methyl 2-methyl-3-oxopentanoate

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

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

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

Procedure: A mixture of 25% sodium methoxide in methanol (24.16 ml, 100 mmol) in methanol was stirred during the addition of formamidine acetate (5.73 g, 55.0 mmol) and methyl 2-methyl-3-oxopentanoate (Intermediate 39, 7.21 g, 50 mmol) and the reaction mixture was stirred at room temperature for 3 hours. Water (20 ml) and acetic acid (20 ml) were then added and the solution was concentrated under reduced pressure removing most of the organic solvent from the reaction mixture which was then washed with brine and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The resulting yellow residue was purified by trituration with ether, the resulting colourless solid was collected, washed with ether and dried to give the title compound as a clear solid (2.8 g); the solution was concentrated under reduced pressure removing most of the organic solvent from the reaction mixture which was then washed with brine extracted with ethyl acetate (×3) dried under magnesium sulfate evaporated under reduced pressure The resulting yellow residue was purified by trituration with ether the resulting colourless solid was collected washed with ether dried

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 3-oxopentanoate (6.27 ml, 50 mmol) in tetrahydrofuran (100 ml) and potassium carbonate (20.73 g, 150 mmol) was heated at reflux under argon for 3 hours, reaction mixture was cooled in an ice bath and and iodomethane (3.75 ml, 60.0 mmol) was added dropwsie. The reaction mixture was stirred at 0° C. for 6 hours, and allowed to warm to room temperature while stirring overnight. The reaction mixture was filtered through a celite and the filtrate was evaporated under reduced pressure to give the title compound as an oil (7.2 g); at reflux under argon for 3 hours reaction mixture was cooled in an ice bath to warm to room temperature while stirring overnight The reaction mixture was filtered through a celite the filtrate was evaporated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 3-oxopentanoate (6.27 ml, 50 mmol) in tetrahydrofuran (100 ml) and potassium carbonate (20.73 g, 150 mmol) was heated at reflux under argon for 3 hours, reaction mixture was cooled in an ice bath and and iodomethane (3.75 ml, 60.0 mmol) was added dropwsie. The reaction mixture was stirred at 0° C. for 6 hours, and allowed to warm to room temperature while stirring overnight. The reaction mixture was filtered through a celite and the filtrate was evaporated under reduced pressure to give the title compound as an oil (7.2 g); at reflux under argon for 3 hours reaction mixture was cooled in an ice bath to warm to room temperature while stirring overnight The reaction mixture was filtered through a celite the filtrate was evaporated under reduced pressure

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

Procedure: A solution of 1.18 g of 3,5-dimethyl-4-(3-(4-trifluoromethylphenoxy)propoxy)aniline, 1.35 g of methyl 2-methyl-3-oxopentanoate, and 0.7 g of p-toluenesulfonic acid dissolved in 38 mL of xylene was heated under reflux for 7 hr. This reaction solution was cooled, and ethyl acetate and sodium bicarbonate water were added thereto, followed by separation. The ethyl acetate layer was washed with brine and was further concentrated under the reduced pressure to give 1.38 g of 2-ethyl-4-hydroxy-3,5,7-trimethyl-6-(3-(4-trifluoromethylphenoxy)propoxy)quinoline. Next, 1.38 g of the product thus obtained was added to 15 mL of dimethylacetamide, and 0.26 g of 60% sodium hydride and 0.6 g of methyl chloroformate were added thereto at room temperature. The reaction solution was stirred at room temperature for 2 hr, and ethyl acetate and distilled water were then added thereto. The organic layer was washed with brine and was concentrated under the reduced pressure. The crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) and was then recrystallized from n-hexane /ethyl acetate to give 1.13 g of 4-methoxycarbonyloxy-2-ethyl-3,5,7-trimethyl-6-(3-(4-trifluoromethylphenoxy)propoxy)quinoline (yield 72.2%). was heated under reflux for 7 hr This reaction solution was cooled followed by separation The ethyl acetate layer was washed with brine was further concentrated under the reduced pressure

