iodomethyl acetate

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The sodium salt of 2-carboxy-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (5.08 g.) is dissolved in dimethylformamide (100 cc.) at 5° C. A solution of iodomethyl acetate (2 g.) in dimethylformamide (10 cc.) is added to this solution and the reaction mixture is stirred for 10 minutes at 5° C. It is then poured into water (500 cc.) and extracted twice with ethyl acetate (200 cc.). The combined organic phases are washed with water (100 cc.), saturated sodium bicarbonate solution (100 cc.), a 5% sodium bisulphite solution (100 cc.) and a saturated sodium chloride solution (100 cc.). The organic phase is dried over magnesium sulphate, filtered in the presence of decolourising charcoal and concentrated to dryness under reduced pressure (15 mm Hg). This gives a white product (5 g.) which is recrystallised from acetonitrile (50 cc.). 2-Acetoxymethoxycarbonyl-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (3 g.) is thus obtained as white crystals m.p. 154° C. extracted twice with ethyl acetate (200 cc.) The combined organic phases are washed with water (100 cc.), saturated sodium bicarbonate solution (100 cc.) The organic phase is dried over magnesium sulphate filtered in the presence of decolourising charcoal concentrated to dryness under reduced pressure (15 mm Hg) This gives a white product (5 g.) which is recrystallised from acetonitrile (50 cc.)

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The sodium salt of 2-carboxy-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (5.08 g.) is dissolved in dimethylformamide (100 cc.) at 5° C. A solution of iodomethyl acetate (2 g.) in dimethylformamide (10 cc.) is added to this solution and the reaction mixture is stirred for 10 minutes at 5° C. It is then poured into water (500 cc.) and extracted twice with ethyl acetate (200 cc.). The combined organic phases are washed with water (100 cc.), saturated sodium bicarbonate solution (100 cc.), a 5% sodium bisulphite solution (100 cc.) and a saturated sodium chloride solution (100 cc.). The organic phase is dried over magnesium sulphate, filtered in the presence of decolourising charcoal and concentrated to dryness under reduced pressure (15 mm Hg). This gives a white product (5 g.) which is recrystallised from acetonitrile (50 cc.). 2-Acetoxymethoxycarbonyl-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (3 g.) is thus obtained as white crystals m.p. 154° C. extracted twice with ethyl acetate (200 cc.) The combined organic phases are washed with water (100 cc.), saturated sodium bicarbonate solution (100 cc.) The organic phase is dried over magnesium sulphate filtered in the presence of decolourising charcoal concentrated to dryness under reduced pressure (15 mm Hg) This gives a white product (5 g.) which is recrystallised from acetonitrile (50 cc.)

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-vinyl-3-cephem-4-carboxylate (syn isomer) (2.2 g) in N,N-dimethylformamide (25 ml) was added dropwise a solution of iodomethyl acetate (1 g) in N,N-dimethylformamide (3 ml) below 5° C. in the course of 2 minutes, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into a mixture of water (100 ml) and ethyl acetate (50 ml), and the separated aqueous solution was extracted with ethyl acetate (30 ml). The combined ethyl acetate solution was washed twice with 5% aqueous sodium bicarbonate and twice with an aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diisopropyl ether and collected by filtration to obtain acetoxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.6 g), mp 78°-83° C. the separated aqueous solution was extracted with ethyl acetate (30 ml) The combined ethyl acetate solution was washed twice with 5% aqueous sodium bicarbonate and twice with an aqueous sodium chloride dried over anhydrous magnesium sulfate Removal of the solvent gave a residue, which collected by filtration

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

Procedure: 20 g (185 mmol) of chloromethyl acetate is dissolved in acetone, to which 35 g (230 mmol) of sodium iodide is added. After stirring for 24 hours, 14.8 g (138 mmol) of salicylaldehyde and 38.20 g (276 mmol) of potassium carbonate are dissolved in 100 mL of acetone. The mixture is stirred at room temperature and freshly prepared suspension of iodomethyl acetate is added. After stirring for 24 hours at 50° C., water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and then concentrated. The residue is purified by silica gel chromatography and eluted with a heptane/ethyl acetate mixture, 7/3. 21.79 g of 2-acetoxymethoxy-benzaldehyde is obtained in the form of a yellow oil at a yield of 98%. is added The mixture is stirred at room temperature is added After stirring for 24 hours at 50° C. the mixture is extracted with ethyl acetate The organic phase is dried over magnesium sulphate filtered concentrated The residue is purified by silica gel chromatography eluted with a heptane/ethyl acetate mixture, 7/3

