ethyl 2-oxocycloheptane-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:57.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-carboethoxycycloheptanone (1 mmol), finely powdered potassium carbonate (2 mmol), allyl bromide (1.5 mmol), and tetrabutyl ammonium iodide (10 mg/mmol) are combined in dry DMF (1.25 mL/mmol) and stirred under N2 at 55 to 60° C. for 16 to 18 hours. The room temperature reaction mixture is poured into water and extracted with Et2O and EtOAc. The combined organics are washed with brine, dried, and stripped of all solvent under reduced pressure to provide 2-allyl-2-carboethoxycycloheptanone. This material is combined with lithium chloride (5 mmol), water (1.05 mmol) and dimethyl sulfoxide (5 mL/mmol) and the mixture refluxed for approximately 4 hrs. The mixture is poured into water and extracted with Et2O and EtOAc. The combined organics are washed with brine, dried, and stripped of all solvent under reduced pressure to provide 2-allylcycloheptanone. A sample of the 2-allylcycloheptanone is converted to the title compound by the method of EXAMPLE 24 using hydroxylamine hydrochloride and NaOAc in a mixture of EtOH and water. The room temperature reaction mixture extracted with Et2O and EtOAc The combined organics are washed with brine dried

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: For example, a solution of 2-carboethoxy-cycloheptanone (I) (92.2 g, 0.5 mole) in toluene (1.6 l) is treated with sodium iodide (1 g) and 60% sodium hydride in mineral oil (23.3 g, 0.58 mole). The mixture is heated at 110° C. until hydrogen gas evolution drops off. Ethyl bromoacetate (98.0 g, 0.58 mole) is added dropwise and the mixture is warmed to 65° C. for 18 hours. The mixture is cooled and water (500 ml) is added. The layers are separated and the aqueous layer is extracted with toluene (2×1 l). The extracts are dried (MgSO4) and filtered. The filtrate is concentrated at reduced pressure and distilled to yield pure 2-carboethoxy-2-carboethoxymethylcycloheptanone (II) with a bp 182°-185° C. at 13 mm. The mixture is cooled The layers are separated the aqueous layer is extracted with toluene (2×1 l) The extracts are dried (MgSO4) filtered The filtrate is concentrated at reduced pressure distilled

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-carboethoxycycloheptanone (1 mmol), finely powdered potassium carbonate (2 mmol), allyl bromide (1.5 mmol), and tetrabutyl ammonium iodide (10 mg/mmol) are combined in dry DMF (1.25 mL/mmol) and stirred under N2 at 55° to 60° C. for 16 to 18 hours. The room temperature reaction mixture is poured into water and extracted with Et2O and EtOAc. The combined organics are washed with brine, dried, and stripped of all solvent under reduced pressure to provide 2-allyl-2-carboethoxycycloheptanone. This material is combined with lithium chloride (5 mmol), water (1.05 mmol) and dimethyl sulfoxide (5 mL/mmol) and the mixture refluxed for approximately 4 hrs. The mixture is poured into water and extracted with Et2O and EtOAc. The combined organics are washed with brine, dried, and stripped of all solvent under reduced pressure to provide 2-allylcycloheptanone. A sample of the 2-allylcycloheptanone is converted to the title compound by the method of EXAMPLE 24 using hydroxylamine hydrochloride and NaOAc in a mixture of EtOH and water. The room temperature reaction mixture extracted with Et2O and EtOAc The combined organics are washed with brine dried