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

Procedure: A solution of 1.52 9 of 4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-3,5-dimethylaniline, 1.75 g of methyl 2-methyl-3-oxopentanoate, and 0.92 g of p-toluenesulfonic acid dissolved in 49 mL of xylene was heated under reflux for 8 hr. This reaction solution was cooled, and the precipitated crystals were then collected by filtration and were washed with n-hexane and distilled water and were dried to give 2.56 g of 6-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-2-ethyl-4-hydroxy-3,5,7-trimethyl-quinoline. Dimethylacetamide (30 mL) was then added to 1.97 g of the crystals thus obtained, and 0.38 g of 60% sodium hydride and 0.9 g of methyl chloroformate were added thereto at room temperature. The mixture was stirred at room temperature for 2 hr, and ethyl acetate and distilled water were then added. The organic layer was washed with brine and was then concentrated under the reduced pressure. The crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane /ethyl acetate) to give 1.25 g of 4-methoxycarbonyloxy-6-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-2-ethyl-3,5,7-trimethylquinoline (yield 55.6%). was heated under reflux for 8 hr This reaction solution was cooled the precipitated crystals were then collected by filtration were washed with n-hexane distilled water were dried

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 2-methyl-3-oxopentanoate (3.24 g) in THF (30 ml) was slowly added to a suspension of NaH (900 mg) in THF (50 ml) at 0° C., and after stirring for 10 minutes, the mixture was cooled to −78° C. and 1.58 M n-BuLi (14.2 ml) was slowly added dropwise. After stirring the reaction solution at −78° C. for 30 minutes, a solution of methyl 6-(benzyloxy)benzofuran-2-carboxylate (4.26 g) in THF (15 ml) was slowly added and the mixture was stirred at −78° C. for 4 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, and after bringing it to room temperature, extraction was performed with AcOEt and the organic layer was dried with MgSO4 and then filtered and concentrated. The residue was dissolved in MeOH (30 ml) and THF (10 ml), a 4 N lithium hydroxide aqueous solution (5 ml) and water (50 ml) were added, and after stirring at room temperature for 4 hours, a saturated KHSO4 aqueous solution (30 ml) was slowly added. The deposited yellow precipitate was filtered off and rinsed with AcOEt to obtain 6-(6-(benzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one. After stirring the reaction solution at −78° C. for 30 minutes the mixture was stirred at −78° C. for 4 hours to room temperature extraction the organic layer was dried with MgSO4 filtered concentrated The residue was dissolved in MeOH (30 ml) THF (10 ml), a 4 N lithium hydroxide aqueous solution (5 ml) and water (50 ml) were added after stirring at room temperature for 4 hours a saturated KHSO4 aqueous solution (30 ml) was slowly added The deposited yellow precipitate was filtered off rinsed with AcOEt

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 2-methyl-3-oxopentanoate (7.5 g) in THF (50 ml) was slowly added to a suspension of NaH (2.1 g) in THF (200 ml), and after stirring for 10 minutes, the mixture was cooled to −78° C. and 1.58 M n-BuLi (32 ml) was slowly added dropwise. After stirring the reaction solution at −78° C. for 30 minutes, a solution of methyl 5-(dimethoxymethyl)benzofuran-2-carboxylate (10 g) in THF (50 ml) was slowly added and the mixture was stirred at −78° C. for 4 hours. A saturated ammonium chloride aqueous solution (30 ml) was added to the reaction solution, and after bringing it to room temperature, extraction was performed with AcOEt and the organic layer was dried with MgSO4 and then filtered and concentrated. The residue was dissolved in MeOH (100 ml) and THF (100 ml), a 4 N lithium hydroxide aqueous solution (25 ml) was added, and after stirring at room temperature for 4 hours, a saturated KHSO4 aqueous solution (50 ml) was slowly added. The deposited yellow precipitate was filtered off and rinsed with AcOEt to obtain 3,5-dimethyl-6-(5-formylbenzofuran-2-yl)-4-hydroxy-2H-pyran-2-one After stirring the reaction solution at −78° C. for 30 minutes the mixture was stirred at −78° C. for 4 hours to room temperature extraction the organic layer was dried with MgSO4 filtered concentrated The residue was dissolved in MeOH (100 ml) THF (100 ml), a 4 N lithium hydroxide aqueous solution (25 ml) was added after stirring at room temperature for 4 hours a saturated KHSO4 aqueous solution (50 ml) was slowly added The deposited yellow precipitate was filtered off rinsed with AcOEt

