tert-butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: tert-Butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (3.10 g, 12.2 mmol) was dissolved in 95% EtOH (50 mL) and the solution was treated with sodium borohydride (2.32 g, 61.2 mmol) and stirred at ambient temperature for 3 hours. The reaction was treated dropwise with 3N HCl until vigorous gas evolution ceased, then stirred at ambient temperature for 20 minutes (pH of the mixture was 3-4 at this point). The reaction was neutralized with saturated NaHCO3 and concentrated in vacuo. The residue was dissolved in ethyl acetate and water and the layers were separated. The aqueous layer was washed with ethyl acetate and the combined organic layers were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to provide the desired product as a white solid (1.39 g). stirred at ambient temperature for 20 minutes (pH of the mixture concentrated in vacuo The residue was dissolved in ethyl acetate water and the layers were separated The aqueous layer was washed with ethyl acetate the combined organic layers were washed with saturated NaCl dried over Na2SO4 concentrated in vacuo

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

実験手順: tert-Butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (3.10 g, 12.2 mmol) was dissolved in 95% EtOH (50 mL) and the solution was treated with sodium borohydride (2.32 g, 61.2 mmol) and stirred at ambient temperature for 3 hours. The reaction was treated dropwise with 3N HCl until vigorous gas evolution ceased, then stirred at ambient temperature for 20 minutes (pH of the mixture was 3-4 at this point). The reaction was neutralized with saturated NaHCO3 and concentrated in vacuo. The residue was dissolved in ethyl acetate and water and the layers were separated. The aqueous layer was washed with ethyl acetate and the combined organic layers were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to provide the desired product as a white solid (1.39 g). stirred at ambient temperature for 20 minutes (pH of the mixture concentrated in vacuo The residue was dissolved in ethyl acetate water and the layers were separated The aqueous layer was washed with ethyl acetate the combined organic layers were washed with saturated NaCl dried over Na2SO4 concentrated in vacuo

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

実験手順: To a suspension of 8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (prepared in analogy to example 66a-c, 200 mg, 757 μmol) and hexachloroethane (215 mg, 908 mmol) under argon in dry THF (10 mL) was added triethylamine (230 mg, 317 μL, 2.27 mmol) followed by trimethylphosphine (1 M in THF, 908 μl, 908 μmol). The reaction mixture was stirred at room temperature for 0.5 hous, then tert-butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (see example 247e, 230 mg, 908 μmol) was added and the mixture was heated to 150° C. in the microwave for 30 minutes. A solution of decaborane (92.5 mg, 98.4 μL, 757 μmol) in MeOH (1 mL) was added to the reaction mixture, then stirred at room temperature for 12 hours. Again a solution of decaborane (92.5 mg, 98.4 μL, 757 μmol) in MeOH (5 mL) was added and heated to 70° C. for 18 hours. Aqueous NaHCO3 solution was added to the reaction mixture, the aqueous phase was extracted with CH2Cl2, the organic layers were combined, dried over Na2SO4, filtered and the solvents evaporated. The residue was purified by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane), whereby 85 mg of intermediate imine, 3,3-difluoro-4-[(E)-8-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylimino]-piperidine-1-carboxylic acid tert-butyl ester, was isolated, which was again dissolved in dry MeOH (3 mL). Decaborane (21.6 mg, 23.0 μL, 177 μmol) was added and heated to 70° C. for 30 minutes. Aqueous NaHCO3 solution was added to the reaction mixture, the aqueous phase was extracted with CH2Cl2, the organic layers were combined, dried over Na2SO4, filtered and the solvents evaporated. The residue was purified (together with impure product fractions from first chromatography) by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane) to yield title compound as white foam (300 mg, 82%). MS ISP (m/e): 484.3/428.1/384.2 (13/100/41) [(M+H)+/(M−tBu)+/(M−Boc)+]. the mixture was heated to 150° C. in the microwave for 30 minutes stirred at room temperature for 12 hours heated to 70° C. for 18 hours the aqueous phase was extracted with CH2Cl2 dried over Na2SO4 filtered the solvents evaporated The residue was purified by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane), whereby 85 mg of intermediate imine, 3,3-difluoro-4-[(E)-8-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylimino]-piperidine-1-carboxylic acid tert-butyl ester was isolated heated to 70° C. for 30 minutes the aqueous phase was extracted with CH2Cl2 dried over Na2SO4 filtered the solvents evaporated The residue was purified (together with impure product fractions from first chromatography) by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane)