Conditions: temp:57.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-carboethoxycycloheptanone (1 mmol), finely powdered potassium carbonate (2 mmol), allyl bromide (1.5 mmol), and tetrabutyl ammonium iodide (10 mg/mmol) are combined in dry DMF (1.25 mL/mmol) and stirred under N2 at 55 to 60° C. for 16 to 18 hours. The room temperature reaction mixture is poured into water and extracted with Et2O and EtOAc. The combined organics are washed with brine, dried, and stripped of all solvent under reduced pressure to provide 2-allyl-2-carboethoxycycloheptanone. This material is combined with lithium chloride (5 mmol), water (1.05 mmol) and dimethyl sulfoxide (5 mL/mmol) and the mixture refluxed for approximately 4 hrs. The mixture is poured into water and extracted with Et2O and EtOAc. The combined organics are washed with brine, dried, and stripped of all solvent under reduced pressure to provide 2-allylcycloheptanone. A sample of the 2-allylcycloheptanone is converted to the title compound by the method of EXAMPLE 24 using hydroxylamine hydrochloride and NaOAc in a mixture of EtOH and water. The room temperature reaction mixture extracted with Et2O and EtOAc The combined organics are washed with brine dried

Conditions: temp:57.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-carboethoxycycloheptanone (1 mmol), finely powdered potassium carbonate (2 mmol), allyl bromide (1.5 mmol), and tetrabutyl ammonium iodide (10 mg/mmol) are combined in dry DMF (1.25 mL/mmol) and stirred under N2 at 55 to 60° C. for 16 to 18 hours. The room temperature reaction mixture is poured into water and extracted with Et2O and EtOAc. The combined organics are washed with brine, dried, and stripped of all solvent under reduced pressure to provide 2-allyl-2-carboethoxycycloheptanone. This material is combined with lithium chloride (5 mmol), water (1.05 mmol) and dimethyl sulfoxide (5 mL/mmol) and the mixture refluxed for approximately 4 hrs. The mixture is poured into water and extracted with Et2O and EtOAc. The combined organics are washed with brine, dried, and stripped of all solvent under reduced pressure to provide 2-allylcycloheptanone. A sample of the 2-allylcycloheptanone is converted to the title compound by the method of EXAMPLE 24 using hydroxylamine hydrochloride and NaOAc in a mixture of EtOH and water. The room temperature reaction mixture extracted with Et2O and EtOAc The combined organics are washed with brine dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The first stage consists of condensing 2-carbetoxycycloheptanone with resorcinol in methanesulphonic acid, the reaction is taken to 25° C. for 4 hours. The intermediate 3-hydroxy-8,9,10,11-tetrahydrocyclohepta[c]chromen-6(7H)-one thus formed precipitates by adding ethanol then water then it is isolated by filtration, dried under vacuum at 60° C. and a yield of 78% is obtained. In a second stage, sulphonylisocyanate chloride is converted, in toluenic solution, to sulphamoyl chloride by the action of the formic acid, then condensed with the previous intermediate dissolved in N,N-dimethylacetamide (DMA). The reaction medium is treated with water and extracted with 2-methyltetrahydrofurane (2-MeTHF). The crude compound 1 is then obtained by filtration of the precipitate obtained by adding methylcyclohexane to the organic phase. Finally, pure compound 1 is obtained by recrystallization of the crude product by dissolution in acetone while hot and precipitation by adding methylcyclohexane (the addition of the antisolvent methylcyclohexane having the main purpose of increasing the yield).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The Applicant has now found that this compound can be synthesized in two chemical stages. The first stage consists of condensing in a strong acid (such as sulphuric acid, trifluoroacetic acid or methanesuiphonic acid) 2-carbetoxycycloheptanone with resorcinol, intermediate 3-hydroxy-8,9,10,11-tetrahydrocyclohepta[c]chromen-6(7H)-one is isolated by precipitation using an alcohol/water mixture (for example by adding ethanol then water). In a second stage, sulphonylisocyanate chloride is converted, in toluenic solution, to sulphamoyl chloride, by the action of formic acid, then condensed with the previous intermediate dissolved in a solvent such as DMA. The reaction medium is treated with water and extracted by an organic solvent (preferably 2-methyltetrahydrofurane: MeTHF), and crude compound 1 is then precipitated from the organic phase by adding an antisolvent (preferably methylcyclohexane). Finally pure compound 1 is obtained by recrystallization of the crude product by dissolution in acetone or ethyl acetate while hot and precipitation by adding an antisolvent (preferably methylcyclohexane). can be synthesized in two chemical stages

