2-bromo-1-(oxan-4-yl)ethanone

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

実験手順: A mixture of 2-bromo-1-(tetrahydro-pyran-4-yl)-ethanone (0.6 g, 2.89 mmol) and 2-picoline (0.4 mL, 4.3 mmol) in methanol (10 mL) was heated to reflux and maintained overnight. The solvent was removed in vacuo to give a residue which was washed with 20% ethyl acetate in hexane to afford 2-methyl-1-[2-oxo-2-(tetrahydro-pyran-4-yl)-ethyl]-pyridinium bromide (0.75 g, 86%) as a semi-solid. was heated to reflux maintained overnight The solvent was removed in vacuo to give a residue which was washed with 20% ethyl acetate in hexane

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: Crude 4-methoxybenzyl (2RS)-2-hydroxy-2-[(3R,4R)-4-mercapto-3-phenylacetamidoazetidin-2-on-1-yl acetate {prepared from 4-methoxybenzyl (2RS)-2-hydroxy-2-[(1R,5R)-3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-7-on-6-yl]acetate (8.35g, 20mmol)} was dissolved in acetone (25ml) and treated with a solution of 4-bromoacetyltetrahydropyran (G. H. Harnest and A. Burger, J. Amer. Chem. Soc., 1943, 65, 370) (4.4g, 20mmol). After 20min., potassium carbonate (1.38g, 10mmol) was added and the mixture stirred again for a further 45min. Excess ethyl acetate was then added and the organic solution washed with water, brine and dried over anhydrous MgSO4. Evaporation of solvent and chromatography of the residue on silica gel using 50% hexane in ethyl acetate to 100% ethyl acetate gave the title compound as a pale yellow foam (8.5g; 76%); vmax (CHCl3) 3420, 1780, 1750, 1680 and 1615cm-1. [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (579)]. the organic solution washed with water, brine dried over anhydrous MgSO4 Evaporation of solvent and chromatography of the residue on silica gel using 50% hexane in ethyl acetate to 100% ethyl acetate

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

実験手順: A suspension of 150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 578.13 mg (1.77 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 146.97 mg (0.709 mmol) of 2-bromo-1-(tetrahydropyran-4-yl)ethanone are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 220 mg of (8S)-2-chloro-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the following characteristics: After stirring overnight at room temperature the reaction mixture is evaporated extracted with ethyl acetate The organic phase is dried over magnesium sulfate evaporated to dryness

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

実験手順: Crude 4-methoxybenzyl (2RS)-2-hydroxy-2-[(3R,4R)-4-mercapto-3-phenylacetamidoazetidin-2-on-1-yl acetate {prepared from 4-methoxybenzyl (2RS)-2-hydroxy-2-[(1R,5R)-3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-7-on-6-yl]acetate (8.35g, 20mmol)} was dissolved in acetone (25ml) and treated with a solution of 4-bromoacetyltetrahydropyran (G. H. Harnest and A. Burger, J. Amer. Chem. Soc., 1943, 65, 370) (4.4g, 20mmol). After 20min., potassium carbonate (1.38g, 10mmol) was added and the mixture stirred again for a further 45min. Excess ethyl acetate was then added and the organic solution washed with water, brine and dried over anhydrous MgSO4. Evaporation of solvent and chromatography of the residue on silica gel using 50% hexane in ethyl acetate to 100% ethyl acetate gave the title compound as a pale yellow foam (8.5g; 76%); vmax (CHCl3) 3420, 1780, 1750, 1680 and 1615cm-1. [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (579)]. the organic solution washed with water, brine dried over anhydrous MgSO4 Evaporation of solvent and chromatography of the residue on silica gel using 50% hexane in ethyl acetate to 100% ethyl acetate

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

実験手順: A mixture of 2-bromo-1-(tetrahydro-pyran-4-yl)-ethanone (0.6 g, 2.89 mmol) and 2-picoline (0.4 mL, 4.3 mmol) in methanol (10 mL) was heated to reflux and maintained overnight. The solvent was removed in vacuo to give a residue which was washed with 20% ethyl acetate in hexane to afford 2-methyl-1-[2-oxo-2-(tetrahydro-pyran-4-yl)-ethyl]-pyridinium bromide (0.75 g, 86%) as a semi-solid. was heated to reflux maintained overnight The solvent was removed in vacuo to give a residue which was washed with 20% ethyl acetate in hexane

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

実験手順: Thionyl chloride (2 mL, 27 mmol) was added to tetrahydro-pyran-4-carboxylic acid (1.1 g, 8.4 mmol) at 10° C. The mixture was warmed to ambient temperature and stirred for 2 h. Excess thionyl chloride was evaporated and the residue co-distilled with toluene to remove the traces of thionyl chloride. The resulting crude acid chloride was dissolved in dry acetonitrile (3 mL) and cooled to 0° C. Trimethylsilyl diazomethane (12.6 mL, 25.3 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. It was then cooled to −10° C. and a solution of 15% HBr in acetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 h then quenched with saturated sodium bicarbonate solution and extracted with ether (3×20 mL). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-bromo-1-(tetrahydro-pyran-4-yl)-ethanone (620 mg, 35%) as an oil. Excess thionyl chloride was evaporated the residue co-distilled with toluene to remove the traces of thionyl chloride The resulting crude acid chloride was dissolved in dry acetonitrile (3 mL) cooled to 0° C the reaction mixture was stirred at ambient temperature for 2 h It was then cooled to −10° C. The mixture was stirred at room temperature for 1 h then quenched with saturated sodium bicarbonate solution extracted with ether (3×20 mL) The combined ether extracts were washed with brine dried over anhydrous sodium sulfate concentrated in vacuo

