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药物详细合成路线

Name Cefoxitin;Mefoxitin;Mefoxin
Chemical Name 3-Carbamoyloxymethyl-7alpha-methoxy-7beta-(2-thienylacetamido)-3-cephem-4-carboxylic acid sodium salt
CAS
Related CAS 35607-66-0 (free acid)
Formula C16H17N3O7S2
Structure
Formula Weight 427.45779
Stage 上市-1977
Company Merck Sharp & Dohme (Originator)
Activity/Mechanism Antibiotics, ANTIINFECTIVE THERAPY
Syn. Route 6
Route 1
3) by reaction of 4-methoxybenzylamine (i) with methyl isothiocyanate (b) in ether to yield n-(4-methoxybenzyl)-n-methylthiourea (iii), which is then methylated with mei in refluxing methanol affording n-(4-methoxybenzyl)-n,s-dimethylisothiourea (iv). finally, this compound is treated first with methylamine in refluxing methanol and then with h2so4.
List of intermediates No.
methyl 3-[5-(2-chlorophenyl)-2-oxo-2,3-dihydro-1h-thieno[2,3-e][1,4]diazepin-7-yl]propanoate (b)
4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2h-1,4-benzothiazine-7-carboxylic acid (a)
n-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2h)-naphthalenylidene]-n-methylamine; n-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2h)-naphthalenylidene]methanamine (c)
ethyl 2-[4-amino-2-cyano-3-(methylamino)phenyl]-2-methyl-3-oxobutanoate (i)
2,6-dichlorophenyl isothiocyanate (ii)
ethyl 2-[2-cyano-4-({[(2,6-dichlorophenyl)amino]carbothioyl}amino)-3-(methylamino)phenyl]-2-methyl-3-oxobutanoate (iii)
ethyl 2-{7-cyano-2-[(2,6-dichlorophenyl)amino]-1-methyl-1h-benzimidazol-6-yl}-2-methyl-3-oxobutanoate (iv)
2-[(2,6-dichlorophenyl)amino]-1,6,7-trimethyl-1,8-dihydro-9h-imidazo[4,5-h]isoquinolin-9-one (v)
2-[(2,6-dichlorophenyl)amino]-1,6-dimethyl-9-oxo-8,9-dihydro-1h-imidazo[4,5-h]isoquinoline-7-carbaldehyde (vi)
2-[(2,6-dichlorophenyl)amino]-7-(1-hydroxy-2-propenyl)-1,6-dimethyl-1,8-dihydro-9h-imidazo[4,5-h]isoquinolin-9-one (vii)
1-{2-[(2,6-dichlorophenyl)amino]-1,6-dimethyl-9-oxo-8,9-dihydro-1h-imidazo[4,5-h]isoquinolin-7-yl}-2-propenyl acetate (viii)
3-(bromomethyl)-1,1-biphenyl (ix)
1-bromo-3,5-dimethyltricyclo[3.3.1.1~3,7~]decane (x)
(xi)
6-[(4-phenylbutyl)oxy]hexyl methanesulfonate (xii)
2-phenyl-2-({6-[(4-phenylbutyl)oxy]hexyl}amino)-1-ethanol (xiii)
methyl 5-(2-bromoacetyl)-2-[(phenylmethyl)oxy]benzoate (xiv)
methyl 5-[2-((2-hydroxy-1-phenylethyl){6-[(4-phenylbutyl)oxy]hexyl}amino)acetyl]-2-[(phenylmethyl)oxy]benzoate (xv)
Reference 1:
    castaner, j.; loren, j.g.; cefoxitin. drugs fut 1978, 3, 6, 434.
Reference 2:
    christensen, b.g.; ratcliffe, r.w.; total synthesis of beta-lactam antibiotics. i. alpha-thioformamido-diethylphosphonioacetates. tetrahedron lett 1973, 46, 4645-48.
Reference 3:
    christensen, b.g.; ratcliffe, r.w.; total synthesis of beta-lactam antibiotics. ii. (rac)-cephalotin. tetrahedron lett 1973, 46, 4649-52.
Reference 4:
    christensen, b.g.; ratcliffe, r.w. (merck & co., inc.); 7-azido-cephalosporin compounds and their preparation. de 2365406; fr 2182953; gb 1424373; jp 49014488 .