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of tert-butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (1 g, 3.36 mmol), and benzylamine (539 mg, 550 μL, 5.03 mmol) in dry toluene (70 mL) was heated to reflux with dean stark apparatus for 12 hours. Further benzyl amine (20 μL, 185 μmol) was added and heated to reflux with dean stark apparatus for another 12 hours. About 50 mL of toluene were distilled off, the residue was cooled to 55° C., ethanol (35 mL) and NaBH4 (508 mg, 13.4 mmol) were added and the reaction mixture stirred at 55° C. for 2 hours. Further NaBH4 (508 mg, 13.4 mmol) was added and stirred for another hour. Further NaBH4 (508 mg, 13.4 mmol) was added. After 2 hours the reaction mixture was concentrated, then 2 N Na2CO3 solution was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvents were evaporated. The residue was purified by flash chromatography (70 g, 0% to 100% EtOAc in hexanes). The title compound was obtained as colorless oil (875 mg, 80%). was heated to reflux with dean stark apparatus for 12 hours heated to reflux with dean stark apparatus for another 12 hours About 50 mL of toluene were distilled off stirred for another hour After 2 hours the reaction mixture was concentrated 2 N Na2CO3 solution was added the aqueous phase was extracted with ethyl acetate The combined organic layers were dried over Na2SO4 the solvents were evaporated The residue was purified by flash chromatography (70 g, 0% to 100% EtOAc in hexanes)

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: tert-Butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (3.10 g, 12.2 mmol) was dissolved in 95% EtOH (50 mL) and the solution was treated with sodium borohydride (2.32 g, 61.2 mmol) and stirred at ambient temperature for 3 hours. The reaction was treated dropwise with 3N HCl until vigorous gas evolution ceased, then stirred at ambient temperature for 20 minutes (pH of the mixture was 3-4 at this point). The reaction was neutralized with saturated NaHCO3 and concentrated in vacuo. The residue was dissolved in ethyl acetate and water and the layers were separated. The aqueous layer was washed with ethyl acetate and the combined organic layers were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to provide the desired product as a white solid (1.39 g). stirred at ambient temperature for 20 minutes (pH of the mixture concentrated in vacuo The residue was dissolved in ethyl acetate water and the layers were separated The aqueous layer was washed with ethyl acetate the combined organic layers were washed with saturated NaCl dried over Na2SO4 concentrated in vacuo

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

実験手順: tert-Butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (3.10 g, 12.2 mmol) was dissolved in 95% EtOH (50 mL) and the solution was treated with sodium borohydride (2.32 g, 61.2 mmol) and stirred at ambient temperature for 3 hours. The reaction was treated dropwise with 3N HCl until vigorous gas evolution ceased, then stirred at ambient temperature for 20 minutes (pH of the mixture was 3-4 at this point). The reaction was neutralized with saturated NaHCO3 and concentrated in vacuo. The residue was dissolved in ethyl acetate and water and the layers were separated. The aqueous layer was washed with ethyl acetate and the combined organic layers were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to provide the desired product as a white solid (1.39 g). stirred at ambient temperature for 20 minutes (pH of the mixture concentrated in vacuo The residue was dissolved in ethyl acetate water and the layers were separated The aqueous layer was washed with ethyl acetate the combined organic layers were washed with saturated NaCl dried over Na2SO4 concentrated in vacuo

