4-fluoro-N,N-dimethylbenzamide

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: A solution of 758 mg. of N,N-dimethyl-4-fluorobenzamide and 0.44 ml. of phosphorous oxychloride in 50 ml. of 1,2-dichloroethane is refluxed for one hour. To this solution is added a solution of 500 mg. of isopropyl 5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate in 10 ml. 1,2-dichloroethane. The reaction mixture is refluxed for 3 hours. A solution of 3.3 g. sodium acetate trihydrate in 9 ml water is added and refluxed for a further 10 hours. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is purified by preparative t.l.c. using hexane:ethyl acetate (90:10). Crystallization from dichloromethane-hexane yields isopropyl 3-p-fluorobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate (XI, R=H, L=p-F, R2 =iC3H7, n=1), m.p. 92° C. To this solution is added a solution of 500 mg The reaction mixture is refluxed for 3 hours refluxed for a further 10 hours The organic phase is separated washed with saturated sodium chloride solution dried over sodium sulfate evaporated to dryness The residue is purified by preparative t.l.c Crystallization from dichloromethane-hexane

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

実験手順: A solution of N,N-dimethyl-4-fluorobenzamide (8.4 g, 0.05 moles) in anhydrous 1,2-dichloroethane (170 ml) containing phosphorus oxychloride (7.7 g, 0.05 moles) was heated at reflux temperature for 1 hour. At the end of this time 2-methylthiopyrrole (2.82 g, 0.025 moles) was added and heating was continued for an additional 0.5 hour. The solution was cooled to room temperature, and to the cooled solution was cautiously added, with good agitation, a solution of sodium acetate (12.3 g, 0.15 moles) in water (50 ml) and the mixture was then boiled under reflux for 1 hour. The organic phase was separated, washed with water, dried, and evaporated. The residue was subjected to column chromatography on silica gel suing ethyl acetate-hexane (1:9) as the eluting solvent. A yellow colored solid 2-(methylthio)-5-(4-fluorobenzoyl)pyrrole (3.2 g, 54%) was obtained which after crystallization from ether-hexane had m.p. 112°-113° C. was heated at reflux temperature for 1 hour heating to the cooled solution was cautiously added, with good agitation under reflux for 1 hour The organic phase was separated washed with water dried evaporated

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

実験手順: A solution of N,N-dimethyl-4-fluorobenzamide (8.4 g, 0.05 moles) in anhydrous 1,2-dichloroethane (170 ml) containing phosphorous oxychloride (7.7 g, 0.05 moles) was heated at reflux temperature for 1 hour. At the end of this time 2-methylthiopyrrole (2.82 g, 0.025 moles) was added and heating was continued for an additional 0.5 hour. The solution was cooled to room temperature, and to the cooled solution was cautiously added, with good agitation, a solution of sodium acetate (12.3 g, 0.15 moles) in water (50 ml) and the mixture was then boiled under reflux for 1 hour. The organic phase was separated, washed with water, dried, and evaporated. The residue was subjected to column chromatography on silica gel using ethyl acetate-hexane (1:9) as the eluting solvent. A yellow colored solid 2-(methylthio)-5-(4-fluorobenzoyl)pyrrole (3.2 g, 54%) was obtained which after crystallization from ether-hexane had m.p. 112°-113° C. was heated at reflux temperature for 1 hour heating to the cooled solution was cautiously added, with good agitation under reflux for 1 hour The organic phase was separated washed with water dried evaporated

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: A solution of N,N-dimethyl-4-fluorobenzamide (8.4 g, 0.05 moles) in anhydrous 1,2-dichloroethane (170 ml) containing phosphorus oxychloride (7.7 g, 0.05 moles) was heated at reflux temperature for 1 hour. At the end of this time 2-methylthiopyrrole (2.82 g, 0.025 moles) was added and heating was continued for an additional 0.5 hour. The solution was cooled to room temperature, and to the cooled solution was cautiously added, with good agitation, a solution of sodium acetate (12.3 g, 0.15 moles) in water (50 ml) and the mixture was then boiled under reflux for 1 hour. The organic phase was separated, washed with water, dried, and evaporated. The residue was subjected to column chromatography on silica gel suing ethyl acetate-hexane (1:9) as the eluting solvent. A yellow colored solid 2-(methylthio)-5-(4-fluorobenzoyl)pyrrole (3.2 g, 54%) was obtained which after crystallization from ether-hexane had m.p. 112°-113° C. was heated at reflux temperature for 1 hour heating to the cooled solution was cautiously added, with good agitation under reflux for 1 hour The organic phase was separated washed with water dried evaporated

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

実験手順: A solution of N,N-dimethyl-4-fluorobenzamide (8.4 g, 0.05 moles) in anhydrous 1,2-dichloroethane (170 ml) containing phosphorous oxychloride (7.7 g, 0.05 moles) was heated at reflux temperature for 1 hour. At the end of this time 2-methylthiopyrrole (2.82 g, 0.025 moles) was added and heating was continued for an additional 0.5 hour. The solution was cooled to room temperature, and to the cooled solution was cautiously added, with good agitation, a solution of sodium acetate (12.3 g, 0.15 moles) in water (50 ml) and the mixture was then boiled under reflux for 1 hour. The organic phase was separated, washed with water, dried, and evaporated. The residue was subjected to column chromatography on silica gel using ethyl acetate-hexane (1:9) as the eluting solvent. A yellow colored solid 2-(methylthio)-5-(4-fluorobenzoyl)pyrrole (3.2 g, 54%) was obtained which after crystallization from ether-hexane had m.p. 112°-113° C. was heated at reflux temperature for 1 hour heating to the cooled solution was cautiously added, with good agitation under reflux for 1 hour The organic phase was separated washed with water dried evaporated

