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藥物詳細合成路線

Name Cefoperazone sodium;T-1551;Cefoperazin;Cefoper;Cefobis
Chemical Name 7-[D-(-)-alpha-(4-Ethyl-2,3-dioxo-1-piperazinecarboxamido)-alpha-(4-hydroxyphenyl)acetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid sodium salt
CAS 62893-20-3
Related CAS 62893-19-0 (free acid)
Formula C25H26N9NaO8S2
Structure
Formula Weight 667.65927
Stage 上市-1981
Company Pfizer (Originator), Malesci (Licensee), Toyama (Licensee)
Activity/Mechanism Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins
Syn. Route 5
Route 1
by condensation of alpha-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphenylacetic acid (i) with 7-amino-3-[(1-methyl-1h-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (ii) by means of ethyl chlorocarbonate and n,o-bis(trimethylsilyl)acetamide in acetonitrile.
List of intermediates No.
(ii)
(2s,3r,4s,6r)-4-(dimethylamino)-2-[[(3r,5r,6r,7r,9r,13s,14r)-13-hydroxy-7-methoxy-3,5,7,9,11,13,14-heptamethyl-2,4,10-trioxooxa-11-cyclotetradecen-6-yl]oxy]-6-methyltetrahydro-2h-pyran-3-yl acetate (i)
(2r,3s,7r,9r,10r,11r,13r)-10-[[(2s,3r,4s,6r)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2h-pyran-2-yl]oxy]-9-methoxy-2,3,5,7,9,11,13-heptamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1h-imidazole-1-carboxylate (a)
Reference 1:
    saikawa, i.; et al.; nouvelles céphaslosporines, leur procédé de préparation et leur application en thérapeutique. be 0837682 .
Reference 2:
    castaner, j.; serradell, m.n.; blancafort, p.; t-1551. drugs fut 1979, 4, 9, 675.

Route 2
the condensation of n-(1-methoxycarbonyl-1-propen-2-yl)-alpha-amino-p-hydroxyphenylacetic sodium salt (iii) with 7-amino-3-[(1-methyl-1h-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylic acid (ii) by means of ethyl chlorocarbonate and n,o-bis(trimethylsilyl)acetamide (a) in acetonitrile gives 7-(alpha-amino-p-hydroxy-phenylacetamido)-3-[(1-methyl-1h-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (iv), which is then condensed with 4-ethyl-2,3-dioxopiperazino-1-carbonyl chloride (v) by means of k2co3 in ethyl acetate water.
List of intermediates No.
2-[2-[2-(3,3-diphenylpropyl)-1h-imidazol-4-yl]ethyl]-1h-isoindole-1,3(2h)-dione (v)
(ii)
(2r,3s,7r,9r,10r,11r,13r)-10-[[(2s,3r,4s,6r)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2h-pyran-2-yl]oxy]-9-methoxy-2,3,5,7,9,11,13-heptamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1h-imidazole-1-carboxylate (a)
4-(4-quinolinyl)butylamine; 4-(4-quinolinyl)-1-butanamine (iii)
(2r)-2-amino-2-(4-hydroxycyclohexyl)ethanoic acid (iv)
Reference 1:
    saikawa, i.; et al.; nouvelles céphaslosporines, leur procédé de préparation et leur application en thérapeutique. be 0837682 .
Reference 2:
    castaner, j.; serradell, m.n.; blancafort, p.; t-1551. drugs fut 1979, 4, 9, 675.

Route 3
the condensation of alpha-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphenylacetic acid (i) with 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (vi) by means of ethyl chlorocarbonate and n,o-bis(trimethylsilyl)acetamide (a) gives the 3-acetoxymethyl derivate (vii), which is then condensed with 1-methyl-5-mercapto-1h-tetrazole (viii) by means of nahco3 in a phosphate buffer.
List of intermediates No.
tert-butyl (1s)-2-[[(1s)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethylcarbamate (viii)
(2s,3r,4s,6r)-4-(dimethylamino)-2-[[(3r,5r,6r,7r,9r,13s,14r)-13-hydroxy-7-methoxy-3,5,7,9,11,13,14-heptamethyl-2,4,10-trioxooxa-11-cyclotetradecen-6-yl]oxy]-6-methyltetrahydro-2h-pyran-3-yl acetate (i)
(2r,3s,7r,9r,10r,11r,13r)-10-[[(2s,3r,4s,6r)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2h-pyran-2-yl]oxy]-9-methoxy-2,3,5,7,9,11,13-heptamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1h-imidazole-1-carboxylate (a)
4-ethoxybenzenesulfonyl chloride (vi)
(2r)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-hydroxycyclohexyl)ethanoic acid (vii)
Reference 1:
    saikawa, i.; et al.; nouvelles céphaslosporines, leur procédé de préparation et leur application en thérapeutique. be 0837682 .
Reference 2:
    castaner, j.; serradell, m.n.; blancafort, p.; t-1551. drugs fut 1979, 4, 9, 675.

Route 4
the condensation of acetoxymethyl derivative (vi) with n-(1-methoxycarbonyl-1-propen-2-yl)-alpha-amino-p-hydroxyphenylacetic sodium salt (iii) by means of ethyl chlorocarbonate and n,o-bis(trimethylsilyl)acetamide (a) gives 7-(alpha-amino-p-hydroxyphenylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid (ix), which is then condensed with acyl chloride (v) by means of k2co3 in ethyl acetate water to afford (vii), which is then condensed with 1-methyl-5-mercapto-1h-tetrazole (viii) by means of nahco3 in a phosphate buffer.
List of intermediates No.
2-[2-[2-(3,3-diphenylpropyl)-1h-imidazol-4-yl]ethyl]-1h-isoindole-1,3(2h)-dione (v)
tert-butyl (1s)-2-[[(1s)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethylcarbamate (viii)
(ix)
(2r,3s,7r,9r,10r,11r,13r)-10-[[(2s,3r,4s,6r)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2h-pyran-2-yl]oxy]-9-methoxy-2,3,5,7,9,11,13-heptamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1h-imidazole-1-carboxylate (a)
4-(4-quinolinyl)butylamine; 4-(4-quinolinyl)-1-butanamine (iii)
4-ethoxybenzenesulfonyl chloride (vi)
(2r)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-hydroxycyclohexyl)ethanoic acid (vii)
Reference 1:
    saikawa, i.; et al.; nouvelles céphaslosporines, leur procédé de préparation et leur application en thérapeutique. be 0837682 .
Reference 2:
    castaner, j.; serradell, m.n.; blancafort, p.; t-1551. drugs fut 1979, 4, 9, 675.

Route 5
the condensation of (ii) with the substituted phenylacetic acid (x) by means of ethyl chlorocarbonate gives the cephalosporin (xi), which is then cyclized by means of nah in ethanol.
List of intermediates No.
(ii)
benzyl (2r)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-hydroxycyclohexyl)ethanoate (x)
benzyl (2r)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-oxocyclohexyl)ethanoate (xi)
Reference 1:
    saikawa, i.; et al. (toyama chemical co., ltd.); process for preparation of novel penicilins and cephalosporins. jp 52036684 .
Reference 2:
    castaner, j.; serradell, m.n.; blancafort, p.; t-1551. drugs fut 1979, 4, 9, 675.

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名頭孢哌酮鈉;英文名Cefoperazone sodium;T-1551;Cefoperazin;Cefoper;Cefobis;CAS[62893-20-3]

 
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