医康传媒

【药物名称】Cefoxitin, Mefoxitin, Mefoxin
【化学名】3-Carbamoyloxymethyl-7alpha-methoxy-7beta-(2-thienylacetamido)-3-cephem-4-carboxylic acid sodium salt
【CAS登记号】35607-66-0 (free acid)
【结构式】
【分子式】C16-H17-N3-O7-S2
【分子量】427.4563
【原研厂家】Merck Sharp & Dohme (Originator)
【作用类别】Antibiotics, ANTIINFECTIVE THERAPY
【研发状态】Launched-1977

【合成情况】　
〖来源〗Drugs Fut
〖合成路线〗
〖标题〗Cefoxitin
〖合成方法〗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.
〖作者〗Castaer, J.; Loren, J.G.
〖参考〗Castaer, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434
〖出处〗Drugs Fut1978,3,(6):434
〖备注〗Synthesis It can be prepared in several different ways: 1) The reaction of 1,3,5-tribenzylhexahydro-s-triazine (I) with diethyl phosphite (A) at 100?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 phenyl lithium 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) (1,5). 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 (2,5) (Scheme 07036901a). The reaction of the Schift base (XV) phenyl lithium and CH3SCl (D) in DMF gives the corresponding methylthioderivative (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) (3,5) 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 (3-5) (Scheme 07036901b). 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 cytrus acetyl sterase in an aqueous phosphate buffer affording the 3-hydroxymethyl derivative (XXIV), which by reaction with chiorosulfonyl 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 phenyl lithium 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 (6-8) (Scheme 07036901c). 3) 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 phenyl lithium and bis(methyl)peroxide in THF [or with phenyl lithium and N-bromosuccinimide to the bromointermediate (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 (6-7) (Scheme 07036901d). 4) 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 amstrong molecular sieve in dichloroethane, and then with HCl methanol (9) (Scheme 07036901e). 5) 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 dixoane 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 (4,10) (Scheme 07036901f). Description Free acid, m.p. 165-7?(6,7,9). Manufacturer Merck and Co. (USA) References 1. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. I. alpha-Thioformamido-diethylphosphonioacetates; Tetrahedron Lett 1973, 46, 4645-4648 2. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. II. (rac)-Cephalotin; Tetrahedron Lett 1973, 46, 4649-4652 3. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. III. (rac)-Cefoxitin; Tetrahedron Lett 1973, 46, 4653-4656 4. Christensen, B.G. and Cama, L.D. (Merck and Co., Inc.); DE 2203653 5. Christensen, B.G. and Ratcliffe, R.W. (Merck and Co., Inc.); DE 2365406 6. Hazen, G.C. (Merck and Co., Inc.); US 3780033 7. Christensen, B.G. and Cama, L.D. (Merck and Co., Inc.); FR 2163144 8. Christensen, B.G. and Firestone, R.A. (Merck and Co., Inc.); US 3775410 9. Weinstock, L.M. (Merck and Co., Inc.); DE 2456528 10. Christensen, B.G. et al. (Merck and Co., Inc.); DE 2143331

〖来源〗Tetrahedron Lett
〖合成路线〗
〖标题〗Total synthesis of beta-lactam antibiotics. I. alpha-Thioformamido-diethylphosphonioacetates
〖合成方法〗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.
〖作者〗Christensen, B.G.; Ratcliffe, R.W.
〖参考〗Christensen, B.G.; Ratcliffe, R.W.; Total synthesis of beta-lactam antibiotics. I. alpha-Thioformamido-diethylphosphonioacetates. Tetrahedron Lett 1973, 46, 4645-48
〖出处〗Tetrahedron Lett1973,46,():4645-48
〖备注〗

