三氟化硼四氢呋喃络合物

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3-ethyl-3-(3-nitrophenyl)-4-pentenoic acid (Preparation 60, assume 7.25 mmol) in tetrahydropyran (43 ml) at 0° C. was added sodium borohydride (0.55 g, 14.5 mmol) and the reaction mixture was stirred at 0° C. for 10 min. To the reaction mixture was added borontrifluoride tetrahydrofuran complex (2.72 g, 19.4 mmol) over 5 min. The reaction mixture was stirred under nitrogen at 0° C. for 30 min then it was allowed to warm to room temperature overnight. Ethanol (10 ml) was added cautiously, followed sequentially by water (10 ml), 2M aqueous sodium hydroxide solution (1.8 ml), water (10 ml) and finally 2M aqueous sodium hydroxide solution (1.8 ml). Solid sodium carbonate (1.8 g) was added followed by 30% w:w aqueous hydrogen peroxide solution (60 ml) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was filtered and the filtrate was partitioned between brine (100 ml) and ethyl acetate (100 ml). The phases were separated and the organic extract was dried (MgSO4), filtered and concentrated in vacuo to give the crude product. This was purified by silica (150 g) column chromatography eluting with a gradient of ethyl acetate:toluene: 0.880 ammonia (49:50:1 to 66:33:1) to give the title compound as a yellow oil (661 mg, 34% over 3 steps). The reaction mixture was stirred under nitrogen at 0° C. for 30 min to warm to room temperature overnight The mixture was filtered the filtrate was partitioned between brine (100 ml) and ethyl acetate (100 ml) The phases were separated the organic extract was dried (MgSO4) filtered concentrated in vacuo to give the crude product This was purified by silica (150 g) column chromatography eluting with a gradient of ethyl acetate

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (0° C.) mixture of (S)-3-(cyanodiphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)acetyl]pyrrolidine (IV) as a toluene solution (7.43 Kg active, 17.59 moles) and sodium borohydride (0.87 Kg, 23 moles) in tetrahydrofuran (29.7 L) is added boron trifluoride tetrahydrofuran complex (4.31 Kg, 30.81 moles) at such a rate as to maintain the temperature of the reaction below 10° C. The reaction is warmed to ambient temperature and stirred for a further 4 hours. Aqueous piperazine solution is added and the mixture is heated at reflux for 8 hours. The aqueous layer is separated and washed with 1% aqueous sodium chloride solution (22.3 L) at 40° C. The organic layer is concentrated and essentially replaced by isopropyl alcohol at atmospheric pressure to a total volume of about 30 L. The product crystallises on cooling and is collected at 0-5° C. by filtration. (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile (V) is washed with chilled isopropyl alcohol and dried under vacuum at 50° C. Yield 6.34 Kg (88%). To a cooled to maintain the temperature of the reaction below 10° C the mixture is heated at reflux for 8 hours The aqueous layer is separated washed with 1% aqueous sodium chloride solution (22.3 L) at 40° C The organic layer is concentrated The product crystallises on cooling is collected at 0-5° C. by filtration (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile (V) is washed with chilled isopropyl alcohol dried under vacuum at 50° C

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (0° C.) mixture of (S)-3-(cyanodiphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)acetyl]pyrrolidine (IV) as a toluene solution (7.43 Kg active, 17.59 moles) and sodium borohydride (0.87 Kg, 23 moles) in tetrahydrofuran (29.7 L) is added boron trifluoride tetrahydrofuran complex (4.31 Kg, 30.81 moles) at such a rate as to maintain the temperature of the reaction below 10° C. The reaction is warmed to ambient temperature and stirred for a further 4 hours. Aqueous piperazine solution is added and the mixture is heated at reflux for 8 hours. The aqueous layer is separated and washed with 1% aqueous sodium chloride solution (22.3 L) at 40° C. The organic layer is concentrated and essentially replaced by isopropyl alcohol at atmospheric pressure to a total volume of about 30 L. The product crystallises on cooling and is collected at 0-5° C. by filtration. (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile (V) is washed with chilled isopropyl alcohol and dried under vacuum at 50° C. Yield 6.34 Kg (88%). To a cooled to maintain the temperature of the reaction below 10° C the mixture is heated at reflux for 8 hours The aqueous layer is separated washed with 1% aqueous sodium chloride solution (22.3 L) at 40° C The organic layer is concentrated The product crystallises on cooling is collected at 0-5° C. by filtration (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile (V) is washed with chilled isopropyl alcohol dried under vacuum at 50° C

