dichlorophosphorylimino(oxo)methane

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

Procedure: A solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in dioxan (20 ml) was added over ca. 1 minute to a stirred solution of dichlorophosphinyl isocyanate (1.46 ml) in 1,2-dichloroethane (30 ml) at 19°, the temperature rising to 28°. The resulting solution was stirred for 15 minutes and then added to a solution of NaHCO3 (5.1 g) in water (70 ml). This mixture was stirred at ca. 30° for 1 hour, and then heated at 40° to 45° for a total of 4.5 hours, the pH being adjusted to 5.0 with hydrochloric acid after 3 hours. The two-phase mixture was adjusted from pH 5.8 to 7.0 with aqueous NaHCO3 solution and the aqueous phase was washed with 1,2-dichloroethane (20 ml) and ethyl acetate (50 ml), and acidified to pH 1.9 with dilute hydrochloric acid in the presence of ethyl acetate. The aqueous phase was re-extracted with ethyl acetate, and the combined ethyl acetate extract washed with 25% aqueous sodium chloride solution and evaporated. The solid residue was slurried with diethyl ether to give the title compound (3.18 g, 75.0%); purity by HPLC 91.6% and by TLC 89.5%. rising to 28° This mixture was stirred at ca. 30° for 1 hour heated at 40° to 45° for a total of 4.5 hours the aqueous phase was washed with 1,2-dichloroethane (20 ml) and ethyl acetate (50 ml) The aqueous phase was re-extracted with ethyl acetate the combined ethyl acetate extract washed with 25% aqueous sodium chloride solution evaporated

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

Procedure: Dichlorophosphinyl isocyanate (1.46 ml,) was added to a solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in THF (50 ml) at 22°, the temperature rising to 31°. The reaction mixture was stirred for 15 minutes and then added to a solution of sodium acetate (5.72 g) in water (50 ml). More sodium acetate (1.64 g) was added over 10 minutes to give a stable pH of 4.6. This solution was stirred at 30° for 1 hour and then heated at 45° for 3.5 hours when TLC (as Example 3) showed the reaction to be complete. The solution, pH 4.6, was clarified by filtration, adjusted to pH 7.0 with aqueous NaHCO3 solution and washed twice with ethyl acetate. The aqueous phase was stirred and acidified to pH 1.9 with dilute hydrochloric acid to precipitate the title compound (2.80 g, 66.0%); purity by HPLC 95.8% and by TLC 96%. rising to 31° to give a stable pH of 4.6 This solution was stirred at 30° for 1 hour heated at 45° for 3.5 hours when TLC (as Example 3) the reaction The solution, pH 4.6, was clarified by filtration washed twice with ethyl acetate The aqueous phase was stirred to precipitate the title compound (2.80 g, 66.0%)

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

Procedure: The process of Example 3 was repeated, using dichlorophosphinyl isocyanate (1.46 ml) and a solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in acetone (50 ml) cooled to 4°, but the reaction mixture was heated at 45° for 2 hours and then kept at 20° overnight, to give the title compound (2.40 g, 56.7%); purity by HPLC 95.6% and by TLC 94.5%. the reaction mixture was heated at 45° for 2 hours

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

Procedure: Dichlorophosphinyl isocyanate (1.46 ml) was added to a stirred suspension of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in acetonitrile (50 ml) cooled to 5°. The reaction mixture was stirred at 5° for 15 minutes and then added to a solution of NaHCO3 (5.1 g) in water (100 ml). This mixture was stirred for 10 minutes when the pH was adjusted from 7.4 to 5.0 with hydrochloric acid. The pH fell to 3.0 after a further 10 minutes so it was readjusted to 5.0 with aqueous sodium hydroxide solution. The mixture was kept at ca. 20° overnight and then heated at 45° for 2 hours when TLC (chloroform:methanol:acetic acid=9:2:1) showed that reaction was essentially complete. The precipitated white solid was removed by filtration and the filtrate was washed with ethyl acetate. The aqueous phase was acidified to pH 1.9 with dilute hydrochloric acid in the presence of ethyl acetate. The aqueous phase was re-extracted with ethyl acetate, and the combined ethyl acetate extracts were washed with 25% aqueous sodium chloride solution and then evaporated. The solid residue was triturated with diethyl ether to give the title compound (3.18 g, 75.0%), purity by HPLC 95.4% and by TLC 91%. cooled to 5° This mixture was stirred for 10 minutes when the pH The pH fell to 3.0 after a further 10 minutes so it The mixture was kept at ca. 20° overnight showed that reaction The precipitated white solid was removed by filtration the filtrate was washed with ethyl acetate The aqueous phase was re-extracted with ethyl acetate the combined ethyl acetate extracts were washed with 25% aqueous sodium chloride solution evaporated The solid residue was triturated with diethyl ether

