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Name Cefpodoxime proxetil;RU-51807;U-76252;CS-807;Otreon;Vantin;Doxef;Orelox;Podomexef;Banan
Chemical Name (6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2(Z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-cephem-4-carboxylic acid 1-(isopropoxycarbonyloxy)ethyl ester
      [6R-(6alpha,7beta(Z)]-7-[(2-Amino-4-thiazolyl)(methoxyimino)acetylamino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1-[(1-methylethoxy)carbonyloxy]ethyl ester
CAS 87239-81-4
Related CAS 62628-58-4 (CS-807)
Formula C21H27N5O9S2
Structure
Formula Weight 557.60544
Stage 上市-1989
Company Sankyo (Originator), Aventis Pharma (Not Determined), Pfizer (Not Determined), Hosbon (Licensee), Ranbaxy (Generic)
Activity/Mechanism Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins
Syn. Route 5
Route 1
1) the methanolysis of 3-(acetoxymethyl)-7-[4-chloro-3-oxo-2(z)-(methoxyimino)butyrylamidol-3-cephem-4-carboxylic acid (i) with methanol and nahco3 gives the corresponding 3-(methoxymethyl) derivative (ii), which is esterified with 1-iodoethylisopropyl carbonate (iii) by means of dicyclohexylamine in dma to afford the corresponding ester (iv). finally, this compound is cyclized with thiourea (v) and methyl iodide in a phosphate buffer.
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 (v)
(4as,10ar)-8-hydroxy-7-isopropyl-4a-methyl-3,4,4a,9,10,10a-hexahydro-1(2h)-phenanthrenone (iii)
2-(benzyloxy)-2-oxoethyl 4-[(z)-2-(4-chlorobenzoyl)-2-(4-methoxyphenyl)hydrazono]pentanoate (i)
2-(benzyloxy)-2-oxoethyl 2-(5-methoxy-2-methyl-1h-indol-3-yl)acetate (ii)
n-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide (vi)
4-(3-methoxyphenyl)-4-oxo-2-phenylbutanenitrile
Reference 1:
    fujimoto, k.; nakayama, e.; nakao, h. (sankyo co., ltd.); process for preparing 3-alkoxymethylcephalosporin derivatives. de 3244457 .
Reference 2:
    fujimoto, k.; ishihara, s.; yanagisawa, h.; ide, j.; nakayama, e.; nakao, h.; sugawara, s.; iwata, m.; studies on orally active cephalosporin esters. j antibiot 1987, 40, 3, 370.
Reference 3:
    castaner, j.; serradell, m.n.; cefpodoxime proxetil. drugs fut 1988, 13, 1, 16.

Route 2
2) the free acid (ii) can be cyclized with thiourea in a similar way as before to give 7-[2 (2-amino-thiazol-4-yl)-2-(z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-cephem 4-carboxylic acid (vi), which is finally esterified with the iodoester (iii) as before.
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 (v)
(4as,10ar)-8-hydroxy-7-isopropyl-4a-methyl-3,4,4a,9,10,10a-hexahydro-1(2h)-phenanthrenone (iii)
2-(benzyloxy)-2-oxoethyl 4-[(z)-2-(4-chlorobenzoyl)-2-(4-methoxyphenyl)hydrazono]pentanoate (i)
2-(benzyloxy)-2-oxoethyl 2-(5-methoxy-2-methyl-1h-indol-3-yl)acetate (ii)
5-chloro-1-(4-piperidinyl)-1,3-dihydro-2h-benzimidazol-2-one; 5-chloro-1-(4-piperidinyl)-2-benzimidazolidinone (iv)
Reference 1:
    fujimoto, k.; nakayama, e.; nakao, h. (sankyo co., ltd.); process for preparing 3-alkoxymethylcephalosporin derivatives. de 3244457 .
Reference 2:
    castaner, j.; serradell, m.n.; cefpodoxime proxetil. drugs fut 1988, 13, 1, 16.
Reference 3:
    fujimoto, k.; ishihara, s.; yanagisawa, h.; ide, j.; nakayama, e.; nakao, h.; sugawara, s.; iwata, m.; studies on orally active cephalosporin esters. j antibiot 1987, 40, 3, 370.

