N-(4-fluorophenyl)-2,2-dimethylpropanamide

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: To an ice-cooled solution of 125 mL of 4-fluoroaniline and 18.4 mL of triethylamine in 300 mL of methylene chloride was added dropwise over 30 min 14.8 mL of trimethylacetyl chloride. After addition was complete, the cooling bath was removed and stirring was continued at ambient temperature for 1 h. The reaction mixture was brought to pH 3 with 6N HCl and was partitioned between methylene chloride and water. Evaporation of the organiclayer afforded a solid which was collected and washed with hexane to afford 21.35 g (83%) of the title compound as a crystalline solid. After addition the cooling bath was removed was partitioned between methylene chloride and water Evaporation of the organiclayer afforded a solid which was collected washed with hexane

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of n-buthyllithium in hexane (80.0 ml of a 1.6 M solution) was added dropwise to a solution of N-(4-fluoro-phenyl)-2,2-dimethyl-propionamide (10.0 g) in dry THF (200 ml) at −5° C. under a N2 atmosphere over 15 min. The resulting solution was stirred at 0° C. for 2 hours, and then a solution of 1-benzyl-piperidin-4-one (9.20 ml) in THF (20 ml) was added dropwise to the above solution of the dianion at 0° C. over a 1 hour period. The reaction mixture was stirred for 2 hours at 0° C. and then overnight at r.t. The solution was the poured into ice water, made acidic with conc. HCl and extracted with ethyl acetate. The water layer was made basic and extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (hexane:ethyl acetate:triethyl amine 49:49:2) to afford the title product (8.3 g). M.p. 172-173° C.; Retention Time HPLC 1.47 min; MS (ES+) 385 (M+H+). The reaction mixture was stirred for 2 hours at 0° C. overnight at r.t extracted with ethyl acetate extracted three times with ethyl acetate The combined organic layers were washed with water dried over sodium sulfate 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 solution of 4-fluoroaniline (50.0 g) and triethylamine (157 ml) in CH2Cl2 (700 ml) were added 2,2-dimethyl-propionyl chloride (58.0 ml) over a 30 minutes period. The resulting solution was stirred at r.t. for 2 hour, then water was added and the mixture extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 86.0 g of the title compound. M.p. 124-125° C.; Retention Time HPLC 2.57 min; MS (ES+) 196 (M+H+). the mixture extracted three times with ethyl acetate The combined organic layers were dried over sodium sulfate 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 solution of 4-fluoroaniline (50.0 g) and triethylamine (157 ml) in CH2Cl2 (700 ml) were added 2,2-dimethyl-propionyl chloride (58.0 ml) over a 30 minutes period. The resulting solution was stirred at r.t. for 2 hour, then water was added and the mixture extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 86.0 g of the title compound. M.p. 124-125° C.; Retention Time HPLC 2.57 min; MS (ES+) 196 (M+H+). the mixture extracted three times with ethyl acetate The combined organic layers were dried over sodium sulfate concentrated in vacuo

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of n-buthyllithium in hexane (80.0 ml of a 1.6M solution) was added dropwise to a solution of N-(4-fluoro-phenyl)-2,2-dimethyl-propionamide (10.0 g) in dry THF (200 ml) at −5° C. under a N2 atmosphere over 15 min. The resulting solution was stirred at 0° C. for 2 hours, and then a solution of 1-benzyl-piperidin-4-one (9.20 ml) in THF (20 ml) was added dropewise to the above solution of the dianion at 0° C. over a 1 hour period. The reaction mixture was stirred for 2 hours at 0° C. and then overnight at r.t. The solution was the poured into ice water, made acidic with conc. HCl and extracted with ethyl acetate. The water layer was made basic and extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (hexane:ethyl acetate:triethyl amine 49:49:2) to afford the title product (8.3 g). M.p. 172-173° C.; Retention Time HPLC 1.47 min; MS (ES+) 385 (M+H+). The reaction mixture was stirred for 2 hours at 0° C. overnight at r.t extracted with ethyl acetate extracted three times with ethyl acetate The combined organic layers were washed with water dried over sodium sulfate 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 solution of 4-fluoroaniline (50.0 g) and triethylamine (157 ml) in CH2Cl2 (700 ml) were added 2,2-dimethyl-propionyl chloride (58.0 ml) over a 30 minutes period. The resulting solution was stirred at r.t. for 2 hour, then water was added and the mixture extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 86.0 g of the title compound. M.p. 124-125° C.; Retention Time HPLC 2.57 min; MS (ES+) 196 (M+H+). the mixture extracted three times with ethyl acetate The combined organic layers were dried over sodium sulfate 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 solution of 4-fluoroaniline (50.0 g) and triethylamine (157 ml) in CH2Cl2 (700 ml) were added 2,2-dimethyl-propionyl chloride (58.0 ml) over a 30 minutes period. The resulting solution was stirred at r.t. for 2 hour, then water was added and the mixture extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 86.0 g of the title compound. M.p. 124-125° C.; Retention Time HPLC 2.57 min; MS (ES+) 196 (M+H+). the mixture extracted three times with ethyl acetate The combined organic layers were dried over sodium sulfate concentrated in vacuo

