tert-butyl 7-bromoheptanoate

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

実験手順: A solution of 11.8 g (0.1 mole) of 1,3,4-thiadiazoline-2,5-dione (1) (Example 1A) in 75 ml of HMPA was stirred with 9.24 g (0.11 mole) of NaHCO3 at room temperature for 18 hrs and then 0.3 g NaI was added followed by 26.5 g (0.1 mole) of tert-butyl 7-bromoheptanoate which was added dropwise over a period of 2 hr. The reaction mixture was stirred at room temperature for 5 days then poured with stirring into 500 ml of ice-cold 5% HCl topped with 200 ml of ether. The ether phase was washed with water and then with three 100-ml portions of 2.5% NaHCO3. The combined NaHCO3 solutions were washed with fresh ether, topped with 200 ml of fresh ether, and while being cooled in ice, acidified by dropwise addition of conc. HCl to pH 2-3. The ether layer was drawn off, two more ether extractions of the aqueous layer were made, and the combined ether extract was washed once with satd. NaCl, dried over Na2SO4, and evaporated. 2,5-Dioxo-1,3,4-thiadiazoline-3-heptanoic acid tert-butyl ester (6.58 g, 22%) was obtained as an oil, IR, (neat) νmax 1735 and 1725 (CO2 t-Bu), and 1675 cm-1 (amide), pmr, (CDCl3, TMS) δ 8.70 (s,1H,OH,NH), 3.75 (t, 2H, NCH2), 2.22 (t, 2H, CH2CO2), and 1.45 ppm (s, 9H C(CH3)3). was added dropwise over a period of 2 hr then poured The ether phase was washed with water The combined NaHCO3 solutions were washed with fresh ether while being cooled in ice acidified by dropwise addition of conc. HCl to pH 2-3 two more ether extractions of the aqueous layer the combined ether extract was washed once with satd NaCl, dried over Na2SO4 evaporated

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

実験手順: A solution of 11.8 g (0.1 mole) of 1,3,4-thiadiazoline-2,5-dione (1) (Example 1A) in 75 ml of HMPA was stirred with 9.24 g (0.11 mole) of NaHCO3 at room temperature for 18 hrs and then 0.3 g NaI was added followed by 26.5 g (0.1 mole) of tert-butyl 7-bromoheptanoate which was added dropwise over a period of 2 hr. The reaction mixture was stirred at room temperature for 5 days then poured with stirring into 500 ml of ice-cold 5% HCl topped with 200 ml of ether. The ether phase was washed with water and then with three 100-ml portions of 2.5% NaHCO3. The combined NaHCO3 solutions were washed with fresh ether, topped with 200 ml of fresh ether, and while being cooled in ice, acidified by dropwise addition of conc. HCl to pH 2-3. The ether layer was drawn off, two more ether extractions of the aqueous layer were made, and the combined ether extract was washed once with satd. NaCl, dried over Na2SO4, and evaporated. 2,5-Dioxo-1,3,4-thiadiazoline-3-heptanoic acid tert-butyl ester (6.58 g, 22%) was obtained as an oil, IR, (neat) νmax 1735 and 1725 (CO2 t-Bu), and 1675 cm-1 (amide), pmr, (CDCl3, TMS) δ 8.70 (s,1H,OH,NH), 3.75 (t, 2H, NCH2), 2.22 (t, 2H, CH2CO2), and 1.45 ppm (s, 9H C(CH3)3). was added dropwise over a period of 2 hr then poured The ether phase was washed with water The combined NaHCO3 solutions were washed with fresh ether while being cooled in ice acidified by dropwise addition of conc. HCl to pH 2-3 two more ether extractions of the aqueous layer the combined ether extract was washed once with satd NaCl, dried over Na2SO4 evaporated

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

実験手順: To 8.5 g of 7-bromoheptanoic acid t-butyl ester (prepared as described in Reference Example 1) in 80 ml of methylene chloride was added dropwise 18.2 ml of a 25% solution of diisobutyl alminium hydride in toluene at -78° C. over a period of 1 hours. The solution was stirred at the same temperature, to which was added 5 ml of methanol at from 0° C. to 10° C. and then added 10 ml of water, and the mixture was stirred at 30° C. to 40° C. for 1 hour. The deposited crystals were filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene and chloride and cyclohexane (1:1) as an eluent to give 5.28 g of the title compound having the following physical characteristic: the mixture was stirred at 30° C. to 40° C. for 1 hour The deposited crystals were filtered out the filtrate was concentrated under reduced pressure The residue was purified by column chromatography on silica gel using a mixture of methylene and chloride and cyclohexane (1:1) as an eluent

