[(2R,3S)-3-[(1R)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxoazetidin-2-yl] acetate

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

Procedure: m-Chloroperbenzoic acid (0.5 g) is added to a solution of the object compound of Example 22 (0.08g) in ethyl acetate (8 ml), and the mixture is stirred at room temperature for 3 days and then poured into a mixture of ethyl acetate (50 ml), aqueous sodium hydrogen carbonate (20 ml) and dimethyl sulfide (0.4 ml). The mixture is stirred at room temperature for 30 minutes. The organic layer is separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (eluent: 15% ethyl acetate-85% hexane) to give 0.045 g of (3S,4R)-4-acetoxy-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone. The mixture is stirred at room temperature for 30 minutes The organic layer is separated washed with brine dried over magnesium sulfate concentrated under reduced pressure

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

Procedure: m-Chloroperbenzoic acid (0.5 g) is added to a solution of the object compound of Example 22 (0.08g) in ethyl acetate (8 ml), and the mixture is stirred at room temperature for 3 days and then poured into a mixture of ethyl acetate (50 ml), aqueous sodium hydrogen carbonate (20 ml) and dimethyl sulfide (0.4 ml). The mixture is stirred at room temperature for 30 minutes. The organic layer is separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (eluent: 15% ethyl acetate-85% hexane) to give 0.045 g of (3S,4R)-4-acetoxy-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone. The mixture is stirred at room temperature for 30 minutes The organic layer is separated washed with brine dried over magnesium sulfate concentrated under reduced pressure

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methylene chloride (2 ml) was added to 0.69 g of tin(II) trifluoromethanesulfonate under an argon atmosphere, and the mixture was cooled to −20° C. A solution of 0.25 g of 2-propionyl-7-(pyridin-3-yl)dimethoxymethylimidazo[5,1-b]thiazole in 1.5 ml of methylene chloride and 0.12 ml of N-ethylpiperidine were added thereto, and the mixture was stirred for 2 hr. A solution of 0.14 g of (3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one in 1 ml of methylene chloride was added at 0° C., and the mixture was stirred at room temperature for one hr. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture to stop the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous sodium bicarbonate solution and a 20% aqueous sodium chloride solution in that order and was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue was analyzed by HPLC (Cosmosil 5C18-MS, 4.6×150 mm, a 70% aqueous acetonitrile solution). As a result, it was found that the yield of (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one was 45 mg. The results of analysis by NMR were in agreement with the results of analysis in Example 18. the mixture was stirred at room temperature for one hr the reaction the reaction mixture was extracted with ethyl acetate The organic layer was washed with a 5% aqueous sodium bicarbonate solution a 20% aqueous sodium chloride solution in that order and was dried over anhydrous magnesium sulfate The solvent was removed by evaporation The results of analysis by NMR results of analysis in Example 18

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

Procedure: A 1 M tetrahydrofuran solution (5.2 ml) of lithium bistrimethylsilylamide was added to a solution of 2.05 g of lithium bromide in 10 ml of tetrahydrofuran under an argon atmosphere, and the mixture was cooled to −78° C. A solution of 0.95 g of 2-propionyl-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole in 4.7 ml of tetrahydrofuran was added thereto, and the mixture was stirred at that temperature for one hr. A solution of 0.81 g of (3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one in 3.8 ml of tetrahydrofuran was added thereto, and the mixture was stirred at that temperature for 2 hr. A 10% aqueous citric acid solution was added to the reaction mixture to stop the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in that order and was then dried over anhydrous magnesium sulfate. The extract was then concentrated by removing the solvent, and the concentrate was purified by column chromatography on silica gel (5 to 10% methanol/methylene chloride) to give 0.80 g of a crude product of (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1-methyl-2-[7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one. the mixture was stirred at that temperature for 2 hr the reaction the reaction mixture was extracted with ethyl acetate The extract was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in that order was then dried over anhydrous magnesium sulfate The extract was then concentrated by removing the solvent the concentrate was purified by column chromatography on silica gel (5 to 10% methanol/methylene chloride)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methylene chloride (2 ml) was added to 0.69 g of tin(II) trifluoromethanesulfonate under an argon atmosphere, and the mixture was cooled to −20° C. A solution of 0.25 g of 2-propionyl-7-(pyridin-3-yl)dimethoxymethylimidazo[5,1-b]thiazole in 1.5 ml of methylene chloride and 0.12 ml of N-ethylpiperidine were added thereto, and the mixture was stirred for 2 hr. A solution of 0.14 g of (3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one in 1 ml of methylene chloride was added at 0° C., and the mixture was stirred at room temperature for one hr. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture to stop the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous sodium bicarbonate solution and a 20% aqueous sodium chloride solution in that order and was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue was analyzed by HPLC (Cosmosil 5C18-MS, 4.6×150 mm, a 70% aqueous acetonitrile solution). As a result, it was found that the yield of (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one was 45 mg. The results of analysis by NMR were in agreement with the results of analysis in Example 18. the mixture was stirred at room temperature for one hr the reaction the reaction mixture was extracted with ethyl acetate The organic layer was washed with a 5% aqueous sodium bicarbonate solution a 20% aqueous sodium chloride solution in that order and was dried over anhydrous magnesium sulfate The solvent was removed by evaporation The results of analysis by NMR results of analysis in Example 18

