ethyl 3-oxocyclohexane-1-carboxylate

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

実験手順: A mixture of ethyl 3-oxocyclohexanecarboxylate (Nallet, J-P., et al, Bull. Soc. Chem. Fr., Part II, No. 3-4, pages 153-156 (1979)) (101.7 g) ethylene glycol (38.9 g) and para-toluenesulfonic acid (5.5 g) in 1000 mL of benzene is refluxed with a Dean-Stark trap for 4 hours. The solution is cooled, washed with 1N sodium hydroxide and brine, dried over magnesium sulfate, and evaporated in vacuo to give 113.1 g of a light oil which is dissolved in 1000 mL of ethanol, treated with sodium hydroxide (25.3 g) in 250 mL of water, and refluxed for 2.5 hours. The mixture is concentrated in vacuo, cooled in an ice bath, and acidified with ice-cold 1N aqueous hydrochloric acid solution to a pH of 2. The title compound is extracted with chloroform (2×500 mL), dried over magnesium sulfate, and concentrated in vacuo. The title compound (99.3 g) is obtained as a yellowish oil, which is determined to be 98% pure by gas chromatography and is carried on without further purification. The solution is cooled washed with 1N sodium hydroxide and brine dried over magnesium sulfate evaporated in vacuo to give 113.1 g of a light oil which refluxed for 2.5 hours The mixture is concentrated in vacuo cooled in an ice bath The title compound is extracted with chloroform (2×500 mL) dried over magnesium sulfate concentrated in vacuo

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

実験手順: A mixture of ethyl 3-oxocyclohexanecarboxylate (Nallet, J-P., et al, Bull. Soc. Chem. Fr., Part II, No. 3-4, pages 153-156 (1979)) (101.7 g) ethylene glycol (38.9 g) and para-toluenesulfonic acid (5.5 g) in 1000 mL of benzene is refluxed with a Dean-Stark trap for 4 hours. The solution is cooled, washed with 1N sodium hydroxide and brine, dried over magnesium sulfate, and evaporated in vacuo to give 113.1 g of a light oil which is dissolved in 1000 mL of ethanol, treated with sodium hydroxide (25.3 g) in 250 mL of water, and refluxed for 2.5 hours. The mixture is concentrated in vacuo, cooled in an ice bath, and acidified with ice-cold 1N aqueous hydrochloric acid solution to a pH of 2. The title compound is extracted with chloroform (2×500 mL), dried over magnesium sulfate, and concentrated in vacuo. The title compound (99.3 g) is obtained as a yellowish oil, which is determined to be 98% pure by gas chromatography and is carried on without further purification. The solution is cooled washed with 1N sodium hydroxide and brine dried over magnesium sulfate evaporated in vacuo to give 113.1 g of a light oil which refluxed for 2.5 hours The mixture is concentrated in vacuo cooled in an ice bath The title compound is extracted with chloroform (2×500 mL) dried over magnesium sulfate concentrated in vacuo

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

実験手順: Step 2 A stirred suspension of 4-bromo-2-hydrazinylbenzoic acid hydrochloric acid salt (16.35 g, 58.1 mmol) in acetic acid (171 mL) was treated with ethyl 3-oxocyclohexanecarboxylate (9.88 g, 58.1 mmol) at rt. The mixture was stirred at reflux for 2.5 h, then was cooled to rt and concentrated to afford a brown solid. This was suspended in EtOAc (20 mL) and the precipitate was collected by filtration, washed with EtOAc and air dried to provide 5-bromo-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (11.46 g). The filtrate was concentrated and the residue was resuspended in EtOAc, the precipitate collected by filtration and dried to provide additional product (0.82 g) for a total of 12.28 g (58%). 1H NMR (400 MHz, DMSO-d6) δ 13.10 (br. s., 1H) 11.06 (s, 1H) 7.50 (d, J=8.13 Hz, 1H) 7.19 (d, J=8.13 Hz, 1H) 4.07-4.15 (m, 2H) 3.08-3.19 (m, 1H) 2.99-3.08 (m, 1H) 2.89-2.99 (m, 2H) 2.79-2.89 (m, 1H) 2.09-2.22 (m, 1H) 1.75-1.89 (m, 1H) 1.20 (t, J=7.14 Hz, 3H). Mass spectrum m/z 366.0, 368.0 (M+H)+. at reflux for 2.5 h concentrated to afford a brown solid the precipitate was collected by filtration washed with EtOAc and air dried