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

実験手順: The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluoro-N,N-dimethylbenzamide (989 mg, 5.91 mmol) and 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) (1.500 g, 5.633 mmol) to give a white solid (154 mg, 7% yield). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=8.59 Hz, 2 H) 7.20 (d, J=16.17 Hz, 2 H) 6.96 (d, J=8.59 Hz, 2 H) 4.87-5.03 (m, 1 H) 3.77-3.87 (m, 1 H) 3.71 (br. s., 1 H) 2.99-3.13 (m, 7 H) 2.90 (dd, J=16.55, 7.20 Hz, 1 H) 1.54 (s, 9 H); LCMS for C23H27NO6 m/z 358.20 (M-tBu+H)+.

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

実験手順: A solution of N,N-dimethyl-4-fluorobenzamide (8.4 g, 0.05 moles) in anhydrous 1,2-dichloroethane (170 ml) containing phosphorous oxychloride (7.7 g, 0.05 moles) was heated at reflux temperature for 1 hour. At the end of this time 2-methylthiopyrrole (2.82 g, 0.025 moles) was added and heating was continued for an additional 0.5 hour. The solution was cooled to room temperature, and to the cooled solution was cautiously added, with good agitation, a solution of sodium acetate (12.3 g, 0.15 moles) in water (50 ml) and the mixture was then boiled under reflux for 1 hour. The organic phase was separated, washed with water, dried, and evaporated. The residue was subjected to column chromatography on silica gel suing ethyl acetate-hexane (1:9) as the eluting solvent. A yellow colored solid 2-(methylthio)-5-(4-fluorobenzoyl)pyrrole (3.2 g, 54%) was obtained which after crystallization from ether-hexane had m.p. 112°-113° C. was heated at reflux temperature for 1 hour heating to the cooled solution was cautiously added, with good agitation under reflux for 1 hour The organic phase was separated washed with water dried evaporated

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

実験手順: A solution of N,N-dimethyl-4-fluorobenzamide (8.4 g, 0.05 moles) in anhydrous 1,2-dichloroethane (170 ml) containing phosphorus oxychloride (7.7 g, 0.05 moles) was heated at reflux temperature for 1 hour. At the end of this time 2-methylthiopyrrole (2.82 g, 0.025 moles) was added and heating was continued for an additional 0.5 hour. The solution was cooled to room temperature, and to the cooled solution was cautiously added, with good agitation, a solution of sodium acetate (12.3 g, 0.15 moles) in water (50 ml) and the mixture was then boiled under reflux for 1 hour. The organic phase was separated, washed with water, dried, and evaporated. The residue was subjected to column chromatography on silica gel suing ethyl acetate-hexane (1:9) as the eluting solvent. A yellow colored solid 2-(methylthio)-5-(4-fluorobenzoyl)pyrrole (3.2 g, 54%) was obtained which after crystallization from ether-hexane had m.p. 112°-113° C. was heated at reflux temperature for 1 hour heating to the cooled solution was cautiously added, with good agitation under reflux for 1 hour The organic phase was separated washed with water dried evaporated

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

実験手順: The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluoro-N,N-dimethylbenzamide (989 mg, 5.91 mmol) and 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) (1.500 g, 5.633 mmol) to give a white solid (154 mg, 7% yield). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=8.59 Hz, 2 H) 7.20 (d, J=16.17 Hz, 2 H) 6.96 (d, J=8.59 Hz, 2 H) 4.87-5.03 (m, 1 H) 3.77-3.87 (m, 1 H) 3.71 (br. s., 1 H) 2.99-3.13 (m, 7 H) 2.90 (dd, J=16.55, 7.20 Hz, 1 H) 1.54 (s, 9 H); LCMS for C23H27NO6 m/z 358.20 (M-tBu+H)+.

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

実験手順: A solution of 758 mg. of N,N-dimethyl-4-fluorobenzamide and 0.44 ml. of phosphorous oxychloride in 50 ml. of 1,2-dichloroethane is refluxed for one hour. To this solution is added a solution of 500 mg. of isopropyl 5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate in 10 ml. 1,2-dichloroethane. The reaction mixture is refluxed for 3 hours. A solution of 3.3 g. sodium acetate trihydrate in 9 ml water is added and refluxed for a further 10 hours. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is purified by preparative t.l.c. using hexane:ethyl acetate (90:10). Crystallization from dichloromethane-hexane yields isopropyl 3-p-fluorobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate (XI, R=H, L=p-F, R2 =iC3H7, n=1), m.p. 92° C. To this solution is added a solution of 500 mg The reaction mixture is refluxed for 3 hours refluxed for a further 10 hours The organic phase is separated washed with saturated sodium chloride solution dried over sodium sulfate evaporated to dryness The residue is purified by preparative t.l.c Crystallization from dichloromethane-hexane