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

Procedure: A 1 M tetrahydrofuran solution (5.2 ml) of lithium bistrimethylsilylamide was added to a solution of 2.05 g of lithium bromide in 10 ml of tetrahydrofuran under an argon atmosphere, and the mixture was cooled to −78° C. A solution of 0.95 g of 2-propionyl-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole in 4.7 ml of tetrahydrofuran was added thereto, and the mixture was stirred at that temperature for one hr. A solution of 0.81 g of (3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one in 3.8 ml of tetrahydrofuran was added thereto, and the mixture was stirred at that temperature for 2 hr. A 10% aqueous citric acid solution was added to the reaction mixture to stop the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in that order and was then dried over anhydrous magnesium sulfate. The extract was then concentrated by removing the solvent, and the concentrate was purified by column chromatography on silica gel (5 to 10% methanol/methylene chloride) to give 0.80 g of a crude product of (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1-methyl-2-[7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one. the mixture was stirred at that temperature for 2 hr the reaction the reaction mixture was extracted with ethyl acetate The extract was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in that order was then dried over anhydrous magnesium sulfate The extract was then concentrated by removing the solvent the concentrate was purified by column chromatography on silica gel (5 to 10% methanol/methylene chloride)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methylene chloride (2 ml) was added to 0.69 g of tin(II) trifluoromethanesulfonate under an argon atmosphere, and the mixture was cooled to −20° C. A solution of 0.25 g of 2-propionyl-7-(pyridin-3-yl)dimethoxymethylimidazo[5,1-b]thiazole in 1.5 ml of methylene chloride and 0.12 ml of N-ethylpiperidine were added thereto, and the mixture was stirred for 2 hr. A solution of 0.14 g of (3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one in 1 ml of methylene chloride was added at 0° C., and the mixture was stirred at room temperature for one hr. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture to stop the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous sodium bicarbonate solution and a 20% aqueous sodium chloride solution in that order and was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue was analyzed by HPLC (Cosmosil 5C18-MS, 4.6×150 mm, a 70% aqueous acetonitrile solution). As a result, it was found that the yield of (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one was 45 mg. The results of analysis by NMR were in agreement with the results of analysis in Example 18. the mixture was stirred at room temperature for one hr the reaction the reaction mixture was extracted with ethyl acetate The organic layer was washed with a 5% aqueous sodium bicarbonate solution a 20% aqueous sodium chloride solution in that order and was dried over anhydrous magnesium sulfate The solvent was removed by evaporation The results of analysis by NMR results of analysis in Example 18

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

Procedure: A 1 M tetrahydrofuran solution (5.2 ml) of lithium bistrimethylsilylamide was added to a solution of 2.05 g of lithium bromide in 10 ml of tetrahydrofuran under an argon atmosphere, and the mixture was cooled to −78° C. A solution of 0.95 g of 2-propionyl-7-(pyridin-3-yl)triethylsilyl oxymethylimidazo[5,1-b]thiazole in 4.7 ml of tetrahydrofuran was added thereto, and the mixture was stirred at that temperature for one hr. A solution of 0.81 g of (3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one in 3.8 ml of tetrahydrofuran was added thereto, and the mixture was stirred at that temperature for 2 hr. A 10% aqueous citric acid solution was added to the reaction mixture to stop the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in that order and was then dried over anhydrous magnesium sulfate. The extract was then concentrated by removing the solvent, and the concentrate was purified by column chromatography on silica gel (5 to 10% methanol/methylene chloride) to give 0.80 g of a crude product of (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1-methyl-2-[7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl]-2-oxo ethyl]azetidin-2-one. the mixture was stirred at that temperature for 2 hr the reaction the reaction mixture was extracted with ethyl acetate The extract was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in that order was then dried over anhydrous magnesium sulfate The extract was then concentrated by removing the solvent the concentrate was purified by column chromatography on silica gel (5 to 10% methanol/methylene chloride)