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (0° C.) mixture of (S)-3-(cyanodiphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)acetyl]pyrrolidine (IV) as a toluene solution (7.43 Kg active, 17.59 moles) and sodium borohydride (0.87 Kg, 23 moles) in tetrahydrofuran (29.7 L) is added boron trifluoride tetrahydrofuran complex (4.31 Kg, 30.81 moles) at such a rate as to maintain the temperature of the reaction below 10° C. The reaction is warmed to ambient temperature and stirred for a further 4 hours. Aqueous piperazine solution is added and the mixture is heated at reflux for 8 hours. The aqueous layer is separated and washed with 1% aqueous sodium chloride solution (22.3 L) at 40° C. The organic layer is concentrated and essentially replaced by isopropyl alcohol at atmospheric pressure to a total volume of about 30 L. The product crystallises on cooling and is collected at 0-5° C. by filtration. (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile (V) is washed with chilled isopropyl alcohol and dried under vacuum at 50° C. Yield 6.34 Kg (88%). To a cooled to maintain the temperature of the reaction below 10° C the mixture is heated at reflux for 8 hours The aqueous layer is separated washed with 1% aqueous sodium chloride solution (22.3 L) at 40° C The organic layer is concentrated The product crystallises on cooling is collected at 0-5° C. by filtration (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile (V) is washed with chilled isopropyl alcohol dried under vacuum at 50° C

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3-ethyl-3-(3-nitrophenyl)-4-pentenoic acid (Preparation 60, assume 7.25 mmol) in tetrahydropyran (43 ml) at 0° C. was added sodium borohydride (0.55 g, 14.5 mmol) and the reaction mixture was stirred at 0° C. for 10 min. To the reaction mixture was added borontrifluoride tetrahydrofuran complex (2.72 g, 19.4 mmol) over 5 min. The reaction mixture was stirred under nitrogen at 0° C. for 30 min then it was allowed to warm to room temperature overnight. Ethanol (10 ml) was added cautiously, followed sequentially by water (10 ml), 2M aqueous sodium hydroxide solution (1.8 ml), water (10 ml) and finally 2M aqueous sodium hydroxide solution (1.8 ml). Solid sodium carbonate (1.8 g) was added followed by 30% w:w aqueous hydrogen peroxide solution (60 ml) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was filtered and the filtrate was partitioned between brine (100 ml) and ethyl acetate (100 ml). The phases were separated and the organic extract was dried (MgSO4), filtered and concentrated in vacuo to give the crude product. This was purified by silica (150 g) column chromatography eluting with a gradient of ethyl acetate:toluene: 0.880 ammonia (49:50:1 to 66:33:1) to give the title compound as a yellow oil (661 mg, 34% over 3 steps). The reaction mixture was stirred under nitrogen at 0° C. for 30 min to warm to room temperature overnight The mixture was filtered the filtrate was partitioned between brine (100 ml) and ethyl acetate (100 ml) The phases were separated the organic extract was dried (MgSO4) filtered concentrated in vacuo to give the crude product This was purified by silica (150 g) column chromatography eluting with a gradient of ethyl acetate

