methyl 1-methyl-2-oxocyclopentane-1-carboxylate

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

Procedure: To methyl 1-methyl-2-oxocyclopentanecarboxylate (20.0 g=128 mmol) in THF (800 ml) add portionwise lithium tri-t-butoxyaluminohydride (40.7 g=160 mmol). Stir 1 hr and partition between Et2O and 1.0N HCl. Dry and concentrate to obtain methyl 1-methyl-2-hydroxycyclopentanecarboxylate, largely the 1β-methyl-2β-hydroxy isomer, as an oil. partition between Et2O and 1.0N HCl Dry concentrate

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

Procedure: To methyl 1-methyl-2-oxocyclopentanecarboxylate (20.0 g=128 mmol) in THF (800 ml) add portionwise lithium tri-t-butoxyaluminohydride (40.7 g=160 mmol). Stir 1 hr and partition between Et2O and 1.0N HCl. Dry and concentrate to obtain methyl 1-methyl-2-hydroxycyclopentanecarboxylate, largely the 1β-methyl-2β-hydroxy isomer, as an oil. partition between Et2O and 1.0N HCl Dry concentrate

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

Procedure: 2.52 g of sodium hydride (60% oily sodium hydride washed with anhydrous benzene) was added to 50 ml of anhydrous dimethylformamide under nitrogen atmosphere while stirring. 14.2 g of 2-methoxycarbonylcylopentanone was added to the mixture, followed by stirring at room temperature until generation of hydrogen was terminated. Next, 15 g of methyl iodide was added, and the mixture was stirred for a further 2 hours at 60° C. The reaction mixture thus obtained was poured into 300 ml of diluted hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent under reduced pressure. The oily residue obtained was purified by vacuum distillation to obtain 14.5 g of the title compound. was terminated Next, 15 g of methyl iodide was added the mixture was stirred for a further 2 hours at 60° C The reaction mixture thus obtained extracted with ethyl acetate The organic layer was washed with water dried over anhydrous sodium sulfate followed by evaporation of the solvent under reduced pressure The oily residue obtained was purified by vacuum distillation

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

Procedure: 2.52 g of sodium hydride (60% oily sodium hydride washed with anhydrous benzene) was added to 50 ml of anhydrous dimethylformamide under nitrogen atmosphere while stirring. 14.2 g of 2-methoxycarbonylcylopentanone was added to the mixture, followed by stirring at room temperature until generation of hydrogen was terminated. Next, 15 g of methyl iodide was added, and the mixture was stirred for a further 2 hours at 60° C. The reaction mixture thus obtained was poured into 300 ml of diluted hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent under reduced pressure. The oily residue obtained was purified by vacuum distillation to obtain 14.5 g of the title compound. was terminated Next, 15 g of methyl iodide was added the mixture was stirred for a further 2 hours at 60° C The reaction mixture thus obtained extracted with ethyl acetate The organic layer was washed with water dried over anhydrous sodium sulfate followed by evaporation of the solvent under reduced pressure The oily residue obtained was purified by vacuum distillation

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

Procedure: To a solution of 3.4 g of sodium hydroxide in 770 ml of water were added 15 g of methyl 1-methyl-2-oxocylopentanecarboxylate (prepared in Reference Example 1 hereinafter) and a solution of 13.5 g of 4-chlorobenzaldehyde in 800 ml of methanol, and the mixture was stirred for 5 hours at room temperature. The reaction mixture was neutralized with diluted hydrochloric acid and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed with water and dried. Ethyl acetate was evaporated under reduced pressure to obtain 25 g of an oily matter. the solvent was evaporated under reduced pressure The residue was extracted with ethyl acetate The organic layer was washed with water dried Ethyl acetate was evaporated under reduced pressure to obtain 25 g of an oily matter

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

Procedure: To a solution of 3.4 g of sodium hydroxide in 770 ml of water were added 15 g of methyl 1-methyl-2-oxocylopentanecarboxylate (prepared in Reference Example 1 hereinafter) and a solution of 13.5 g of 4-chlorobenzaldehyde in 800 ml of methanol, and the mixture was stirred for 5 hours at room temperature. The reaction mixture was neutralized with diluted hydrochloric acid and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed with water and dried. Ethyl acetate was evaporated under reduced pressure to obtain 25 g of an oily matter. the solvent was evaporated under reduced pressure The residue was extracted with ethyl acetate The organic layer was washed with water dried Ethyl acetate was evaporated under reduced pressure to obtain 25 g of an oily matter

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

Procedure: To methyl 1-methyl-2-oxocyclopentanecarboxylate (20.0 g=128 mmol) in THF (800 ml) add portionwise lithium tri-t-butoxyaluminohydride (40.7 g=160 mmol). Stir 1 hr and partition between Et2O and 1.0N HCl. Dry and concentrate to obtain methyl 1-methyl-2-hydroxycyclopentanecarboxylate, largely the 1β-methyl-2β-hydroxy isomer, as an oil. partition between Et2O and 1.0N HCl Dry concentrate

