ethyl 1-iodoethyl carbonate

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

Procedure: Sodium(1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (71.9 mg) was dissolved in 2.0 ml of DMF. 1-(Ethoxycarbonyloxy)ethyl iodide (66.3 mg) was added to the solution in an argon atmosphere at −20° C. The mixture was stirred for 2 hr while raising the temperature to −10° C. Ethyl acetate (20 ml) was added to the reaction solution. The mixture was extracted twice, followed by washing twice with 10 ml of semisaturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under the reduced pressure to a volume of 2 ml. The residue was purified by column chromatography on silica gel (chloroform:methanol=15:1) and Sephadex LH-20 (dichloromethane:methanol=1:1) in that order to give 57.4 mg of the title compound. The mixture was extracted twice by washing twice with 10 ml of semisaturated brine The organic layer was dried over anhydrous magnesium sulfate filtered The filtrate was concentrated under the reduced pressure to a volume of 2 ml The residue was purified by column chromatography on silica gel (chloroform:methanol=15:1) and Sephadex

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

Procedure: Sodium(1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (71.9 mg) was dissolved in 2.0 ml of DMF. 1-(Ethoxycarbonyloxy)ethyl iodide (66.3 mg) was added to the solution in an argon atmosphere at −20° C. The mixture was stirred for 2 hr while raising the temperature to −10° C. Ethyl acetate (20 ml) was added to the reaction solution. The mixture was extracted twice, followed by washing twice with 10 ml of semisaturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under the reduced pressure to a volume of 2 ml. The residue was purified by column chromatography on silica gel (chloroform:methanol=15:1) and Sephadex LH-20 (dichloromethane:methanol=1:1) in that order to give 57.4 mg of the title compound. The mixture was extracted twice by washing twice with 10 ml of semisaturated brine The organic layer was dried over anhydrous magnesium sulfate filtered The filtrate was concentrated under the reduced pressure to a volume of 2 ml The residue was purified by column chromatography on silica gel (chloroform:methanol=15:1) and Sephadex

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

Procedure: 1-Chloroethyl ethyl carbonate (5.0 g, 32.8 mmol) was dissolved in 125 mL acetonitrile. Sodium iodide (22.1 g, 147.5 mmol) was added and stirred at 60° C. for 1.5 hours. The reaction was evaporated, diluted with ether and filtered. The filtrate was evaporated to a dark red oil, to afford 1-iodoethyl ethyl carbonate (4.12 g, 51% yield). N016 (2.07 g, 11.3 mmol) and freshly made 1-iodoethyl ethyl carbonate (4.12 g, 16.9 mmol) were dissolved in 15 mL acetonitrile and stirred at room temperature overnight. The reaction was evaporated, diluted with ethyl acetate, washed with 0.2N Na2S2O3 and brine, dried over magnesium sulfate and evaporated. Chromatography was performed using 50% ethyl acetate/hexanes to yield a colorless oil (890 mg, 28% yield). 1H NMR (400 MHz, d-DMSO) δ 6.28 (dq, J=2.6, 5.6 Hz, 1H), 4.76 (dt, J=2.9, 5.7 Hz, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.97-3.86 (m, 1H), 3.55-3.31 (m, 4H), 1.96-1.77 (m, 4H), 1.47 (d, J=5.5 Hz, 3H), 1.17 (dt, J=18.4, 7.1 Hz, 3H). LC tr=2.98 minutes (C-18 column, 5 to 95% acetonitrile/water over 6 minutes at 1.7 mL/min with detection 254 nm, at 23° C.). ES(pos)MS m/z 300 (M+Na calcd for C10H19N3O6 requires 300). The reaction was evaporated diluted with ether filtered The filtrate was evaporated to a dark red oil

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

Procedure: 3.00 g of 1-chloroethyl ethyl carbonate was dissolved in 90 mL of acetonitrile, to which 13.3 g of sodium iodide was added, and this mixture was stirred for 1.5 hours at 60° C. This mixture was cooled to room temperature, followed by concentration thereof under reduced pressure, and then insoluble substances were filtered out thereof by adding diethyl ether to the residue. The resultant filtrate was concentrated under reduced pressure to yield 4.60 g of ethyl 1-iodoethyl carbonate as orange oil. was added This mixture was cooled to room temperature followed by concentration under reduced pressure, and then insoluble substances were filtered out thereof by adding diethyl ether to the residue The resultant filtrate was concentrated under reduced pressure

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

Procedure: 3.00 g of 1-chloroethyl ethyl carbonate was dissolved in 90 mL of acetonitrile, to which 13.3 g of sodium iodide was added, and this mixture was stirred for 1.5 hours at 60° C. This mixture was cooled to room temperature, followed by concentration thereof under reduced pressure, and then insoluble substances were filtered out thereof by adding diethyl ether to the residue. The resultant filtrate was concentrated under reduced pressure to yield 4.60 g of ethyl 1-iodoethyl carbonate as orange oil. was added This mixture was cooled to room temperature followed by concentration under reduced pressure, and then insoluble substances were filtered out thereof by adding diethyl ether to the residue The resultant filtrate was concentrated under reduced pressure

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

Procedure: In the same manner as in Example 81, 167 mg of the title compound was prepared from 145 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 and 148 mg of 1-(ethoxycarbonyloxy)ethyl iodide.

