1,3-bis(trimethylsilyl)urea

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

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

Procedure: Vilsmeier reagent was prepared from phosphorus oxychloride (1.7 g) and N,N-dimethylformamide (0.8 g) in ethyl acetate (3.2 ml) in a usual manner. 2-tert-Butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (2.7 g) was added to a stirred suspension of the Vilsmeier reagent prepared above in ethyl acetate (30 ml) under ice-cooling, and the stirring was continued for 40 minutes at the same temperature to produce an activated acid solution. Bis(trimethylsilyl)urea (5.8 g) was added to a stirred suspension of p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (3.8 g) in tetrahydrofuran (40 ml), and the mixture was stirred for 20 minutes at 35° to 40° C. To this solution was added the above activated acid solution at -10° C., followed by stirring for 20 minutes at the same temperature. After water and ethyl acetate were added to the reaction mixture, the separated organic layer was washed with a saturated aqueous sodium bicarbonate and aqueous sodium chloride, and then dried over magnesium sulfate. The solution was evaporated to give p-nitrobenzyl 7-[2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer) (4.97 g). cooling to produce an activated acid solution To this solution was added the above activated acid solution at -10° C. by stirring for 20 minutes at the same temperature the separated organic layer was washed with a saturated aqueous sodium bicarbonate and aqueous sodium chloride dried over magnesium sulfate The solution was evaporated

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under nitrogen atmosphere, to a suspension of diphenylmethyl 7β-amino-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (30.2 g) in THF (800 ml) was added herein 1,3-bis(trimethylsilyl)urea (25.8 g) was added at the room temperature. The reaction mixture was warmed at 35° C. and dissolved, and then it was cooled below 0° C. A suspension of 2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetylchloride monohydrochiloride salt (17.93 g) in acetonitrile (200 ml) was dropped into the above reaction mixture below 0° C. After stirring at the same temperature for 10 minutes, it was poured into a mixture of ethyl acetate (1.2 l) and ice-water (1.5 l). The aqueous layer was adjusted at pH 6.5 with saturated sodium bicarbonate solution. The organic layer was separated, washed with brine (1.0 l), and dried over magnesium sulfate, and then evaporated until the volume amounted to 500 ml. The solution was poured into IPE (1.5 l). The resulting precipitate was filtered, dried under reduced pressure to give diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (41.3 g) as powder. was added at the room temperature dissolved it was cooled below 0° C was dropped into the above reaction mixture below 0° C The organic layer was separated washed with brine (1.0 l) dried over magnesium sulfate evaporated until the volume The solution was poured into IPE (1.5 l) The resulting precipitate was filtered dried under reduced pressure

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

Procedure: To a suspension of 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-mesyloxy-3-cephem-4-carboxylic acid (syn isomer)(1 g) in tetrahydrofuran (30 ml) was added bis(trimethylsilyl)urea (444 mg) at ambient temperature. The mixture was stirred at 30°-35° C. for 30 minutes to give a clear solution. On the other hand, to a solution of (Z)-2-acetylthiovinylbenzene (780 mg) in tetrahydrofuran (6 ml) was added sodium methoxide (240 mg) at 0° C. The mixture was stirred for 30 minutes. This solution was added to the above-mentioned clear solution. The mixture was stirred for 2 hours at -20°~30° C. The mixture was poured into water (300 ml), and then the mixture was neutralized with sodium bicarbonate and washed with ethyl acetate. After stirring, the aqueous layer was separated. The aqueous solution was adjusted to pH 2.5 with 1N hydrochloric acid. To this solution was added ethyl acetate (200 ml). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give a solid. The solid was triturated with diisopropyl ether to give 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[(Z)-2-phenylvinylthio]-3-cephem-4-carboxylic acid (syn isomer)(550 mg). to give a clear solution The mixture was stirred for 30 minutes This solution was added to the above-mentioned clear solution The mixture was stirred for 2 hours at -20°~30° C washed with ethyl acetate After stirring the aqueous layer was separated To this solution was added ethyl acetate (200 ml) The organic layer was separated dried over magnesium sulfate concentrated in vacuo to give a solid The solid was triturated with diisopropyl ether

