methyl 4-oxooxolane-3-carboxylate

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

実験手順: To a stirred solution of 3.9 g (60 mmol) KCN in 5.5 ml of water at 4° C., a solution of 2.9 g (20 mmol) of 4-oxo-tetrahydro furane 3-carboxylic acid methyl ester in ether (26 ml) was added. To the precipitate of salts, 3.5 ml H2SO4 (18 N) was added and stirred for 16 hours. Then the organic solution was separated, the salts were washed twice with benzene, dried over sodium sulfate and concentrated in vacuo to give 4-cyano-tetrahydro furane 3-carboxylic acid methyl ester. Then the organic solution was separated the salts were washed twice with benzene dried over sodium sulfate concentrated in vacuo

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of 4-oxo-tetrahydrofuran-3-carboxylic acid methyl ester (prepared according to Dowd, P.; Choi, S-C. Tetrahedron, 1991, 47, 4847-4860; 800 mg, 5.55 mmol, 1 eq) in ethanol (20 ml) was added a solution of 2-fluoro-5-chloro-benzamidine (961 mg, 5.55 mmol, 1 eq) in EtOH (10 ml). The reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to r.t. and the white precipitate was filtered and washed with cold ethyl actetate (2×20 ml). The crude residue was partitioned between chloroform and water. The aqueous layer was acidified to pH 4 and the product was extracted with chloroform (3×50 ml). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude solid which was purified by flash column chromatography (5% MeOH in EtOAc) to give a white solid 2-(5-chloro-2-fluoro-phenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (440 mg, 30%). The reaction mixture was cooled to r.t. the white precipitate was filtered washed with cold ethyl The crude residue was partitioned between chloroform and water the product was extracted with chloroform (3×50 ml) washed with brine dried over MgSO4 filtered concentrated in vacuo to give a crude solid which was purified by flash column chromatography (5% MeOH in EtOAc)

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

実験手順: To a suspension of NaH (6.66 g, 166.5 mmol) in ether (500 mL) add methyl glycolate (15.0 g, 166.5 mmol) drop wise. Stir the reaction until evolution of H2 gas ceases. Concentrate and dissolve the solid in DMSO (300 mL). Cool the reaction to 0° C. and add methyl acrylate (16.6 mL, 183.17 mmol) drop wise. Warm the reaction to room temperature and stir overnight. Acidify the reaction with 10% HCl and extract with ether (3×). Combine organic extracts and wash with brine. Dry the organic solution (Na2SO4), filter, and concentrate in vacuo. Purify by flash chromatography (250 g SiO2, 40 mL/min, 0-50% ethyl acetate/hexane for 20 minutes and then 50% ethyl acetate/hexane for 13 minutes) to yield 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester 4a (12.9 g, 89.2 mmol, 54%) as a colorless oil. 1H NMR (δ, 400 MHz, CDCl3): 4.50 (dd, 1H, J=8.4, 9.6 Hz), 4.46 (dd, 1H, J=8.4, 9.6 Hz), 4.05 (d, 1H, J=16.8 Hz), 3.79, (s, 3H), 3.97 (d, 1H, J=16.8, Hz), 3.54 (t, 1H, J=8.4 Hz). MS calcd. 144; found (EI) 144. the reaction until evolution of H2 gas ceases Concentrate dissolve the solid in DMSO (300 mL) Cool the reaction to 0° C. Warm the reaction to room temperature stir overnight extract with ether (3×) Combine organic extracts and wash with brine Dry the organic solution (Na2SO4) filter concentrate in vacuo Purify by flash chromatography (250 g SiO2, 40 mL/min, 0-50% ethyl acetate/hexane for 20 minutes

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

実験手順: To a suspension of NaH (6.66 g, 166.5 mmol) in ether (500 mL) add methyl glycolate (15.0 g, 166.5 mmol) drop wise. Stir the reaction until evolution of H2 gas ceases. Concentrate and dissolve the solid in DMSO (300 mL). Cool the reaction to 0° C. and add methyl acrylate (16.6 mL, 183.17 mmol) drop wise. Warm the reaction to room temperature and stir overnight. Acidify the reaction with 10% HCl and extract with ether (3×). Combine organic extracts and wash with brine. Dry the organic solution (Na2SO4), filter, and concentrate in vacuo. Purify by flash chromatography (250 g SiO2, 40 mL/min, 0-50% ethyl acetate/hexane for 20 minutes and then 50% ethyl acetate/hexane for 13 minutes) to yield 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester 4a (12.9 g, 89.2 mmol, 54%) as a colorless oil. 1H NMR (δ, 400 MHz, CDCl3): 4.50 (dd, 1H, J=8.4, 9.6 Hz), 4.46 (dd, 1H, J=8.4, 9.6 Hz), 4.05 (d, 1H, J=16.8 Hz), 3.79, (s, 3H), 3.97 (d, 1H, J=16.8, Hz), 3.54 (t, 1H, J=8.4 Hz). MS calcd. 144; found (EI) 144. the reaction until evolution of H2 gas ceases Concentrate dissolve the solid in DMSO (300 mL) Cool the reaction to 0° C. Warm the reaction to room temperature stir overnight extract with ether (3×) Combine organic extracts and wash with brine Dry the organic solution (Na2SO4) filter concentrate in vacuo Purify by flash chromatography (250 g SiO2, 40 mL/min, 0-50% ethyl acetate/hexane for 20 minutes