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

実験手順: To an ice-cooled solution of 125 mL of 4-fluoroaniline and 18.4 mL of triethylamine in 300 mL of methylene chloride was added dropwise over 30 min 14.8 mL of trimethylacetyl chloride. After addition was complete, the cooling bath was removed and stirring was continued at ambient temperature for 1 h. The reaction mixture was brought to pH 3 with 6N HCl and was partitioned between methylene chloride and water. Evaporation of the organiclayer afforded a solid which was collected and washed with hexane to afford 21.35 g (83%) of the title compound as a crystalline solid. After addition the cooling bath was removed was partitioned between methylene chloride and water Evaporation of the organiclayer afforded a solid which was collected washed with hexane

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

実験手順: To an ice-cooled solution of 4.0 g of N-(4-fluorophenyl)-2,2-dimethylpropanamide in 80 mL of dry THF was added dropwise over 30 min 30.8 mL of a 1.6 M solution of n-butyllithium in hexane. After addition was complete, the reaction mixture was stirred an additional 1 h at 0° after which time 5.63 mL of ethyl trifluoroacetate was added quickly dropwise. The cooling bath was removed and the reaction was allowed to proceed at ambient temperature for 40 min. The reaction was quenched by the addition of aqueous ammonium chloride and the reaction mixture was partitioned between ether and water. The ether layer was washed with brine, dried and evaporated to 6.29 g of the title compound as an orange oil. The bulk of this material (6.0 g) was dissloved in ethylene glycol dimethyl ether, 30 mL of 6N HCl was added nd the mixture was heated at reflux for 1.5 h. The cooled reaction mixture was diluted with water, and made basic by the addition of solid sodium carbonate. This was extracted with ether, and the combined extacts were dried and evaporated. The residue was purified by column chromatography over silica gel (elution with 10-20% ethyl acetate in hexanes) affording 2.10 g of the title compound as an orange solid. After addition was added quickly dropwise The cooling bath was removed The reaction was quenched by the addition of aqueous ammonium chloride the reaction mixture was partitioned between ether and water The ether layer was washed with brine dried evaporated to 6.29 g of the title compound as an orange oil 30 mL of 6N HCl was added nd the mixture was heated at reflux for 1.5 h The cooled reaction mixture This was extracted with ether the combined extacts were dried evaporated The residue was purified by column chromatography over silica gel (elution with 10-20% ethyl acetate in hexanes)

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

実験手順: To an ice-cooled solution of 4.0 g of N-(4-fluorophenyl)-2,2-dimethylpropanamide in 80 mL of dry THF was added dropwise over 30 min 30.8 mL of a 1.6 M solution of n-butyllithium in hexane. After addition was complete, the reaction mixture was stirred an additional 1 h at 0° after which time 5.63 mL of ethyl trifluoroacetate was added quickly dropwise. The cooling bath was removed and the reaction was allowed to proceed at ambient temperature for 40 min. The reaction was quenched by the addition of aqueous ammonium chloride and the reaction mixture was partitioned between ether and water. The ether layer was washed with brine, dried and evaporated to 6.29 g of the title compound as an orange oil. The bulk of this material (6.0 g) was dissloved in ethylene glycol dimethyl ether, 30 mL of 6N HCl was added nd the mixture was heated at reflux for 1.5 h. The cooled reaction mixture was diluted with water, and made basic by the addition of solid sodium carbonate. This was extracted with ether, and the combined extacts were dried and evaporated. The residue was purified by column chromatography over silica gel (elution with 10-20% ethyl acetate in hexanes) affording 2.10 g of the title compound as an orange solid. After addition was added quickly dropwise The cooling bath was removed The reaction was quenched by the addition of aqueous ammonium chloride the reaction mixture was partitioned between ether and water The ether layer was washed with brine dried evaporated to 6.29 g of the title compound as an orange oil 30 mL of 6N HCl was added nd the mixture was heated at reflux for 1.5 h The cooled reaction mixture This was extracted with ether the combined extacts were dried evaporated The residue was purified by column chromatography over silica gel (elution with 10-20% ethyl acetate in hexanes)

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

実験手順: To an ice-cooled solution of 125 mL of 4-fluoroaniline and 18.4 mL of triethylamine in 300 mL of methylene chloride was added dropwise over 30 min 14.8 mL of trimethylacetyl chloride. After addition was complete, the cooling bath was removed and stirring was continued at ambient temperature for 1 h. The reaction mixture was brought to pH 3 with 6N HCl and was partitioned between methylene chloride and water. Evaporation of the organic layer afforded a solid which was collected and washed with hexane to afford 21.35 g (83%) of the title compound as a crystalline solid. After addition the cooling bath was removed was partitioned between methylene chloride and water Evaporation of the organic layer afforded a solid which was collected washed with hexane