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药物详细合成路线

Name Ceftibuten;Sch-39720;7432-S;Ceprifran;Keimax;Isocef;Cedax;Seftem
Chemical Name (6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-cephem-4-carboxylic acid
      (+)-(6R,7R)-7-[(Z)-2-(2-Amino-4-thiazolyl)-4-carboxycrotonamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid
CAS 97519-39-6
Related CAS 97518-16-6 (diNa salt), 97519-41-0 (monoHCl)
Formula C15H14N4O6S2
Structure
Formula Weight 410.43003
Stage 上市-1992
Company Shionogi (Originator), Biovail (Marketer), Essex (Licensee), Juste (Licensee), Recordati (Licensee), Schering-Plough (Licensee)
Activity/Mechanism Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins
Syn. Route 8
Route 1
the condensation of 2-[2-(benzoyloxycarbonylamino)thiazol-4-yl]-4-(benzyloxycarbonyl)-2-butenoic acid (i) with 7beta-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (ii) by means of mesyl chloride, phosphorus oxychloride or thionyl chloride in basic medium and dichloromethane as solvent gives the protected derivative of the desired product (iii), which is then treated with alcl3 and anisole and acidified with diluted hcl.
List of intermediates No.
2-benzhydryl 1-benzyl (2s,5r)-6-hydroxy-5-methyl-1,2-piperidinedicarboxylate (i)
methyl (2s,4r)-2-((1r,4s)-5-(benzhydryloxy)-4-[[(benzyloxy)carbonyl]amino]-1-methyl-5-oxopentyl)-1,3-thiazolidine-4-carboxylate (ii)
methyl (2r,4r)-2-((1r,4s)-5-(benzhydryloxy)-4-[[(benzyloxy)carbonyl]amino]-1-methyl-5-oxopentyl)-1,3-thiazolidine-4-carboxylate (iii)
Reference 1:
    hamashima, y. (shionogi & co. ltd.); 7-carboxyalkenoylamido-3-cephem-4-carboxylic acid derivs.. ep 0136721; es 8604602; es 8605278; es 8700222; gb 2154580; gb 2198727; jp 1985078987; jp 1985163884; jp 1985246388; us 4634697; us 4748170 .

Route 2
synthesis of intermediate (i):1a) dimethyl acetonedicarboxylate (iv) is treated with mgcl2 and triethylamine, giving the corresponding magnesium complex (v), which by cyclocondensation with chloroacetyl chloride and thiourea yields methyl 2-(2-aminothiazol-4-yl)-3-hydroxy-4-(methoxycarbonyl)-2-butenoate (vi). the reduction of (vi) with nabh4 affords dimethyl 2-(2-aminothiazol-4-yl)-3-hydroxyglutarate (vii), which by successive treatments with benzyloxycarbonyl chloride (to protect the amino group), and with mesyl chloride - triethylamine (to dehydrate the oh group) is converted to methyl 2-[2 (benzyloxycarbonylamino)thiazol-4-y]-4-(methoxycarbonyl)-2-butenoate (viii). the hydrolysis of (viii) with aqueous naoh in toluene gives the corresponding diacid (ix), which is selectively esterified with benzyl alcohol in acidic medium yielding (i).1b) the reaction of methyl 2-(2-aminothiazol-4-yl)acetate (x) with beozyloxycarbonyl chloride and nahco3 gives the protected compound (xi), which is condensed with methyl 3-methoxyacrylate (xii) by means of sodium methoxide in dmf to yield dimethyl ester (viii), already obtained.
List of intermediates No.
methyl (1s,3as,4s,5s,7as)-4-(cyanomethyl)-7a-methyl-5-[(1r,3r,6r)-3-methyl-2-oxo-7-oxabicyclo[4.1.0]hept-3-yl]octahydro-1h-indene-1-carboxylate
1-(methylamino)-3-tetracyclo[6.6.2.0(2,7).0(9,14)]hexadeca-2,4,6,9,11,13-hexaen-1-yl-2-propanol
2-benzhydryl 1-benzyl (2s,5r)-6-hydroxy-5-methyl-1,2-piperidinedicarboxylate (i)
(2s,5r)-2-[[(benzyloxy)carbonyl]amino]-5-[(2r,4r)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid (iv)
(2s,5r)-2-[[(benzyloxy)carbonyl]amino]-5-[(2s,4r)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid (v)
methyl (3r,6s,9r,9ar)-6-[[(benzyloxy)carbonyl]amino]-9-methyl-5-oxooctahydro[1,3]thiazolo[3,2-a]azepine-3-carboxylate (vi)
(3r,6s,9r,9ar)-6-[[(benzyloxy)carbonyl]amino]-9-methyl-5-oxooctahydro[1,3]thiazolo[3,2-a]azepine-3-carboxylic acid (vii)
(3r,6s,9r,9ar)-6-amino-9-methyl-5-oxooctahydro[1,3]thiazolo[3,2-a]azepine-3-carboxylic acid (viii)
(2s,3s)-2-(acetylsulfanyl)-3-methylpentanoic acid (ix)
2,4-difluorobenzoic acid (x)
4-fluoro-2-hydroxybenzoic acid (xi)
(3-nitrophenyl)methanamine; 3-nitrobenzylamine (xii)
Reference 1:
    yoshioka, m.; synthetic studies related to oral beta-lactam antibiotics. pure appl chem 1987, 59, 8, 1041.