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-vinyl-3-cephem-4-carboxylate (syn isomer)(2.2 g) in N,N-dimethylformamide (25 ml) was added dropwise a solution of iodomethyl acetate (1 g) in N,N-dimethylformamide (3 ml) below 5° C. in the course of 2 minutes, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into a mixture of water (100 ml) and ethyl acetate (50 ml), and the separated aqueous solution was extracted with ethyl acetate (30 ml). The combined ethyl acetate solution was washed twice with 5% aqueous sodium bicarbonate and twice with an aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diisopropyl ether and collected by filtration to obtain acetoxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer)(1.6 g), mp 78°-83° C. the separated aqueous solution was extracted with ethyl acetate (30 ml) The combined ethyl acetate solution was washed twice with 5% aqueous sodium bicarbonate and twice with an aqueous sodium chloride dried over anhydrous magnesium sulfate Removal of the solvent gave a residue, which collected by filtration

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

Procedure: A mixture of 141 mg of chloromethyl acetate, 225 mg of sodium iodide and 4 ml of acetone was refluxed for 40 minutes and was cooled to obtain a suspension of iodomethyl acetate. Using the procedure of Step B of Example 6, 739 mg of 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid and the said suspension were reacted to obtain 698 mg of the syn isomer of acetoxymethyl 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxyethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate. was refluxed for 40 minutes was cooled to obtain the said suspension were reacted

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

Procedure: A portion of this iodomethyl acetate (661 mg, 3.31 mmol) was added to a suspension of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200.1 mg, 0.325 mmol) and cesium carbonate (964.4 mg, 2.93 mmol) in dimethylformamide (8 mL) and the reaction was stirred in the dark overnight. It was then taken up in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography (hexane/ethyl acetate, 80/20 to 10/90) to give chiral-4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid acetoxymethyl ester as a white solid (42.8 mg, 19% yield). MS (ES+) m/z calcd. for C34H34Cl2F2N3O6: [(M+H)+]: 688, found: 688 washed with water and brine dried over anhydrous sodium sulfate concentrated The crude product was purified by flash chromatography (hexane/ethyl acetate, 80/20 to 10/90)

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

Procedure: A portion of this iodomethyl acetate (661 mg, 3.31 mmol) was added to a suspension of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200.1 mg, 0.325 mmol) and cesium carbonate (964.4 mg, 2.93 mmol) in dimethylformamide (8 mL) and the reaction was stirred in the dark overnight. It was then taken up in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography (hexane/ethyl acetate, 80/20 to 10/90) to give chiral-4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid acetoxymethyl ester as a white solid (42.8 mg, 19% yield). MS (ES+) m/z calcd. for C34H34Cl2F2N3O6: [(M+H)+]: 688, found: 688 washed with water and brine dried over anhydrous sodium sulfate concentrated The crude product was purified by flash chromatography (hexane/ethyl acetate, 80/20 to 10/90)