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

Procedure: To a suspension of 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-mesyloxy-3-cephem-4-carboxylic acid (syn isomer)(1 g) in tetrahydrofuran (30 ml) was added bis(trimethylsilyl)urea (444 mg) at ambient temperature. The mixture was stirred at 30°-35° C. for 30 minutes to give a clear solution. On the other hand, to a solution of (Z)-2-acetylthiovinylbenzene (780 mg) in tetrahydrofuran (6 ml) was added sodium methoxide (240 mg) at 0° C. The mixture was stirred for 30 minutes. This solution was added to the above-mentioned clear solution. The mixture was stirred for 2 hours at -20°~30° C. The mixture was poured into water (300 ml), and then the mixture was neutralized with sodium bicarbonate and washed with ethyl acetate. After stirring, the aqueous layer was separated. The aqueous solution was adjusted to pH 2.5 with 1N hydrochloric acid. To this solution was added ethyl acetate (200 ml). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give a solid. The solid was triturated with diisopropyl ether to give 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[(Z)-2-phenylvinylthio]-3-cephem-4-carboxylic acid (syn isomer)(550 mg). to give a clear solution The mixture was stirred for 30 minutes This solution was added to the above-mentioned clear solution The mixture was stirred for 2 hours at -20°~30° C washed with ethyl acetate After stirring the aqueous layer was separated To this solution was added ethyl acetate (200 ml) The organic layer was separated dried over magnesium sulfate concentrated in vacuo to give a solid The solid was triturated with diisopropyl ether

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

Procedure: A mixture of benzhydryl 7-amino-3-[(Z)-2-(2-pyridyl)vinylthio]-3-cephem-4-carboxylate (600 ml) and bis(trimethylsilyl)urea (981 mg) in methylene chloride (6 ml) was stirred at 30°~35° C. for 30 minutes to give a clear solution. To the clear solution was added 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride monohydrochloride (syn isomer) (480 mg) at 20° C. and the mixture was stirred for 30 minutes at -10°~-15° C. The mixture was poured into a mixture of chloroform and water. The organic layer was separated and concentrated in vacuo to give a residue. The residue was dissolved in a mixture of tetrahydrofuran, ethyl acetate and dilute aqueous solution of sodium bicarbonate. The organic layer was separated, washed with dilute aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and concentrated in vacuo, and the residue was triturated with diisopropyl ether to give benzhydryl 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[(Z)-2-(2-pyridyl)vinylthio]-3-cephem-4-carboxylate (syn isomer) (848 mg). to give a clear solution the mixture was stirred for 30 minutes at -10°~-15° C The organic layer was separated concentrated in vacuo to give a residue The organic layer was separated washed with dilute aqueous solution of sodium bicarbonate a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate concentrated in vacuo the residue was triturated with diisopropyl ether

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

Procedure: To a solution of phosphorus pentachloride (455 mg) in methylene chloride (15 ml) was added 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-cyclopenten-1-yl)oxyiminoacetic acid (syn isomer) (557 mg) at -20° C. The mixture was stirred at -20~-10° C. for 30 minutes. The resultant mixture was added to a solution of benzhydryl 7-amino-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (1 g) and bis(trimethylsilyl)urea (2 g) in methylene chloride (20 ml) at -20° C. The mixture was stirred at -20~-10° C. for 30 minutes. The mixture was concentrated in vacuo and the residue was dissolved in a mixture of water (100 ml), sodium bicarbonate (920 mg), ethyl acetate and tetrahydrofuran. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate, concentrated in vacuo, and the residue was triturated with diethyl ether to give benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-cyclopenten-1-yl)oxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (syn isomer) (1.12 g). The mixture was stirred at -20~-10° C. for 30 minutes The mixture was concentrated in vacuo the residue was dissolved in a mixture of water (100 ml), sodium bicarbonate (920 mg), ethyl acetate and tetrahydrofuran The organic layer was separated washed with water a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate concentrated in vacuo the residue was triturated with diethyl ether

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

Procedure: To a solution of phosphorus pentachloride (455 mg) in methylene chloride (15 ml) was added 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-cyclopenten-1-yl)oxyiminoacetic acid (syn isomer) (557 mg) at -20° C. The mixture was stirred at -20~-10° C. for 30 minutes. The resultant mixture was added to a solution of benzhydryl 7-amino-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (1 g) and bis(trimethylsilyl)urea (2 g) in methylene chloride (20 ml) at -20° C. The mixture was stirred at -20~-10° C. for 30 minutes. The mixture was concentrated in vacuo and the residue was dissolved in a mixture of water (100 ml), sodium bicarbonate (920 mg), ethyl acetate and tetrahydrofuran. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate, concentrated in vacuo, and the residue was triturated with diethyl ether to give benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-cyclopenten-1-yl)oxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (syn isomer) (1.12 g). The mixture was stirred at -20~-10° C. for 30 minutes The mixture was concentrated in vacuo the residue was dissolved in a mixture of water (100 ml), sodium bicarbonate (920 mg), ethyl acetate and tetrahydrofuran The organic layer was separated washed with water a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate concentrated in vacuo the residue was triturated with diethyl ether

