Methoxy-3-cephem-4-carboxylic acid 94 ---acetate

To a solution of 37.4 g of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid l-(isopropoxycarbonyloxy)ethyl ester in 689 ml ethyl acetate at 2-3°C is added for 25 min 0.105 moles Z-(2-formamidothiazol-4-yl)-methoxy-acetyl chloride hydrochloride. After 25 min pH is adjusted to ca. 6.5-7.3. After 1 hour the organic layer is washed with water and concentrated. It was obtained a crude 5-thia-l-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-(((2Z)-(2-amino-4-thiazolyl)(methoxyimino)acetyl)amino)-3-(methoxymethyl)-8-oxo-, l-(((l-methylethoxy)carbonyl)oxy)ethyl ester, (6R,7R)- (Cefpodoxime proxetil). Diastereoisomeric ratio 0.49. 

To a solution of 7p(a-p-hydroxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(l-methyl-tetrazol-5-yl)thiomethyll-oxadethia-3-cephem-4-carboxylic acid (359 mg) in methanol (7 ml) is added a solution of sodium 2-ethylhexanoate in methanol (2 mols/liter 1.73 ml) at room temperature. After stirring for 10 minutes, the reaction mixture is diluted with ethyl acetate, stirred for 5 minutes, and filtered to collect separated solid, which is washed with ethyl acetate, and dried to give disodium salt of 7P(a-p-hydroxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(l-methyl-tetrazol-5-yl)thiomethyll-oxadethia-3-cephem-4-carboxylic acid (342 mg). Yield 888%. Colorless powder. MP decomposition from 170°C. 

For example, treatment of imino chloride 144 derived from 7p-(2-phenyl-2-bromo) acetamido-3-methyl 3-cephem benzhydryl ester (143) and phosphorus pentachloride, with an excess of methanolic lithium methoxide in THF at -78°C for 20 min, followed by quenching with acetic acid, afforded 7 -phenylketenimino-7a-methoxy- -lactam (146) in 60% yield. This material was reasonably stable to silica gel chromatography and, when treated with trifluoroacetic acid followed by aqueous quenching, quantitatively afforded 7p-phenylacetamido-7a-methoxy-3-methyl-3-cephem-4-carboxylic acid. Similar treatment of imino chlorides (144) or ketenimines (146) with lithium methoxide at -20 C provided iminoethers (147) in good yield. In the case of the imino chloride formed from 7p-dichloroacetamido-7-deacetoxycephalosporanic acid methyl ester, the corresponding iminoether (147) was obtained in 80% yield with lithium methoxide, even at — 78°C. The same imino chloride reacted... 

To a stirred suspension of p-(p-methoxybenzyloxy)-phenylmalonic acid (125 mg) in methylene chloride (3 ml) are added triethylamine (55 I) and oxalyl chloride (26 I) at -15°C, and the suspension is stirred for 40 minutes at 0°C. The mixture is added to a solution of diphenylmethyl 7p-amino-7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (100 mg) in methylene chloride (3 ml) and pyridine (63 I), and the mixture is stirred for 30 minutes at 0°C. The reaction mixture is diluted with ethyl acetate, washed with aqueous 2N-hydrochloric acid and water, dried over sodium sulfate, and concentrated to give crude product (212 mg), which is chromatographed on silica gel (20 g) and eluted with a mixture of ethyl acetate and acetic acid (99 1) to give diphenylmethyl-7p-[a-p-(p-methoxybenzyloxy)phenyl-a-carboxyacetamido]-7a-methoxy-3-(l-methyltetrazol-5yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate as foam (71 mg). Yield 45%. 

---