Route 3
3) the iodoester (iii) is obtained as follows: the chlorination of ethyl chloroformate (vii) with so2cl2 and benzoyl peroxide gives 1-chloroethyl-chloroformate (viii), which is esterified with o-propanol in pyridine to afford 1-chloroethyl isopropyl carbonate (ix). finally, this compound is iodinated with nai and 18-crown-6 in refluxing benzene.
List of intermediates No.
(4as,10ar)-8-hydroxy-7-isopropyl-4a-methyl-3,4,4a,9,10,10a-hexahydro-1(2h)-phenanthrenone (iii)
[5-chloro-2-(methylamino)phenyl](phenyl)methanone (vii)
n-(2-benzoyl-4-chlorophenyl)-2-bromo-n-methylacetamide (viii)
2-amino-n-(2-benzoyl-4-chlorophenyl)-n-methylacetamide (ix)
Reference 1:
    fujimoto, k.; nakayama, e.; nakao, h. (sankyo co., ltd.); process for preparing 3-alkoxymethylcephalosporin derivatives. de 3244457 .
Reference 2:
    castaner, j.; serradell, m.n.; cefpodoxime proxetil. drugs fut 1988, 13, 1, 16.
Reference 3:
    fujimoto, k.; ishihara, s.; yanagisawa, h.; ide, j.; nakayama, e.; nakao, h.; sugawara, s.; iwata, m.; studies on orally active cephalosporin esters. j antibiot 1987, 40, 3, 370.

Route 4
a new process for the preparation of cefpodoxime, which can be converted into cefpodoxime proxetil by known methods, has been described:the condensation of 2-(2-aminothiazol-4-yl)-2(z)-(methoxyimino)acetic acid 2-benzothiazolyl ester (i) with (6r,7r)-7-amino-3-(methoxymethyl)-3-cephem-4-carboxylic acid (ii) by means of an organic base such as et3n, pyridine, n-methylpiperidine, dbu or dmap in either thf/water, acetone/water, dmf/water, dimethylacetamide or dichloromethane directly gives cefpodoxime (iii).
List of intermediates No.
n-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide (iii)
(2r,4ar,6r,7r,8r,8as)-6-{[(2r,3s,4r,5r,6s)-6-{[(1r,2s,3r,4r,5r)-3,4-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2h-pyran-3-yl]oxy}-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-7,8-diol (i)
(2r,4ar,6r,7r,8s,8ar)-7-(acetyloxy)-6-[((2r,3r,4s,5r,6r)-4,5-bis(acetyloxy)-2-[(acetyloxy)methyl]-6-{[(1r,2r,3s,4r,5r)-3,4-bis(acetyloxy)-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}tetrahydro-2h-pyran-3-yl)oxy]-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl acetate (ii)
Reference 1:
    nizar, h.; singh, k.; khanna, j.m.; kumar, y.; de, s.; arora, r.k. (ranbaxy laboratories ltd.); process for the preparation of cefpodoxime acid. wo 0068234 .

Route 5
the condensation of 7-amino-3-(methoxymethyl)-3-cephem-4-carboxylic acid (i) with 4-bromo-2-(methoxyimino)-3-oxobutyric acid (ii) by means of pcl5 and hmds in dichloromethane gives the butyramide (iii), which is cyclized with thiourea (iv) by means of na-oac in water to yield the thiazol derivative (iv). finally, the carboxy group of (iv) is esterified with 1-iodoethyl isopropyl carbonate (vi) by means of dbu in dma to afford the target cefpodoxime proxetil.
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 (iv)
n-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide (v)
(2r,4ar,6r,7r,8s,8ar)-7-(acetyloxy)-6-[((2r,3r,4s,5r,6r)-4,5-bis(acetyloxy)-2-[(acetyloxy)methyl]-6-{[(1r,2r,3s,4r,5r)-3,4-bis(acetyloxy)-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}tetrahydro-2h-pyran-3-yl)oxy]-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl acetate (i)
Reference 1:
    kumar, y.; nizar, h.; tewari, n.; rai, b.p.; aryan, r.c. (ranbaxy laboratories ltd.); process for the preparation of cefpodoxime acid. wo 0283634 .

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泊肟酯;英文名Cefpodoxime proxetil;RU-51807;U-76252;CS-807;Otreon;Vantin;Doxef;Orelox;Podomexef;Banan;CAS[87239-81-4]

 
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