合成路线1

1) The protection of the amino group of 2-(2-aminothiazol-4-yl)-2(Z)-(hydroxyimino)acetic acid ethyl ester (I) with di-tert-butyl dicarbonate, dimethylaminopyridine and NaOH gives 2-[2-(tert-butoxycarbonylamino)thiazol-4-yl]-2(Z)-(hydroxyimino)acetic acid (II), which is then treated with triphenylmethyl chloride (Tr-Cl) and K2CO3 in DMF to afford 2-[2-(tert-butoxycarbonylamino)thiazol-4-yl]-2(Z)-(triphenylmethoxyimino)acetic acid (III). The condensation of (III) with 7beta-amino-3-(methanesulfonyloxy)-3-cephem-4-carboxylic acid diphenylmethyl ester (IV) by means of phenylphosphoryl dichloride and N-methylmorpholine gives the 7beta-acetamido derivative (V), which is then condensed with 4-(acetylsulfanylmethylsulfanyl)-1-(triphenylmethyl)-1,2,3-triazole (VI) by means of NaOMe in THF/DMF/methanol to yield the fully protected compound (IX). Finally, this compound is deprotected by a treatment with AlCl3 anisole. The triazole (VI) can be obtained by reaction of the sodium salt of 1,2,3-triazole-4-thiol (VII) with thioacetic acid S-(chloromethyl)ester (VIII) in DMS followed by NH-protection with triphenylmethyl chloride.

合成路线2

Conversion of alcohol (I) into chloro derivative (II) by reaction with PCl3 in DMF, followed by reaction with PCl5/pyridine in CH2Cl2, treatment with iBuOH and acidic treatment with TsOH, provides 7-amino-3-chlorocephalosporanic acid diphenylmethyl ester toluene sulfonic acid salt (III). Separately, O-protection of thiazole derivative (IV) by reaction with TrtCl and tert-BuOK in THF affords trityl protected compound (V), whose ethyl carboxylate group is hydrolyzed by means of KOH in EtOH to furnish carboxylic acid (VI). Chlorination of the thiazol ring of (VI) by means of N-chlorosuccinimide (NCS) in DMF yields chlorothiazole derivative (VII), which is then condensed with 7-amino-3-chlorocephalosporanic acid derivative (III) by means of POCl3 in THF to give acetamido derivative (VIII). Separately, the synthesis of pyridine derivative (XIV) is performed by following these steps: alkylation of chloropyridine (IX) by means of LDA and ethyl formate provides derivative (X), which is then reduced by means of NaBH4 to furnish alcohol (XI). Finally, (XIV) is obtained by first chlorination of (XI) with SOCl2 in DMF to afford chloromethyl derivative (XII), and subsequent condensation of (XII) with N-Boc-ethanethiol (XIII) either by means of Et3N in CH2Cl2 or by means of NaI and DIEA in DMF. Treatment of derivative (VIII) with NaSH in DMF, followed by coupling with chloropyridine derivative (XIV) in DMF, furnishes compound (XV), which is finally converted into the desired product by protecting groups removal with TFA/anisole or TFA/triethylsilane in CH2Cl2, and treatment with MsOH in H2O.

合成路线3

The reaction of ethyl acetoacetate (I) with NaNO2 in acetic acid-water gives ethyl 2-(hydroxyimino)-3-oxobutyrate (II), which is cyclized with thiourea (III) by means of SO2Cl2 in methylene chloride yielding ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate (IV). The treatment of (IV) with trityl chloride (V) and triethylamine in DMF affords ethyl 2-(hydroxyimino)-2-(2-tritylaminothiazol-4-yl)acetate (VI), which by condensation with tert-butyl 2-bromo-2-methylpropionate (VII) by means of K2CO3 in DMSO is converted into ethyl 2-(2-tert-butoxycarbonyl-2-propyloxymino)-2-(2-tritylaminothiazol-4-yl)acetate (VIII). The hydrolysis of (VIII) with NaOH in refluxing methanol gives 2-(2-tert-butoxycarbonyl-2-propyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (IX), which by condensation with tert-butyl 7-aminocephalosporanate (X) by means of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide in DMF yields tert-butyl 7-[2-(2-tert-butoxycarbonyl-2-propyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]cephalosporanate (XI). The hydrolysis of (XI) with trifluoroacetic acid in anisole affords 7-[2-(2-aminothiazol-4-yl)-2-(2-carboxy-2-propyloxyimino)acetamido]cephalosporanic acid (XII), which is finally treated with pyridine (A) and NaI.

合成路线4

Bicyclic enol compound (I) was phosphorylated by means of diphenyl phosphorochloridate and diisopropylethylamine, and the resulting enol phosphate was displaced with thioacetic acid yielding thioacetate ester (II). Cleavage of the phenylacetamido group of (II) to afford amine (III) was then effected by treatment with PCl5 and pyridine, followed by quenching with isobutyl alcohol. On the other side, thiazole (IV) was chlorinated with N-chlorosuccinimide to provide the 5-chlorothiazole (V). Protection of the amino group of (V) with di-tert-butyl dicarbonate, followed by ester hydrolysis gave (VI). The oximino group of (VI) was then protected as the O-trityl derivative (VII) by treatment with triphenylmethyl chloride. Coupling of carboxylic acid (VII) with amine (III) employing POCl3 and pyridine provided amide (VIII). Optionally, hydrolysis of the thioacetate ester using morpholine and pyridine, followed by S-alkylation with chloroiodomethane furnished the chloromethylsulfanyl derivative (IX).

合成路线5

The title compound was obtained by solid-phase peptide synthesis using a methylbenzhydrylamine resin. After attachment of N-Boc-D-alanine (I) to the resin by means of diisopropylcarbodiimide (DIC), the N-Boc protecting group was cleaved by treatment with a solution of trifluoroacetic in CH2Cl2 in the presence of 1,2-ethanedithiol, yielding the alanine-bound resin (II). To this were sequentially coupled the appropriate protected amino acids using DIC, each followed by the Boc group cleavage with trifluoroacetic acid. Coupling/deprotection cycles with N-Boc-L-proline (III), N-alpha-Boc-N-epsilon-benzyloxycarbonyl-N-epsilon-isopropyl-L-lysine (V), N-Boc-L-leucine (VII), N-alpha-Boc-N-4-Fmoc-L-4-aminophenylalanine (IX), N-alpha-Boc-N-4-Fmoc-D-4-aminophenylalanine (XI) and N-Boc-O-benzyl-L-serine (XIII), furnished the peptide resins (IV), (VI), (VIII), (X), (XII) and (XIV).

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