The reaction of the Schift base (XV) phenyllithium and CH3SCl (D) in DMF gives the corresponding methylthio derivative (XVI), which is debenzylated with 2,4-DNPH p-toluenesulfonate in ethanol yielding p-methoxybenzyl-7beta-amino-7alpha-thiomethyl-3-acetoxymethyl-3-cephem-4-carboxylate (XVII). The acylation of (XVII) with 2-thienylacetyl chloride (E) / pyridine in CH2Cl2 provided the corresponding 2-thienylacetamido derivative (XVIII), which by methanolysis in the presence of thallium trinitrate gives the 7alpha-methoxy derivative (XIX). The p-methoxybenzyl ester of (XIX) is cleaved with TFA-anisole affording 7alpha-methoxycephalothin-(7alpha-methoxy-7-(2-thienylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid) (XX), which is deacetylated with citrus acetyl enzyme yielding the corresponding hydroxymethyl compound (XXI). Finally, this compound is treated with chlorosulfonyl isocyanate in THF or acetonitrile.

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.

The reaction of 1,3,5-tribenzylhexahydro-s-triazine (I) with diethyl phosphite (A) at 100 C gives N-benzylaminomethyldiethylphosphonate (II), which is debenzylated with H2 over Pd/C in ethanol yielding aminomethyldiethylphosphonate (III). The reaction of (III) with benzaldehyde (B) affords the Schiff base (IV), which by reaction with p-methoxybenzyl chloroformate (V) by means of phenyllithium in THF is converted into the acylated Schiff base (VI). The benzylidene group of (VI) is eliminated by reaction with 2,4-DNPH p-toluenesulfonate in ethanol, or the free acid in ether giving p-methoxybenzyl alpha-amino-diethylphosphonoacetate (VII), which is condensed with ethyl thionoformate (VIII) yielding the thioformamide (IX). The cyclization of the thioformamide (IX) with 1-chloro-3-acetoxy-2-propanone (X) by means of K2CO3 in acetone affords the thiazine (XI), which by a new cyclization with azidoacetyl chloride (XII) by means of triethylamine in CH2Cl2 is converted into p-methoxybenzyl-3-acetoxymethyl-7-azido-3-cephem-4-carboxylate (XIII). The hydrogenation of (XIII) with H2 over PtO2 in benzene yields the corresponding amino compound (XIV), which is converted into the 7beta-Schiff base (XV) by treatment with p-nitrobenzaldehyde (C) in CH2Cl2.

The reaction of the Schift base (XV) phenyllithium and CH3SCl (D) in DMF gives the corresponding methylthio derivative (XVI), which is debenzylated with 2,4-DNPH p-toluenesulfonate in ethanol yielding p-methoxybenzyl-7beta-amino-7alpha-thiomethyl-3-acetoxymethyl-3-cephem-4-carboxylate (XVII). The acylation of (XVII) with 2-thienylacetyl chloride (E) / pyridine in CH2Cl2 provided the corresponding 2-thienylacetamido derivative (XVIII), which by methanolysis in the presence of thallium trinitrate gives the 7alpha-methoxy derivative (XIX). The p-methoxybenzyl ester of (XIX) is cleaved with TFA-anisole affording 7alpha-methoxycephalothin-(7alpha-methoxy-7-(2-thienylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid) (XX), which is deacetylated with citrus acetyl enzyme yielding the corresponding hydroxymethyl compound (XXI). Finally, this compound is treated with chlorosulfonyl isocyanate in THF or acetonitrile.

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.

By reaction of acylated ester (XXVIII) with PCl5 and methanol in CH2Cl2 is converted into benzhydryl-3-carbamoyloxymethyl-7beta-[1-methoxy-2-(2-thienyl)ethylideneamino]-3-cephem-4-carboxylate (XXIX). The methoxylation of (XXIX) in the 7 position is performed either by reaction with phenyllithium and bis(methyl)peroxide in THF [or with phenyllithium and N-bromosuccinimide to the bromo intermediate (XXXI), which is then treated with silver oxide in methanol] yielding, in both cases, the benzhydryl ester of cefoxitin (XXX). Finally, this compound is hydrolyzed with trifluoroacetic acid.

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.

