1) The methanolysis of 3-(acetoxymethyl)-7-[4-chloro-3-oxo-2(Z)-(methoxyimino)butyrylamidol-3-cephem-4-carboxylic acid (I) with methanol and NaHCO3 gives the corresponding 3-(methoxymethyl) derivative (II), which is esterified with 1-iodoethylisopropyl carbonate (III) by means of dicyclohexylamine or tetramethylguanidine or DIEA (diisopropylethylamine) in DMA to afford the corresponding ester (IV). Finally, this compound is cyclized with thiourea (V) and methyl iodide in a phosphate buffer.

2) The free acid (II) can be cyclized with thiourea in a similar way as before to give 7-[2 (2-amino-thiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-cephem 4-carboxylic acid (VI), which is finally esterified with the iodoester (III) as before.

3) The iodoester (III) is obtained as follows: The chlorination of ethyl chloroformate (VII) with SO2Cl2 and benzoyl peroxide gives 1-chloroethyl-chloroformate (VIII), which is esterified with o-propanol in pyridine to afford 1-chloroethyl isopropyl carbonate (IX). Finally, this compound is iodinated with NaI and 18-crown-6 in refluxing benzene.

A new process for the preparation of cefpodoxime, which can be converted into cefpodoxime proxetil by known methods, has been described: The condensation of 2-(2-aminothiazol-4-yl)-2(Z)-(methoxyimino)acetic acid 2-benzothiazolyl ester (I) with (6R,7R)-7-amino-3-(methoxymethyl)-3-cephem-4-carboxylic acid (II) by means of an organic base such as Et3N, pyridine, N-methylpiperidine, DBU or DMAP in either THF/water, acetone/water, DMF/water, dimethylacetamide or dichloromethane directly gives cefpodoxime (III).

The condensation of 7-amino-3-(methoxymethyl)-3-cephem-4-carboxylic acid (I) with 4-bromo-2-(methoxyimino)-3-oxobutyric acid (II) by means of PCl5 and HMDS in dichloromethane gives the butyramide (III), which is cyclized with thiourea (IV) by means of Na-OAc in water to yield the thiazol derivative (IV). Finally, the carboxy group of (IV) is esterified with 1-iodoethyl isopropyl carbonate (VI) by means of DBU in DMA to afford the target cefpodoxime proxetil.

1) The methanolysis of 3-(acetoxymethyl)-7-[4-chloro-3-oxo-2(Z)-(methoxyimino)butyrylamidol-3-cephem-4-carboxylic acid (I) with methanol and NaHCO3 gives the corresponding 3-(methoxymethyl) derivative (II), which is esterified with 1-iodoethylisopropyl carbonate (III) by means of dicyclohexylamine or tetramethylguanidine or DIEA (diisopropylethylamine) in DMA to afford the corresponding ester (IV). Finally, this compound is cyclized with thiourea (V) and methyl iodide in a phosphate buffer.

2) The free acid (II) can be cyclized with thiourea in a similar way as before to give 7-[2 (2-amino-thiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-cephem 4-carboxylic acid (VI), which is finally esterified with the iodoester (III) as before.

3) The iodoester (III) is obtained as follows: The chlorination of ethyl chloroformate (VII) with SO2Cl2 and benzoyl peroxide gives 1-chloroethyl-chloroformate (VIII), which is esterified with o-propanol in pyridine to afford 1-chloroethyl isopropyl carbonate (IX). Finally, this compound is iodinated with NaI and 18-crown-6 in refluxing benzene.

1) The methanolysis of 3-(acetoxymethyl)-7-[4-chloro-3-oxo-2(Z)-(methoxyimino)butyrylamidol-3-cephem-4-carboxylic acid (I) with methanol and NaHCO3 gives the corresponding 3-(methoxymethyl) derivative (II), which is esterified with 1-iodoethylisopropyl carbonate (III) by means of dicyclohexylamine or tetramethylguanidine or DIEA (diisopropylethylamine) in DMA to afford the corresponding ester (IV). Finally, this compound is cyclized with thiourea (V) and methyl iodide in a phosphate buffer.

The condensation of 7-amino-3-(methoxymethyl)-3-cephem-4-carboxylic acid (I) with 4-bromo-2-(methoxyimino)-3-oxobutyric acid (II) by means of PCl5 and HMDS in dichloromethane gives the butyramide (III), which is cyclized with thiourea (IV) by means of Na-OAc in water to yield the thiazol derivative (IV). Finally, the carboxy group of (IV) is esterified with 1-iodoethyl isopropyl carbonate (VI) by means of DBU in DMA to afford the target cefpodoxime proxetil.

1) The methanolysis of 3-(acetoxymethyl)-7-[4-chloro-3-oxo-2(Z)-(methoxyimino)butyrylamidol-3-cephem-4-carboxylic acid (I) with methanol and NaHCO3 gives the corresponding 3-(methoxymethyl) derivative (II), which is esterified with 1-iodoethylisopropyl carbonate (III) by means of dicyclohexylamine or tetramethylguanidine or DIEA (diisopropylethylamine) in DMA to afford the corresponding ester (IV). Finally, this compound is cyclized with thiourea (V) and methyl iodide in a phosphate buffer.

2) The free acid (II) can be cyclized with thiourea in a similar way as before to give 7-[2 (2-amino-thiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-cephem 4-carboxylic acid (VI), which is finally esterified with the iodoester (III) as before.

3) The iodoester (III) is obtained as follows: The chlorination of ethyl chloroformate (VII) with SO2Cl2 and benzoyl peroxide gives 1-chloroethyl-chloroformate (VIII), which is esterified with o-propanol in pyridine to afford 1-chloroethyl isopropyl carbonate (IX). Finally, this compound is iodinated with NaI and 18-crown-6 in refluxing benzene.