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

Procedure: In the same manner as in Example 81, 167 mg of the title compound was prepared from 145 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 and 148 mg of 1-(ethoxycarbonyloxy)ethyl iodide.

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

Procedure: In the same manner as in Example 81, 167 mg of the title compound was prepared from 145 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 and 148 mg of 1-(ethoxycarbonyloxy)ethyl iodide.

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

Procedure: Sodium (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (71.9 mg) was dissolved in 2.0 ml of DMF. 1-(Ethoxycarbonyloxy)ethyl iodide (66.3 mg) was added to the solution in an argon atmosphere at −20° C. The mixture was stirred for 2 hr while raising the temperature to −10° C. Ethyl acetate (20 ml) was added to the reaction solution. The mixture was extracted twice, followed by washing twice with 10 ml of semisaturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under the reduced pressure to a volume of 2 ml. The residue was purified by column chromatography on silica gel (chloroform:methanol=15:1) and Sephadex LH-20 (dichloromethane:methanol=1:1) in that order to give 57.4 mg of the title compound. The mixture was extracted twice by washing twice with 10 ml of semisaturated brine The organic layer was dried over anhydrous magnesium sulfate filtered The filtrate was concentrated under the reduced pressure to a volume of 2 ml The residue was purified by column chromatography on silica gel (chloroform:methanol=15:1) and Sephadex

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

Procedure: In the same manner as in Example 81, 167 mg of the title compound was prepared from 145 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 and 148 mg of 1-(ethoxycarbonyloxy)ethyl iodide.

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

Procedure: Sodium(1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (71.9 mg) was dissolved in 2.0 ml of DMF. 1-(Ethoxycarbonyloxy)ethyl iodide (66.3 mg) was added to the solution in an argon atmosphere at −20° C. The mixture was stirred for 2 hr while raising the temperature to −10° C. Ethyl acetate (20 ml) was added to the reaction solution. The mixture was extracted twice, followed by washing twice with 10 ml of semisaturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under the reduced pressure to a volume of 2 ml. The residue was purified by column chromatography on silica gel (chloroform:methanol=15:1) and Sephadex LH-20 (dichloromethane:methanol=1:1) in that order to give 57.4 mg of the title compound. The mixture was extracted twice by washing twice with 10 ml of semisaturated brine The organic layer was dried over anhydrous magnesium sulfate filtered The filtrate was concentrated under the reduced pressure to a volume of 2 ml The residue was purified by column chromatography on silica gel (chloroform:methanol=15:1) and Sephadex

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

Procedure: 1-Chloroethyl ethyl carbonate (5.0 g, 32.8 mmol) was dissolved in 125 mL acetonitrile. Sodium iodide (22.1 g, 147.5 mmol) was added and stirred at 60° C. for 1.5 hours. The reaction was evaporated, diluted with ether and filtered. The filtrate was evaporated to a dark red oil, to afford 1-iodoethyl ethyl carbonate (4.12 g, 51% yield). N016 (2.07 g, 11.3 mmol) and freshly made 1-iodoethyl ethyl carbonate (4.12 g, 16.9 mmol) were dissolved in 15 mL acetonitrile and stirred at room temperature overnight. The reaction was evaporated, diluted with ethyl acetate, washed with 0.2N Na2S2O3 and brine, dried over magnesium sulfate and evaporated. Chromatography was performed using 50% ethyl acetate/hexanes to yield a colorless oil (890 mg, 28% yield). 1H NMR (400 MHz, d-DMSO) δ 6.28 (dq, J=2.6, 5.6 Hz, 1H), 4.76 (dt, J=2.9, 5.7 Hz, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.97-3.86 (m, 1H), 3.55-3.31 (m, 4H), 1.96-1.77 (m, 4H), 1.47 (d, J=5.5 Hz, 3H), 1.17 (dt, J=18.4, 7.1 Hz, 3H). LC tr=2.98 minutes (C-18 column, 5 to 95% acetonitrile/water over 6 minutes at 1.7 mL/min with detection 254 nm, at 23° C.). ES(pos)MS m/z 300 (M+Na calcd for C10H19N3O6 requires 300). The reaction was evaporated diluted with ether filtered The filtrate was evaporated to a dark red oil