〖来源〗Tetrahedron Lett
〖合成路线〗
〖标题〗Total synthesis of beta-lactam antibiotics. II. (rac)-Cephalotin
〖合成方法〗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.
〖作者〗Christensen, B.G.; Ratcliffe, R.W.
〖参考〗Christensen, B.G.; Ratcliffe, R.W.; Total synthesis of beta-lactam antibiotics. II. (rac)-Cephalotin. Tetrahedron Lett 1973, 46, 4649-52
〖出处〗Tetrahedron Lett1973,46,():4649-52
〖备注〗

〖来源〗Drugs Fut
〖合成路线〗
〖标题〗Cefoxitin
〖合成方法〗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.
〖作者〗Castaer, J.; Loren, J.G.
〖参考〗Castaer, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434
〖出处〗Drugs Fut1978,3,(6):434
〖备注〗Synthesis It can be prepared in several different ways: 1) The reaction of 1,3,5-tribenzylhexahydro-s-triazine (I) with diethyl phosphite (A) at 100?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 phenyl lithium 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) (1,5). 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 (2,5) (Scheme 07036901a). The reaction of the Schift base (XV) phenyl lithium and CH3SCl (D) in DMF gives the corresponding methylthioderivative (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) (3,5) 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 (3-5) (Scheme 07036901b). 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 cytrus acetyl sterase in an aqueous phosphate buffer affording the 3-hydroxymethyl derivative (XXIV), which by reaction with chiorosulfonyl 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 phenyl lithium 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 (6-8) (Scheme 07036901c). 3) 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 phenyl lithium and bis(methyl)peroxide in THF [or with phenyl lithium and N-bromosuccinimide to the bromointermediate (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 (6-7) (Scheme 07036901d). 4) 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 amstrong molecular sieve in dichloroethane, and then with HCl methanol (9) (Scheme 07036901e). 5) 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 dixoane 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 (4,10) (Scheme 07036901f). Description Free acid, m.p. 165-7?(6,7,9). Manufacturer Merck and Co. (USA) References 1. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. I. alpha-Thioformamido-diethylphosphonioacetates; Tetrahedron Lett 1973, 46, 4645-4648 2. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. II. (rac)-Cephalotin; Tetrahedron Lett 1973, 46, 4649-4652 3. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. III. (rac)-Cefoxitin; Tetrahedron Lett 1973, 46, 4653-4656 4. Christensen, B.G. and Cama, L.D. (Merck and Co., Inc.); DE 2203653 5. Christensen, B.G. and Ratcliffe, R.W. (Merck and Co., Inc.); DE 2365406 6. Hazen, G.C. (Merck and Co., Inc.); US 3780033 7. Christensen, B.G. and Cama, L.D. (Merck and Co., Inc.); FR 2163144 8. Christensen, B.G. and Firestone, R.A. (Merck and Co., Inc.); US 3775410 9. Weinstock, L.M. (Merck and Co., Inc.); DE 2456528 10. Christensen, B.G. et al. (Merck and Co., Inc.); DE 2143331

〖来源〗Tetrahedron Lett
〖合成路线〗
〖标题〗Total synthesis of beta-lactam antibiotics. III. (rac)-Cefoxitin
〖合成方法〗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.
〖作者〗Ratcliffe, R.W.; Christensen, B.G.
〖参考〗Ratcliffe, R.W.; Christensen, B.G.; Total synthesis of beta-lactam antibiotics. III. (rac)-Cefoxitin. Tetrahedron Lett 1973, 46, 4653-56
〖出处〗Tetrahedron Lett1973,46,():4653-56
〖备注〗

