(Z)-oct-3-ene

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

実験手順: 1.25 g of the mixture of 3-(1,1-methylene-5-acetoxypentyl)-6β-[3α-(2-tetrahydropyranyloxy)-5(R),9-dimethyl-1,8-decadienyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and its oct-3-ene isomer (prepared as described in Example 8) was dissolved in 30 ml of methanol. 0.25 g of anhydrous potassium carbonate was added to the mixture, and the mixture was stirred for 2.5 hours at room temperature. The reaction mixture was then diluted with 150 ml of water, and the solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to medium pressure liquid chromatography using a Lobar (trade mark) column (size C), eluted with a 1:2 by volume mixture of ethyl acetate and hexane, yielding 0.68 g of the oct-2-ene compound and 0.51 g of the oct-3-ene compound. the solution was extracted with ethyl acetate The extract was washed with water dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure eluted with a 1:2 by volume mixture of ethyl acetate and hexane

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 85% pure m-chloroperbenzoic acid (1.6 g) in methylene chloride (50 cc) is added, in the course of 20 minutes, to a solution, cooled to 0° C., of a mixture of the 3-acetonyl-2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene and -oct-3-ene isomers (6.7 g) in methylene chloride (100 cc). The mixture is stirred for 11/2 hours at 0° C. and a saturated solution of sodium bicarbonate (50 cc) is then added. The organic phase is decanted, dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is chromatographed on a column of Merck silica gel (0.06-0.20) (75 g) (diameter of the column: 3 cm; height: 21 cm). Elution is carried out with a 70/30 (by volumne) ethyl acetate/cyclohexane mixture (1.5 liters), 100 cc fractions being collected. Fractions 7 to 10 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the syn isomer of 3-acetonyl-2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (5 g) in the form of a hard yellow foam. The organic phase is decanted dried over sodium sulphate concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C The residue is chromatographed on a column of Merck silica gel (0.06-0.20) (75 g) (diameter of the column Elution being collected Fractions 7 to 10 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene and -oct-3-ene (0.22 g) in methylene chloride (10 cc) is cooled to 0° C. A solution of 85% pure m-chloroperbenzoic acid (0.07 g) in methylene chloride (5 cc) is added dropwise in the course of 20 minutes. The solution is then stirred for 5 minutes at 0° C., washed with a saturated solution of sodium bicarbonate (20 cc), dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (4 g) (diameter of the column: 1 cm; height: 10 cm). Elution is carried out with a 60/40 (by volume) ethyl acetate/cyclohexane mixture (100 cc) and and 3 cc fractions are collected. Fractions 11 to 22 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (0.12 g) in the form of a hard white foam. washed with a saturated solution of sodium bicarbonate (20 cc) dried over sodium sulphate concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (4 g) (diameter of the column Elution are collected Fractions 11 to 22 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene and -oct-3-ene (0.22 g) in methylene chloride (10 cc) is cooled to 0° C. A solution of 85% pure m-chloroperbenzoic acid (0.07 g) in methylene chloride (5 cc) is added dropwise in the course of 20 minutes. The solution is then stirred for 5 minutes at 0° C., washed with a saturated solution of sodium bicarbonate (20 cc), dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (4 g) (diameter of the column: 1 cm; height: 10 cm). Elution is carried out with a 60/40 (by volume) ethyl acetate/cyclohexane mixture (100 cc) and and 3 cc fractions are collected. Fractions 11 to 22 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (0.12 g) in the form of a hard white foam. washed with a saturated solution of sodium bicarbonate (20 cc) dried over sodium sulphate concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (4 g) (diameter of the column Elution are collected Fractions 11 to 22 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of diphenyldiazomethane (12.3 g) in acetonitrile (200 cc) is added, in the course of 15 minutes, to a suspension of a mixture (28.8 g) of 2-carboxy-3-methyl-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (40%) and its oct-3-ene isomer (60%) in acetonitrile (500 cc), and the reaction mixture is then stirred for 2 hours at 25° C. The solvent is evaporated under reduced pressure (40 mm Hg) at 30° C. and the oily residue is redissolved in ethyl acetate (500 cc). The solution is washed successively with normal hydrochloric acid (until colourless), with a saturated sodium bicarbonate solution (3×100 cc), with water (100 cc) and with a saturated sodium chloride solution (100 cc), and is then dried and concentrated to dryness, to give a mixture (35.4 g) of 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (40%) and its oct-3-ene isomer (60%), in the form of a cream-coloured froth. The solvent is evaporated under reduced pressure (40 mm Hg) at 30° C. the oily residue is redissolved in ethyl acetate (500 cc) The solution is washed successively with normal hydrochloric acid (until colourless), with a saturated sodium bicarbonate solution (3×100 cc), with water (100 cc) and with a saturated sodium chloride solution (100 cc) is then dried concentrated to dryness