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

Procedure: To a solution of benzhydryl 7-amino-3-mesyloxy-3-cephem-4-carboxylate (6.91 g) and bis(trimethylsilyl)urea (18.4 g) in methylene chloride (69 ml) was added 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride hydrochloride (syn isomer) (4.08 g) at -10° C. under stirring and the mixture was stirred at the same temperature for 30 minutes. After the reaction mixture was added to a stirred mixture of water and methylene chloride, the solution was adjusted to pH 7.0 with a saturated aqueous solution of sodium bicarbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give benzhydryl 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-mesyloxy-3-cephem-4-carboxylate (syn isomer) (8.90 g). the mixture was stirred at the same temperature for 30 minutes The separated organic layer was washed with brine dried over magnesium sulfate evaporated in vacuo

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

Procedure: To a solution of benzhydryl 7-amino-3-mesyloxy-3-cephem-4-carboxylate (6.91 g) and bis(trimethylsilyl)urea (18.4 g) in methylene chloride (69 ml) was added 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride hydrochloride (syn isomer) (4.08 g) at -10° C. under stirring and the mixture was stirred at the same temperature for 30 minutes. After the reaction mixture was added to a stirred mixture of water and methylene chloride, the solution was adjusted to pH 7.0 with a saturated aqueous solution of sodium bicarbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give benzhydryl 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-mesyloxy-3-cephem-4-carboxylate (syn isomer) (8.90 g). the mixture was stirred at the same temperature for 30 minutes The separated organic layer was washed with brine dried over magnesium sulfate evaporated in vacuo

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

Procedure: To a solution of 4-methoxybenzyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (681 mg) in N-methylmorpholine (2 ml) was added 1,3-bis(trimethylsilyl)urea (1.02 g) and the mixture was stirred at room temperature for 30 minutes. To the solution was added potassium iodide (183 mg) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added di-tert-butyl {(Z)-[((1S)-1-{[(tert-butoxycarbonyl)amino]methyl}-2-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-2-oxoethyl)amino]methylylidene}biscarbamate (939 mg) and the whole mixture was stirred at 35° C. overnight. To the resulting reaction mixture was added ethyl acetate (1.7 L) and the mixture was washed successively with water, 10% aqueous sodium thiosulfate solution, 10% aqueous sodium trifluoroacetate solution and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to about 1 L in vacuo. The concentrate was poured into diisopropyl ether and the resulting precipitate was collected by filtration and dried in vacuo. To a solution of the solid in methylene chloride (3.6 ml) were added anisole (1.2 ml) and trifluoroacetic acid (3.6 ml). The resulting solution was stirred at room temperature for 4 hours and poured into diisopropyl ether. The resulting precipitate was collected by filtration and dried in vacuo to give a crude product. The crude product was purified by preparative HPLC utilizing ODS column. The eluate containing a desired product was concentrated to about 30 ml in vacuo. The concentrate was adjusted to about pH 3 by addition of concentrated hydrochloric acid and chromatographed on Diaion (registered trademark) HP-20 eluting with 30% aqueous 2-propanol. The eluate was concentrated to about 30 ml in vacuo and 1 equivalent of 0.1M aqueous sulfuric acid solution was added. The mixture was lyophilized to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(3-amino-4-{[(2S)-3-amino-2-(guanidino)propanoyl]amino}-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylic acid hydrogensulfate (115 mg) as an amorphous solid. the mixture was stirred at room temperature for 30 minutes the whole mixture was stirred at 35° C. overnight To the resulting reaction mixture the mixture was washed successively with water, 10% aqueous sodium thiosulfate solution, 10% aqueous sodium trifluoroacetate solution and brine dried over magnesium sulfate filtered The filtrate was concentrated to about 1 L in vacuo The concentrate was poured into diisopropyl ether the resulting precipitate was collected by filtration dried in vacuo To a solution of the solid in methylene chloride (3.6 ml) were added anisole (1.2 ml) and trifluoroacetic acid (3.6 ml) The resulting solution was stirred at room temperature for 4 hours poured into diisopropyl ether The resulting precipitate was collected by filtration dried in vacuo to give a crude product The crude product was purified by preparative HPLC The eluate containing a desired product was concentrated to about 30 ml in vacuo The concentrate was adjusted to about pH 3 by addition of concentrated hydrochloric acid chromatographed on Diaion (registered trademark) eluting with 30% aqueous 2-propanol was added

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

Procedure: 10 ml of hexamethyldisilazane (48 mmoles) were added to 2.4 g (40 mmoles) of urea and 73 mg (0.4 mmole) of saccharin in 15 ml of refluxing ethyl acetate and evolution of ammonia started immediately and was completed after refluxing for 20 minutes established by titration with 1 N HCl. The volatile material was evaporated under vacuum and the residue was vacuum dried to obtain 8.06 (99%) of N,N'-bis-(trimethylsilyl)-urea melting at 219°-222° C. Without the addition of saccharin as a catalyst, evolution of ammonia was slow and the reaction had to be carried out for at least 24 hours for completion. after refluxing for 20 minutes The volatile material was evaporated under vacuum dried