol) in portions to EtOH (53.6 kg) while maintaining the temperature below 60° C. Stir the reaction mixture until the sodium dissolves, then cool the mixture to 20-30° C. Add a solution of ethyl difluoroacetate (34 kg, 274 mol) in EtOAc (63 kg) to the sodium ethoxide at a temperature of 25-40° C. Heat the reaction mixture to 65° C. while stirring. After 2 h cool the mixture to room temperature. Add 10% HCl (30 kg HCl and 204 kg water) to the mixture until the pH of the mixture is 6-7. Extract the mixture with EtOAc (64 kg); separate; and extract the aqueous layer again with EtOAc (60 kg). Combine organic phases, and wash with brine (NaCl (48 kg) in water (136 kg)). Dry the organic phase with 4 A molecular sieve powder (15 kg), and concentrate to give the title compound as a brown-yellow oil (33 kg, 73% yield, 96% GC purity). 1H NMR (500 MHz, CDCl3,) δ 5.91 (t, J=54 Hz, 1H), 4.23 (m, 2H), 3.70 (s, 2H), 1.27 (m, 3H). while maintaining the temperature below 60° C dissolves Heat the reaction mixture to 65° C. After 2 h cool the mixture to room temperature Extract the mixture with EtOAc (64 kg) separate and extract the aqueous layer again with EtOAc (60 kg) Combine organic phases, and wash with brine (NaCl (48 kg) in water (136 kg)) Dry the organic phase with 4 A molecular sieve powder (15 kg) concentrate

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add sodium metal (7 kg, 300 mol) in portions to EtOH (53.6 kg) while maintaining the temperature below 60° C. Stir the reaction mixture until the sodium dissolves, then cool the mixture to 20-30° C. Add a solution of ethyl difluoroacetate (34 kg, 274 mol) in EtOAc (63 kg) to the sodium ethoxide at a temperature of 25-40° C. Heat the reaction mixture to 65° C. while stirring. After 2 h cool the mixture to room temperature. Add 10% HCl (30 kg HCl and 204 kg water) to the mixture until the pH of the mixture is 6-7. Extract the mixture with EtOAc (64 kg); separate; and extract the aqueous layer again with EtOAc (60 kg). Combine organic phases, and wash with brine (NaCl (48 kg) in water (136 kg)). Dry the organic phase with 4 A molecular sieve powder (15 kg), and concentrate to give the title compound as a brown-yellow oil (33 kg, 73% yield, 96% GC purity). 1H NMR (500 MHz, CDCl3,) δ 5.91 (t, J=54 Hz, 1H), 4.23 (m, 2H), 3.70 (s, 2H), 1.27 (m, 3H). while maintaining the temperature below 60° C dissolves Heat the reaction mixture to 65° C. After 2 h cool the mixture to room temperature Extract the mixture with EtOAc (64 kg) separate and extract the aqueous layer again with EtOAc (60 kg) Combine organic phases, and wash with brine (NaCl (48 kg) in water (136 kg)) Dry the organic phase with 4 A molecular sieve powder (15 kg) concentrate

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a sulfonation flask, N,N-diethyl-2,2-difluoroacetamide (1.51 g; 10 mmol) was dissolved in ethyl acetate (20 ml) before ethanolic sodium ethoxide (15 ml of a 21% solution; 40.2 mmol) was added dropwise. The resulting mixture was stirred at 60° C. for 6 hours. After cooling, the mixture was poured into ice-water (20 ml), acidified with hydrochloric acid (10%) and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated in a water jet vacuum. The residue was purified by distillation under reduced pressure to give the desired 4,4-difluoro-3-oxo-butanoic acid ethyl ester in the form of a colourless oil. 40.2 mmol) was added dropwise After cooling extracted with ethyl acetate The organic phase was washed with brine dried over sodium sulfate evaporated in a water jet vacuum The residue was purified by distillation under reduced pressure

