methyl 2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate

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

実験手順: An ethanol (50 mL) suspension of (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (6.57 g) obtained in Example (1a) and palladium carbon (10% by weight) was hydrogen-reduced at room temperature for 24 hours. The reaction mixture was filtered and concentrated. The residue was purified by chromatography (hexane/ethyl acetate=5:1) to obtain the title compound (4.99 g, 75%) as a colorless oil. The reaction mixture was filtered concentrated The residue was purified by chromatography (hexane/ethyl acetate=5:1)

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

実験手順: To a DMF (50 mL) solution of trimethyl phosphonoacetate (26 mL), sodium hydride (purity: 55% or higher, 7.03 g) was added in small portions at 0° C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. A DMF (50 mL) solution of 1,4-cyclohexanedione monoethylene ketal (25.2 g) was added, thereto in small portions at room temperature. This suspension was stirred for 19 hours and diluted with a saturated aqueous solution of ammonium chloride, followed by two extractions with ethyl acetate. The organic layer was washed with saturated brine, then dried over sodium sulfate, and then concentrated. The residue was purified by chromatography (hexane/ethyl acetate=5:1) to obtain the title compound (29.7 g, 87%) as a colorless oil. at room temperature This suspension was stirred for 19 hours followed by two extractions with ethyl acetate The organic layer was washed with saturated brine dried over sodium sulfate concentrated The residue was purified by chromatography (hexane/ethyl acetate=5:1)

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

実験手順: A solution of (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (5.50 g, 25.9 mmol) in 14 mL of dry THF was treated by nitromethane (2.10 mL, 38.9 mmol) followed by a 1M solution of tetrabutylammonium fluoride in THF (26.5 mL, 26.5 mmol). The resulting mixture was stirred at reflux for 20 h under nitrogen. After cooling, the mixture was diluted with water and extracted with three portions of ether. The etheral portions were combined, washed with a 10% aqueous solution of potassium hydrogensulfate, dried over anhydrous Na2SO4 and concentrated. The crude was purified by silica gel column chromatography using a 20% EtOAc:hexanes mixture as eluent to afford (8-Nitromethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-acetic acid methyl ester (5.34 g, 75%) as a colorless oil. at reflux for 20 h under nitrogen After cooling extracted with three portions of ether washed with a 10% aqueous solution of potassium hydrogensulfate dried over anhydrous Na2SO4 concentrated The crude was purified by silica gel column chromatography

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

実験手順: A solution of 1,4-dioxa-spiro[4.5]decan-8-one (5.00 g, 32.0 mmol) in 65 mL of anhydrous toluene was treated with methyl(triphenylphosphoranylidene)acetate (13.9 g, 41.6 mmol). The mixture was stirred at reflux for 18 h under nitrogen. Solvent was removed and the crude was purified by silica gel column chromatography using a 20% EtOAc:hexanes mixture as eluent to afford (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (5.51 g, 81%) as a colorless oil. at reflux for 18 h under nitrogen Solvent was removed the crude was purified by silica gel column chromatography

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

実験手順: A solution of (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (5.50 g, 25.9 mmol) in 14 mL of dry THF was treated by nitromethane (2.10 mL, 38.9 mmol) followed by a 1M solution of tetrabutylammonium fluoride in THF (26.5 mL, 26.5 mmol). The resulting mixture was stirred at reflux for 20 h under nitrogen. After cooling, the mixture was diluted with water and extracted with three portions of ether. The etheral portions were combined, washed with a 10% aqueous solution of potassium hydrogensulfate, dried over anhydrous Na2SO4 and concentrated. The crude was purified by silica gel column chromatography using a 20% EtOAc:hexanes mixture as eluent to afford (8-Nitromethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-acetic acid methyl ester (5.34 g, 75%) as a colorless oil. at reflux for 20 h under nitrogen After cooling extracted with three portions of ether washed with a 10% aqueous solution of potassium hydrogensulfate dried over anhydrous Na2SO4 concentrated The crude was purified by silica gel column chromatography

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

実験手順: A solution of 1,4-dioxa-spiro[4.5]decan-8-one (5.00 g, 32.0 mmol) in 65 mL of anhydrous toluene was treated with methyl(triphenylphosphoranylidene) acetate (13.9 g, 41.6 mmol). The mixture was stirred at reflux for 18 h under nitrogen. Solvent was removed and the crude was purified by silica gel column chromatography using a 20% EtOAc:hexanes mixture as eluent to afford (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (5.51 g, 81%) as a colorless oil. at reflux for 18 h under nitrogen Solvent was removed the crude was purified by silica gel column chromatography