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

実験手順: To a suspension of 8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (prepared in analogy to example 66a-c, 200 mg, 757 μmol) and hexachloroethane (215 mg, 908 mmol) under argon in dry THF (10 mL) was added triethylamine (230 mg, 317 μL, 2.27 mmol) followed by trimethylphosphine (1 M in THF, 908 μl, 908 μmol). The reaction mixture was stirred at room temperature for 0.5 hous, then tert-butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (see example 247e, 230 mg, 908 μmol) was added and the mixture was heated to 150° C. in the microwave for 30 minutes. A solution of decaborane (92.5 mg, 98.4 μL, 757 μmol) in MeOH (1 mL) was added to the reaction mixture, then stirred at room temperature for 12 hours. Again a solution of decaborane (92.5 mg, 98.4 μL, 757 μmol) in MeOH (5 mL) was added and heated to 70° C. for 18 hours. Aqueous NaHCO3 solution was added to the reaction mixture, the aqueous phase was extracted with CH2Cl2, the organic layers were combined, dried over Na2SO4, filtered and the solvents evaporated. The residue was purified by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane), whereby 85 mg of intermediate imine, 3,3-difluoro-4-[(E)-8-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylimino]-piperidine-1-carboxylic acid tert-butyl ester, was isolated, which was again dissolved in dry MeOH (3 mL). Decaborane (21.6 mg, 23.0 μL, 177 μmol) was added and heated to 70° C. for 30 minutes. Aqueous NaHCO3 solution was added to the reaction mixture, the aqueous phase was extracted with CH2Cl2, the organic layers were combined, dried over Na2SO4, filtered and the solvents evaporated. The residue was purified (together with impure product fractions from first chromatography) by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane) to yield title compound as white foam (300 mg, 82%). MS ISP (m/e): 484.3/428.1/384.2 (13/100/41) [(M+H)+/(M−tBu)+/(M−Boc)+]. the mixture was heated to 150° C. in the microwave for 30 minutes stirred at room temperature for 12 hours heated to 70° C. for 18 hours the aqueous phase was extracted with CH2Cl2 dried over Na2SO4 filtered the solvents evaporated The residue was purified by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane), whereby 85 mg of intermediate imine, 3,3-difluoro-4-[(E)-8-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylimino]-piperidine-1-carboxylic acid tert-butyl ester was isolated heated to 70° C. for 30 minutes the aqueous phase was extracted with CH2Cl2 dried over Na2SO4 filtered the solvents evaporated The residue was purified (together with impure product fractions from first chromatography) by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane)

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of tert-butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (1 g, 3.36 mmol), and benzylamine (539 mg, 550 μL, 5.03 mmol) in dry toluene (70 mL) was heated to reflux with dean stark apparatus for 12 hours. Further benzyl amine (20 μL, 185 μmol) was added and heated to reflux with dean stark apparatus for another 12 hours. About 50 mL of toluene were distilled off, the residue was cooled to 55° C., ethanol (35 mL) and NaBH4 (508 mg, 13.4 mmol) were added and the reaction mixture stirred at 55° C. for 2 hours. Further NaBH4 (508 mg, 13.4 mmol) was added and stirred for another hour. Further NaBH4 (508 mg, 13.4 mmol) was added. After 2 hours the reaction mixture was concentrated, then 2 N Na2CO3 solution was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvents were evaporated. The residue was purified by flash chromatography (70 g, 0% to 100% EtOAc in hexanes). The title compound was obtained as colorless oil (875 mg, 80%). was heated to reflux with dean stark apparatus for 12 hours heated to reflux with dean stark apparatus for another 12 hours About 50 mL of toluene were distilled off stirred for another hour After 2 hours the reaction mixture was concentrated 2 N Na2CO3 solution was added the aqueous phase was extracted with ethyl acetate The combined organic layers were dried over Na2SO4 the solvents were evaporated The residue was purified by flash chromatography (70 g, 0% to 100% EtOAc in hexanes)