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

実験手順: 1.25 g of the mixture of 3-(1,1-methylene-5-acetoxypentyl)-6β-[3α-(2-tetrahydropyranyloxy)-5(R),9-dimethyl-1,8-decadienyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and its oct-3-ene isomer (prepared as described in Example 8) was dissolved in 30 ml of methanol. 0.25 g of anhydrous potassium carbonate was added to the mixture, and the mixture was stirred for 2.5 hours at room temperature. The reaction mixture was then diluted with 150 ml of water, and the solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to medium pressure liquid chromatography using a Lobar (trade mark) column (size C), eluted with a 1:2 by volume mixture of ethyl acetate and hexane, yielding 0.68 g of the oct-2-ene compound and 0.51 g of the oct-3-ene compound. the solution was extracted with ethyl acetate The extract was washed with water dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure eluted with a 1:2 by volume mixture of ethyl acetate and hexane

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 5 ml of dioxane and 200 mg of a suspension of 55% w/w sodium hydride in mineral oil was added 1 ml of diethyl carbonate, and the mixture was heated, with stirring, at an external temperature of 90° C. To the mixture was then added dropwise a solution of 150 ml of 3-(5-benzyloxypentyl)-7-oxo-cis-bicyclo[3,3,0]oct-2-ene (prepared as described in Preparation 5) in 3 ml of dioxane. During this addition, a catalytic amount of ethanol was also added. The mixture was stirred for 1 hour at 0° C., after which it was poured into ice-water, acidified with acetic acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the resulting residue was purified by silica gel column chromatography. 72 mg of the oct-2-ene isomer of the title compound and 57 mg of the oct-3-ene isomer were obtained from the fractions eluted with hexane containing 3% by volume of ethyl acetate and 5% by volume of ethyl acetate, respectively. the mixture was heated During this addition The mixture was stirred for 1 hour at 0° C. extracted with ethyl acetate The extract was washed with a saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate The solvent was evaporated off under reduced pressure the resulting residue was purified by silica gel column chromatography

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 5 ml of dioxane and 200 mg of a suspension of 55% w/w sodium hydride in mineral oil was added 1 ml of diethyl carbonate, and the mixture was heated, with stirring, at an external temperature of 90° C. To the mixture was then added dropwise a solution of 150 ml of 3-(5-benzyloxypentyl)-7-oxo-cis-bicyclo[3,3,0]oct-2-ene (prepared as described in Preparation 5) in 3 ml of dioxane. During this addition, a catalytic amount of ethanol was also added. The mixture was stirred for 1 hour at 0° C., after which it was poured into ice-water, acidified with acetic acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the resulting residue was purified by silica gel column chromatography. 72 mg of the oct-2-ene isomer of the title compound and 57 mg of the oct-3-ene isomer were obtained from the fractions eluted with hexane containing 3% by volume of ethyl acetate and 5% by volume of ethyl acetate, respectively. the mixture was heated During this addition The mixture was stirred for 1 hour at 0° C. extracted with ethyl acetate The extract was washed with a saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate The solvent was evaporated off under reduced pressure the resulting residue was purified by silica gel column chromatography