〖来源〗Drugs Fut
〖合成路线〗
〖标题〗Cefoxitin
〖合成方法〗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.
〖作者〗Castaer, J.; Loren, J.G.
〖参考〗Castaer, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434
〖出处〗Drugs Fut1978,3,(6):434
〖备注〗Synthesis It can be prepared in several different ways: 1) The reaction of 1,3,5-tribenzylhexahydro-s-triazine (I) with diethyl phosphite (A) at 100?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 phenyl lithium 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) (1,5). 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 (2,5) (Scheme 07036901a). The reaction of the Schift base (XV) phenyl lithium and CH3SCl (D) in DMF gives the corresponding methylthioderivative (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) (3,5) 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 (3-5) (Scheme 07036901b). 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 cytrus acetyl sterase in an aqueous phosphate buffer affording the 3-hydroxymethyl derivative (XXIV), which by reaction with chiorosulfonyl 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 phenyl lithium 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 (6-8) (Scheme 07036901c). 3) 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 phenyl lithium and bis(methyl)peroxide in THF [or with phenyl lithium and N-bromosuccinimide to the bromointermediate (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 (6-7) (Scheme 07036901d). 4) 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 amstrong molecular sieve in dichloroethane, and then with HCl methanol (9) (Scheme 07036901e). 5) 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 dixoane 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 (4,10) (Scheme 07036901f). Description Free acid, m.p. 165-7?(6,7,9). Manufacturer Merck and Co. (USA) References 1. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. I. alpha-Thioformamido-diethylphosphonioacetates; Tetrahedron Lett 1973, 46, 4645-4648 2. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. II. (rac)-Cephalotin; Tetrahedron Lett 1973, 46, 4649-4652 3. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. III. (rac)-Cefoxitin; Tetrahedron Lett 1973, 46, 4653-4656 4. Christensen, B.G. and Cama, L.D. (Merck and Co., Inc.); DE 2203653 5. Christensen, B.G. and Ratcliffe, R.W. (Merck and Co., Inc.); DE 2365406 6. Hazen, G.C. (Merck and Co., Inc.); US 3780033 7. Christensen, B.G. and Cama, L.D. (Merck and Co., Inc.); FR 2163144 8. Christensen, B.G. and Firestone, R.A. (Merck and Co., Inc.); US 3775410 9. Weinstock, L.M. (Merck and Co., Inc.); DE 2456528 10. Christensen, B.G. et al. (Merck and Co., Inc.); DE 2143331

〖来源〗Drugs Fut
〖合成路线〗
〖标题〗Cefoxitin
〖合成方法〗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.
〖作者〗Castaer, J.; Loren, J.G.
〖参考〗Castaer, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434
〖出处〗Drugs Fut1978,3,(6):434
〖备注〗Synthesis It can be prepared in several different ways: 1) The reaction of 1,3,5-tribenzylhexahydro-s-triazine (I) with diethyl phosphite (A) at 100?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 phenyl lithium 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) (1,5). 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 (2,5) (Scheme 07036901a). The reaction of the Schift base (XV) phenyl lithium and CH3SCl (D) in DMF gives the corresponding methylthioderivative (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) (3,5) 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 (3-5) (Scheme 07036901b). 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 cytrus acetyl sterase in an aqueous phosphate buffer affording the 3-hydroxymethyl derivative (XXIV), which by reaction with chiorosulfonyl 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 phenyl lithium 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 (6-8) (Scheme 07036901c). 3) 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 phenyl lithium and bis(methyl)peroxide in THF [or with phenyl lithium and N-bromosuccinimide to the bromointermediate (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 (6-7) (Scheme 07036901d). 4) 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 amstrong molecular sieve in dichloroethane, and then with HCl methanol (9) (Scheme 07036901e). 5) 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 dixoane 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 (4,10) (Scheme 07036901f). Description Free acid, m.p. 165-7?(6,7,9). Manufacturer Merck and Co. (USA) References 1. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. I. alpha-Thioformamido-diethylphosphonioacetates; Tetrahedron Lett 1973, 46, 4645-4648 2. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. II. (rac)-Cephalotin; Tetrahedron Lett 1973, 46, 4649-4652 3. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. III. (rac)-Cefoxitin; Tetrahedron Lett 1973, 46, 4653-4656 4. Christensen, B.G. and Cama, L.D. (Merck and Co., Inc.); DE 2203653 5. Christensen, B.G. and Ratcliffe, R.W. (Merck and Co., Inc.); DE 2365406 6. Hazen, G.C. (Merck and Co., Inc.); US 3780033 7. Christensen, B.G. and Cama, L.D. (Merck and Co., Inc.); FR 2163144 8. Christensen, B.G. and Firestone, R.A. (Merck and Co., Inc.); US 3775410 9. Weinstock, L.M. (Merck and Co., Inc.); DE 2456528 10. Christensen, B.G. et al. (Merck and Co., Inc.); DE 2143331