By reaction of acylated ester (XXVIII) with PCl5 and methanol in CH2Cl2 is converted into benzhydryl-3-carbamoyloxymethyl-7beta-[1-methoxy-2-(2-thienyl)ethylideneamino]-3-cephem-4-carboxylate (XXIX). The methoxylation of (XXIX) in the 7 position is performed either by reaction with phenyllithium and bis(methyl)peroxide in THF [or with phenyllithium and N-bromosuccinimide to the bromo intermediate (XXXI), which is then treated with silver oxide in methanol] yielding, in both cases, the benzhydryl ester of cefoxitin (XXX). Finally, this compound is hydrolyzed with trifluoroacetic acid.

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.

The reaction of 1,3,5-tribenzylhexahydro-s-triazine (I) with diethyl phosphite (A) at 100 C gives N-benzylaminomethyldiethylphosphonate (II), which is debenzylated with H2 over Pd/C in ethanol yielding aminomethyldiethylphosphonate (III). The reaction of (III) with benzaldehyde (B) affords the Schiff base (IV), which by reaction with p-methoxybenzyl chloroformate (V) by means of phenyllithium in THF is converted into the acylated Schiff base (VI). The benzylidene group of (VI) is eliminated by reaction with 2,4-DNPH p-toluenesulfonate in ethanol, or the free acid in ether giving p-methoxybenzyl alpha-amino-diethylphosphonoacetate (VII), which is condensed with ethyl thionoformate (VIII) yielding the thioformamide (IX). The cyclization of the thioformamide (IX) with 1-chloro-3-acetoxy-2-propanone (X) by means of K2CO3 in acetone affords the thiazine (XI), which by a new cyclization with azidoacetyl chloride (XII) by means of triethylamine in CH2Cl2 is converted into p-methoxybenzyl-3-acetoxymethyl-7-azido-3-cephem-4-carboxylate (XIII). The hydrogenation of (XIII) with H2 over PtO2 in benzene yields the corresponding amino compound (XIV), which is converted into the 7beta-Schiff base (XV) by treatment with p-nitrobenzaldehyde (C) in CH2Cl2.

The reaction of the Schift base (XV) phenyllithium and CH3SCl (D) in DMF gives the corresponding methylthio derivative (XVI), which is debenzylated with 2,4-DNPH p-toluenesulfonate in ethanol yielding p-methoxybenzyl-7beta-amino-7alpha-thiomethyl-3-acetoxymethyl-3-cephem-4-carboxylate (XVII). The acylation of (XVII) with 2-thienylacetyl chloride (E) / pyridine in CH2Cl2 provided the corresponding 2-thienylacetamido derivative (XVIII), which by methanolysis in the presence of thallium trinitrate gives the 7alpha-methoxy derivative (XIX). The p-methoxybenzyl ester of (XIX) is cleaved with TFA-anisole affording 7alpha-methoxycephalothin-(7alpha-methoxy-7-(2-thienylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid) (XX), which is deacetylated with citrus acetyl enzyme yielding the corresponding hydroxymethyl compound (XXI). Finally, this compound is treated with chlorosulfonyl isocyanate in THF or acetonitrile.

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.

By reaction of acylated ester (XXVIII) with PCl5 and methanol in CH2Cl2 is converted into benzhydryl-3-carbamoyloxymethyl-7beta-[1-methoxy-2-(2-thienyl)ethylideneamino]-3-cephem-4-carboxylate (XXIX). The methoxylation of (XXIX) in the 7 position is performed either by reaction with phenyllithium and bis(methyl)peroxide in THF [or with phenyllithium and N-bromosuccinimide to the bromo intermediate (XXXI), which is then treated with silver oxide in methanol] yielding, in both cases, the benzhydryl ester of cefoxitin (XXX). Finally, this compound is hydrolyzed with trifluoroacetic acid.

Fermentation of Streptomyces lactamdurans NRRL-3802 produces sodium 7beta-(D-5-amino-S-carboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3-cephem-4-carboxylate (XXXIII), which is tosylated as usual to the N-tosyl derivative (XXXIV). The esterification of (XXXIV) with methyl chloromethyl ether (H) in CH2Cl2 yields the methoxymethyl ester (XXXV), which is finally treated first with 2-thienylcarbonyl chloride (E) on a 4-angstrom molecular sieve in dichloroethane, and then with HCl methanol.

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.