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 2-methyl-3-oxopentanoate (865 mg) in THF (30 ml) was slowly added to a suspension of NaH (240 mg) in THF (50 ml), and after stirring for 10 minutes, the mixture was cooled to −78° C. and 1.58 M n-BuLi (3.8 ml) was slowly added dropwise. After stirring the reaction solution at −78° C. for 30 minutes, a solution of methyl 6-morpholinylbenzofuran-2-carboxylate (1.3 g) in THF (15 ml) was slowly added and the mixture was stirred at −78° C. for 4 hours. A saturated ammonium chloride aqueous solution (30 ml) was added to the reaction solution, and after bringing it to room temperature, extraction was performed with AcOEt and the organic layer was dried with MgSO4 and then filtered and concentrated. The residue was dissolved in MeOH (30 ml) and THF (30 ml), a 4 N lithium hydroxide aqueous solution (10 ml) was added, and after stirring at room temperature for 4 hours, a saturated KHSO4 aqueous solution (50 ml) was slowly added. The deposited yellow precipitate was filtered off and rinsed with AcOEt to obtain 3,5-dimethyl-4-hydroxy-6-(6-morpholinylbenzofuran-2-yl)-2H-pyran-2-one. After stirring the reaction solution at −78° C. for 30 minutes the mixture was stirred at −78° C. for 4 hours to room temperature extraction the organic layer was dried with MgSO4 filtered concentrated The residue was dissolved in MeOH (30 ml) THF (30 ml), a 4 N lithium hydroxide aqueous solution (10 ml) was added after stirring at room temperature for 4 hours a saturated KHSO4 aqueous solution (50 ml) was slowly added The deposited yellow precipitate was filtered off rinsed with AcOEt

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: After adding 60% NaH (220 mg) to a solution of methyl 2-methyl-3-oxopentanoate (750 mg) in THF (5 ml) at 0° C. and stirring at 0° C. for 5 minutes, the mixture was cooled to −78° C. To this reaction solution there was added 1.63 M n-BuLi (3.3 ml), and the mixture was stirred at −78° C. for 30 minutes to prepare a dienolate. A solution of methyl 2-benzofurancarboxylate (300 mg) in THF (10 ml) was added to the dienolate, and the mixture was stirred at −78° C. for 20 minutes. The reaction solution was allowed to return to 0° C., aqueous KHSO4 was added for quenching, and extraction was performed with AcOEt. The organic layer was rinsed with saturated saline and dried with MgSO4, and then filtered and concentrated. The residue was crudely purified by silica gel column chromatography (n-hexane/AcOEt=3/1→2/1) to obtain methyl 5-(benzofuran-2-yl)-2,4-dimethyl-3,5-dioxopentanoate. the mixture was cooled to −78° C the mixture was stirred at −78° C. for 30 minutes to prepare a dienolate the mixture was stirred at −78° C. for 20 minutes to return to 0° C. for quenching extraction The organic layer was rinsed with saturated saline dried with MgSO4 filtered concentrated The residue was crudely purified by silica gel column chromatography (n-hexane/AcOEt=3/1→2/1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 2-methyl-3-oxopentanoate (13.05 g) in THF (100 ml) was added to a suspension of NaH (3.80 g) in THF (100 ml) at 0° C., and after stirring at 0° C. for 15 minutes, 1.63 M n-BuLi (58 ml) was added and the mixture was stirred at 0° C. for 20 minutes to prepare a light yellow dienolate. The reaction solution was cooled to −78° C., a solution of ethyl 2-(benzyloxy)acetate (17.56 g) in THF (30 ml) was added, and the mixture was stirred at −78° C. for 5 minutes and then at 0° C. for one hour. Diluted hydrochloric acid was poured into the reaction solution for quenching, and extraction was performed with AcOEt at near neutral. The organic layer was rinsed with saturated saline and dried with MgSO4, and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1→3/1) to obtain methyl 6-benzyloxy-2,4-dimethyl-3,5-dioxohexanoate. the mixture was stirred at 0° C. for 20 minutes to prepare a light yellow dienolate The reaction solution was cooled to −78° C. the mixture was stirred at −78° C. for 5 minutes at 0° C. for one hour for quenching extraction The organic layer was rinsed with saturated saline dried with MgSO4 filtered concentrated The residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1→3/1)