1-iodoethyl propan-2-yl carbonate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 48 mg of sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate in 1 ml of DMF was added 73 mg of 1-(isopropoxycarbonyloxy)ethyl iodide under the atmosphere of argon at −20° C., and the mixture was stirred for 3 hours during which the temperature was raised up to −10° C. The reaction mixture was extracted twice with 20 ml of ethyl acetate, and washed twice with 10 ml of semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a volume of 2 ml. The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=9:1) and on Sephadex LH-20 (dichloromethane:methanol=1:1) in this sequence to give the title compound in a yield of 22 mg. The reaction mixture was extracted twice with 20 ml of ethyl acetate washed twice with 10 ml of semi-saturated aqueous saline The organic layer was dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure to a volume of 2 ml The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=9:1) and on Sephadex

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

Procedure: A solution of (RS)-1-iodo-1-(propan-2-yl)oxycarbonyloxyethane (516mg) in 1-methyl-2-pyrrolidinone (2ml) was added dropwise over 45 mins to an ice-cold mixture of sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(S) -tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (237mg) and finely powdered potassium carbonate (276mg) in 1-methyl-2-pyrrolidinone (5ml). The mixture was stirred for an additional 15 mins, diluted with ethyl acetate, washed with water, brine, dried (magnesium sulphate), concentrated and flash chromatographed on silica gel eluting with 50, 60, 70, 80% ethyl acetate in hexane to give the title compound as a foam (58mg); vmax (CHCl3) 2960, 1787, 1760, 1682, 1633, 1519 and 1377cm-1 ; δ(CDCl3, 250MHz) 1.20-2.50 (13H, m), 3.35-3.80 (2H, m), 3.80-4.20 (2H, m), 4.22 (3H, s), 4.83-5.10 (2H, m), 5.85-6.00 (1H, m), 6.85-7.08 (1H, m), 7.27 (1H, s) and 7.76 (1H, br, m). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (606)]. washed with water, brine dried (magnesium sulphate) concentrated flash chromatographed on silica gel eluting with 50, 60, 70, 80% ethyl acetate in hexane

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium iodide (20.69 g, 138.0 mmol) was added to the crude solution of chloroethyl isopropyl carbonate (5.11 g, 30.67 mmol) in acetonitrile (50 mL). The resulting mixture was heated to 60° C. for 2 hours and then allowed to cool to 25° C. The reaction mixture was concentrated under reduced pressure and the resulting mixture was treated with diethyl ether. The solids were filtered off and the filtrate was concentrated under reduced pressure to obtain 1-iodoethyl isopropyl carbonate as a dark orange oil (5.43 g, 69% yield). to cool to 25° C The reaction mixture was concentrated under reduced pressure the resulting mixture was treated with diethyl ether The solids were filtered off the filtrate was concentrated under reduced pressure

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 48 mg of sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate in 1 ml of DMF was added 73 mg of 1-(isopropoxycarbonyloxy)ethyl iodide under the atmosphere of argon at −20° C., and the mixture was stirred for 3 hours during which the temperature was raised up to −10° C. The reaction mixture was extracted twice with 20 ml of ethyl acetate, and washed twice with 10 ml of semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a volume of 2 ml. The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=9:1) and on Sephadex LH-20 (dichloromethane:methanol=1:1) in this sequence to give the title compound in a yield of 22 mg. The reaction mixture was extracted twice with 20 ml of ethyl acetate washed twice with 10 ml of semi-saturated aqueous saline The organic layer was dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure to a volume of 2 ml The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=9:1) and on Sephadex

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

Procedure: A solution of (RS)-1-iodo-1-(propan-2-yl)oxycarbonyloxyethane (516mg) in 1-methyl-2-pyrrolidinone (2ml) was added dropwise over 45 mins to an ice-cold mixture of sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(S) -tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (237mg) and finely powdered potassium carbonate (276mg) in 1-methyl-2-pyrrolidinone (5ml). The mixture was stirred for an additional 15 mins, diluted with ethyl acetate, washed with water, brine, dried (magnesium sulphate), concentrated and flash chromatographed on silica gel eluting with 50, 60, 70, 80% ethyl acetate in hexane to give the title compound as a foam (58mg); vmax (CHCl3) 2960, 1787, 1760, 1682, 1633, 1519 and 1377cm-1 ; δ(CDCl3, 250MHz) 1.20-2.50 (13H, m), 3.35-3.80 (2H, m), 3.80-4.20 (2H, m), 4.22 (3H, s), 4.83-5.10 (2H, m), 5.85-6.00 (1H, m), 6.85-7.08 (1H, m), 7.27 (1H, s) and 7.76 (1H, br, m). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (606)]. washed with water, brine dried (magnesium sulphate) concentrated flash chromatographed on silica gel eluting with 50, 60, 70, 80% ethyl acetate in hexane

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: In the same manner as in Example 81, 137 mg of the title compound was prepared from 133 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate prepared in Example 41 and 110 mg of 1-(isopropyloxycarbonyloxy)ethyl iodide.

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-chloroethyl isopropyl carbonate (1.00 g) in toluene (30 mL), sodium iodide (2.10 g) and 18-crown-6 (185 mg) were added at room temperature, and the mixture was stirred at 100° C. for 5 hours. To the reaction solution, ethyl acetate was added, and the mixture was washed with water and 5% aqueous sodium thiosulfate in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of the title compound (1.51 g). the mixture was washed with water and 5% aqueous sodium thiosulfate in this order dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure

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 1-(isopropyloxycarbonyloxy)ethyl 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 (85 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 (85 mg) was obtained

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

Procedure: In the same manner as in Example 81, 137 mg of the title compound was prepared from 133 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate prepared in Example 41 and 110 mg of 1-(isopropyloxycarbonyloxy)ethyl iodide.

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

Procedure: To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (4.0 g) in dimethylsulfoxide (40 ml) was added isopropyl 1-iodoethoxyformate (5.1 g). The mixture was stirred for 30 minutes at ambient temperature and poured into a mixture of cold water and ethyl acetate. The organic layer was separated out and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was subjected to column chromatography on silica gel (50 g) using a mixture of benzene and ethyl acetate (3:2) as an eluent. The eluates containing an object compound were collected and evaporated to dryness to give 1-isopropoxycarbonyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (1.5 g), mp 120° to 125° C. (dec.). The organic layer was separated out the aqueous layer was extracted with ethyl acetate washed with water dried over magnesium sulfate evaporated to dryness a mixture of benzene and ethyl acetate (3:2) as an eluent The eluates containing an object compound were collected evaporated to dryness