1-iodoethyl 2,2-dimethylpropanoate

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

Procedure: 25.7 g (100 mmol) of 1-iodoethyl 2,2-dimethylpropionate are added to 42.8 g (107 mmol) of sodium 3-methoxymethyl7-phenoxyacetamido-3-cephem-4-carboxylate in 430 ml of dry dimethylformamide. The reaction mixture is stirred at room temperature for a further hour and then poured onto a mixture of 2.5 1 of water and 1.5 1 of ethyl acetate. The aqueous phase is extracted again with ethyl acetate. The combined organic phases are washed with saturated sodium chloride-solution, dried over magnesium sulfate and evaporated in vacuo. The aqueous phase is extracted again with ethyl acetate The combined organic phases are washed with saturated sodium chloride-solution dried over magnesium sulfate evaporated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9.5 ml (64 mmol) of DBU are slowly added to a suspension of 14.0 g (57 mmol) of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid in 160 ml of anhydrous methylene chloride at 0° C. and the mixture is subsequently stirred at 0° C. for 30 minutes. 20.8 g (81 mmol) of 1-iodoethyl 2,2-dimethylpropionate are then added and the mixture is stirred at 0° C. for a further 30 minutes and then allowed to warm to room temperature in the course of 30 minutes. After renewed cooling to 0° C., the crude 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetyl chloride (≃54 mmol), dissolved in 100 ml of methylene chloride, is added dropwise and the mixture is then stirred at 0° C. for a further 2 hours. The reaction mixture is concentrated in vacuo and the residue is taken up in ethyl acetate. The mixture is washed successively with 5% sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, and the organic phase is dried over sodium sulfate and concentrated to dryness in vacuo. The crude product is purified by chromatography on silica gel (35-70 μm) (column: 50 cm×8.5 cm, toluene/ethyl acetate=5/1). the mixture is stirred at 0° C. for a further 30 minutes to warm to room temperature in the course of 30 minutes After renewed cooling to 0° C. is added dropwise the mixture is then stirred at 0° C. for a further 2 hours The reaction mixture is concentrated in vacuo The mixture is washed successively with 5% sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution the organic phase is dried over sodium sulfate concentrated to dryness in vacuo The crude product is purified by chromatography on silica gel (35-70 μm) (column: 50 cm×8.5 cm, toluene/ethyl acetate=5/1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9.5 ml (64 mmol) of DBU are slowly added to a suspension of 14.0 g (57 mmol) of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid in 160 ml of anhydrous methylene chloride at 0° C. and the mixture is subsequently stirred at 0° C. for 30 minutes. 20.8 g (81 mmol) of 1-iodoethyl 2,2-dimethylpropionate are then added and the mixture is stirred at 0° C. for a further 30 minutes and then allowed to warm to room temperature in the course of 30 minutes. After renewed cooling to 0° C., the crude 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetyl chloride (≃ 54 mmol), dissolved in 100 ml of methylene chloride, is added dropwise and the mixture is then stirred at 0° C. for a further 2 hours. The reaction mixture is concentrated in vacuo and the residue is taken up in ethyl acetate. The mixture is washed successively with 5% sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, and the organic phase is dried over sodium sulfate and concentrated to dryness in vacuo. The crude product is purified by chromatography on silica gel (35-70 μm) (column: 50 cm×8.5 cm, toluene/ethyl acetate=5/1). the mixture is stirred at 0° C. for a further 30 minutes to warm to room temperature in the course of 30 minutes After renewed cooling to 0° C. is added dropwise the mixture is then stirred at 0° C. for a further 2 hours The reaction mixture is concentrated in vacuo The mixture is washed successively with 5% sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution the organic phase is dried over sodium sulfate concentrated to dryness in vacuo The crude product is purified by chromatography on silica gel (35-70 μm) (column: 50 cm×8.5 cm, toluene/ethyl acetate=5/1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9.5 ml (64 mmol) of DBU are slowly added to a suspension of 14.0 g (57 mmol) of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid in 160 ml of anhydrous methylene chloride at 0° C. and the mixture is subsequently stirred at 0° C. for 30 minutes. 20.8 g (81 mmol) of 1-iodoethyl 2,2-dimethylpropionate are then added and the mixture is stirred at 0° C. for a further 30 minutes and then allowed to warm to room temperature in the course of 30 minutes. After renewed cooling to 0° C., the crude 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetyl chloride (≃ 54 mmol), dissolved in 100 ml of methylene chloride, is added dropwise and the mixture is then stirred at 0° C. for a further 2 hours. The reaction mixture is concentrated in vacuo and the residue is taken up in ethyl acetate. The mixture is washed successively with 5% sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, and the organic phase is dried over sodium sulfate and concentrated to dryness in vacuo. The crude product is purified by chromatography on silica gel (35-70 μm) (column: 50 cm×8.5 cm, toluene/ethyl acetate=5/1). the mixture is stirred at 0° C. for a further 30 minutes to warm to room temperature in the course of 30 minutes After renewed cooling to 0° C. is added dropwise the mixture is then stirred at 0° C. for a further 2 hours The reaction mixture is concentrated in vacuo The mixture is washed successively with 5% sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution the organic phase is dried over sodium sulfate concentrated to dryness in vacuo The crude product is purified by chromatography on silica gel (35-70 μm) (column: 50 cm×8.5 cm, toluene/ethyl acetate=5/1)