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

Procedure: Starting from 960 mg (3.35 mmol) of (3S, 4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one and 1.03 g (5.0 mmol) of methyl 4-oxochroman-6-yl carboxylate, 370 mg (25%) of the less polar diastereomer were obtained after chromatography (eluent: toluene/ethyl acetate=10: 1, 1.11, then 2:1) as described under step 1 in Example 14. -1H-NMR (270 MHz, CDCl3): 6 m 0.08 and 0.10 (2×1s, 2×3H, SiCH3); 0.90 (s, 9H, SiC(CH3)3); 1.28 (d, 3H, CH--CH3); 2.85-2.98 (m, 2H, O--CH2 --CH and H-3); 3.72 (dd, 1H, H-4); 3.92 (s, 3H, CO2CH3); 4.18 (mc, 1H, CH--CH3); 4.32 and 4.65 (2×mc, 2×1H, O--CH2 --CH); 6.26 (bs, 1H, NH); 7.03 (d, 1H, aromatic H); 8.18 (dd, 1H, aromatic H) 8.59 (d, 1H, aromatic H). were obtained after chromatography (eluent

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

Procedure: m-Chloroperbenzoic acid (0.5 g) is added to a solution of the object compound of Example 22 (0.08g) in ethyl acetate (8 ml), and the mixture is stirred at room temperature for 3 days and then poured into a mixture of ethyl acetate (50 ml), aqueous sodium hydrogen carbonate (20 ml) and dimethyl sulfide (0.4 ml). The mixture is stirred at room temperature for 30 minutes. The organic layer is separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (eluent: 15% ethyl acetate-85% hexane) to give 0.045 g of (3S,4R)-4-acetoxy-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone. The mixture is stirred at room temperature for 30 minutes The organic layer is separated washed with brine dried over magnesium sulfate concentrated under reduced pressure

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methylene chloride (2 ml) was added to 0.69 g of tin(II) trifluoromethanesulfonate under an argon atmosphere, and the mixture was cooled to −20° C. A solution of 0.25 g of 2-propionyl-7-(pyridin-3-yl)dimethoxymethylimidazo[5,1-b]thiazole in 1.5 ml of methylene chloride and 0.12 ml of N-ethylpiperidine were added thereto, and the mixture was stirred for 2 hr. A solution of 0.14 g of (3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one in 1 ml of methylene chloride was added at 0° C., and the mixture was stirred at room temperature for one hr. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture to stop the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous sodium bicarbonate solution and a 20% aqueous sodium chloride solution in that order and was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue was analyzed by HPLC (Cosmosil 5C18-MS, 4.6×150 mm, a 70% aqueous acetonitrile solution). As a result, it was found that the yield of (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one was 45 mg. The results of analysis by NMR were in agreement with the results of analysis in Example 18. the mixture was stirred at room temperature for one hr the reaction the reaction mixture was extracted with ethyl acetate The organic layer was washed with a 5% aqueous sodium bicarbonate solution a 20% aqueous sodium chloride solution in that order and was dried over anhydrous magnesium sulfate The solvent was removed by evaporation The results of analysis by NMR results of analysis in Example 18

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

Procedure: A 1 M tetrahydrofuran solution (5.2 ml) of lithium bistrimethylsilylamide was added to a solution of 2.05 g of lithium bromide in 10 ml of tetrahydrofuran under an argon atmosphere, and the mixture was cooled to −78° C. A solution of 0.95 g of 2-propionyl-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole in 4.7 ml of tetrahydrofuran was added thereto, and the mixture was stirred at that temperature for one hr. A solution of 0.81 g of (3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one in 3.8 ml of tetrahydrofuran was added thereto, and the mixture was stirred at that temperature for 2 hr. A 10% aqueous citric acid solution was added to the reaction mixture to stop the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in that order and was then dried over anhydrous magnesium sulfate. The extract was then concentrated by removing the solvent, and the concentrate was purified by column chromatography on silica gel (5 to 10% methanol/methylene chloride) to give 0.80 g of a crude product of (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1-methyl-2-[7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one. the mixture was stirred at that temperature for 2 hr the reaction the reaction mixture was extracted with ethyl acetate The extract was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in that order was then dried over anhydrous magnesium sulfate The extract was then concentrated by removing the solvent the concentrate was purified by column chromatography on silica gel (5 to 10% methanol/methylene chloride)