合成路线: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.
合成路线: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.
参考文献标题:7-Azido-cephalosporin compounds and their preparation
文献作者:Christensen,B.G.; Ratcliffe,R.W.(Merck & Co.,Inc.)
参考来源:DE 2365406; FR 2182953; GB 1424373; JP 49014488
合成路线: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: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.
参考文献标题:Process for preparin cephalosporin compounds
文献作者:Hazen,G.C.(Merck & Co.,Inc.)
参考来源:DD 100957; ES 408969; US 3780033
合成路线: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: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.
参考文献标题:Process for preparing penicillin and cephalosporin compounds
文献作者:Christensen,B.G.; Cama,L.D.(Merck & Co.,Inc.)
参考来源:FR 2163144; GB 1401060; US 3843641
合成路线: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.
参考文献标题:Process for preparing cephalosporin compounds
文献作者:Christensen,B.G.; Firestone,R.A.
参考来源:DD 100956; ES 408970; US 3775410
合成路线: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.
合成路线: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.
合成路线: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: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.
合成路线: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.
合成路线: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.
参考文献标题:Cefoxitin
文献作者:Casta馿r,J.; Loren,J.G.
参考来源:Drugs Fut 1978,3(6),434
合成路线: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.
参考文献标题:Total synthesis of beta-lactam antibiotics.I.alpha-Thioformamido-diethylphosphonioacetates
文献作者:Christensen,B.G.; Ratcliffe,R.W.
参考来源:Tetrahedron Lett 1973,464645-48
产品链接: CAS No. 35607-66-0››