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

実験手順: Step 2 A stirred suspension of 4-bromo-2-hydrazinylbenzoic acid hydrochloric acid salt (16.35 g, 58.1 mmol) in acetic acid (171 mL) was treated with ethyl 3-oxocyclohexanecarboxylate (9.88 g, 58.1 mmol) at rt. The mixture was stirred at reflux for 2.5 h, then was cooled to rt and concentrated to afford a brown solid. This was suspended in EtOAc (20 mL) and the precipitate was collected by filtration, washed with EtOAc and air dried to provide 5-bromo-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (11.46 g). The filtrate was concentrated and the residue was resuspended in EtOAc, the precipitate collected by filtration and dried to provide additional product (0.82 g) for a total of 12.28 g (58%). 1H NMR (400 MHz, DMSO-d6) δ 13.10 (br. s., 1H) 11.06 (s, 1H) 7.50 (d, J=8.13 Hz, 1H) 7.19 (d, J=8.13 Hz, 1H) 4.07-4.15 (m, 2H) 3.08-3.19 (m, 1H) 2.99-3.08 (m, 1H) 2.89-2.99 (m, 2H) 2.79-2.89 (m, 1H) 2.09-2.22 (m, 1H) 1.75-1.89 (m, 1H) 1.20 (t, J=7.14 Hz, 3H). Mass spectrum m/z 366.0, 368.0 (M+H)+. at reflux for 2.5 h concentrated to afford a brown solid the precipitate was collected by filtration washed with EtOAc and air dried

反応条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 4-bromo-5-chloro-2-hydrazinylbenzoic acid hydrochloride (12.89 g, 37.6 mmol), ethyl 3-oxocyclohexanecarboxylate (7.03 g, 41.3 mmol), and acetic acid (6.45 mL, 113 mmol) in toluene (188 mL) was heated at 105° C. overnight. After 16 h, more acetic acid (6 mL) and ethyl 3-oxocyclohexanecarboxylate (2.00 g) were added and the mixture was heated at 110° C. for 4.5 h. The mixture was concentrated, and the residue was combined with toluene (100 mL) and TFA (20 mL). The suspension was heated at 90° C. overnight. The cooled mixture was concentrated and the residue was suspended in EtOAc. The resulting solid was collected by filtration, washed with EtOAc and air-dried to give 5-bromo-6-chloro-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a yellow solid (11.0 g, 73% yield). Mass spectrum m/z 400, 402 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.44 (br. s., 1H), 11.24 (s, 1H), 7.69 (s, 1H), 4.12 (qd, J=7.1, 2.3 Hz, 2H), 3.23-2.81 (m, 5H), 2.23-2.09 (m, 1H), 1.91-1.75 (m, 1H), 1.22 (t, J=7.0 Hz, 3H). the mixture was heated at 110° C. for 4.5 h The mixture was concentrated The suspension was heated at 90° C. overnight The cooled mixture was concentrated The resulting solid was collected by filtration washed with EtOAc air-dried

反応条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 4-bromo-5-chloro-2-hydrazinylbenzoic acid hydrochloride (12.89 g, 37.6 mmol), ethyl 3-oxocyclohexanecarboxylate (7.03 g, 41.3 mmol), and acetic acid (6.45 mL, 113 mmol) in toluene (188 mL) was heated at 105° C. overnight. After 16 h, more acetic acid (6 mL) and ethyl 3-oxocyclohexanecarboxylate (2.00 g) were added and the mixture was heated at 110° C. for 4.5 h. The mixture was concentrated, and the residue was combined with toluene (100 mL) and TFA (20 mL). The suspension was heated at 90° C. overnight. The cooled mixture was concentrated and the residue was suspended in EtOAc. The resulting solid was collected by filtration, washed with EtOAc and air-dried to give 5-bromo-6-chloro-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a yellow solid (11.0 g, 73% yield). Mass spectrum m/z 400, 402 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.44 (br. s., 1H), 11.24 (s, 1H), 7.69 (s, 1H), 4.12 (qd, J=7.1, 2.3 Hz, 2H), 3.23-2.81 (m, 5H), 2.23-2.09 (m, 1H), 1.91-1.75 (m, 1H), 1.22 (t, J=7.0 Hz, 3H). the mixture was heated at 110° C. for 4.5 h The mixture was concentrated The suspension was heated at 90° C. overnight The cooled mixture was concentrated The resulting solid was collected by filtration washed with EtOAc air-dried

