合成路线1

The reaction of 7-(5-amino-5-carboxypentanamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid (I), first with benzoyl chloride in acetone-water, and then with diphenyldiazomethane, gives benzhydryl 7-[5-benzamido-5-(benzhydryloxycarbonyl)pentanamido]-3-hydroxymethyl-3-cephem-4-carboxylate (II), which by reaction with PCl5 is converted into the corresponding chloromethyl derivative (III). The reaction of (III) with triphenyl phosphine and NaI in DMF yields the phosphonium iodide (IV), which by a Wittig condensation with formaldehyde in methylene chloride affords benzhydryl-7-[5-benzamido-5-(benzhydryloxycarbonyl)pentanamido]-3-vinyl-3-cephem-4-carboxylate (V). The cleavage of (V) with PCl-pyridine in methylene chloride gives benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate (VI), which is condensed with 2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (VII) [prepared from 2-formamidothiazol-4-yl)oxoacetic acid (VIII) and tert-butyl aminooxyacetate (IX)] yielding benzhydryl 7-[2-tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido-3-vinyl-3-cephem-4-carboxylate (X). The hydrolysis of (X) with HCl in methanol affords the 2-amino derivative (XI), which is finally fully deprotected by treatment with trifluoroacetic acid in anisole.

合成路线2

The condensation of 2-(tert-butoxycarbonylmethoxyimino)-2-(4 thiazolyl)acetic acid (I) with 7-amino 3-cephem-4-carboxylic acid (II) by means of the Vusmejer reagent (POCl3 and dimethylformamide) in ethyl acetate gives 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (III), which is then de protected with trifluoroacetic acid and anisole in methylene chloride. The starting acetic acid derivative (I) can be obtained by several different ways: 1) The partial hydrolysis of 2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4yl) acetic acid (IV) with concentrated HCl in methanol gives 2-(tert-butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetic acid (V), which is then deaminated with tert butyl nitrite in refluxing THF. 2) The preceding deamination of (IV) can be performed in a similar way with previous esterification with diphenyldiazomethane, through compounds (VI), (VII) and (VIII). Compound (VIII) is submitted to a partial hydrolysis with trifluoroacetic acid. 3) Compound (I) can also be obtained by condensation of 2-(4-thiazolylglyoxylic acid (IX) with tert-butyl-2-(aminooxy)acetate (X) by means of NaHCO3 in ethyl acetate.

合成路线3