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

実験手順: A mixture of 2-bromo-1-(tetrahydro-pyran-4-yl)-ethanone (0.6 g, 2.89 mmol) and 2-picoline (0.4 mL, 4.3 mmol) in methanol (10 mL) was heated to reflux and maintained overnight. The solvent was removed in vacuo to give a residue which was washed with 20% ethyl acetate in hexane to afford 2-methyl-1-[2-oxo-2-(tetrahydro-pyran-4-yl)-ethyl]-pyridinium bromide (0.75 g, 86%) as a semi-solid. was heated to reflux maintained overnight The solvent was removed in vacuo to give a residue which was washed with 20% ethyl acetate in hexane

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

実験手順: Thionyl chloride (2 mL, 27 mmol) was added to tetrahydro-pyran-4-carboxylic acid (1.1 g, 8.4 mmol) at 10° C. The mixture was warmed to ambient temperature and stirred for 2 h. Excess thionyl chloride was evaporated and the residue co-distilled with toluene to remove the traces of thionyl chloride. The resulting crude acid chloride was dissolved in dry acetonitrile (3 mL) and cooled to 0° C. Trimethylsilyl diazomethane (12.6 mL, 25.3 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. It was then cooled to −10° C. and a solution of 15% HBr in acetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 h then quenched with saturated sodium bicarbonate solution and extracted with ether (3×20 mL). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-bromo-1-(tetrahydro-pyran-4-yl)-ethanone (620 mg, 35%) as an oil. Excess thionyl chloride was evaporated the residue co-distilled with toluene to remove the traces of thionyl chloride The resulting crude acid chloride was dissolved in dry acetonitrile (3 mL) cooled to 0° C the reaction mixture was stirred at ambient temperature for 2 h It was then cooled to −10° C. The mixture was stirred at room temperature for 1 h then quenched with saturated sodium bicarbonate solution extracted with ether (3×20 mL) The combined ether extracts were washed with brine dried over anhydrous sodium sulfate concentrated in vacuo

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

実験手順: A suspension of 150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 578.13 mg (1.77 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 146.97 mg (0.709 mmol) of 2-bromo-1-(tetrahydropyran-4-yl)ethanone are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 220 mg of (8S)-2-chloro-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the following characteristics: After stirring overnight at room temperature the reaction mixture is evaporated extracted with ethyl acetate The organic phase is dried over magnesium sulfate evaporated to dryness

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

実験手順: Crude 4-methoxybenzyl (2RS)-2-hydroxy-2-[(3R,4R)-4-mercapto-3-phenylacetamidoazetidin-2-on-1-yl]acetate (prepared from 4-methoxybenzyl (2RS)-2-hydroxy-2-[(1R,5R)-3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-7-on-6-yl]acetate (8.35 g, 20 mmol)) was dissolved in acetone (25 ml) and treated with a solution of 4-bromoacetyltetrahydropyran (G. H. Harnest and A. Burger, J. Amer. Chem. Soc., 1943, 65, 370) (4.4 g, 20 mmol). After 20 min., potassium carbonate (1.38 g, 10 mmol) was added and the mixture stirred again for a further 45 min. Excess ethyl acetate was then added and the organic solution washed with water, brine and dried over anhydrous MGSO4. Evaporation of solvent and chromatography of the residue on silica gel using 50% hexane in ethyl acetate to 100% ethyl acetate gave the title compound as a pale yellow foam (8.5 g; 76%); νmax (CHCl3) 3420, 1780, 1750, 1680 and 1615 cm-1. [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (579)]. the organic solution washed with water, brine dried over anhydrous MGSO4 Evaporation of solvent and chromatography of the residue on silica gel using 50% hexane in ethyl acetate to 100% ethyl acetate

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

実験手順: Crude 4-methoxybenzyl (2RS)-2-hydroxy-2-[(3R,4R)-4-mercapto-3-phenylacetamidoazetidin-2-on-1-yl acetate {prepared from 4-methoxybenzyl (2RS)-2-hydroxy-2-[(1R,5R)-3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-7-on-6-yl]acetate (8.35g, 20mmol)} was dissolved in acetone (25ml) and treated with a solution of 4-bromoacetyltetrahydropyran (G. H. Harnest and A. Burger, J. Amer. Chem. Soc., 1943, 65, 370) (4.4g, 20mmol). After 20min., potassium carbonate (1.38g, 10mmol) was added and the mixture stirred again for a further 45min. Excess ethyl acetate was then added and the organic solution washed with water, brine and dried over anhydrous MgSO4. Evaporation of solvent and chromatography of the residue on silica gel using 50% hexane in ethyl acetate to 100% ethyl acetate gave the title compound as a pale yellow foam (8.5g; 76%); vmax (CHCl3) 3420, 1780, 1750, 1680 and 1615cm-1. [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (579)]. the organic solution washed with water, brine dried over anhydrous MgSO4 Evaporation of solvent and chromatography of the residue on silica gel using 50% hexane in ethyl acetate to 100% ethyl acetate