(2S,5S)-2,5-bis(methoxymethyl)pyrrolidine

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 0.30 g (0.56 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.11 g (0.68 mmol) (2S,5S)-(−)-2,5-bis(methoxymethyl)pyrrolidine, 5 mg (0.01 mmol) cetyltrimethylammonium bromide, 0.014 g (0.027 mmol) bis(tri-t-butylphosphine)palladium(0), 0.07 ml NaOH 50% and 2 ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated under argon at 90° C. over night. After cooling to room temperature the mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 0.09 g of the crude coupling product. This material was dissolved in 2 ml dichloromethane and treated with 1.1 ml (1.1 mmol) of a 1 M solution of boron tribromide in dichloromethane at 0° C. After 15 min. the reaction was quenched by the addition of water, followed by extraction with three portions of dichloromethane. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 7 mg (2%) of (2R,5S)—N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light brown solid and 6 mg (2%) of (2S,5S)—N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light brown solid. was degassed by two freeze-thaw cycles After cooling to room temperature the mixture was diluted with water extracted with three portions of tert-butyl methyl ether The combined organic layers were dried over sodium sulphate concentrated in vacuo Flash column chromatography gave 0.09 g of the crude coupling product After 15 min. the reaction was quenched by the addition of water followed by extraction with three portions of dichloromethane The combined organic layers were dried over sodium sulphate concentrated in vacuo

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 0.30 g (0.56 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.11 g (0.68 mmol) (2S,5S)-(−)-2,5-bis(methoxymethyl)pyrrolidine, 5 mg (0.01 mmol) cetyltrimethylammonium bromide, 0.014 g (0.027 mmol) bis(tri-t-butylphosphine)palladium(0), 0.07 ml NaOH 50% and 2 ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated under argon at 90° C. over night. After cooling to room temperature the mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 0.09 g of the crude coupling product. This material was dissolved in 2 ml dichloromethane and treated with 1.1 ml (1.1 mmol) of a 1 M solution of boron tribromide in dichloromethane at 0° C. After 15 min. the reaction was quenched by the addition of water, followed by extraction with three portions of dichloromethane. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 7 mg (2%) of (2R,5S)—N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light brown solid and 6 mg (2%) of (2S,5S)—N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light brown solid. was degassed by two freeze-thaw cycles After cooling to room temperature the mixture was diluted with water extracted with three portions of tert-butyl methyl ether The combined organic layers were dried over sodium sulphate concentrated in vacuo Flash column chromatography gave 0.09 g of the crude coupling product After 15 min. the reaction was quenched by the addition of water followed by extraction with three portions of dichloromethane The combined organic layers were dried over sodium sulphate concentrated in vacuo

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 0.30 g (0.56 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.11 g (0.68 mmol) (2S,5S)-(−)-2,5-bis(methoxymethyl)pyrrolidine, 5 mg (0.01 mmol) cetyltrimethylammonium bromide, 0.014 g (0.027 mmol) bis(tri-t-butylphosphine)palladium(0), 0.07 ml NaOH 50% and 2 ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated under argon at 90° C. over night. After cooling to room temperature the mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 0.09 g of the crude coupling product. This material was dissolved in 2 ml dichloromethane and treated with 1.1 ml (1.1 mmol) of a 1 M solution of boron tribromide in dichloromethane at 0° C. After 15 min. the reaction was quenched by the addition of water, followed by extraction with three portions of dichloromethane. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 7 mg (2%) of (2R,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light brown solid and 6 mg (2%) of (2S,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light brown solid. was degassed by two freeze-thaw cycles After cooling to room temperature the mixture was diluted with water extracted with three portions of tert-butyl methyl ether The combined organic layers were dried over sodium sulphate concentrated in vacuo Flash column chromatography gave 0.09 g of the crude coupling product After 15 min. the reaction was quenched by the addition of water followed by extraction with three portions of dichloromethane The combined organic layers were dried over sodium sulphate concentrated in vacuo

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 0.30 g (0.56 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.11 g (0.68 mmol) (2S,5S)-(−)-2,5-bis(methoxymethyl)pyrrolidine, 5 mg (0.01 mmol) cetyltrimethylammonium bromide, 0.014 g (0.027 mmol) bis(tri-t-butylphosphine)palladium(0), 0.07 ml NaOH 50% and 2 ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated under argon at 90° C. over night. After cooling to room temperature the mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 0.09 g of the crude coupling product. This material was dissolved in 2 ml dichloromethane and treated with 1.1 ml (1.1 mmol) of a 1 M solution of boron tribromide in dichloromethane at 0° C. After 15 min. the reaction was quenched by the addition of water, followed by extraction with three portions of dichloromethane. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 7 mg (2%) of (2R,5S)—N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light brown solid and 6 mg (2%) of (2S,5S)—N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light brown solid. was degassed by two freeze-thaw cycles After cooling to room temperature the mixture was diluted with water extracted with three portions of tert-butyl methyl ether The combined organic layers were dried over sodium sulphate concentrated in vacuo Flash column chromatography gave 0.09 g of the crude coupling product After 15 min. the reaction was quenched by the addition of water followed by extraction with three portions of dichloromethane The combined organic layers were dried over sodium sulphate concentrated in vacuo