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The Applicant has now found that this compound can be synthesized in two chemical stages. The first stage consists of condensing in a strong acid (such as sulphuric acid, trifluoroacetic acid or methanesuiphonic acid) 2-carbetoxycycloheptanone with resorcinol, intermediate 3-hydroxy-8,9,10,11-tetrahydrocyclohepta[c]chromen-6(7H)-one is isolated by precipitation using an alcohol/water mixture (for example by adding ethanol then water). In a second stage, sulphonylisocyanate chloride is converted, in toluenic solution, to sulphamoyl chloride, by the action of formic acid, then condensed with the previous intermediate dissolved in a solvent such as DMA. The reaction medium is treated with water and extracted by an organic solvent (preferably 2-methyltetrahydrofurane: MeTHF), and crude compound 1 is then precipitated from the organic phase by adding an antisolvent (preferably methylcyclohexane). Finally pure compound 1 is obtained by recrystallization of the crude product by dissolution in acetone or ethyl acetate while hot and precipitation by adding an antisolvent (preferably methylcyclohexane). can be synthesized in two chemical stages

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 9.3 parts of 2-carbethoxycycloheptanone [prepared by the method of G. Stork, et al., J. Am. Chem. Soc., 85, 207 (1963)], 8.1 parts of 4-chloro-2-fluorophenyl hydrazine, 100 parts of toluene and 0.5 parts of acetic acid was refluxed for 4 hours until all water was evolved. The resulting solution was cooled to -50° and filtered to yield 12 parts of 2-(4-chloro-2-fluorophenyl)-1,4,5,6,7,8-hexahydrocycloheptapyrazol-3(2H)-one melting at 197°-201°. Four parts of the pyrazolone was mixed with 4.4 parts of phosphorous oxybromide and 2.2 parts of N,N-diethylaniline in 200 parts of xylene and the mixture refluxed for 3 hours. 0.5 Part of N,N-dimethyl formamide was added and the mixture refluxed for 1 hour. The mixture was poured over 100 parts of ice and the phases separated. The organic phase was evaporated under reduced pressure of 50 mm. Hg at 70° to a crude product. The product was dissolved in 100 parts of chloroform, washed with 100 parts of 10% aqueous sodium carbonate, dried with anhydrous magnesium sulfate and evaporated to an oil under reduced pressure of 500 mm. Hg at 40°. Purification by chromatography on alumina using 3% ether in hexane as the eluent gave 0.8 parts of 3-bromo-2-(4-chloro-2-fluorophenyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazole melting at 59°-60°. prepared by the method of G The resulting solution was cooled to -50° filtered

Conditions: temp:57.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-carboethoxycycloheptanone (1 mmol), finely powdered potassium carbonate (2 mmol), allyl bromide (1.5 mmol), and tetrabutyl ammonium iodide (10 mg/mmol) are combined in dry DMF (1.25 mL/mmol) and stirred under N2 at 55 to 60° C. for 16 to 18 hours. The room temperature reaction mixture is poured into water and extracted with Et2O and EtOAc. The combined organics are washed with brine, dried, and stripped of all solvent under reduced pressure to provide 2-allyl-2-carboethoxycycloheptanone. This material is combined with lithium chloride (5 mmol), water (1.05 mmol) and dimethyl sulfoxide (5 mL/mmol) and the mixture refluxed for approximately 4 hrs. The mixture is poured into water and extracted with Et2O and EtOAc. The combined organics are washed with brine, dried, and stripped of all solvent under reduced pressure to provide 2-allylcycloheptanone. A sample of the 2-allylcycloheptanone is converted to the title compound by the method of EXAMPLE 24 using hydroxylamine hydrochloride and NaOAc in a mixture of EtOH and water. The room temperature reaction mixture extracted with Et2O and EtOAc The combined organics are washed with brine dried