反応条件: temp:117.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-2-hydrazinyl-5-methylbenzoic acid hydrochloride (2.17 g, 7.71 mmol), ethyl 3-oxocyclohexanecarboxylate (1.44 g, 8.48 mmol) and acetic acid (1.32 mL, 23.1 mmol) in toluene (40 mL) was heated in an oil bath at 117° C. for 5 h. The mixture was concentrated and dried under vacuum, and the residue was diluted with toluene (18 mL) and TFA (4.5 mL). The mixture was heated at 90° C. overnight. The cooled mixture was diluted with EtOAc, sonicated, and the precipitate was collected by filtration and washed with EtOAc to give a yellow solid. The filtrate was concentrated and the residue was suspended in EtOAc with sonication. The precipitate was collected by filtration and combined with the first precipitate. The solid was triturated with MeOH to give 5-bromo-2-(ethoxycarbonyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a pale yellow solid (1.60 g, 55% yield). Mass spectrum m/z 380, 382 (M+H)+. The mixture was concentrated dried under vacuum the residue was diluted with toluene (18 mL) and TFA (4.5 mL) The mixture was heated at 90° C. overnight The cooled mixture was diluted with EtOAc sonicated the precipitate was collected by filtration washed with EtOAc to give a yellow solid The filtrate was concentrated the residue was suspended in EtOAc with sonication The precipitate was collected by filtration The solid was triturated with MeOH

反応条件: temp:117.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-2-hydrazinyl-5-methylbenzoic acid hydrochloride (2.17 g, 7.71 mmol), ethyl 3-oxocyclohexanecarboxylate (1.44 g, 8.48 mmol) and acetic acid (1.32 mL, 23.1 mmol) in toluene (40 mL) was heated in an oil bath at 117° C. for 5 h. The mixture was concentrated and dried under vacuum, and the residue was diluted with toluene (18 mL) and TFA (4.5 mL). The mixture was heated at 90° C. overnight. The cooled mixture was diluted with EtOAc, sonicated, and the precipitate was collected by filtration and washed with EtOAc to give a yellow solid. The filtrate was concentrated and the residue was suspended in EtOAc with sonication. The precipitate was collected by filtration and combined with the first precipitate. The solid was triturated with MeOH to give 5-bromo-2-(ethoxycarbonyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a pale yellow solid (1.60 g, 55% yield). Mass spectrum m/z 380, 382 (M+H)+. The mixture was concentrated dried under vacuum the residue was diluted with toluene (18 mL) and TFA (4.5 mL) The mixture was heated at 90° C. overnight The cooled mixture was diluted with EtOAc sonicated the precipitate was collected by filtration washed with EtOAc to give a yellow solid The filtrate was concentrated the residue was suspended in EtOAc with sonication The precipitate was collected by filtration The solid was triturated with MeOH

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride (5.37 g, 18.8 mmol), ethyl 3-oxocyclohexanecarboxylate (3.52 g, 20.7 mmol) and acetic acid (3.23 mL, 56.4 mmol) in toluene (90 mL) was heated at 110° C. for 20 h. The solvent was removed under reduced pressure, and the residue was diluted with toluene (43 mL) and trifluoroacetic acid (11 mL). The mixture was stirred at 90-94° C. overnight. The cooled mixture was diluted with EtOAc, sonicated, and the precipitate was collected by filtration. The filtrate was concentrated and resuspended in EtOAc with sonication, resulting in another precipitate which was also collected by filtration and washed with EtOAc. The combined solids were triturated twice with MeOH to give a solid. The combined filtrates were concentrated and the residue was triturated with MeOH to give additional solid. The solids were combined to give 5-bromo-2-ethoxycarbonyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a pale yellow solid (3.38 g). Mass spectrum m/z 384, 386 (M+H)+. The solvent was removed under reduced pressure the residue was diluted with toluene (43 mL) and trifluoroacetic acid (11 mL) The cooled mixture was diluted with EtOAc sonicated the precipitate was collected by filtration The filtrate was concentrated resuspended in EtOAc with sonication resulting in another precipitate which was also collected by filtration washed with EtOAc The combined solids were triturated twice with MeOH to give a solid The combined filtrates were concentrated the residue was triturated with MeOH to give additional solid

