2,4,5,6-tetrafluorobenzene-1,3-diamine;dihydrochloride

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

Procedure: N-((3S)-6-oxo(3-piperidyl))(tert-butoxy)carboxamide (3.9 mmol, 0.83 g) were dissolved in ethanol (10 mL) and cooled to 0° C. Acetyl chloride (2 mL) was added and the reaction was allowed to reach room temperature. The reaction was stirred for 1 hour after which the solvent was removed in vacuo to yield the title compound (725 mg, 99% yield) as the dihydrochloride salt. ES-MS: 115 (M+1). to reach room temperature was removed in vacuo

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

Procedure: 1.81 g of oxalyl chloride are added at 5° to 0° C. to 45 ml of chloroform containing 1.15 ml of dimethylformamide, and the mixture is stirred at the same temperature for 15 minutes. A solution of 4.90 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]acetic acid and 0.97 g of triethylamine in 45 ml of chloroform is added to said mixture at -30° C. The mixture is stirred at the same temperature for 5 minutes. Then, a solution of (6R, 7R)-7-amino-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate in chloroform (said solution is prepared by suspending 5.8 g of the dihydrochloride of said cephem compound in 45 ml of chloroform and adding 12.7 ml of N,O-bis(trimethylsilyl)acetamide thereto to dissolve said salt therein) is added to the mixture at -30° to -10° C. After the mixture is stirred at the same temperature for 30 minutes, said mixture is concentrated to dryness under reduced pressure. 100 ml of 80% aqueous formic acid are added to the residue, and the aqueous mixture is stirred at room temperature for one hours. 110 ml of water are added to the mixture, and insoluble materials are filtered off. The filtrate is washed with ethyl acetate and is concentrated to dryness under reduced pressure. The residue thus obtained is dissolved in water and chromatographed on a column of non-ionic polymer resin Diaion HP-20 (resistered trade mark, manufactured by Mitsubish Chemical Industries Ltd., Japan). The column is washed with water, followed by elution with 20% aqueous methanol. The franctions containing the cephalosporin compound are collected and concentrated to dryness under reduced pressure. Acetone is added to the residue, and the resulting powder is collected by filtration. 2.22 g of (6R, 7R)-7-{(Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]acetamido}-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate are obtained. at -30° C The mixture is stirred at the same temperature for 5 minutes is prepared to dissolve ) is added to the mixture at -30° to -10° C After the mixture is stirred at the same temperature for 30 minutes is concentrated to dryness under reduced pressure 100 ml of 80% aqueous formic acid are added to the residue the aqueous mixture is stirred at room temperature for one hours 110 ml of water are added to the mixture, and insoluble materials are filtered off The filtrate is washed with ethyl acetate is concentrated to dryness under reduced pressure The residue thus obtained chromatographed on a column of non-ionic polymer resin Diaion The column is washed with water followed by elution with 20% aqueous methanol The franctions containing the cephalosporin compound are collected concentrated to dryness under reduced pressure Acetone is added to the residue the resulting powder is collected by filtration

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

Procedure: 4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 4-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder. condensed by the same manner

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

Procedure: 4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder. condensed by the same manner

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

Procedure: 4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 4-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave yellow powder of the title compound. condensed by the same manner

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

Procedure: 4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder. condensed by the same manner

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

Procedure: 4-(p-Anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (139 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder. condensed by the same manner

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

Procedure: A mixture of tert-butyl 4-(5-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)pyridin-2-yl)piperazine-1-carboxylate (0.227 g, 0.47 mmol) in DCM (3 mL) and 4N HCl in dioxane (2 mL, 8.0 mmol) was stirred at room temperature for 48 hours. The solvent was removed in vacuo to give 2-(2,6-difluorophenyl)-5-(6-(piperazin-1-yl)pyridin-3-yl)oxazole-4-carboxamide (0.211 g, 0.46 mmol, 98%) as a white solid as the dihydrochloride salt. 1H NMR (DMSO) 3.20 (4H, m), 3.90 (4H, t), 7.11 (1H, d), 7.39 (2H, t), 7.73 (3H, m), 8.44 (1H, dd), 9.0 (1H, d), 9.24 (1H, br. s), 9.30 (1H, br. s). LCMS (2) Rt: 2.38 min; m/z (ES+) 386. The solvent was removed in vacuo

