methyl 2-oxocyclohexane-1-carboxylate

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

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

Procedure: 3.2 g of borane/tert-butylamine complex was added to 200 ml of diethyl ether solution containing 15.6 g (0.10 mol) of methyl cyclohexanone-2-carboxylate and stirred overnight at room temperature. An aqueous diluted hydrochloric acid was added thereto to make it weakly acidic, which was then subjected to liquid-liquid separation. The organic layer separated was dried, concentrated and then distilled under reduced pressure to obtain 13.4 g of ethyl 2-hydroxycyclohexanecarboxylate. Yield: 84.8%. b.p. 60° to 62° C. (0.3 mmHg). which was then subjected to liquid-liquid separation The organic layer separated was dried concentrated distilled under reduced pressure

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

Procedure: A solution of 2-carbomethoxycyclohexanone in DMF is reacted with 2-(2-bromoethyl)-1,3-dioxane and potassium carbonate by the method of Example 102 to generate the title compound.

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

Procedure: A solution of 2-carbomethoxycyclohexanone (2.0 g, 12.8 mmoles) in 50 mL of DMF was reacted at 70° C. for 15 h with 2-(2-bromoethyl)-1,3-dioxolane (4.6 g, 25 moles) and potassium carbonate (4.8 g, 34.8 mmoles). The reaction mixture was diluted to 500 mL with water and extracted with ethyl ether/ethyl acetate. The organic extracts were dried over sodium sulfate, and the solvent was evaporated to generate the title compound as an oil. extracted with ethyl ether/ethyl acetate The organic extracts were dried over sodium sulfate the solvent was evaporated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To sodium hydride (60% oil dispersion, 10 g) was added a solution of dimethyl carbonate (18.02 g, 200 mmol) in dry THF (50 mL). The mixture was stirred at reflux temperature (100° C.), and then, a solution of cyclohexanone (7.8 g, 80 mmol) in dry THF (20 mL) was added dropwise to the mixture using a syringe pump. After two minutes of addition, potassium hydride (30% oil dispersion, 0.9 g) was added to initiate the reaction. The addition of cyclohexanone was continued over a period of 1 h. The mixture was refluxed and stirred for an additional 30 min after complete addition of cyclohexanone, when the reaction mixture lumped. It was cooled down in an ice bath for 20 min. The mixture was hydrolyzed by the slow addition of 3M aqueous acetic acid (75 mL), then poured into brine (100 mL) and extracted with CH2Cl2 (150 mL×4). The combined organic layers were dried over MgSO4 and filtered. The filtrate was evaporated in vacuo to give a thick yellow liquid (17.2 g). The liquid was distilled under reduced pressure to give 2 (11.3 g, 91%) as a colorless liquid [bp 38-43° C. (0.05-0.075 mm Hg, bath temp: 75-78° C.)]. See Ruest et al., 1976. was added the reaction The mixture was refluxed stirred for an additional 30 min It was cooled down in an ice bath for 20 min extracted with CH2Cl2 (150 mL×4) The combined organic layers were dried over MgSO4 filtered The filtrate was evaporated in vacuo

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To sodium hydride (60% oil dispersion, 10 g) was added a solution of dimethyl carbonate (18.02 g, 200 mmol) in dry THF (50 mL). The mixture was stirred at reflux temperature (100° C.), and then, a solution of cyclohexanone (7.8 g, 80 mmol) in dry THF (20 mL) was added dropwise to the mixture using a syringe pump. After two minutes of addition, potassium hydride (30% oil dispersion, 0.9 g) was added to initiate the reaction. The addition of cyclohexanone was continued over a period of 1 h. The mixture was refluxed and stirred for an additional 30 min after complete addition of cyclohexanone, when the reaction mixture lumped. It was cooled down in an ice bath for 20 min. The mixture was hydrolyzed by the slow addition of 3M aqueous acetic acid (75 mL), then poured into brine (100 mL) and extracted with CH2Cl2 (150 mL×4). The combined organic layers were dried over MgSO4 and filtered. The filtrate was evaporated in vacuo to give a thick yellow liquid (17.2 g). The liquid was distilled under reduced pressure to give 2 (11.3 g, 91%) as a colorless liquid [bp 38-43° C. (0.05-0.075 mm Hg, bath temp: 75-78° C.)]. See Ruest et al., 1976. was added the reaction The mixture was refluxed stirred for an additional 30 min It was cooled down in an ice bath for 20 min extracted with CH2Cl2 (150 mL×4) The combined organic layers were dried over MgSO4 filtered The filtrate was evaporated in vacuo