Route 3
synthesis of intermediate (i):1c) the bromination of diketene (xiii) followed by reaction with diphenylmethanol gives diphenylmethyl 4-bromoacetoacetate (xiv), which by cyclization with thiourea by means of k2co3 yields diphenylmethyl 2-(2-aminothiazol-4-yl)acetate (xv). the reaction of (xv) with benzyloxycarbonyl chloride and pyridine affords the protected compound (xvi), which is formylated with diphenyl methyl formiate (xvii) and nah to afford diphenyl methyl 2-(2-benzyloxycarbonylamino)thiazol-4-yl-3-hydroxyacrylate (xviii) the wittig condensation of (xviii) with benzyl triphenylphosphoranylidene acetate (xix) gives diphenylmethyl 2-[2-(benzyloxycarbonylamino)thiazol-4-yl]-4-(benzyloxycarbonyl)-2-butenoate (xx), which is selectively hydrolyzed with trifluoroacetic acid and anisole lo acid.
List of intermediates No.
methyl (1s,3as,4s,5s,7as)-4-(cyanomethyl)-7a-methyl-5-[(1r,3r,6r)-3-methyl-2-oxo-7-oxabicyclo[4.1.0]hept-3-yl]octahydro-1h-indene-1-carboxylate
2-[6-nitro-4-oxo-2h-chromen-3(4h)-ylidene]acetic acid (xiii)
(8s,11r,12s)-12-[[(benzyloxy)amino]carbonyl]-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8-carboxylic acid (xix)
2-benzhydryl 1-benzyl (2s,5r)-6-hydroxy-5-methyl-1,2-piperidinedicarboxylate (i)
3-methyltetrahydro-2h-pyran-2-one (xiv)
(2s,3s,5r,6s,11r)-2-[(benzyloxy)methyl]-3,11-dimethyl-1,7-dioxaspiro[5.5]undec-5-yl phenyl sulfone; (2s,3s,5r,6s,11r)-2-[(benzyloxy)methyl]-3,11-dimethyl-5-(phenylsulfonyl)-1,7-dioxaspiro[5.5]undecane (xv)
benzhydryl (2s,5r,6r)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate (xvi)
benzhydryl (2s,5r,6r)-6-[[(allyloxy)carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate (xvii)
benzhydryl (2s,5r,6r)-6-[[(allyloxy)carbonyl]amino]-3,3-dimethyl-4,7-dioxo-4lambda(4)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate (xviii)
2-[3,4-di(tert-butoxy)phenyl]acetic acid (xx)
Reference 1:
    yoshioka, m.; synthetic studies related to oral beta-lactam antibiotics. pure appl chem 1987, 59, 8, 1041.