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

Procedure: Methyl 1-methyl-2-oxocyclopentanecarboxylate (61.0 g, 0.39 mol) was added dropwise to a freshly prepared solution of NaOMe (0.78 mol) in MeOH (1 L) at ambient temperature. The solution was heated under reflux for 3 h and then concentrated. The residue was dissolved in toluene (1 L) and the resulting solution was heated under reflux for 5 h. The mixture was cooled to ambient temperature, washed with saturated aqueous NaHCO3 (500 mL×3) and brine (300 mL×1), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by distillation to afford methyl 3-methyl-2-oxocyclopentanecarboxylate (39.0 g, 64% yield). The solution was heated under reflux for 3 h concentrated The residue was dissolved in toluene (1 L) the resulting solution was heated under reflux for 5 h washed with saturated aqueous NaHCO3 (500 mL×3) and brine (300 mL×1) dried over anhydrous sodium sulfate concentrated to dryness The residue was purified by distillation

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

Procedure: A mixture of methyl 2-oxocyclopentanecarboxylate (67 g, 0.47 mol), K2CO3 (163 g, 1.18 mol) and MeI (167 g, 1.18 mol) in acetone (500 mL) was heated under reflux for 12 h. The mixture was cooled to ambient temperature and then concentrated. The residue was dissolved in EtOAc (800 mL) and the resulting solution was washed with saturated aqueous NaHCO3 (500 mL×3) and brine (300 mL×1), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by distillation to afford methyl 1-methyl-2-oxocyclopentanecarboxylate (60.5 g, 82% yield). was heated under reflux for 12 h concentrated The residue was dissolved in EtOAc (800 mL) the resulting solution was washed with saturated aqueous NaHCO3 (500 mL×3) and brine (300 mL×1) dried over anhydrous sodium sulfate concentrated to dryness The residue was purified by distillation

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

Procedure: Methyl 1-methyl-2-oxocyclopentanecarboxylate (61.0 g, 0.39 mol) was added dropwise to a freshly prepared solution of NaOMe (0.78 mol) in MeOH (1 L) at ambient temperature. The solution was heated under reflux for 3 h and then concentrated. The residue was dissolved in toluene (1 L) and the resulting solution was heated under reflux for 5 h. The mixture was cooled to ambient temperature, washed with saturated aqueous NaHCO3 (500 mL×3) and brine (300 mL×1), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by distillation to afford methyl 3-methyl-2-oxocyclopentanecarboxylate (39.0 g, 64% yield). The solution was heated under reflux for 3 h concentrated The residue was dissolved in toluene (1 L) the resulting solution was heated under reflux for 5 h washed with saturated aqueous NaHCO3 (500 mL×3) and brine (300 mL×1) dried over anhydrous sodium sulfate concentrated to dryness The residue was purified by distillation

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

Procedure: A mixture of methyl 2-oxocyclopentanecarboxylate (67 g, 0.47 mol), K2CO3 (163 g, 1.18 mol) and MeI (167 g, 1.18 mol) in acetone (500 mL) was heated under reflux for 12 h. The mixture was cooled to ambient temperature and then concentrated. The residue was dissolved in EtOAc (800 mL) and the resulting solution was washed with saturated aqueous NaHCO3 (500 mL×3) and brine (300 mL×1), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by distillation to afford methyl 1-methyl-2-oxocyclopentanecarboxylate (60.5 g, 82% yield). was heated under reflux for 12 h concentrated The residue was dissolved in EtOAc (800 mL) the resulting solution was washed with saturated aqueous NaHCO3 (500 mL×3) and brine (300 mL×1) dried over anhydrous sodium sulfate concentrated to dryness The residue was purified by distillation

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

Procedure: 2.52 g of sodium hydride (60% oily sodium hydride washed with anhydrous benzene) was added to 50 ml of anhydrous dimethylformamide under nitrogen atmosphere while stirring. 14.2 g of 2-methoxycarbonylcylopentanone was added to the mixture, followed by stirring at room temperature until generation of hydrogen was terminated. Next, 15 g of methyl iodide was added, and the mixture was stirred for a further 2 hours at 60° C. The reaction mixture thus obtained was poured into 300 ml of diluted hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent under reduced pressure. The oily residue obtained was purified by vacuum distillation to obtain 14.5 g of the title compound. was terminated Next, 15 g of methyl iodide was added the mixture was stirred for a further 2 hours at 60° C The reaction mixture thus obtained extracted with ethyl acetate The organic layer was washed with water dried over anhydrous sodium sulfate followed by evaporation of the solvent under reduced pressure The oily residue obtained was purified by vacuum distillation