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride (5.37 g, 18.8 mmol), ethyl 3-oxocyclohexanecarboxylate (3.52 g, 20.7 mmol) and acetic acid (3.23 mL, 56.4 mmol) in toluene (90 mL) was heated at 110° C. for 20 h. The solvent was removed under reduced pressure, and the residue was diluted with toluene (43 mL) and trifluoroacetic acid (11 mL). The mixture was stirred at 90-94° C. overnight. The cooled mixture was diluted with EtOAc, sonicated, and the precipitate was collected by filtration. The filtrate was concentrated and resuspended in EtOAc with sonication, resulting in another precipitate which was also collected by filtration and washed with EtOAc. The combined solids were triturated twice with MeOH to give a solid. The combined filtrates were concentrated and the residue was triturated with MeOH to give additional solid. The solids were combined to give 5-bromo-2-ethoxycarbonyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a pale yellow solid (3.38 g). Mass spectrum m/z 384, 386 (M+H)+. The solvent was removed under reduced pressure the residue was diluted with toluene (43 mL) and trifluoroacetic acid (11 mL) The cooled mixture was diluted with EtOAc sonicated the precipitate was collected by filtration The filtrate was concentrated resuspended in EtOAc with sonication resulting in another precipitate which was also collected by filtration washed with EtOAc The combined solids were triturated twice with MeOH to give a solid The combined filtrates were concentrated the residue was triturated with MeOH to give additional solid

反応条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Then, to a round bottom flask was added N,N-diisopropylamine (3.97 mL, 28.4 mmol) and THF (22.1 mL). The mixture was cooled at −20° C. 1.6 M of n-butyllithium in hexane (15.8 mL) was added. The crude mixture was stirred at 0° C. for 30 min and then cooled down at −20° C., and 1,4-dioxa-spiro[4.5]dicane-7-carboxylic acid ethyl ester (4.50 g, 21.0 mmol) from step 1 was added dropwise. The mixture was stirred at 0° C. for 30 min, and then cooled at −20° C., and allyl bromide (2.00 mL, 23.1 mmol) was added. The mixture was warmed up to rt slowly and stirred at rt for 30 min. The reaction mixture was quenched with ice, diluted with ethyl acetate (60 mL), and washed sequentially with 1N aqueous HCl (5 mL), water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 4.30 g (81%) of the title compound, 7-allyl-1,4-dioxa-spiro[4.5]decane-7-carboxylic acid ethyl ester, as a yellow oil. It was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ5.64-5.74 (m, 1H), 4.97-5.05 (m, 2H), 4.05-4.17 (m, 2H), 3.82-3.99 (m, 4H), 2.34-2.41 (m, 1H), 2.27 (dt, J=13.6, 2.1 Hz, 1H), 2.08-2.16 (m, 2H), 1.76-1.88 (m, 1H), 1.60-1.72 (m, 2H), 1.46-1.54 (m, 1H), 1.42 (d, J=13.6 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H), 1.08-1.16 (m, 1H). cooled down at −20° C. cooled at −20° C. The mixture was warmed up to rt slowly stirred at rt for 30 min The reaction mixture was quenched with ice diluted with ethyl acetate (60 mL) washed sequentially with 1N aqueous HCl (5 mL), water and brine The organic layer was dried over Na2SO4 concentrated under reduced pressure

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

実験手順: To a round bottom flask was added 3-oxo-1-cyclohexanecarboxylic acid (3.85 g, 27.1 mmol), ethanol (7.91 mL), p-toluenesulfonic acid (0.097 g, 0.56 mmol) and toluene (65.9 mL). The mixture was refluxed with Dean-star trap overnight. The reaction mixture was cooled down and concentrated under reduced pressure to afford 4.61 g (100%) of the title compound, 3-oxo-cyclohexanecarboxylic acid ethyl ester, as a yellow oil, which was used in the next step without further purification. The mixture was refluxed with Dean-star trap overnight The reaction mixture was cooled down concentrated under reduced pressure