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

Procedure: (6R,7R)-3-Acetoxymethyl-7-[Z-2-methoxycarbamoylmethoxyimino-2-(fur-2-yl)acetamido]-ceph-3-em-4-carboxylic acid (992 mg) was dissolved in dry N,N-dimethylformamide (8 ml). Dried potassium carbonate (138 mg) was added and the mixture was stirred at 0°. Iodomethyl acetate (1.1 g) in a little dimethylformamide was added, stirring was continued at 0° for 1 hr, and the mixture was poured into hydrochloric acid (N, 50 ml) and extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were washed with N-hydrochloric acid (2×50 ml), water (100 ml) and saturated sodium hydrogen carbonate solution (2×30 ml), dried (Na2SO4) and evaporated. The residue in a little ethyl acetate was added dropwise to well-stirred light petroleum (b.p. 40°-60°), when the ester separated as an off-white powder, 513 mg, λmax (EtOH) 277.5 nm, νmax (Nujol) 3240 (--NH), 1786 (β-lactam), 1765, 1742 (acetate+--CO2CH2OCOCH3), 1680, 1540 cm-1 (--CONH--), τ(DMSOd6) 6.25 (--OCH3, 2--CH2 --), 5.38 (--O--CH2 --CO--), 2.01, 3.11, 3.22 (fur-2-yl), 0.18 (--CONH--), 4.05 (7H), 4.69 (6H), 4.99, 5.25 (3--CH2 --), 7.86, 7.96 (--COCH3), 4.09 (--OCH2O--). stirring extracted with ethyl acetate (3×50 ml) The ethyl acetate extracts were washed with N-hydrochloric acid (2×50 ml), water (100 ml) and saturated sodium hydrogen carbonate solution (2×30 ml) dried (Na2SO4) evaporated The residue in a little ethyl acetate was added dropwise to well-stirred light petroleum (b.p. 40°-60°), when the ester separated as an off-white powder, 513 mg, λmax (EtOH) 277.5 nm, νmax (Nujol) 3240 (--NH), 1786 (β-lactam), 1765, 1742 (acetate+--CO2CH2OCOCH3), 1680, 1540 cm-1 (--CONH--), τ(DMSOd6) 6.25 (--OCH3, 2--CH2 --), 5.38 (--O--CH2 --CO--), 2.01, 3.11, 3.22 (fur-2-yl), 0.18 (--CONH--), 4.05 (7H), 4.69 (6H), 4.99, 5.25 (3--CH2 --), 7.86, 7.96 (--COCH3), 4.09 (--OCH2O--)

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-vinyl-3-cephem-4-carboxylate (syn isomer) (2.2 g) in N,N-dimethylformamide (25 ml) was added dropwise a solution of iodomethyl acetate (1 g) in N,N-dimethylformamide (3 ml) below 5° C. in the course of 2 minutes, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into a mixture of water (100 ml) and ethyl acetate (50 ml), and the separated aqueous solution was extracted with ethyl acetate (30 ml). The combined ethyl acetate solution was washed twice with 5% aqueous sodium bicarbonate and twice with an aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diisopropyl ether and collected by filtration to obtain acetoxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.6 g), mp 78°-83° C. the separated aqueous solution was extracted with ethyl acetate (30 ml) The combined ethyl acetate solution was washed twice with 5% aqueous sodium bicarbonate and twice with an aqueous sodium chloride dried over anhydrous magnesium sulfate Removal of the solvent gave a residue, which collected by filtration

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-vinyl-3-cephem-4-carboxylate (syn isomer) (2.2 g) in N,N-dimethylformamide (25 ml) was added dropwise a solution of iodomethyl acetate (1 g) in N,N-dimethylformamide (3 ml) below 5° C. in the course of 2 minutes, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into a mixture of water (100 ml) and ethyl acetate (50 ml), and the separated aqueous solution was extracted with ethyl acetate (30 ml). The combined ethyl acetate solution was washed twice with 5% aqueous sodium bicarbonate and twice with an aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diisopropyl ether and collected by filtration to obtain acetoxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.6 g), mp 78°-83° C. the separated aqueous solution was extracted with ethyl acetate (30 ml) The combined ethyl acetate solution was washed twice with 5% aqueous sodium bicarbonate and twice with an aqueous sodium chloride dried over anhydrous magnesium sulfate Removal of the solvent gave a residue, which collected by filtration

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

Procedure: (1R, 5S, 6S)-2-[(4R)-N-methylpyrrolidine-2-thion-4ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid sodium salt (400 mg) is suspended in N,N-dimethylformamide (5 ml), and thereto is added potassium carbonate (146 mg). To the mixture is added acetoxymethyl iodide (275 mg) at 5°-7° C., and the mixture is stirred at the same temperature for one hour. The reaction mixture is poured into phosphate buffer (pH 7.0) and extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness under reduced pressure. The residue is purified by silica gel column chromatography (eluent, chloroform - chloroform:ethanol=98:2), followed by crystallization from tetrahydrofuran and diethyl ether to give (1R, 5S, 6S)-2-[(4R)-N-methylpyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid acetoxymethyl ester (250 mg) as colorless needles. extracted with ethyl acetate The organic layer is washed with water dried concentrated to dryness under reduced pressure The residue is purified by silica gel column chromatography (eluent, chloroform - chloroform:ethanol=98:2) followed by crystallization from tetrahydrofuran and diethyl ether