The reaction of 1,3,5-tribenzylhexahydro-s-triazine (I) with diethyl phosphite (A) at 100 C gives N-benzylaminomethyldiethylphosphonate (II), which is debenzylated with H2 over Pd/C in ethanol yielding aminomethyldiethylphosphonate (III). The reaction of (III) with benzaldehyde (B) affords the Schiff base (IV), which by reaction with p-methoxybenzyl chloroformate (V) by means of phenyllithium in THF is converted into the acylated Schiff base (VI). The benzylidene group of (VI) is eliminated by reaction with 2,4-DNPH p-toluenesulfonate in ethanol, or the free acid in ether giving p-methoxybenzyl alpha-amino-diethylphosphonoacetate (VII), which is condensed with ethyl thionoformate (VIII) yielding the thioformamide (IX). The cyclization of the thioformamide (IX) with 1-chloro-3-acetoxy-2-propanone (X) by means of K2CO3 in acetone affords the thiazine (XI), which by a new cyclization with azidoacetyl chloride (XII) by means of triethylamine in CH2Cl2 is converted into p-methoxybenzyl-3-acetoxymethyl-7-azido-3-cephem-4-carboxylate (XIII). The hydrogenation of (XIII) with H2 over PtO2 in benzene yields the corresponding amino compound (XIV), which is converted into the 7beta-Schiff base (XV) by treatment with p-nitrobenzaldehyde (C) in CH2Cl2.

The reaction of 1,3,5-tribenzylhexahydro-s-triazine (I) with diethyl phosphite (A) at 100 C gives N-benzylaminomethyldiethylphosphonate (II), which is debenzylated with H2 over Pd/C in ethanol yielding aminomethyldiethylphosphonate (III). The reaction of (III) with benzaldehyde (B) affords the Schiff base (IV), which by reaction with p-methoxybenzyl chloroformate (V) by means of phenyllithium in THF is converted into the acylated Schiff base (VI). The benzylidene group of (VI) is eliminated by reaction with 2,4-DNPH p-toluenesulfonate in ethanol, or the free acid in ether giving p-methoxybenzyl alpha-amino-diethylphosphonoacetate (VII), which is condensed with ethyl thionoformate (VIII) yielding the thioformamide (IX). The cyclization of the thioformamide (IX) with 1-chloro-3-acetoxy-2-propanone (X) by means of K2CO3 in acetone affords the thiazine (XI), which by a new cyclization with azidoacetyl chloride (XII) by means of triethylamine in CH2Cl2 is converted into p-methoxybenzyl-3-acetoxymethyl-7-azido-3-cephem-4-carboxylate (XIII). The hydrogenation of (XIII) with H2 over PtO2 in benzene yields the corresponding amino compound (XIV), which is converted into the 7beta-Schiff base (XV) by treatment with p-nitrobenzaldehyde (C) in CH2Cl2.

The reaction of the Schift base (XV) phenyllithium and CH3SCl (D) in DMF gives the corresponding methylthio derivative (XVI), which is debenzylated with 2,4-DNPH p-toluenesulfonate in ethanol yielding p-methoxybenzyl-7beta-amino-7alpha-thiomethyl-3-acetoxymethyl-3-cephem-4-carboxylate (XVII). The acylation of (XVII) with 2-thienylacetyl chloride (E) / pyridine in CH2Cl2 provided the corresponding 2-thienylacetamido derivative (XVIII), which by methanolysis in the presence of thallium trinitrate gives the 7alpha-methoxy derivative (XIX). The p-methoxybenzyl ester of (XIX) is cleaved with TFA-anisole affording 7alpha-methoxycephalothin-(7alpha-methoxy-7-(2-thienylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid) (XX), which is deacetylated with citrus acetyl enzyme yielding the corresponding hydroxymethyl compound (XXI). Finally, this compound is treated with chlorosulfonyl isocyanate in THF or acetonitrile.

Fermentation of Streptomyces lactamdurans NRRL-3802 produces sodium 7beta-(D-5-amino-S-carboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3-cephem-4-carboxylate (XXXIII), which is tosylated as usual to the N-tosyl derivative (XXXIV). The esterification of (XXXIV) with methyl chloromethyl ether (H) in CH2Cl2 yields the methoxymethyl ester (XXXV), which is finally treated first with 2-thienylcarbonyl chloride (E) on a 4-angstrom molecular sieve in dichloroethane, and then with HCl methanol.

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.