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of diphenyldiazomethane (12.3 g) in acetonitrile (200 cc) is added, in the course of 15 minutes, to a suspension of a mixture (28.8 g) of 2-carboxy-3-methyl-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (40%) and its oct-3-ene isomer (60%) in acetonitrile (500 cc), and the reaction mixture is then stirred for 2 hours at 25° C. The solvent is evaporated under reduced pressure (40 mm Hg) at 30° C. and the oily residue is redissolved in ethyl acetate (500 cc). The solution is washed successively with normal hydrochloric acid (until colourless), with a saturated sodium bicarbonate solution (3×100 cc), with water (100 cc) and with a saturated sodium chloride solution (100 cc), and is then dried and concentrated to dryness, to give a mixture (35.4 g) of 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (40%) and its oct-3-ene isomer (60%), in the form of a cream-coloured froth. The solvent is evaporated under reduced pressure (40 mm Hg) at 30° C. the oily residue is redissolved in ethyl acetate (500 cc) The solution is washed successively with normal hydrochloric acid (until colourless), with a saturated sodium bicarbonate solution (3×100 cc), with water (100 cc) and with a saturated sodium chloride solution (100 cc) is then dried concentrated to dryness

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 5 ml of dioxane and 200 mg of a suspension of 55% w/w sodium hydride in mineral oil was added 1 ml of diethyl carbonate, and the mixture was heated, with stirring, at an external temperature of 90° C. To the mixture was then added dropwise a solution of 150 ml of 3-(5-benzyloxypentyl)-7-oxo-cis-bicyclo[3,3,0]oct-2-ene (prepared as described in Preparation 5) in 3 ml of dioxane. During this addition, a catalytic amount of ethanol was also added. The mixture was stirred for 1 hour at 0° C., after which it was poured into ice-water, acidified with acetic acid and then extracted with ethyl acetate: The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the resulting residue was purified by silica gel column chromatography. 72 mg of the oct-2-ene isomer of the title compound and 57 mg of the oct-3-ene isomer were obtained from the fractions eluted with hexane containing 3% by volume of ethyl acetate and 5% by volume of ethyl acetate, respectively. the mixture was heated During this addition The mixture was stirred for 1 hour at 0° C. extracted with ethyl acetate The extract was washed with a saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate The solvent was evaporated off under reduced pressure the resulting residue was purified by silica gel column chromatography

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 85% pure m-chloroperbenzoic acid (1.6 g) in methylene chloride (50 cc) is added, in the course of 20 minutes, to a solution, cooled to 0° C., of a mixture of the 3-acetonyl-2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene and -oct-3-ene isomers (6.7 g) in methylene chloride (100 cc). The mixture is stirred for 11/2 hours at 0° C. and a saturated solution of sodium bicarbonate (50 cc) is then added. The organic phase is decanted, dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is chromatographed on a column of Merck silica gel (0.06-0.20) (75 g) (diameter of the column: 3 cm; height: 21 cm). Elution is carried out with a 70/30 (by volumne) ethyl acetate/cyclohexane mixture (1.5 liters), 100 cc fractions being collected. Fractions 7 to 10 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the syn isomer of 3-acetonyl-2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (5 g) in the form of a hard yellow foam. The organic phase is decanted dried over sodium sulphate concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C The residue is chromatographed on a column of Merck silica gel (0.06-0.20) (75 g) (diameter of the column Elution being collected Fractions 7 to 10 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene and -oct-3-ene (0.22 g) in methylene chloride (10 cc) is cooled to 0° C. A solution of 85% pure m-chloroperbenzoic acid (0.07 g) in methylene chloride (5 cc) is added dropwise in the course of 20 minutes. The solution is then stirred for 5 minutes at 0° C., washed with a saturated solution of sodium bicarbonate (20 cc), dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (4 g) (diameter of the column: 1 cm; height: 10 cm). Elution is carried out with a 60/40 (by volume) ethyl acetate/cyclohexane mixture (100 cc) and and 3 cc fractions are collected. Fractions 11 to 22 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (0.12 g) in the form of a hard white foam. washed with a saturated solution of sodium bicarbonate (20 cc) dried over sodium sulphate concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (4 g) (diameter of the column Elution are collected Fractions 11 to 22 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C