〖来源〗Drugs Fut
〖合成路线〗
〖标题〗Cefoxitin
〖合成方法〗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.
〖作者〗Castaer, J.; Loren, J.G.
〖参考〗Castaer, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434
〖出处〗Drugs Fut1978,3,(6):434
〖备注〗Synthesis It can be prepared in several different ways: 1) The reaction of 1,3,5-tribenzylhexahydro-s-triazine (I) with diethyl phosphite (A) at 100?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 phenyl lithium 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) (1,5). 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 (2,5) (Scheme 07036901a). The reaction of the Schift base (XV) phenyl lithium and CH3SCl (D) in DMF gives the corresponding methylthioderivative (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) (3,5) 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 (3-5) (Scheme 07036901b). 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 cytrus acetyl sterase in an aqueous phosphate buffer affording the 3-hydroxymethyl derivative (XXIV), which by reaction with chiorosulfonyl 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 phenyl lithium 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 (6-8) (Scheme 07036901c). 3) 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 phenyl lithium and bis(methyl)peroxide in THF [or with phenyl lithium and N-bromosuccinimide to the bromointermediate (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 (6-7) (Scheme 07036901d). 4) 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 amstrong molecular sieve in dichloroethane, and then with HCl methanol (9) (Scheme 07036901e). 5) 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 dixoane 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 (4,10) (Scheme 07036901f). Description Free acid, m.p. 165-7?(6,7,9). Manufacturer Merck and Co. (USA) References 1. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. I. alpha-Thioformamido-diethylphosphonioacetates; Tetrahedron Lett 1973, 46, 4645-4648 2. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. II. (rac)-Cephalotin; Tetrahedron Lett 1973, 46, 4649-4652 3. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. III. (rac)-Cefoxitin; Tetrahedron Lett 1973, 46, 4653-4656 4. Christensen, B.G. and Cama, L.D. (Merck and Co., Inc.); DE 2203653 5. Christensen, B.G. and Ratcliffe, R.W. (Merck and Co., Inc.); DE 2365406 6. Hazen, G.C. (Merck and Co., Inc.); US 3780033 7. Christensen, B.G. and Cama, L.D. (Merck and Co., Inc.); FR 2163144 8. Christensen, B.G. and Firestone, R.A. (Merck and Co., Inc.); US 3775410 9. Weinstock, L.M. (Merck and Co., Inc.); DE 2456528 10. Christensen, B.G. et al. (Merck and Co., Inc.); DE 2143331