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

Procedure: 25.7 g (100 mmol) of 1-iodoethyl 2,2-dimethylpropionate are added to 42.8 g (107 mmol) of sodium 3-methoxymethyl7-phenoxyacetamido-3-cephem-4-carboxylate in 430 ml of dry dimethylformamide. The reaction mixture is stirred at room temperature for a further hour and then poured onto a mixture of 2.5 1 of water and 1.5 1 of ethyl acetate. The aqueous phase is extracted again with ethyl acetate. The combined organic phases are washed with saturated sodium chloride-solution, dried over magnesium sulfate and evaporated in vacuo. The aqueous phase is extracted again with ethyl acetate The combined organic phases are washed with saturated sodium chloride-solution dried over magnesium sulfate evaporated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9.5 ml (64 mmol) of DBU are slowly added to a suspension of 14.0 g (57 mmol) of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid in 160 ml of anhydrous methylene chloride at 0° C. and the mixture is subsequently stirred at 0° C. for 30 minutes. 20.8 g (81 mmol) of 1-iodoethyl 2,2-dimethylpropionate are then added and the mixture is stirred at 0° C. for a further 30 minutes and then allowed to warm to room temperature in the course of 30 minutes. After renewed cooling to 0° C., the crude 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetyl chloride (≃54 mmol), dissolved in 100 ml of methylene chloride, is added dropwise and the mixture is then stirred at 0° C. for a further 2 hours. The reaction mixture is concentrated in vacuo and the residue is taken up in ethyl acetate. The mixture is washed successively with 5% sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, and the organic phase is dried over sodium sulfate and concentrated to dryness in vacuo. The crude product is purified by chromatography on silica gel (35-70 μm) (column: 50 cm×8.5 cm, toluene/ethyl acetate=5/1). the mixture is stirred at 0° C. for a further 30 minutes to warm to room temperature in the course of 30 minutes After renewed cooling to 0° C. is added dropwise the mixture is then stirred at 0° C. for a further 2 hours The reaction mixture is concentrated in vacuo The mixture is washed successively with 5% sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution the organic phase is dried over sodium sulfate concentrated to dryness in vacuo The crude product is purified by chromatography on silica gel (35-70 μm) (column: 50 cm×8.5 cm, toluene/ethyl acetate=5/1)

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

Procedure: To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-1-propenyl]-3-cephem-4-carboxylic acid (250 mg, 0.61 mmol), K2CO3 (124 mg, 0.90 mmol) and 18-crown-6 (24 mg) in DMF (2.5 ml) was added 1-pivaloyloxyethyl iodide (461 mg, 1.8 mmol) at 5° C. and the mixture was stirred for 45 min at the same temperature. The mixture was diluted with ethyl acetate, washed with water and evaporated under reduced pressure. The residue was chromatographed on a column of silica gel (10 g) and the column was eluted with chloroform containing 1% methanol. The fractions containing the desired product were combined and evaporated under reduced pressure. The residue was dissolved in a small amount of benzene and freeze-dried to give 72 mg (21%) of the product as an amorphous powder. washed with water evaporated under reduced pressure The residue was chromatographed on a column of silica gel (10 g) the column was eluted with chloroform containing 1% methanol The fractions containing the desired product evaporated under reduced pressure The residue was dissolved in a small amount of benzene freeze-dried

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

Procedure: To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-1-propenyl]-3-cephem-4-carboxylic acid (250 mg, 0.61 mmol), K2CO3 (124 mg, 0.90 mmol) and 18-crown-6 (24 mg) in DMF (2.5 ml) was added 1-pivaloyloxyethyl iodide (461 mg, 1.8 mmol) at 5° C. and the mixture was stirred for 45 min at the same temperature. The mixture was diluted with ethyl acetate, washed with water and evaporated under reduced pressure. The residue was chromatographed on a column of silica gel (10 g) and the column was eluted with chloroform containing 1% methanol. The fractions containing the desired product were combined and evaporated under reduced pressure. The residue was dissolved in a small amount of benzene and freeze-dried to give 72 mg (21%) of the product as an amorphous powder. washed with water evaporated under reduced pressure The residue was chromatographed on a column of silica gel (10 g) the column was eluted with chloroform containing 1% methanol The fractions containing the desired product evaporated under reduced pressure The residue was dissolved in a small amount of benzene freeze-dried