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

Procedure: Prepared according to the procedure described in Example 5, Step 5, using the following starting materials: [3-(3-ethylaminomethyl-quinolin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester; dihydrochloride and methoxyacetyl chloride. Prepared

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

Procedure: Prepared according to the procedure described in Example 5, Step 5, using the following starting materials: [3-(3-ethylaminomethyl-quinolin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester; dihydrochloride and acetic anhydride. Prepared

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

Procedure: This example illustrates methods according to the invention of preparing the dialkyl substituted phenyl compounds of the invention. In this example, 50 ml. of isopropanol and 1.8 g. of sodium methoxide is added to a solution contraining 4.2 g. of the dihydrochloride salt of β-methylamino-β-(2,3-dimethylphenyl)-ethylamine dissolved in 10 ml. of water. The mixture is stirred for 15 minutes and then a solution containing 3.4 g. of a mixture of 1-mono and 1,3-bis(methoxycarbonyl)-S-methylisothiourea in 50 ml. of chloroform is added and then stirred for about two weeks at room temperature. The mixture is then concentrated by evaporation to near dryness and swirled with water, collected, and stirred in 50 ml. of aqueous 1 Normal hydrochloric acid for one hour. The resulting mixture is washed with ethyl ether, then treated with aqueous sodium bicarbonate and filtered. The collected solid is then stirred with distilled water, refiltered and washed in this manner three more times, then dried overnight at room temperature affording a crude product which is then puriified by recrystallization from isopropanol affording 1-methyl-4,5-dihydro-5-(2,3-dimethylphenyl)-2-methoxycarbonylaminoimidazole. a solution containing 3.4 g stirred for about two weeks at room temperature The mixture is then concentrated by evaporation collected stirred in 50 ml of aqueous 1 Normal hydrochloric acid for one hour The resulting mixture is washed with ethyl ether treated with aqueous sodium bicarbonate filtered The collected solid is then stirred with distilled water washed in this manner three more times dried overnight at room temperature affording a crude product which is then puriified by recrystallization from isopropanol

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

Procedure: This example illustrates methods according to the invention of preparing the methylenedioxy substituted phenyl compounds of the invention. In this example 9.0 g. of the dihydrochloride salt of β-methylamino-β-(3,4-methylenedioxyphenyl)-ethylamine is dissolved in 40 ml. of water. This solution is stirred and added successively to it is 150 ml. of isopropanol, 4.1 g. of sodium methoxide and finally 8 g. of a mixture of 1-mono and 1,3-bis(methoxycarbonyl)-S-methylisothiourea in 100 ml. of chloroform. The mixture is then stirred for 12 days at room temperature. It is then concentrated under vacuum affording a gummy residue which is then incompletely dissolved in 100 ml. of approximately 1N aqueous hydrochloric acid. The resulting mixture is first filtered and then washed with ethyl ether, heated with charcoal and filtered again. The crude product is then precipitated from the filtrate by addition of aqueous sodium bicarbonate. The precipitate is collected by filtration, stirred with distilled water, collected again and then dried under vacuum affording crude of 1-methyl-4,5-dihydro-5-(3,4-methylenedioxyphenyl)-2-methoxycarbonylaminoimidazole which is recrystallized from isopropanol yielding the purified product. A hydrogen-ion addition salt may be prepared according to the methods set forth in part A of Examples 1-3. added successively to it The mixture is then stirred for 12 days at room temperature It is then concentrated under vacuum affording a gummy residue which is then incompletely dissolved in 100 ml The resulting mixture is first filtered washed with ethyl ether heated with charcoal filtered again The crude product is then precipitated from the filtrate by addition of aqueous sodium bicarbonate The precipitate is collected by filtration stirred with distilled water collected again dried under vacuum