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药物详细合成路线

Name Cefonicid sodium;SK&F-D-75073-Z2;Monocid
Chemical Name [6R-[6alpha,7beta(R*)]]-7-[(Hydroxyphenylacetyl)amino]-8-oxo-3-[[[1-(sulfomethyl)-1H-tetrazol-5-yl]thio]methyl]-5-thia]-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt;(6R,7R)-[(R)-Mandelamido]-8-oxo-3-[[[(1-sulfomethyl)-1H-tetrazol-5-yl]thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt
CAS 61270-78-8
Related CAS 61270-58-4 (free acid)
Formula C18H16N6Na2O8S3
Structure
Formula Weight 586.53522
Stage 上市-1984
Company GlaxoSmithKline (Originator)
Activity/Mechanism Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins
Syn. Route 3
Route 1
the reaction of aminomethansulfonic acid (i) with phthalic anhydride (ii) by means of potassium acetate in refluxing acetic acid gives phthalimidomethansulfonic acid (iii), which by reaction with pcl5 in refluxing benzene is converted into its acyl chloride (iv). the condensation of (iv) with tert-butylamine (a) in chcl3 affords n-tert-butylphthalimidomethansulfonamide (v), which by reaction with hydrazine hydrate in refluxing ethanol yields 2-aminomethan-n-tert-butylsulfonamide (vi). the reaction of (vi) with cs2 and mei by means of triethylamine in ethanol gives n-tert-butylsulfamoylmethyldithiocarbamic acid methyl ester (vii), which is cyclized with nan3 in hot water to afford 1-(n-tert-butylsulfamoylmethyl)tetrazol-5-thiol (viii). the hydrolysis of (viii) with trifluoroacetic acid yields compound 1-sulfamoylmethyltetrazol-5-thiol (ix).
List of intermediates No.
2-isopropoxy-1-ethanol (ii)
(1s,5s,7r,9r,12r)-10-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-(4-methoxyphenyl)-6,8-dioxatetracyclo[10.4.1.0(1,5).0(5,9)]heptadeca-2,10-diene-4,17-dione (a)
(2s)-2-amino-3-cyclohexylpropanamide (i)
1-methylpiperidine (iii)
benzyl (3s)-3-amino-4-[[(1r)-2-amino-1-(cyclohexylmethyl)-2-oxoethyl]amino]-4-oxobutanoate (iv)
2-[(tert-butoxycarbonyl)(ethyl)amino]acetic acid (v)
benzyl (3s)-4-[[(1r)-2-amino-1-(cyclohexylmethyl)-2-oxoethyl]amino]-3-[[2-(ethylamino)acetyl]amino]-4-oxobutanoate (vi)
4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butyric acid (vii)
tert-butyl 4-[4-[(2-[[(1s)-1-([[(1r)-2-amino-1-(cyclohexylmethyl)-2-oxoethyl]amino]carbonyl)-3-(benzyloxy)-3-oxopropyl]amino]-2-oxoethyl)(ethyl)amino]-4-oxobutyl]-1-piperidinecarboxylate (viii)
2-(4-piperidinyl)acetic acid; 4-piperidinylacetic acid (ix)
Reference 1:
    berges, d.a.; 7-acyl-3-(sulfonic acid and sulfamoyl substituted tetrazolyl thiomethyl)cephalosporins.. de 2611270; fr 2304343; us 4048311 .
Reference 2:
    castaner, j.; serradell, m.n.; thorpe, p.; blancafort, p.; cefonicid sodium. drugs fut 1979, 4, 9, 634.

Route 2
compound 1-sulfamoylmethyltetrazol-5-thiol (ix) can also be obtained by reaction of (i) with cs2 and mei by means of koh in refluxing ethanol to give sulfomethyldithiocarbamic acid methyl ester (xiii), which is then cyclized with nan3 in hot water.
List of intermediates No.
(2s)-2-amino-3-cyclohexylpropanamide (i)
2-(4-piperidinyl)acetic acid; 4-piperidinylacetic acid (ix)
diethyl 2-[2-(4-pyridinyl)ethyl]malonate (xiii)
Reference 1:
    berges, d.a.; 7-acyl-3-(sulfonic acid and sulfamoyl substituted tetrazolyl thiomethyl)cephalosporins.. de 2611270; fr 2304343; us 4048311 .
Reference 2:
    castaner, j.; serradell, m.n.; thorpe, p.; blancafort, p.; cefonicid sodium. drugs fut 1979, 4, 9, 634.

Route 3
a) by reaction of 1-sulfamoylmethyltetrazol-5-thiol (ix) with 7-mandelamidocephalosporanic acid (xii) by means of nahco3.b) bycondensation of 1-sulfamoylmethyltetrazol-5-thiol (ix) with 7-aminocephalosporanic acid (x) by means of nahco3 in acetone - water to give 7-amino-3-(1-sulfamoyl-methyltetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (xi). finally, this compound is acylated with d-o-dichloroacetylmandeloyl chloride (a) by means of nahco3 in acetone-water to afford the target compound.b) bycondensation of 1-sulfamoylmethyltetrazol-5-thiol (ix) with 7-aminocephalosporanic acid (x) by means of nahco3 in acetone - water to give 7-amino-3-(1-sulfamoyl-methyltetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (xi). finally, this compound is acylated with d-o-dichloroacetylmandeloyl chloride (a) by means of nahco3 in acetone-water to afford the target compound.
List of intermediates No.
tert-butyl (1r)-1-[(1s)-2-[(2s)-2-([[(1s)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-1-hydroxy-2-oxoethyl]-3-methylbutylcarbamate (x)
2-(4-piperidinyl)acetic acid; 4-piperidinylacetic acid (ix)
tert-butyl 4-[(e)-4-methoxy-4-oxo-2-butenyl]-1-piperidinecarboxylate (xii)
tert-butyl 4-(4-methoxy-4-oxobutyl)-1-piperidinecarboxylate (xi)
4-vinylpyridine (a)
Reference 1:
    berges, d.a.; 7-acyl-3-(sulfonic acid and sulfamoyl substituted tetrazolyl thiomethyl)cephalosporins.. de 2611270; fr 2304343; us 4048311 .
Reference 2:
    castaner, j.; serradell, m.n.; thorpe, p.; blancafort, p.; cefonicid sodium. drugs fut 1979, 4, 9, 634.

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尼西钠;英文名Cefonicid sodium;SK&F-D-75073-Z2;Monocid;CAS[61270-78-8]

 
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