iodomethyl 2-ethylbutanoate

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

Procedure: The compound (100 mg) of Example 16 was dissolved in N,N-dimethylacetamide (2 ml), followed by the addition of 2-ethylbutanoyloxymethyl iodide (50 mg). They were reacted for 1 hour. Ethyl acetate (50 ml) was added. The resulting mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. Ether was added to the residue and the resulting solid was collected by filtration, whereby the title compound (55 mg) was obtained. They were reacted for 1 hour The resulting mixture was washed with water dried over magnesium sulfate concentrated under reduced pressure Ether was added to the residue the resulting solid was collected by filtration, whereby the title compound (55 mg) was obtained

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

Procedure: The semi-crude tert-butyl methyl ether solution of 2-ethyl butyric acid iodomethyl ester from Step 3 was added to a slurry of sulopenem (750 g) in acetone (5.9 L). N,N-Diisopropylethylamine (DIEA) (319 g) in acetone (0.5 L) was added and the mixture was stirred at ambient temperature until reaction completion. Low pyrogen water (6.5 L) and heptane (3.75 L) were added and the phases were separated. The aqueous layer was extracted first with heptane (5 L) and then with ethyl acetate (2×6 L). The ethyl acetate extracts were combined and washed with 5% aqueous sodium thiosulfate (6 L), low pyrogen water (6 L) and 10% aqueous sodium chloride (6 L). The organic extract was treated with activated carbon (75 g) and magnesium sulfate (150 g), then was filtered. The filter cake was washed with ethyl acetate (2×1 L) and the filtrate was evaporated to dryness to provide the crude product (0.8 kg). Ethyl acetate (2.4 L) was added and the solution was heated (45° C.) to achieve dissolution. This solution was then hot-filtered and tert-butyl methyl ether (4.7 L) was added. The resulting slurry was granulated for 10 minutes at 40° C. to 50° C. and was then cooled slowly to less than 10° C. The resulting solid was collected, washed with a 1:2 mixture of ethyl acetate and tert-butyl methyl ether (4×0.5 L) and dried to constant weight under vacuum at up to 50° C. to give 0.57 kg of the desired product (60% yield). the phases were separated The aqueous layer was extracted first with heptane (5 L) washed with 5% aqueous sodium thiosulfate (6 L), low pyrogen water (6 L) and 10% aqueous sodium chloride (6 L) The organic extract was treated with activated carbon (75 g) and magnesium sulfate (150 g) was filtered The filter cake was washed with ethyl acetate (2×1 L) the filtrate was evaporated to dryness to provide the crude product (0.8 kg) the solution was heated (45° C.) dissolution This solution was then hot-filtered tert-butyl methyl ether (4.7 L) was added was then cooled slowly to less than 10° C The resulting solid was collected washed with a 1:2 mixture of ethyl acetate and tert-butyl methyl ether (4×0.5 L) dried to constant weight under vacuum at up to 50° C.

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

Procedure: 2-Ethyl butyric acid chloromethyl ester (700 g) was dissolved in acetone (3 L). To this solution was added sodium iodide (1.0 kg). The resulting reaction mixture was heated at reflux until reaction completion (2 h (hours), monitored by GC). The solution was then cooled to ambient temperature where tert-butyl methyl ether (7 L) and 5% aqueous sodium thiosulfate (4 L) were added. The phases were separated and the organic phase was washed with aqueous sodium thiosulfate (4 L), low pyrogen water (4 L) and 10% sodium chloride solution (4 L). The organic layer was dried over magnesium sulfate (350 g), filtered, and the filter cake was washed with tert-butyl methyl ether (2×0.7 L). The filtrate was evaporated to a small volume (ca. 2 L) to give 2-ethyl butyric acid iodomethyl ester, as a solution in tert-butyl methyl ether. The resulting reaction mixture was heated at reflux until reaction completion (2 h (hours), monitored by GC) were added The phases were separated the organic phase was washed with aqueous sodium thiosulfate (4 L), low pyrogen water (4 L) and 10% sodium chloride solution (4 L) The organic layer was dried over magnesium sulfate (350 g) filtered the filter cake was washed with tert-butyl methyl ether (2×0.7 L) The filtrate was evaporated to a small volume (ca. 2 L)