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3-ethyl-3-(3-nitrophenyl)-4-pentenoic acid (Preparation 60, assume 7.25 mmol) in tetrahydropyran (43 ml) at 0° C. was added sodium borohydride (0.55 g, 14.5 mmol) and the reaction mixture was stirred at 0° C. for 10 min. To the reaction mixture was added borontrifluoride tetrahydrofuran complex (2.72 g, 19.4 mmol) over 5 min. The reaction mixture was stirred under nitrogen at 0° C. for 30 min then it was allowed to warm to room temperature overnight. Ethanol (10 ml) was added cautiously, followed sequentially by water (10 ml), 2M aqueous sodium hydroxide solution (1.8 ml), water (10 ml) and finally 2M aqueous sodium hydroxide solution (1.8 ml). Solid sodium carbonate (1.8 g) was added followed by 30% w:w aqueous hydrogen peroxide solution (60 ml) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was filtered and the filtrate was partitioned between brine (100 ml) and ethyl acetate (100 ml). The phases were separated and the organic extract was dried (MgSO4), filtered and concentrated in vacuo to give the crude product. This was purified by silica (150 g) column chromatography eluting with a gradient of ethyl acetate:toluene: 0.880 ammonia (49:50:1 to 66:33:1) to give the title compound as a yellow oil (661 mg, 34% over 3 steps). The reaction mixture was stirred under nitrogen at 0° C. for 30 min to warm to room temperature overnight The mixture was filtered the filtrate was partitioned between brine (100 ml) and ethyl acetate (100 ml) The phases were separated the organic extract was dried (MgSO4) filtered concentrated in vacuo to give the crude product This was purified by silica (150 g) column chromatography eluting with a gradient of ethyl acetate

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-[1,4]oxazin-2-one (5 g, 26.4 mmol, see WO-A-02/051983) in anhydrous 2-methyltetrahydrofuran (50 ml) was added boron trifluoride tetrahydrofuran complex (5.8 ml, 52.8 mmol) with stirring under nitrogen at −78° C. The resultant solution was then stirred at −78° C. for 1 hour. (2-Ethylbutyl)magnesium bromide as a solution in tetrahydrofuran (170 ml, 0.16 M, 27.7 mmol) was then added maintaining the temperature below −60° C. during the addition. The resultant solution was stirred at −78° C. for a further 2 hours. Acetic acid (0.6 ml 10.6 mmol) was then added and the solution warmed to 22° C. Saturated aqueous ammonium chloride (50 ml) was then added followed by water (100 ml). The phases were separated and the organic phase retained. The resultant solution was then distilled to dryness under vacuum. Toluene (75 ml) was then added and the organic solution was washed with water (25 ml) then saturated aqueous sodium chloride solution (25 ml) and the phases separated and the organic phase retained. Aqueous hydrochloric acid (100 ml, 1.5 M) was then added and the resultant biphasic mixture warmed to 30° C. and stirred for 2 hours. The phases were separated and the aqueous phase retained. Aqueous sodium hydroxide (47% w/w, 6 ml then 2M, 16 ml) was then added to give a pH of 5 by pH paper. The resultant slurry was stirred at 22° C. for 30 minutes and the solid was then isolated by filtration. The filter cake was washed with water (25 ml) and dried at 60° C. overnight under vacuum to give the title compound (4.1 g crude weight, 95% purity, 14.0 mmol, 53% yield): mp 149° C.; 1H-NMR (CD3OD, 300 MHz), δ: 0.83 (3H, t), 0.90 (3H, t), 1.06 (3H, s), 1.31-1.54 (5H, m) 1.73 (2H, d), 4.40 (1H, t), 7.46-7.50 (5H, m); LRMS (ES): m/z 293 [M]+. maintaining the temperature below −60° C. during the addition the solution warmed to 22° C The phases were separated The resultant solution was then distilled to dryness under vacuum Toluene (75 ml) was then added the organic solution was washed with water (25 ml) saturated aqueous sodium chloride solution (25 ml) and the phases separated Aqueous hydrochloric acid (100 ml, 1.5 M) was then added the resultant biphasic mixture warmed to 30° C. stirred for 2 hours The phases were separated Aqueous sodium hydroxide (47% w/w, 6 ml then 2M, 16 ml) was then added to give a pH of 5 by pH paper The resultant slurry was stirred at 22° C. for 30 minutes the solid was then isolated by filtration The filter cake was washed with water (25 ml) dried at 60° C. overnight under vacuum

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (0° C.) mixture of (S)-3-(cyanodiphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)acetyl]pyrrolidine (IV) as a toluene solution (7.43 Kg active, 17.59 moles) and sodium borohydride (0.87 Kg, 23 moles) in tetrahydrofuran (29.7 L) is added boron trifluoride tetrahydrofuran complex (4.31 Kg, 30.81 moles) at such a rate as to maintain the temperature of the reaction below 10° C. The reaction is warmed to ambient temperature and stirred for a further 4 hours. Aqueous piperazine solution is added and the mixture is heated at reflux for 8 hours. The aqueous layer is separated and washed with 1% aqueous sodium chloride solution (22.3 L) at 40° C. The organic layer is concentrated and essentially replaced by isopropyl alcohol at atmospheric pressure to a total volume of about 30 L. The product crystallises on cooling and is collected at 0-5° C. by filtration. (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile (V) is washed with chilled isopropyl alcohol and dried under vacuum at 50° C. Yield 6.34 Kg (88%). To a cooled to maintain the temperature of the reaction below 10° C the mixture is heated at reflux for 8 hours The aqueous layer is separated washed with 1% aqueous sodium chloride solution (22.3 L) at 40° C The organic layer is concentrated The product crystallises on cooling is collected at 0-5° C. by filtration (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile (V) is washed with chilled isopropyl alcohol dried under vacuum at 50° C

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (0° C.) mixture of (S)-3-(cyanodiphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)acetyl]pyrrolidine (IV) as a toluene solution (7.43 Kg active, 17.59 moles) and sodium borohydride (0.87 Kg, 23 moles) in tetrahydrofuran (29.7 L) is added boron trifluoride tetrahydrofuran complex (4.31 Kg, 30.81 moles) at such a rate as to maintain the temperature of the reaction below 10° C. The reaction is warmed to ambient temperature and stirred for a further 4 hours. Aqueous piperazine solution is added and the mixture is heated at reflux for 8 hours. The aqueous layer is separated and washed with 1% aqueous sodium chloride solution (22.3 L) at 40° C. The organic layer is concentrated and essentially replaced by isopropyl alcohol at atmospheric pressure to a total volume of about 30 L. The product crystallises on cooling and is collected at 0-5° C. by filtration. (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile (V) is washed with chilled isopropyl alcohol and dried under vacuum at 50° C. Yield 6.34 Kg (88%). To a cooled to maintain the temperature of the reaction below 10° C the mixture is heated at reflux for 8 hours The aqueous layer is separated washed with 1% aqueous sodium chloride solution (22.3 L) at 40° C The organic layer is concentrated The product crystallises on cooling is collected at 0-5° C. by filtration (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile (V) is washed with chilled isopropyl alcohol dried under vacuum at 50° C

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3-ethyl-3-(3-nitrophenyl)-4-pentenoic acid (Preparation 60, assume 7.25 mmol) in tetrahydropyran (43 ml) at 0° C. was added sodium borohydride (0.55 g, 14.5 mmol) and the reaction mixture was stirred at 0° C. for 10 min. To the reaction mixture was added borontrifluoride tetrahydrofuran complex (2.72 g, 19.4 mmol) over 5 min. The reaction mixture was stirred under nitrogen at 0° C. for 30 min then it was allowed to warm to room temperature overnight. Ethanol (10 ml) was added cautiously, followed sequentially by water (10 ml), 2M aqueous sodium hydroxide solution (1.8 ml), water (10 ml) and finally 2M aqueous sodium hydroxide solution (1.8 ml). Solid sodium carbonate (1.8 g) was added followed by 30% w:w aqueous hydrogen peroxide solution (60 ml) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was filtered and the filtrate was partitioned between brine (100 ml) and ethyl acetate (100 ml). The phases were separated and the organic extract was dried (MgSO4), filtered and concentrated in vacuo to give the crude product. This was purified by silica (150 g) column chromatography eluting with a gradient of ethyl acetate:toluene: 0.880 ammonia (49:50:1 to 66:33:1) to give the title compound as a yellow oil (661 mg, 34% over 3 steps). The reaction mixture was stirred under nitrogen at 0° C. for 30 min to warm to room temperature overnight The mixture was filtered the filtrate was partitioned between brine (100 ml) and ethyl acetate (100 ml) The phases were separated the organic extract was dried (MgSO4) filtered concentrated in vacuo to give the crude product This was purified by silica (150 g) column chromatography eluting with a gradient of ethyl acetate