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

実験手順: To 6.94 ml of diisopropylamine in 100 ml of anhydrous tetrahydrofuran was added dropwise 34 ml of a 1.45 M solution of n-butyl lithium in hexane at -70° C. and the mixture was stirred for 15 minutes. To the solution was added dropwise a solution of 6.63 ml of t-butyl acetate in 30 ml of anhydrous tetrahydrofuran and the mixture was stirred for 30 minutes, and then 8 ml of 1,5-dibromopentane in 10 ml of anhydrous tetrahydrofuran were added thereto and the mixture was stirred for 5 minutes. To it was added 17 ml of hexamethylphosphamide, the mixture was stirred at -78° C. for 1 hour and at from -40° C. to -30° C. for 30 minutes. To the reaction mixture was added an aqueous solution of ammonium chloride, and was separated aqueous layer from organic layer. The aqueous layer was extracted with diethyl ether, and the extract was added that organic layer and washed with water, a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and cyclohexane (1:1) as an eluent to give 8.5 g of the title compound having the following physical characteristic: the mixture was stirred for 30 minutes the mixture was stirred for 5 minutes To it was added 17 ml of hexamethylphosphamide the mixture was stirred at -78° C. for 1 hour and at from -40° C. to -30° C. for 30 minutes was separated aqueous layer from organic layer The aqueous layer was extracted with diethyl ether the extract was added that organic layer washed with water a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate concentrated under reduced pressure The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and cyclohexane (1:1) as an eluent

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

実験手順: To 8.5 g of 7-bromoheptanoic acid t-butyl ester (prepared as described in Reference Example 1) in 80 ml of methylene chloride was added dropwise 18.2 ml of a 25% solution of diisobutyl alminium hydride in toluene at -78° C. over a period of 1 hours. The solution was stirred at the same temperature, to which was added 5 ml of methanol at from 0° C. to 10° C. and then added 10 ml of water, and the mixture was stirred at 30° C. to 40° C. for 1 hour. The deposited crystals were filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene and chloride and cyclohexane (1:1) as an eluent to give 5.28 g of the title compound having the following physical characteristic: the mixture was stirred at 30° C. to 40° C. for 1 hour The deposited crystals were filtered out the filtrate was concentrated under reduced pressure The residue was purified by column chromatography on silica gel using a mixture of methylene and chloride and cyclohexane (1:1) as an eluent

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

実験手順: To 6.94 ml of diisopropylamine in 100 ml of anhydrous tetrahydrofuran was added dropwise 34 ml of a 1.45 M solution of n-butyl lithium in hexane at -70° C. and the mixture was stirred for 15 minutes. To the solution was added dropwise a solution of 6.63 ml of t-butyl acetate in 30 ml of anhydrous tetrahydrofuran and the mixture was stirred for 30 minutes, and then 8 ml of 1,5-dibromopentane in 10 ml of anhydrous tetrahydrofuran were added thereto and the mixture was stirred for 5 minutes. To it was added 17 ml of hexamethylphosphamide, the mixture was stirred at -78° C. for 1 hour and at from -40° C. to -30° C. for 30 minutes. To the reaction mixture was added an aqueous solution of ammonium chloride, and was separated aqueous layer from organic layer. The aqueous layer was extracted with diethyl ether, and the extract was added that organic layer and washed with water, a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and cyclohexane (1:1) as an eluent to give 8.5 g of the title compound having the following physical characteristic: the mixture was stirred for 30 minutes the mixture was stirred for 5 minutes To it was added 17 ml of hexamethylphosphamide the mixture was stirred at -78° C. for 1 hour and at from -40° C. to -30° C. for 30 minutes was separated aqueous layer from organic layer The aqueous layer was extracted with diethyl ether the extract was added that organic layer washed with water a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate concentrated under reduced pressure The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and cyclohexane (1:1) as an eluent