Route 2
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.
List of intermediates No.
(3ar,6as)-4-[(z,3s)-2-bromo-3-hydroxy-4-methyl-1-octenyl]hexahydro-2h-cyclopenta[b]furan-2-one (e)
methyl 5-[2-((2-hydroxy-1-phenylethyl){6-[(4-phenylbutyl)oxy]hexyl}amino)acetyl]-2-[(phenylmethyl)oxy]benzoate (xv)
(1r)-1-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[(1r)-2-hydroxy-1-phenylethyl][6-(4-phenylbutoxy)hexyl]amino}-1-ethanol (d)
2-bromo-1-(2,2-dimethyl-4h-1,3-benzodioxin-6-yl)-1-ethanone (xvi)
1-(2,2-dimethyl-4h-1,3-benzodioxin-6-yl)-2-[(2-hydroxy-1-phenylethyl)amino]-1-ethanone (xvii)
(1r)-1-(2,2-dimethyl-4h-1,3-benzodioxin-6-yl)-2-{[(1s)-2-hydroxy-1-phenylethyl]amino}-1-ethanol (xviii)
6-[(4-phenylbutyl)oxy]hexanal (xix)
(1r)-1-(2,2-dimethyl-4h-1,3-benzodioxin-6-yl)-2-{[(1s)-2-hydroxy-1-phenylethyl][6-(4-phenylbutoxy)hexyl]amino}-1-ethanol (xx)
2,3,4,5-tetrahydroxypentanal (xxi)
Reference 1:
    ratcliffe, r.w.; christensen, b.g.; total synthesis of beta-lactam antibiotics. iii. (rac)-cefoxitin. tetrahedron lett 1973, 46, 4653-56.
Reference 2:
    castaner, j.; loren, j.g.; cefoxitin. drugs fut 1978, 3, 6, 434.
Reference 3:
    christensen, b.g.; ratcliffe, r.w. (merck & co., inc.); 7-azido-cephalosporin compounds and their preparation. de 2365406; fr 2182953; gb 1424373; jp 49014488 .
Reference 4:
    christensen, b.g.; cama, l.d. (merck & co., inc.); antibiotics and processes for their production. de 2203653; fr 2161866; gb 1350772 .

Route 3
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.
List of intermediates No.
3-sulfanyl-1-propanol (g)
(3ar,6as)-4-[(z,3s)-2-bromo-3-hydroxy-4-methyl-1-octenyl]hexahydro-2h-cyclopenta[b]furan-2-one (e)
tert-butyl (1r)-1-[(1s)-2-[(2s)-2-([[(1s)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-1-hydroxy-2-oxoethyl]-3-methylbutylcarbamate (xxii)
1,1-dimethylethyl 2,2-dimethyl-4-(phenylmethyl)-5-[4-(2-pyridinyloxy)butanoyl]-1,3-oxazolidine-3-carboxylate (xxvii)
2-amino-3-hydroxy-1-phenyl-7-(2-pyridinyloxy)-4-heptanone (xxvi)
methyl 5-(2-bromoacetyl)-2-[(phenylmethyl)oxy]benzoate (xiv)
5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)tetrahydro-2,3,4-furantriol (f)
2,4-bis(acetyloxy)-5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)tetrahydro-3-furanyl acetate (xxiii)
4-(acetyloxy)-2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3-furanyl acetate (xxiv)
4-(acetyloxy)-2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3-furanyl acetate (xxv)
2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3,4-furandiol (xxviii)
4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-2-(2-propenyl)tetrahydro-3-furanol (xxxii)
(1,1-dimethylethyl)({[3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-(methyloxy)-5-(2-propenyl)tetrahydro-2-furanyl]methyl}oxy)diphenylsilane; (1,1-dimethylethyl)(dimethyl)silyl 2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-4-(methyloxy)-5-(2-propenyl)tetrahydro-3-furanyl ether (xxx)
Reference 1:
    castaner, j.; loren, j.g.; cefoxitin. drugs fut 1978, 3, 6, 434.
Reference 2:
    hazen, g.c. (merck & co., inc.); process for preparin cephalosporin compounds. dd 100957; es 408969; us 3780033 .
Reference 3:
    christensen, b.g.; firestone, r.a.; process for preparing cephalosporin compounds. dd 100956; es 408970; us 3775410 .
Reference 4:
    christensen, b.g.; cama, l.d. (merck & co., inc.); process for preparing penicillin and cephalosporin compounds. fr 2163144; gb 1401060; us 3843641 .