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

Procedure: To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-1-propenyl]-3-cephem-4-carboxylic acid (250 mg, 0.61 mmol), K2CO3 (124 mg, 0.90 mmol) and 18-crown-6 (24 mg) in DMF (2.5 ml) was added 1-pivaloyloxyethyl iodide (461 mg, 1.8 mmol) at 5° C. and the mixture was stirred for 45 min at the same temperature. The mixture was diluted with ethyl acetate, washed with water and evaporated under reduced pressure. The residue was chromatographed on a column of silica gel (10 g) and the column was eluted with chloroform containing 1% methanol. The fractions containing the desired product were combined and evaporated under reduced pressure. The residue was dissolved in a small amount of benzene and freeze-dried to give 72 mg (21%) of the product as an amorphous powder. washed with water evaporated under reduced pressure The residue was chromatographed on a column of silica gel (10 g) the column was eluted with chloroform containing 1% methanol The fractions containing the desired product evaporated under reduced pressure The residue was dissolved in a small amount of benzene freeze-dried

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

Procedure: In the same manner as Example 1, sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer) was reacted with 1-iodoethyl pivalate in the presence of sodium iodide to give 1-pivaloyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer), mp 110°-115° C. (decompn.).

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

Procedure: A mixture of {-4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl-)phenoxy]-phenyl}-phosphonic acid (250 mg, 0.58 mmol) and DIEA (0.193 mL, 1.16 mmol) in 6 mL of acetonitrile was stirred for 15 min and then 1-iodoethyl pivalate (177 mg, 0.69 mmol) was added. The resulting mixture was stirred for 2 h at rt, then diluted with CH2Cl2, washed with 1 M aqueous NaHSO4, dried (MgSO4) and evaporated. The residue was dissolved in 3:1 acetonitrile/water and subjected to MPLC purification through a 25 g C18 column eluting with % acetonitrile in water (time): 15-50 (15 min). Lyophilization of the eluent containing the desired product provided 31 mg (10%) of the title compound as an amorphous solid: 1H NMR (500 MHz, DMSO-d6): δ 0.91 (s, 9H), 1.29 (d, 6H, J=6 Hz), 1.30 (d, 3H, J=6 Hz), 4.73 (septet, 1H, J=6 Hz), 6.34 (br s, 1H), 6.75 (s, 1H), 7.01 (d, 2H, 1=7 Hz), 7.24 (s, 1H), 7.28 (d, 1H, J=3 Hz), 7.45 (s, 1H), 7.56 (d, 1H, J=3 Hz), 7.63 (br s, 2H), 12.61 (br s, 1H); LCMS (m/z): 563.4 [C26H31N2O8PS+H]+. Anal. calcd. for (C26H31N2O8PS+1H2O): C, 53.79; H, 5.73; N, 4.82. Found: C, 52.93; 11, 5.93; N, 5.92. The resulting mixture was stirred for 2 h at rt washed with 1 M aqueous NaHSO4 dried (MgSO4) evaporated The residue was dissolved in 3:1 acetonitrile/water subjected to MPLC purification through a 25 g C18 column eluting with % acetonitrile in water (time) 15-50 (15 min) Lyophilization of the eluent containing the desired product

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9.5 ml (64 mmol) of DBU are slowly added to a suspension of 14.0 g (57 mmol) of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid in 160 ml of anhydrous methylene chloride at 0° C. and the mixture is subsequently stirred at 0° C. for 30 minutes. 20.8 g (81 mmol) of 1-iodoethyl 2,2-dimethylpropionate are then added and the mixture is stirred at 0° C. for a further 30 minutes and then allowed to warm to room temperature in the course of 30 minutes. After renewed cooling to 0° C., the crude 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetyl chloride (≃ 54 mmol), dissolved in 100 ml of methylene chloride, is added dropwise and the mixture is then stirred at 0° C. for a further 2 hours. The reaction mixture is concentrated in vacuo and the residue is taken up in ethyl acetate. The mixture is washed successively with 5% sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, and the organic phase is dried over sodium sulfate and concentrated to dryness in vacuo. The crude product is purified by chromatography on silica gel (35-70 μm) (column: 50 cm×8.5 cm, toluene/ethyl acetate=5/1). the mixture is stirred at 0° C. for a further 30 minutes to warm to room temperature in the course of 30 minutes After renewed cooling to 0° C. is added dropwise the mixture is then stirred at 0° C. for a further 2 hours The reaction mixture is concentrated in vacuo The mixture is washed successively with 5% sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution the organic phase is dried over sodium sulfate concentrated to dryness in vacuo The crude product is purified by chromatography on silica gel (35-70 μm) (column: 50 cm×8.5 cm, toluene/ethyl acetate=5/1)