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

実験手順: A solution of Methyl 1,4-dioxaspiro[4.5]dec-8-ylideneacetate (4 g, 18.8 mmol) in dry THF (20 mL) was treated by nitromethane (1.5 mL, 28.3 mmol) followed by tertbutylammonium fluoride (18.8 mLot a 1M solution in THF, 0.0188 mol). The resulting mixture was stirred at reflux for 18 h under nitrogen. After cooling to RT, the mixture was diluted with water and extracted with MTBE (3×100 mL). Combined organic layers were washed with 10% sodium bicarbonate solution (20 mL), water (100 mL) and brine (50 mL), dried over sodium sulphate filtered and concentrated. Purification by flash chromatography on silica (Pet.Ether:EtOAc) afforded the title compound as a colorless liquid (2.5 g, 49%). 1H NMR (400 MHz, DMSO) δ 4.7 (s, 2H), 3.94 (s, 4H), 3.69 (s, 3H), 2.57 (s, 2H), 1.74 (m, 8H). at reflux for 18 h under nitrogen extracted with MTBE (3×100 mL) Combined organic layers were washed with 10% sodium bicarbonate solution (20 mL), water (100 mL) and brine (50 mL) dried over sodium sulphate filtered concentrated Purification by flash chromatography on silica (Pet.Ether:EtOAc)

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

実験手順: A solution of (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (5.50 g, 25.9 mmol) in 14 mL of dry THF was treated by nitromethane (2.10 mL, 38.9 mmol) followed by a 1M solution of tetrabutylammonium fluoride in THF (26.5 mL, 26.5 mmol). The resulting mixture was stirred at reflux for 20 h under nitrogen. After cooling, the mixture was diluted with water and extracted with three portions of ether. The etheral portions were combined, washed with a 10% aqueous solution of potassium hydrogensulfate, dried over anhydrous Na2SO4 and concentrated. The crude was purified by silica gel column chromatography using a 20% EtOAc:hexanes mixture as eluent to afford (8-Nitromethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-acetic acid methyl ester (5.34 g, 75%) as a colorless oil. at reflux for 20 h under nitrogen After cooling extracted with three portions of ether washed with a 10% aqueous solution of potassium hydrogensulfate dried over anhydrous Na2SO4 concentrated The crude was purified by silica gel column chromatography

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

実験手順: A solution of 1,4-dioxa-spiro[4.5]decan-8-one (5.00 g, 32.0 mmol) in 65 mL of anhydrous toluene was treated with methyl(triphenylphosphoranylidene) acetate (13.9 g, 41.6 mmol). The mixture was stirred at reflux for 18 h under nitrogen. Solvent was removed and the crude was purified by silica gel column chromatography using a 20% EtOAc:hexanes mixture as eluent to afford (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (5.51 g, 81%) as a colorless oil. at reflux for 18 h under nitrogen Solvent was removed the crude was purified by silica gel column chromatography

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

実験手順: An ethanol (50 mL) suspension of (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (6.57 g) obtained in Example (1a) and palladium carbon (10% by weight) was hydrogen-reduced at room temperature for 24 hours. The reaction mixture was filtered and concentrated. The residue was purified by chromatography (hexane/ethyl acetate=5:1) to obtain the title compound (4.99 g, 75%) as a colorless oil. The reaction mixture was filtered concentrated The residue was purified by chromatography (hexane/ethyl acetate=5:1)

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

実験手順: To a DMF (50 mL) solution of trimethyl phosphonoacetate (26 mL), sodium hydride (purity: 55% or higher, 7.03 g) was added in small portions at 0° C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. A DMF (50 mL) solution of 1,4-cyclohexanedione monoethylene ketal (25.2 g) was added, thereto in small portions at room temperature. This suspension was stirred for 19 hours and diluted with a saturated aqueous solution of ammonium chloride, followed by two extractions with ethyl acetate. The organic layer was washed with saturated brine, then dried over sodium sulfate, and then concentrated. The residue was purified by chromatography (hexane/ethyl acetate=5:1) to obtain the title compound (29.7 g, 87%) as a colorless oil. at room temperature This suspension was stirred for 19 hours followed by two extractions with ethyl acetate The organic layer was washed with saturated brine dried over sodium sulfate concentrated The residue was purified by chromatography (hexane/ethyl acetate=5:1)