〖来源〗Drugs Fut
〖合成路线〗
〖标题〗Cefoxitin
〖合成方法〗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.
〖作者〗Castaer, J.; Loren, J.G.
〖参考〗Castaer, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434
〖出处〗Drugs Fut1978,3,(6):434
〖备注〗Synthesis It can be prepared in several different ways: 1) The reaction of 1,3,5-tribenzylhexahydro-s-triazine (I) with diethyl phosphite (A) at 100?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 phenyl lithium 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) (1,5). 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 (2,5) (Scheme 07036901a). The reaction of the Schift base (XV) phenyl lithium and CH3SCl (D) in DMF gives the corresponding methylthioderivative (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) (3,5) 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 (3-5) (Scheme 07036901b). 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 cytrus acetyl sterase in an aqueous phosphate buffer affording the 3-hydroxymethyl derivative (XXIV), which by reaction with chiorosulfonyl 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 phenyl lithium 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 (6-8) (Scheme 07036901c). 3) 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 phenyl lithium and bis(methyl)peroxide in THF [or with phenyl lithium and N-bromosuccinimide to the bromointermediate (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 (6-7) (Scheme 07036901d). 4) 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 amstrong molecular sieve in dichloroethane, and then with HCl methanol (9) (Scheme 07036901e). 5) 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 dixoane 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 (4,10) (Scheme 07036901f). Description Free acid, m.p. 165-7?(6,7,9). Manufacturer Merck and Co. (USA) References 1. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. I. alpha-Thioformamido-diethylphosphonioacetates; Tetrahedron Lett 1973, 46, 4645-4648 2. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. II. (rac)-Cephalotin; Tetrahedron Lett 1973, 46, 4649-4652 3. Ratcliffe, R.W. and Christensen, B.G.; Total synthesis of beta-lactam antibiotics. III. (rac)-Cefoxitin; Tetrahedron Lett 1973, 46, 4653-4656 4. Christensen, B.G. and Cama, L.D. (Merck and Co., Inc.); DE 2203653 5. Christensen, B.G. and Ratcliffe, R.W. (Merck and Co., Inc.); DE 2365406 6. Hazen, G.C. (Merck and Co., Inc.); US 3780033 7. Christensen, B.G. and Cama, L.D. (Merck and Co., Inc.); FR 2163144 8. Christensen, B.G. and Firestone, R.A. (Merck and Co., Inc.); US 3775410 9. Weinstock, L.M. (Merck and Co., Inc.); DE 2456528 10. Christensen, B.G. et al. (Merck and Co., Inc.); DE 2143331

〖来源〗DE 2365406; FR 2182953; GB 1424373; JP 49014488
〖合成路线〗
〖标题〗7-Azido-cephalosporin compounds and their preparation
〖合成方法〗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.
〖作者〗Christensen, B.G.; Ratcliffe, R.W. (Merck & Co., Inc.)
〖参考〗Christensen, B.G.; Ratcliffe, R.W. (Merck & Co., Inc.); 7-Azido-cephalosporin compounds and their preparation. DE 2365406; FR 2182953; GB 1424373; JP 49014488
〖出处〗DE 2365406; FR 2182953; GB 1424373; JP 49014488,,():
〖备注〗

〖来源〗DE 2203653; FR 2161866; GB 1350772
〖合成路线〗
〖标题〗Antibiotics and processes for their production
〖合成方法〗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.
〖作者〗Christensen, B.G.; Cama, L.D. (Merck & Co., Inc.)
〖参考〗Christensen, B.G.; Cama, L.D. (Merck & Co., Inc.); Antibiotics and processes for their production. DE 2203653; FR 2161866; GB 1350772
〖出处〗DE 2203653; FR 2161866; GB 1350772,,():
〖备注〗

〖来源〗DE 2365406; FR 2182953; GB 1424373; JP 49014488
〖合成路线〗
〖标题〗7-Azido-cephalosporin compounds and their preparation
〖合成方法〗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.
〖作者〗Christensen, B.G.; Ratcliffe, R.W. (Merck & Co., Inc.)
〖参考〗Christensen, B.G.; Ratcliffe, R.W. (Merck & Co., Inc.); 7-Azido-cephalosporin compounds and their preparation. DE 2365406; FR 2182953; GB 1424373; JP 49014488
〖出处〗DE 2365406; FR 2182953; GB 1424373; JP 49014488,,():
〖备注〗

〖来源〗DD 100957; ES 408969; US 3780033
〖合成路线〗
〖标题〗Process for preparin cephalosporin compounds
〖合成方法〗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.
〖作者〗Hazen, G.C. (Merck & Co., Inc.)
〖参考〗Hazen, G.C. (Merck & Co., Inc.); Process for preparin cephalosporin compounds. DD 100957; ES 408969; US 3780033
〖出处〗DD 100957; ES 408969; US 3780033,,():
〖备注〗