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

実験手順: To a stirred solution of 3.9 g (60 mmol) KCN in 5.5 ml of water at 4° C., a solution of 2.9 g (20 mmol) of 4-oxo-tetrahydro furane 3-carboxylic acid methyl ester in ether (26 ml) was added. To the precipitate of salts, 3.5 ml H2SO4 (18 N) was added and stirred for 16 hours. Then the organic solution was separated, the salts were washed twice with benzene, dried over sodium sulfate and concentrated in vacuo to give 4-cyano-tetrahydro furane 3-carboxylic acid methyl ester. Then the organic solution was separated the salts were washed twice with benzene 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 stirred solution of 3.9 g (60 mmol) KCN in 5.5 ml of water at 4° C., a solution of 2.9 g (20 mmol) of 4-oxo-tetrahydro furane 3-carboxylic acid methyl ester in ether (26 ml) was added. To the precipitate of salts, 3.5 ml H2SO4 (18 N) was added and stirred for 16 hours. Then the organic solution was separated, the salts were washed twice with benzene, dried over sodium sulfate and concentrated in vacuo to give 4-cyano-tetrahydro furane 3-carboxylic acid methyl ester. Then the organic solution was separated the salts were washed twice with benzene 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 stirred solution of 3.9 g (60 mmol) KCN in 5.5 ml of water at 4° C., a solution of 2.9 g (20 mmol) of 4-oxo-tetrahydro furane 3-carboxylic acid methyl ester in ether (26 ml) was added. To the precipitate of salts, 3.5 ml H2SO4 (18 N) was added and stirred for 16 hours. Then the organic solution was separated, the salts were washed twice with benzene, dried over sodium sulfate and concentrated in vacuo to give 4-cyano-tetrahydro furane 3-carboxylic acid methyl ester. Then the organic solution was separated the salts were washed twice with benzene 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 stirred solution of 3.9 g (60 mmol) KCN in 5.5 ml of water at 4° C., a solution of 2.9 g (20 mmol) of 4-oxo-tetrahydro furane 3-carboxylic acid methyl ester in ether (26 ml) was added. To the precipitate of salts, 3.5 ml H2SO4 (18 N) was added and stirred for 16 hours. Then the organic solution was separated, the salts were washed twice with benzene, dried over sodium sulfate and concentrated in vacuo to give 4-cyano-tetrahydro furane 3-carboxylic acid methyl ester. Then the organic solution was separated the salts were washed twice with benzene 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: Using the method described for the preparation of 6,7,8,9-Tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-ol, the reaction of 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester and 2H-pyrazol-3-ylamine in acetic acid provided the desired 5H,7H-6-Oxa-1,4,8a-triaza-s-indacen-8-ol.

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

実験手順: To a stirred slurry of sodium hydride (1.67 g, 60% in mineral oil, 44.0 mmol) in dried ether was added with ethyl glycolate, dropwise over 15 minutes. The reaction was warmed up to room temperature for 30 min while stirring and concentrated in vacuo to provide white solid. The solid was treated with methyl acrylate (4.16 g, 49 mmol) in DMSO (20 mL) at 0° C. for 15 minutes and room temperature for 45 minutes. The mixture was poured into 5% H2SO4 and extracted with ethyl acetate. Organic layer was washed with brine, dried over Mg2SO4 and concentrated to give 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester as a colorless oil. concentrated in vacuo to provide white solid extracted with ethyl acetate Organic layer was washed with brine dried over Mg2SO4 concentrated

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

実験手順: To a stirred slurry of sodium hydride (1.67 g, 60% in mineral oil, 44.0 mmol) in dried ether was added with ethyl glycolate, dropwise over 15 minutes. The reaction was warmed up to room temperature for 30 min while stirring and concentrated in vacuo to provide white solid. The solid was treated with methyl acrylate (4.16 g, 49 mmol) in DMSO (20 mL) at 0° C. for 15 minutes and room temperature for 45 minutes. The mixture was poured into 5% H2SO4 and extracted with ethyl acetate. Organic layer was washed with brine, dried over Mg2SO4 and concentrated to give 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester as a colorless oil. concentrated in vacuo to provide white solid extracted with ethyl acetate Organic layer was washed with brine dried over Mg2SO4 concentrated

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

実験手順: To a stirred slurry of sodium hydride (1.67 g, 60% in mineral oil, 44.0 mmol) in dried ether was added with ethyl glycolate, dropwise over 15 minutes. The reaction was warmed up to room temperature for 30 min while stirring and concentrated in vacuo to provide white solid. The solid was treated with methyl acrylate (4.16 g, 49 mmol) in DMSO (20 mL) at 0° C. for 15 minutes and room temperature for 45 minutes. The mixture was poured into 5% H2SO4 and extracted with ethyl acetate. Organic layer was washed with brine, dried over Mg2SO4 and concentrated to give 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester as a colorless oil. concentrated in vacuo to provide white solid extracted with ethyl acetate Organic layer was washed with brine dried over Mg2SO4 concentrated