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

Procedure: BF3.OEt2 (2.7 ml, 22.0 mmol) was added to a solution of TFEDMA (2.5 ml, 22.0 mmol) in dry dichloromethane (20 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (20 ml). In a second Teflon flask, ethyl 4,4-difluoroacetoacetate (2.8 ml, 20.0 mmol) was added to a solution of pyridine (7.1 g, 90.0 mmol) in dry acetonitrile (40 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. tert-Butyl hydrazine hydrochloride (3.74 g, 30.0 mmol) was added to a solution of potassium hydroxide (1.68 g, 30 mmol) in methanol (10 ml) and the mixture was stirred at room temperature for 30 minutes. This mixture was then added to the previously prepared intermediate (ethyl 2-(2,2-difluoroacetyl)-3-(dimethylamino)-4,4-difluorobut-2-enoate) and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1). N-tert-Butyl-3,5-di(difluoromethyl)-4-pyrazolecarboxylic acid ethyl ester (1.77 g, 5.98 mmol, 30%) was isolated as an orange oil. was removed under reduced pressure To this were added dropwise, at −30° C. was brought to room temperature in the cold bath stirred overnight the mixture was stirred at room temperature for 30 minutes the mixture was stirred overnight The solvent was removed under reduced pressure the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1)

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

Procedure: BF3.OEt2 (1.24 ml, 10.0 mmol) was added to a solution of TFEDMA (1.20 ml, 10.0 mmol) in dry dichloromethane (10 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (10 ml). In a second Teflon flask, ethyl 4,4-difluoroacetoacetate (1.03 ml, 10.0 mmol) was added to a solution of pyridine (1.6 ml, 20.0 mmol) in dry acetonitrile (20 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. Methyl hydrazine (0.79 ml, 15.0 mmol) was then added dropwise at room temperature and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (10:0-8:2). (10:0 to 8:2). N-Methyl-3,5-difluoromethyl-4-pyrazolecarboxylic acid ethyl ester (1.75 g, 6.89 mmol, 69%) was obtained as a colourless oil, which crystallized when left to stand. was removed under reduced pressure To this were added dropwise, at −30° C. was brought to room temperature in the cold bath stirred overnight the mixture was stirred overnight The solvent was removed under reduced pressure the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (10:0-8:2)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetic anhydride (3.6 moles) is heated to 100 to 105° C., to which a mixture of crude ethyl difluoroacetoacetate (˜0.96 moles) and triethyl orthoformate (1.8 moles) is added drop-wise. The reaction mixture is kept at 100 to 105° C. for 6 hours. The reaction mixture is cooled to 60 to 70° C. and then concentrated under vacuum to remove excessive acetic anhydride, triethyl orthoformate, and generated ethyl acetate. A pale brown liquid is obtained. is added drop-wise concentrated under vacuum to remove excessive acetic anhydride, triethyl orthoformate A pale brown liquid is obtained

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Process step c): 778.1 g (5.25 mol) of triethyl orthoformate were charged in a stirred vessel, the pressure within the vessel was slowly reduced to 170 mbar and the triethyl orthoformate was heated to 92° C. 134.3 g (0.35 mol-100% conversion in process steps a) and b) assumed) of ethyl 4,4-difluoroacetoacetate (in the form of a suspension coming from process step b)) were added at 92° C. to 95° C. within 4 hours. Thereafter, the reaction mixture was stirred at 95° C. for further 30 minutes. During the entire reaction time low boiling compounds were continuously removed by distillation under reduced pressure. Afterwards, the triethyl orthoformate was distilled by lowering the pressure accordingly. The resulting concentrated product suspension was cooled down to room temperature and 70.2 g of xylenes were added. The resulting suspension (178 g) comprised 40.0% (w/w) of the desired product (GC analysis, quantification with internal standard). This corresponds to an overall yield over the two synthetic steps of 91.6%, based on ethyl difluoroacetate used. were added at 92° C. to 95° C. within 4 hours During the entire reaction time low boiling compounds were continuously removed by distillation under reduced pressure Afterwards, the triethyl orthoformate was distilled The resulting concentrated product suspension was cooled down to room temperature 70.2 g of xylenes were added This corresponds to an overall yield over the two synthetic steps of 91.6%