Conditions: temp:6.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 105.6 mg (0.518 mmol) of (S)-N-(2-oxo-3-azetidinyl)benzeneacetamide, produced as in Example I, 6 mL of dimethoxyethane, and 2 mL of CH2Cl2 was stirred and cooled to 6° C.; 0.084 mL (0.776 mmol) of phosphorisocyanatidic dichloride was added, and stirring continued at 6°. After 15 minutes complete solution resulted. After an additional 45 minutes at 6° C., the mixture was cooled to -15°, and a solution of 0.216 mL of triethylamine, 0.125 mL of pyridine, and 1.5 mL of methanol was added. The resulting solution was stirred 1.5 hours at room temperature, and then concentrated under reduced pressure. A solution of the residue in CH2Cl2 was washed sequentially with water, 1N HCl, and brine, dried (MgSO4), treated with charcoal, filtered, and concentrated to dryness under reduced pressure. The residue was triturated with two 4 mL portions of ether, the ether decanted, and residual solvent removed from the remaining oil under reduced pressure to leave 72 mg of product. stirring continued at 6° After 15 minutes complete solution resulted the mixture was cooled to -15° The resulting solution was stirred 1.5 hours at room temperature concentrated under reduced pressure A solution of the residue in CH2Cl2 was washed sequentially with water, 1N HCl, and brine dried (MgSO4) treated with charcoal filtered concentrated to dryness under reduced pressure The residue was triturated with two 4 mL portions of ether the ether decanted residual solvent removed from the remaining oil under reduced pressure

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

Procedure: A solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in dioxan (20 ml) was added over ca. 1 minute to a stirred solution of dichlorophosphinyl isocyanate (1.46 ml) in 1,2-dichloroethane (30 ml) at 19°, the temperature rising to 28°. The resulting solution was stirred for 15 minutes and then added to a solution of NaHCO3 (5.1 g) in water (70 ml). This mixture was stirred at ca. 30° for 1 hour, and then heated at 40° to 45° for a total of 4.5 hours, the pH being adjusted to 5.0 with hydrochloric acid after 3 hours. The two-phase mixture was adjusted from pH 5.8 to 7.0 with aqueous NaHCO3 solution and the aqueous phase was washed with 1,2-dichloroethane (20 ml) and ethyl acetate (50 ml), and acidified to pH 1.9 with dilute hydrochloric acid in the presence of ethyl acetate. The aqueous phase was re-extracted with ethyl acetate, and the combined ethyl acetate extract washed with 25% aqueous sodium chloride solution and evaporated. The solid residue was slurried with diethyl ether to give the title compound (3.18 g, 75.0%); purity by HPLC 91.6% and by TLC 89.5%. rising to 28° This mixture was stirred at ca. 30° for 1 hour heated at 40° to 45° for a total of 4.5 hours the aqueous phase was washed with 1,2-dichloroethane (20 ml) and ethyl acetate (50 ml) The aqueous phase was re-extracted with ethyl acetate the combined ethyl acetate extract washed with 25% aqueous sodium chloride solution evaporated

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

Procedure: Dichlorophosphinyl isocyanate (1.46 ml,) was added to a solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in THF (50 ml) at 22°, the temperature rising to 31°. The reaction mixture was stirred for 15 minutes and then added to a solution of sodium acetate (5.72 g) in water (50 ml). More sodium acetate (1.64 g) was added over 10 minutes to give a stable pH of 4.6. This solution was stirred at 30° for 1 hour and then heated at 45° for 3.5 hours when TLC (as Example 3) showed the reaction to be complete. The solution, pH 4.6, was clarified by filtration, adjusted to pH 7.0 with aqueous NaHCO3 solution and washed twice with ethyl acetate. The aqueous phase was stirred and acidified to pH 1.9 with dilute hydrochloric acid to precipitate the title compound (2.80 g, 66.0%); purity by HPLC 95.8% and by TLC 96%. rising to 31° to give a stable pH of 4.6 This solution was stirred at 30° for 1 hour heated at 45° for 3.5 hours when TLC (as Example 3) the reaction The solution, pH 4.6, was clarified by filtration washed twice with ethyl acetate The aqueous phase was stirred to precipitate the title compound (2.80 g, 66.0%)

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

Procedure: The process of Example 3 was repeated, using dichlorophosphinyl isocyanate (1.46 ml) and a solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in acetone (50 ml) cooled to 4°, but the reaction mixture was heated at 45° for 2 hours and then kept at 20° overnight, to give the title compound (2.40 g, 56.7%); purity by HPLC 95.6% and by TLC 94.5%. the reaction mixture was heated at 45° for 2 hours

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

Procedure: Dichlorophosphinyl isocyanate (1.46 ml) was added to a stirred suspension of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in acetonitrile (50 ml) cooled to 5°. The reaction mixture was stirred at 5° for 15 minutes and then added to a solution of NaHCO3 (5.1 g) in water (100 ml). This mixture was stirred for 10 minutes when the pH was adjusted from 7.4 to 5.0 with hydrochloric acid. The pH fell to 3.0 after a further 10 minutes so it was readjusted to 5.0 with aqueous sodium hydroxide solution. The mixture was kept at ca. 20° overnight and then heated at 45° for 2 hours when TLC (chloroform:methanol:acetic acid=9:2:1) showed that reaction was essentially complete. The precipitated white solid was removed by filtration and the filtrate was washed with ethyl acetate. The aqueous phase was acidified to pH 1.9 with dilute hydrochloric acid in the presence of ethyl acetate. The aqueous phase was re-extracted with ethyl acetate, and the combined ethyl acetate extracts were washed with 25% aqueous sodium chloride solution and then evaporated. The solid residue was triturated with diethyl ether to give the title compound (3.18 g, 75.0%), purity by HPLC 95.4% and by TLC 91%. cooled to 5° This mixture was stirred for 10 minutes when the pH The pH fell to 3.0 after a further 10 minutes so it The mixture was kept at ca. 20° overnight showed that reaction The precipitated white solid was removed by filtration the filtrate was washed with ethyl acetate The aqueous phase was re-extracted with ethyl acetate the combined ethyl acetate extracts were washed with 25% aqueous sodium chloride solution evaporated The solid residue was triturated with diethyl ether