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

Procedure: The semi-crude tert-butyl methyl ether solution of 2-ethyl butyric acid iodomethyl ester from Step 3 was added to a slurry of sulopenem (750 g) in acetone (5.9 L). N,N-Diisopropylethylamine (DIEA) (319 g) in acetone (0.5 L) was added and the mixture was stirred at ambient temperature until reaction completion. Low pyrogen water (6.5 L) and heptane (3.75 L) were added and the phases were separated. The aqueous layer was extracted first with heptane (5 L) and then with ethyl acetate (2×6 L). The ethyl acetate extracts were combined and washed with 5% aqueous sodium thiosulfate (6 L), low pyrogen water (6 L) and 10% aqueous sodium chloride (6 L). The organic extract was treated with activated carbon (75 g) and magnesium sulfate (150 g), then was filtered. The filter cake was washed with ethyl acetate (2×1 L) and the filtrate was evaporated to dryness to provide the crude product (0.8 kg). Ethyl acetate (2.4 L) was added and the solution was heated (45° C.) to achieve dissolution. This solution was then hot-filtered and tert-butyl methyl ether (4.7 L) was added. The resulting slurry was granulated for 10 minutes at 40° C. to 50° C. and was then cooled slowly to less than 10° C. The resulting solid was collected, washed with a 1:2 mixture of ethyl acetate and tert-butyl methyl ether (4×0.5 L) and dried to constant weight under vacuum at up to 50° C. to give 0.57 kg of the desired product (60% yield). the phases were separated The aqueous layer was extracted first with heptane (5 L) washed with 5% aqueous sodium thiosulfate (6 L), low pyrogen water (6 L) and 10% aqueous sodium chloride (6 L) The organic extract was treated with activated carbon (75 g) and magnesium sulfate (150 g) was filtered The filter cake was washed with ethyl acetate (2×1 L) the filtrate was evaporated to dryness to provide the crude product (0.8 kg) the solution was heated (45° C.) dissolution This solution was then hot-filtered tert-butyl methyl ether (4.7 L) was added was then cooled slowly to less than 10° C The resulting solid was collected washed with a 1:2 mixture of ethyl acetate and tert-butyl methyl ether (4×0.5 L) dried to constant weight under vacuum at up to 50° C.

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

Procedure: 2-Ethyl butyric acid chloromethyl ester (700 g) was dissolved in acetone (3 L). To this solution was added sodium iodide (1.0 kg). The resulting reaction mixture was heated at reflux until reaction completion (2 h (hours), monitored by GC). The solution was then cooled to ambient temperature where tert-butyl methyl ether (7 L) and 5% aqueous sodium thiosulfate (4 L) were added. The phases were separated and the organic phase was washed with aqueous sodium thiosulfate (4 L), low pyrogen water (4 L) and 10% sodium chloride solution (4 L). The organic layer was dried over magnesium sulfate (350 g), filtered, and the filter cake was washed with tert-butyl methyl ether (2×0.7 L). The filtrate was evaporated to a small volume (ca. 2 L) to give 2-ethyl butyric acid iodomethyl ester, as a solution in tert-butyl methyl ether. The resulting reaction mixture was heated at reflux until reaction completion (2 h (hours), monitored by GC) were added The phases were separated the organic phase was washed with aqueous sodium thiosulfate (4 L), low pyrogen water (4 L) and 10% sodium chloride solution (4 L) The organic layer was dried over magnesium sulfate (350 g) filtered the filter cake was washed with tert-butyl methyl ether (2×0.7 L) The filtrate was evaporated to a small volume (ca. 2 L)

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

Procedure: In the same manner as Example 8, 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer) was reacted with iodomethyl 2-ethylbutyrate in the presence of triethylamine to give 2-ethylbutyryloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer).