合成路线1

The protection of the amino group of ethyl 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetate (I) with trityl chloride (B) by means of triethylamine in CH2Cl2 gives ethyl 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino acetate (II), which is hydrolyzed to the corresponding acid (III) with NaOH in refluxing dioxane-water. The condensation of (III) with 7-aminocephalosporanic acid (IV) by means of dicyclohexylcarbodiimide in CH2Cl2 containing triethylamine affords 7-(2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetamido]cephalosporanic acid (V). The elimination of the trityl group is performed with hot 55% formic acid yielding the corresponding free acid, which is finally treated with NaHCO3 in water.

合成路线2

The hydrolysis of p-methoxybenzyl-7-aminocephalosporanate (XIV) with trifluoroacetic acid gives the corresponding tree acid (XXII), which is treated with tert-butoxycarbonylazide (F) yielding the tert-butoxycarbonylamidocephalosporanic acid (XXIII). This compound is deacetylated by treatment with citrus acetyl sterase in an aqueous phosphate buffer affording the 3-hydroxymethyl derivative (XXIV), which by reaction with chlorosulfonyl isocyanate gives the 3-carbamoyloxymethyl compound (XXV). The hydrolysis of (XXV) with TFA yields 3-carbamoyloxymethyl-7beta-amino-3-cephem-4-carboxylic acid (XXVI), which is esterified with diphenyldiazomethane in dioxane affording the benzhydryl ester (XXVII). The acylation of (XXVII) with 2-thienylcarbonyl chloride (E) in CH2Cl2 gives the acylated ester (XXVIII), which by methoxylation of (XXVIII) can also be performed through hydroxylation with phenyllithium and tert-butyl hypochlorite (G) in tert-butanol to the 7-hydroxy compound (XXXII), which is then methylated with diazomethane to (XXX). Finally, this compound is hydrolyzed with trifluoroacetic acid.

合成路线3

The acylation and methoxylation of 7-aminocephalosporanic acid (XXII) to (XX) can also be performed as follows: The acid (XXII) is esterified with diphenyldiazomethane in dioxane giving the ester (XXXVI), which is treated with NaNO2 and p-toluenesulfonic acid in CH2Cl2 yielding benzhydryl 7-diazocephalosporanate (XXXVII). The reaction of this compound with BrN3 in CH2Cl2-acetonitrile affords benzhydryl 7alpha-bromo-7beta-azidocephalosporanate (XXXVIII), which by hydrolysis with MeOH and AgBF4 is converted into the corresponding 7beta-methoxy compound (XXXIX). Hydrogenation of the azido group of (XXXIX) with H2 over PtO2 in dioxane gives 7alpha-methoxy-7beta-aminocephalosporanate (XL), which is acylated with 2-thienylcarbonyl chloride (E) in CH2Cl2 affording benzhydryl-7alpha-methoxy-7beta-(2-thienylacetamido)cephalosporanate (XLI). Finally, this compound is hydrolyzed to (XX) with trifluoroacetic acid.

合成路线4

The protection of 7-aminocephalosporanic acid (I) with di-tert-butyl dicarbonate gives 7-(tert-butoxycarbonylamino)cephalosporanic acid (II), which is condensed with 2,3-cyclopentenopyridine (III) by means of KI and NaHCO3 in hot water affording 7-(tert-butoxycarbonylamino)-3-[(2,3-cyclopenteno-1-pyridinium)methyl]ceph-3-em-4-carboxylate (IV). Deprotection of (IV) with trifluoroacetic acid anisole gives 7-amino-3-[(2,3-cyclopenteno-1-pyridinium)methyl]ceph-3-em-4-carboxylate (V), which is finally condensed with 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetic acid (VI) by means of phosgene in toluene.

合成路线5

The reaction of 7-aminocephalosporanic acid (I) with alpha-sulfophenylacetyl chloride (II) by means of NaOH and NaHCO3 in ether gives 7-(alpha-sulfophenylacetamido)cephalosporanic acid (III), which is then condensed with isonicotinamide (IV) by means of KSCN and pyridine in water.

合成路线6

a) By reaction of 1-sulfamoylmethyltetrazol-5-thiol (IX) with 7-mandelamidocephalosporanic acid (XII) by means of NaHCO3. b) ByCondensation of 1-sulfamoylmethyltetrazol-5-thiol (IX) with 7-aminocephalosporanic acid (X) by means of NaHCO3 in acetone - water to give 7-amino-3-(1-sulfamoyl-methyltetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (XI). Finally, this compound is acylated with D-O-dichloroacetylmandeloyl chloride (A) by means of NaHCO3 in acetone-water to afford the target compound. b) ByCondensation of 1-sulfamoylmethyltetrazol-5-thiol (IX) with 7-aminocephalosporanic acid (X) by means of NaHCO3 in acetone - water to give 7-amino-3-(1-sulfamoyl-methyltetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (XI). Finally, this compound is acylated with D-O-dichloroacetylmandeloyl chloride (A) by means of NaHCO3 in acetone-water to afford the target compound.

合成路线7

The reaction of methylhydrazin (I) with potassium thiocyanate (II) gives N-methyl-N-aminothiourea (III), which is cyclized with dimethyl oxalate (IV) by means of sodium methoxide in methanol to afford 2,5-dihydro-6-hydroxy-2-methyl-3-mercapto-5-oxo-1,2,4-triazine (V). The reaction of (V) with 7-aminocephalosporanic acid (VI) in a buffer solution at pH 6.5 gives 7-amino-3,4-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (VII), which is condensed with 2-(2-chloroacetamido-4-thiazolyl)-2-[(Z)-methoxyimino]acetyl chloride (VIII) at pH 2 yielding 7-]2-(2-chloroacetamido-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (IX). Finally, this compound is hydrolyzed and treated with sodium hydroxide.

合成路线8

The condensation of 7-aminocephalosporanic acid (I) with sodium 1,2,3-thiadiazole-5-thiolate (II) gives 7-amino-3-[1,2,3-thiadiazol-5-ylmethyl]-3-cephem-4-carboxylic acid (III). Following the first step, condensation of (III) with 2-(2-chloroacetamidothiazol-4-yl)-sulfanyl-(Z)-2-methoxyiminoacetyl chloride hydrochloride (IV) followed by deprotection with sodium N-methyldithiocarbamate (V) affords sodium 7-[(Z)-2-(2-aminothiazol-4yl)-2-(methoxyimino)acetamido)-3-(1,2,3-thiadiazol-5-ylsulfanylmethyl)-3-cephem-4-carboxylate.

合成路线9

7-Aminocephalosporanic acid (I) was converted to tert-butyl ester (II) by treatment with isobutylene and sulfuric acid. Subsequent diazotization, followed by reaction with methanol and rhodium catalyst, provided the 7-methoxy derivative (IIIa-b) as a diastereomeric mixture. The desired 7S-isomer was then deprotected with trifluoroacetic acid in anisole, yielding carboxylic acid (IV). Coupling of acid (IV) with 3-iodobenzylamine (VI) via activation as the mixed anhydride (V) with ethyl chloroformate gave rise to amide (VII). The sulfide group of (VII) was finally converted into the title sulfone by oxidation with oxone.

合成路线10

The formylation of 7-aminocephalosporanic acid (I) by the usual techniques produces 7-formamidocephalosporanic acid (II), which is then treated with the sodium salt of 1-methyl-1H-tetrazole-5-thiol (III) to yield 7-formamido-3-(1-methyl-1H-tetrazol-5-ylthio)methyl-3-cephem-4-carboxylic acid (IV). The resulting product (IV) is deformylated affording 7-amino-3-(1-methyl-1H-tetrazol-5-ylthio)methyl-3-cephem-4-carboxylic acid (V), which is finally acylated with anhydro-O-carboxymandelic acid (VI) using the usual techniques.

合成路线11

7-Aminocephalosporanic acid (I) was esterified with diphenyldiazomethane to produce the benzhydryl ester (II). Diazotization of (II) with isopropyl nitrite in the presence of trifluoroacetic acid, followed by treatment of the resulting diazo compound with propylene oxide and a catalytic amount of rhodium (II) octanoate, gave the corresponding 7-oxocephalosporanate (III). Wittig reaction of ketone (III) with the ylide resulting from 2-picolyltriphenylphosphonium chloride (IV) and NaNH2 in cold THF yielded olefin (V). Cephem double-bond isomerization upon treatment with triethylamine produced the 2-cephem derivative (VI) as the major compound, which was separated from the unreacted 3-cephem by flash chromatography. Acid hydrolysis of acetate ester (VI) gave rise to the corresponding alcohol (VII), which was further oxidized to aldehyde (VIII) by using pyridinium dichromate. Condensation of aldehyde (VIII) with the Wittig reagent (III) produced adduct (IX).

合成路线12

Acylation of 7-aminocephalosporanic acid (I) with 2-thienyleacetyl chloride (II) in the presence of NaOH led to amide (III). The carboxylate group of (III) was then protected as the corresponding benzhydryl ester (IV) upon treatment with diphenyldiazomethane. Mitsunobu coupling of the hydroxymethyl cephem (IV) with triclosan (V), with partial double-bond isomerization, gave rise to a mixture of the desired delta-3 ether (VI) and its delta-2 isomer (VII), which were separated by repeated column chromatography. Isomerization was minimized by conducting the reaction at -20 C. Finally, removal of the benzhydryl ester group of (VI) was accomplished by treatment with trifluoroacetic acid in the presence of anisole.

合成路线13