Route 4
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.
List of intermediates No.
2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3,4-furandiol (xxviii)
(1,1-dimethylethyl)({[3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-(methyloxy)-5-(2-propenyl)tetrahydro-2-furanyl]methyl}oxy)diphenylsilane; (1,1-dimethylethyl)(dimethyl)silyl 2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-4-(methyloxy)-5-(2-propenyl)tetrahydro-3-furanyl ether (xxxi)
2-(hydroxymethyl)-4-(methyloxy)-5-(2-propenyl)tetrahydro-3-furanol (xxix)
[3-hydroxy-4-(methyloxy)-5-(2-propenyl)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate (xxx)
Reference 1:
    castaner, j.; loren, j.g.; cefoxitin. drugs fut 1978, 3, 6, 434.
Reference 2:
    christensen, b.g.; cama, l.d. (merck & co., inc.); process for preparing penicillin and cephalosporin compounds. fr 2163144; gb 1401060; us 3843641 .
Reference 3:
    hazen, g.c. (merck & co., inc.); process for preparin cephalosporin compounds. dd 100957; es 408969; us 3780033 .

Route 5
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.
List of intermediates No.
(3ar,6as)-4-[(z,3s)-2-bromo-3-hydroxy-4-methyl-1-octenyl]hexahydro-2h-cyclopenta[b]furan-2-one (e)
6-(2-oxiranyl)-2-phenyl-4h-[1,3]dioxino[5,4-b]pyridine (h)
[4-(methyloxy)-3-[(phenylmethyl)oxy]-5-(2-propenyl)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate (xxxiii)
{5-(2,3-dihydroxypropyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate (xxxiv)
{5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate (xxxv)
Reference 1:
    weinstock, l.m.; preparation of 7-acylaminocephalosporin derivatives. de 2456528; fr 2253022; gb 1480757; jp 50105687 .
Reference 2:
    castaner, j.; loren, j.g.; cefoxitin. drugs fut 1978, 3, 6, 434.

Route 6
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.
List of intermediates No.
(3ar,6as)-4-[(z,3s)-2-bromo-3-hydroxy-4-methyl-1-octenyl]hexahydro-2h-cyclopenta[b]furan-2-one (e)
tert-butyl (1r)-1-[(1s)-2-[(2s)-2-([[(1s)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-1-hydroxy-2-oxoethyl]-3-methylbutylcarbamate (xxii)
(1r)-1-(2,2-dimethyl-4h-1,3-benzodioxin-6-yl)-2-{[(1s)-2-hydroxy-1-phenylethyl][6-(4-phenylbutoxy)hexyl]amino}-1-ethanol (xx)
[5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-hydroxy-4-(methyloxy)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate (xxxvi)
[5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-oxotetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate (xxxvii)
[(2r,4r,5r)-5-((2s)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-methoxy-3-methylenetetrahydro-2-furanyl]methyl pivalate (xxxviii)
[(2r,3s,4r,5r)-5-((2s)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-methoxytetrahydro-2-furanyl]methyl pivalate (xxxix)
[(2r,3r,4r,5r)-5-((2s)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-formyl-4-methoxytetrahydro-2-furanyl]methyl pivalate (xl)
[5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate (xli)
Reference 1:
    christensen, b.g.; et al.; in 7-stellung substituierte cephalosphoransaureester und verfahren zu ihrer herstellung. de 2143331 .
Reference 2:
    castaner, j.; loren, j.g.; cefoxitin. drugs fut 1978, 3, 6, 434.
Reference 3:
    christensen, b.g.; cama, l.d. (merck & co., inc.); antibiotics and processes for their production. de 2203653; fr 2161866; gb 1350772 .

 
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