Route 4
synthesis of intermediate (ii):2) the esterification of penicillin g (xxi) with diphenylmetbanol and pyridine gives the corresponding ester (xxii), which is oxidized with h2o2 and formic acid to the sulfoxide (xxiii). the reaction of (xxiii) with trimethyl phosphite in refluxing toluene yields the bicyclic thiazoline (xxiv), which is ozonolyzed with o3 in methanol dichloromethane affording the enol (xxv). the condensation of (xxv) with morpholine by means of p-toluenesulfonyl chloride in thf gives the enamine (xxvi), which by bromination with br2 in pyridine and hydrolysis with h2so4 in aqueous methanol is converted to diphenylmethyl 7beta-(phenylacetylamino)-3-hydroxy 3-cephem 4-carboxylate (xxviii) through the intermediate (xxvii).
List of intermediates No.
benzhydryl (2s,3r,5r,6r)-6-[[(allyloxy)carbonyl]amino]-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate (xxi)
benzhydryl (2r,3s,7r)-7-[[(allyloxy)carbonyl]amino]-3-([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylate (xxii)
benzhydryl (2s,3r,5r,6r)-6-amino-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate (xxiii)
benzhydryl (2s,3r,5r)-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-6,7-dioxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate (xxiv)
triphenyl(2-pyridinylmethyl)phosphonium chloride (xxv)
benzhydryl (2s,3r,5r)-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-6-[(z)-2-pyridinylmethylidene]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate (xxvi)
n-methoxy-n-methyl-3-(trifluoromethyl)benzamide (xxvii)
2-(2-fluoro-4-pyridinyl)-1-[3-(trifluoromethyl)phenyl]-1-ethanone (xxviii)
Reference 1:
    yoshioka, m.; synthetic studies related to oral beta-lactam antibiotics. pure appl chem 1987, 59, 8, 1041.

Route 5
synthesis of intermediate (ii):2a) the hydrogenation of (xxviii) with nabh4 in methanol - dichloromethane yields the cepham derivative (xxix), which by mesylation with mesyl chloride and hydrolysis with pcl5 and isobutanol is converted to diphenylmethyl 7beta-amino-3-(methanesulfonyloxy)cepham-4-carboxylate (xxx). finally, this compound is treated with triethylamine or nahco3 to obtain the cephem derivative (ii).2b) the elimination of the oh group of (xxviii) can also be performed by mesylation with mesyl chloride and hydrolysis with pcl5 and isobutanol to give diphenylmethyl 7beta-amino-3-(methanesulfonyloxy)-3-cephem-4-carboxylate (xxxi), which is then treated with zn in acidic medium to yield cephem derivative (ii).
List of intermediates No.
methyl (2s,4r)-2-((1r,4s)-5-(benzhydryloxy)-4-[[(benzyloxy)carbonyl]amino]-1-methyl-5-oxopentyl)-1,3-thiazolidine-4-carboxylate (ii)
2-(2-fluoro-4-pyridinyl)-1-[3-(trifluoromethyl)phenyl]-1-ethanone (xxviii)
1-(2-fluoro-4-pyridinyl)-2-[3-(trifluoromethyl)phenyl]-1,2-ethanedione 1-oxime (xxix)
4-formyl-n-cbz-piperidine; benzyl 4-formyl-1-piperidinecarboxylate (xxx)
benzyl 4-[5-(2-fluoro-4-pyridinyl)-1-hydroxy-4-[3-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]-1-piperidinecarboxylate (xxxi)
Reference 1:
    yoshioka, m.; synthetic studies related to oral beta-lactam antibiotics. pure appl chem 1987, 59, 8, 1041.

Route 6
the wittig condensation of diphenylmethyl 2-[2-(benzyloxycarbonylamino)thiazol-4 yl-2-formyl acetate with benzyloxycarbonylmethylene triphenylphosphorane (ii) in toluene or dioxane gives 2-[2-(benzyloxycarbonylamino)thiazol-4-yl]-4 (benzyloxycarbonyl)-2-butenoic acid diphenylmethyl ester (iii), which is hydrolyzed partiaily wth trifluoroacetic acid and anisole to the 2-butenoic acid (iv). the condensation of (iv) with 7-beta-amino-3-cephem-4-carboxylic acid benzyl ester (v) by means of dicyclohexylcarbodiimide (dcc) in dichloromethane affords the protected final product (vi), which is finally debenzylated by means of alcl3 and anisole in methylene chloride.
List of intermediates No.
(8s,11r,12s)-12-[[(benzyloxy)amino]carbonyl]-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8-carboxylic acid (ii)
2-benzhydryl 1-benzyl (2s,5r)-6-hydroxy-5-methyl-1,2-piperidinedicarboxylate (iv)
2-[3,4-di(tert-butoxy)phenyl]acetic acid (iii)
2-hydroxy-2-methyl-1-[4-(methylsulfanyl)phenyl]-1-propanone (i)
potassium 5-bromo-2-pyridinolate (v)
(2s,4s)-1-[(benzyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid (vi)
Reference 1:
    yoshida, t.; synthesis and biological properties of 7beta-[(z)-2-(2-amino-4-thiazoyl)-4-carboxy-2-butenoylamino]-3-cephem-4-carboxilic acid (7432-s), a new oral cephem antibiotic. j antibiot 1987, 40, 10, 1468.
Reference 2:
    hamashima, y. (shionogi & co. ltd.); 7-carboxyalkenoylamido-3-cephem-4-carboxylic acid derivs.. ep 0136721; es 8604602; es 8605278; es 8700222; gb 2154580; gb 2198727; jp 1985078987; jp 1985163884; jp 1985246388; us 4634697; us 4748170 .
Reference 3:
    castaner, j.; prous, j.; 7432-s. drugs fut 1987, 12, 12, 1117.