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-oxocyclohexanecarboxylate (1.0 g, 6.4 mmol), methyl 3-amino-4-methylbenzoate (1.06 g, 6.4 mmol), polyphosphoric acid (4 mL) and dioxane (6 mL) was heated at 130° C. for 2 hours. After cooling to room temperature, the mixture was diluted with water (100 mL) and the resulting precipitate was collected by filtration and dried. The solid was suspended in methanol (100 mL) and SOCl2 (10 mL) was added. The mixture was stirred at reflux for 5 hours, concentrated and treated with water (80 mL), extracted with ethyl acetate (3×80 mL). The organic layer was separated, concentrated to give the crude product. Then the mixture was purified by chromatography column on silica gel (eluted with CH2Cl2/MeOH) to afford crude product, and the final product (0.55 g) was obtained from recrystallization using MeOH as solvent. 1H NMR (DMSO-d6) δ 10.3 (s, 1H), 7.41 (d, 1H, J=7.8 Hz), 6.99 (d, 1H, J=7.8 Hz), 3.73 (s, 3H), 2.78-2.81 (m, 2H), 2.50 (s, 3H), 2.35-2.37 (m, 2H), and 1.64-1.73 (m, 4H). MS (ESI) m/e [M+1]+272.0. After cooling to room temperature the resulting precipitate was collected by filtration dried SOCl2 (10 mL) was added at reflux for 5 hours concentrated treated with water (80 mL) extracted with ethyl acetate (3×80 mL) The organic layer was separated concentrated to give the crude product Then the mixture was purified by chromatography column on silica gel (eluted with CH2Cl2/MeOH) to afford crude product

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-oxocyclohexanecarboxylate (1.0 g, 6.4 mmol), methyl 3-amino-4-methylbenzoate (1.06 g, 6.4 mmol), polyphosphoric acid (4 mL) and dioxane (6 mL) was heated at 130° C. for 2 hours. After cooling to room temperature, the mixture was diluted with water (100 mL) and the resulting precipitate was collected by filtration and dried. The solid was suspended in methanol (100 mL) and SOCl2 (10 mL) was added. The mixture was stirred at reflux for 5 hours, concentrated and treated with water (80 mL), extracted with ethyl acetate (3×80 mL). The organic layer was separated, concentrated to give the crude product. Then the mixture was purified by chromatography column on silica gel (eluted with CH2Cl2/MeOH) to afford crude product, and the final product (0.55 g) was obtained from recrystallization using MeOH as solvent. 1H NMR (DMSO-d6) δ 10.3 (s, 1H), 7.41 (d, 1H, J=7.8 Hz), 6.99 (d, 1H, J=7.8 Hz), 3.73 (s, 3H), 2.78-2.81 (m, 2H), 2.50 (s, 3H), 2.35-2.37 (m, 2H), and 1.64-1.73 (m, 4H). MS (ESI) m/e [M+1]+272.0. After cooling to room temperature the resulting precipitate was collected by filtration dried SOCl2 (10 mL) was added at reflux for 5 hours concentrated treated with water (80 mL) extracted with ethyl acetate (3×80 mL) The organic layer was separated concentrated to give the crude product Then the mixture was purified by chromatography column on silica gel (eluted with CH2Cl2/MeOH) to afford crude product

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

Procedure: The title compound is prepared by the method of Example 12, except that 2-carbomethoxycyclohexanone is used in place of 2-carbomethoxycyclopentanone, and that the title product of Example 3 is used in place of the title product of Example 11.

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

Procedure: The title compound is prepared by the method of Example 12, except that 2-carbomethoxycyclohexanone is used in place of 2-carbomethoxycyclopentanone, and that the title product of Example 3 is used in place of the title product of Example 11.

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

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

Procedure: 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 2-oxo-cyclohexanecarboxylic acid methyl ester and 2H-pyrazol-3-ylamine in acetic acid provided the title compound.