〖来源〗FR 2163144; GB 1401060; US 3843641
〖合成路线〗
〖标题〗Process for preparing penicillin and cephalosporin compounds
〖合成方法〗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.
〖作者〗Christensen, B.G.; Cama, L.D. (Merck & Co., Inc.)
〖参考〗Christensen, B.G.; Cama, L.D. (Merck & Co., Inc.); Process for preparing penicillin and cephalosporin compounds. FR 2163144; GB 1401060; US 3843641
〖出处〗FR 2163144; GB 1401060; US 3843641,,():
〖备注〗

〖来源〗DD 100956; ES 408970; US 3775410
〖合成路线〗
〖标题〗Process for preparing cephalosporin compounds
〖合成方法〗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.
〖作者〗Christensen, B.G.; Firestone, R.A.
〖参考〗Christensen, B.G.; Firestone, R.A.; Process for preparing cephalosporin compounds. DD 100956; ES 408970; US 3775410
〖出处〗DD 100956; ES 408970; US 3775410,,():
〖备注〗

〖来源〗DD 100957; ES 408969; US 3780033
〖合成路线〗
〖标题〗Process for preparin cephalosporin compounds
〖合成方法〗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.
〖作者〗Hazen, G.C. (Merck & Co., Inc.)
〖参考〗Hazen, G.C. (Merck & Co., Inc.); Process for preparin cephalosporin compounds. DD 100957; ES 408969; US 3780033
〖出处〗DD 100957; ES 408969; US 3780033,,():
〖备注〗

〖来源〗FR 2163144; GB 1401060; US 3843641
〖合成路线〗
〖标题〗Process for preparing penicillin and cephalosporin compounds
〖合成方法〗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.
〖作者〗Christensen, B.G.; Cama, L.D. (Merck & Co., Inc.)
〖参考〗Christensen, B.G.; Cama, L.D. (Merck & Co., Inc.); Process for preparing penicillin and cephalosporin compounds. FR 2163144; GB 1401060; US 3843641
〖出处〗FR 2163144; GB 1401060; US 3843641,,():
〖备注〗

〖来源〗DE 2456528; FR 2253022; GB 1480757; JP 50105687
〖合成路线〗
〖标题〗Preparation of 7-acylaminocephalosporin derivatives
〖合成方法〗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.
〖作者〗Weinstock, L.M.
〖参考〗Weinstock, L.M.; Preparation of 7-acylaminocephalosporin derivatives. DE 2456528; FR 2253022; GB 1480757; JP 50105687
〖出处〗DE 2456528; FR 2253022; GB 1480757; JP 50105687,,():
〖备注〗

〖来源〗DE 2203653; FR 2161866; GB 1350772
〖合成路线〗
〖标题〗Antibiotics and processes for their production
〖合成方法〗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.
〖作者〗Christensen, B.G.; Cama, L.D. (Merck & Co., Inc.)
〖参考〗Christensen, B.G.; Cama, L.D. (Merck & Co., Inc.); Antibiotics and processes for their production. DE 2203653; FR 2161866; GB 1350772
〖出处〗DE 2203653; FR 2161866; GB 1350772,,():
〖备注〗

〖来源〗DE 2143331
〖合成路线〗
〖标题〗In 7-Stellung substituierte Cephalosphoransureester und Verfahren zu ihrer Herstellung
〖合成方法〗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.
〖作者〗Christensen, B.G.; et al.
〖参考〗Christensen, B.G.; et al.; In 7-Stellung substituierte Cephalosphoransureester und Verfahren zu ihrer Herstellung. DE 2143331
〖出处〗DE 2143331,,():
〖备注〗

益母草	菊花
百合花	西洋参

Cefoxitin, Mefoxitin, Mefoxin,35607-66-0 (free acid),C16-H17