Route 7
the fermentation of cephalosporin c (i) with immobilized rhodoturula gracilis gives 3-(acetoxymethyl)-7(r)-(glutaroylamino)-3-cephem-4-carboxylic acid (ii), which is oxidized to the corresponding sulfoxide (iii). the electrochemical reduction of (ii) yields the exo-methylene derivative (iv), which is esterified with diphenyldiazomethane to afford the diphenylmethyl diester (v). the ozonolysis of (v) provides the enol (vi), which is reduced with nabh4 to the secondary alcohol (vii). the reaction of (vii) with ms-cl and tea gives the mesylate (viii), which by treatment with dea, yields the 3-cephem derivative (ix). the cleavage of the amido group of (ix) with pcl5 and pyridine affords 7(r)-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (x).
List of intermediates No.
Reference 1:
    chai, d.; et al.; ceftibuten: development of a commercial process based on cephalosporin c. part iv. pilot-plant scale electrochemical reduction of 3acetoxymethyl-7(s)-glytaroylaminoceph-3-em-4-carboxylic acid 1(s)-oxide. org process res dev 2002, 6, 2, 178.
Reference 2:
    bernasconi, e.; et al.; deftibuten: development of a commercial process based on cephalosporin c. part i. process for the manufacture of 3-acetoxymethyl-7(r-glutaroylaminoceph-3-em-4-carboxylic acid 1(s)-oxide. org process res dev 2002, 6, 2, 152.
Reference 3:
    bernasconi, e.; et al.; ceftibuten: development of a commercial process based on cephalosporin c. part iii. process for the conversion of 3-exomethylene-7(s)-glytaroylaminocepham-4-carboxylic acid 1(s)-oxide to ceftibuten. org process res dev 2002, 6, 2, 169.
Reference 4:
    bernasconi, e.; et al.; ceftibuten: development of commerci i process b sed on ceph losporin c. part ii. process for the manufacture of 3-exomethylene-7(r)-glutaroyllaminoceph m-4-carboxylic acid 1(s)-oxide. org process res dev 2002, 6, 2, 158.

Route 8
the condensation of the 7(r)-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (x) with 2-[2-(benzyloxycarbonylamino)thiazol-4-yl]-4-(3-methyl-2-butenyloxycarbonyl)-2-butenoic acid (xi) by means of pocl3 and tea gives the corresponding amide (xii), which is finally deprotected by means of alcl3 and anisole to afford the target ceftibuten.
List of intermediates No.
Reference 1:
    chai, d.; et al.; ceftibuten: development of a commercial process based on cephalosporin c. part iv. pilot-plant scale electrochemical reduction of 3acetoxymethyl-7(s)-glytaroylaminoceph-3-em-4-carboxylic acid 1(s)-oxide. org process res dev 2002, 6, 2, 178.
Reference 2:
    bernasconi, e.; et al.; ceftibuten: development of commerci i process b sed on ceph losporin c. part ii. process for the manufacture of 3-exomethylene-7(r)-glutaroyllaminoceph m-4-carboxylic acid 1(s)-oxide. org process res dev 2002, 6, 2, 158.
Reference 3:
    bernasconi, e.; et al.; ceftibuten: development of a commercial process based on cephalosporin c. part iii. process for the conversion of 3-exomethylene-7(s)-glytaroylaminocepham-4-carboxylic acid 1(s)-oxide to ceftibuten. org process res dev 2002, 6, 2, 169.
Reference 4:
    bernasconi, e.; et al.; deftibuten: development of a commercial process based on cephalosporin c. part i. process for the manufacture of 3-acetoxymethyl-7(r-glutaroylaminoceph-3-em-4-carboxylic acid 1(s)-oxide. org process res dev 2002, 6, 2, 152.

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名头孢布烯;英文名Ceftibuten;Sch-39720;7432-S;Ceprifran;Keimax;Isocef;Cedax;Seftem;CAS[97519-39-6]

 
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