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

実験手順: A solution of 11.8 g (0.1 mole) of 1,3,4-thiadiazoline-2,5-dione (1) (Example 1A) in 75 ml of HMPA was stirred with 9.24 g (0.11 mole) of NaHCO3 at room temperature for 18 hrs and then 0.3 g NaI was added followed by 26.5 g (0.1 mole) of tert-butyl 7-bromoheptanoate which was added dropwise over a period of 2 hr. The reaction mixture was stirred at room temperature for 5 days then poured with stirring into 500 ml of ice-cold 5% HCl topped with 200 ml of ether. The ether phase was washed with water and then with three 100-ml portions of 2.5% NaHCO3. The combined NaHCO3 solutions were washed with fresh ether, topped with 200 ml of fresh ether, and while being cooled in ice, acidified by dropwise addition of conc. HCl to pH 2-3. The ether layer was drawn off, two more ether extractions of the aqueous layer were made, and the combined ether extract was washed once with satd. NaCl, dried over Na2SO4, and evaporated. 2,5-Dioxo-1,3,4-thiadiazoline-3-heptanoic acid tert-butyl ester (6.58 g, 22%) was obtained as an oil, IR, (neat) νmax 1735 and 1725 (CO2 t-Bu), and 1675 cm-1 (amide), pmr, (CDCl3, TMS) δ 8.70 (s,1H,OH,NH), 3.75 (t, 2H, NCH2), 2.22 (t, 2H, CH2CO2), and 1.45 ppm (s, 9H C(CH3)3). was added dropwise over a period of 2 hr then poured The ether phase was washed with water The combined NaHCO3 solutions were washed with fresh ether while being cooled in ice acidified by dropwise addition of conc. HCl to pH 2-3 two more ether extractions of the aqueous layer the combined ether extract was washed once with satd NaCl, dried over Na2SO4 evaporated

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

実験手順: To 8.5 g of 7-bromoheptanoic acid t-butyl ester (prepared as described in Reference Example 1) in 80 ml of methylene chloride was added dropwise 18.2 ml of a 25% solution of diisobutyl alminium hydride in toluene at -78° C. over a period of 1 hours. The solution was stirred at the same temperature, to which was added 5 ml of methanol at from 0° C. to 10° C. and then added 10 ml of water, and the mixture was stirred at 30° C. to 40° C. for 1 hour. The deposited crystals were filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene and chloride and cyclohexane (1:1) as an eluent to give 5.28 g of the title compound having the following physical characteristic: the mixture was stirred at 30° C. to 40° C. for 1 hour The deposited crystals were filtered out the filtrate was concentrated under reduced pressure The residue was purified by column chromatography on silica gel using a mixture of methylene and chloride and cyclohexane (1:1) as an eluent

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

実験手順: To 6.94 ml of diisopropylamine in 100 ml of anhydrous tetrahydrofuran was added dropwise 34 ml of a 1.45 M solution of n-butyl lithium in hexane at -70° C. and the mixture was stirred for 15 minutes. To the solution was added dropwise a solution of 6.63 ml of t-butyl acetate in 30 ml of anhydrous tetrahydrofuran and the mixture was stirred for 30 minutes, and then 8 ml of 1,5-dibromopentane in 10 ml of anhydrous tetrahydrofuran were added thereto and the mixture was stirred for 5 minutes. To it was added 17 ml of hexamethylphosphamide, the mixture was stirred at -78° C. for 1 hour and at from -40° C. to -30° C. for 30 minutes. To the reaction mixture was added an aqueous solution of ammonium chloride, and was separated aqueous layer from organic layer. The aqueous layer was extracted with diethyl ether, and the extract was added that organic layer and washed with water, a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and cyclohexane (1:1) as an eluent to give 8.5 g of the title compound having the following physical characteristic: the mixture was stirred for 30 minutes the mixture was stirred for 5 minutes To it was added 17 ml of hexamethylphosphamide the mixture was stirred at -78° C. for 1 hour and at from -40° C. to -30° C. for 30 minutes was separated aqueous layer from organic layer The aqueous layer was extracted with diethyl ether the extract was added that organic layer washed with water a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate concentrated under reduced pressure The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and cyclohexane (1:1) as an eluent