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药物详细合成路线

Name Cefoselis sulfate;FK-037;Wincef
Chemical Name 5-Amino-2-[(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2(Z)-(methoxyimino)acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-ylmethyl]-1-(2-hydroxyethyl)-1H-pyrazolium sulfate (1:1)
      (6R,7R)-3-[3-Amino-2-(2-hydroxyethyl)-1-pyrazoliomethyl]-7-[2-(2-aminothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]-3-cephem-4-carboxylic acid hydrogen sulfate
CAS 122841-12-7
Related CAS 122841-10-5 (free base)
Formula C19H24N8O10S3
Structure
Formula Weight 620.64273
Stage 上市-1998
Company Fujisawa (Originator), Johnson & Johnson (Licensee)
Activity/Mechanism Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins
Syn. Route 2
Route 1
fk-037 can be obtained by related ways:1) the formylation of 5-amino-1-(2-hydroxyethyl)pyrazole (i) with formic acid - acetic anhydride gives 5-formamido-1-(2-hydroxyethyl)pyrazole (ii), which is condensed with 7beta-(tert-butoxycarbonylamino)-3-(chloromethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester (iii) by means of nai in dmf, yielding 7beta-(tert-butoxycarbonylamino)-3-[3-formamido-2-(2-formyloxyethyl)-1-pyrazoliomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester iodide (iv). the treatment of (iv), first with trifluoroacetic acid and anisole and then with hcl, affords 7beta-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazoliomethyl]-3-cephem-4-carboxylic acid chloride (v). the condensation of (v) with 2-(2-formamidothiazol-4-yl)-2(z)-(methoxyimino)acetic acid (vi) by means of pocl3 in ethyl acetate gives 3-[3-amino-2-(2-hydroxyethyl)-1-pyrazoliomethyl]-7beta-[2-(2-formamido-thiazol-4-yl)-2(z)-(methoxyimino)acetamido]-3-cephem-4-carboxylate (vii), which is deformylated with hcl affording 3-[3-amino-2-(2-hydroxyethyl)-1-pyrazoliomethyl]-7beta-[2-(2-aminothiazol-4-yl)-2(z)-(methoxyimino)acetamido]-3-cephem-4-carboxylate (viii). finally, this compound is treated with h2so4 to give fk-037.2) compound (viii) can also be obtained by condensation of (v) with 1-[2-(2-aminothiazol-4-yl)-2(z)-(methoxyimino)acetyl]benzo- triazole-3-oxide (ix) in thf.
List of intermediates No.
methyl 4-(2-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (i)
4-[1-(4-chlorobenzyl)hydrazino]phenyl methyl ether (ii)
methyl 5-(tert-butylsulfanyl)-2,2-dimethyl-4-oxopentanoate (iii)
methyl 3-[3-(tert-butylsulfanyl)-1-(4-chlorobenzyl)-5-methoxy-1h-indol-2-yl]-2,2-dimethylpropanoate (iv)
methyl 3-[3-(tert-butylsulfanyl)-1-(4-chlorobenzyl)-5-hydroxy-1h-indol-2-yl]-2,2-dimethylpropanoate (v)
2-(bromomethyl)pyridine (vi)
methyl 3-[3-(tert-butylsulfanyl)-1-(4-chlorobenzyl)-5-(2-pyridinylmethoxy)-1h-indol-2-yl]-2,2-dimethylpropanoate (vii)
(2s)-2-[(tert-butoxycarbonyl)amino]-3-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid (viii)
(2s)-2-[((2s)-2-[(tert-butoxycarbonyl)amino]-3-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)amino]-4-methylpentanoic acid (ix)
Reference 1:
    sakane, k.; kawabata, k.; miyai, k.; inamoto, y. (fujisawa pharmaceutical co., ltd.); new cephem cpd. and process for preparation thereof. au 8822271; ep 0307804; jp 1989151589; us 4952578 .
Reference 2:
    sakane, k.; kawabata, k.; ohki, h. (fujisawa pharmaceutical co., ltd.); process for the preparation of cephalosporin cpd. jp 1992173792 .
Reference 3:
    ohki, h.; kawabata, k.; okuda, s.; kamimura, t.; sakane, k.; fk037, a new parenteral cephalosporin with a broad antibacterial spectrum: synthesis and antibacterial activity. j antibiot 1993, 46, 2, 359.
Reference 4:
    prous, j.; graul, a.; castaner, j.; fk-037. drugs fut 1994, 19, 4, 325.

Route 2
3) the condensation of 4-chloro-2(z)-(methoxyimino)-3-oxobutyric acid (ix) with 7beta-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazoliomethyl]-3-cephem-4-carboxylate (x) by means of pocl3 in dmf gives the corresponding acetamide (xi), which is then cyclized with thiourea by means of sodium acetate in water to obtain compound (vii). finally, this compound is treated with h2so4 to give fk-037.
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 (xii)
(2s)-2-[(tert-butoxycarbonyl)amino]-3-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid (viii)
(6s,9s,12s)-6-benzyl-9-([[(9h-fluoren-9-ylmethoxy)carbonyl]amino]methyl)-12-isobutyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid (ix)
(6s,9s,12s,15s)-9-benzyl-12-([[(9h-fluoren-9-ylmethoxy)carbonyl]amino]methyl)-6-[(1-formyl-1h-indol-3-yl)methyl]-15-isobutyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-oic acid (x)
(2s)-2-[(tert-butoxycarbonyl)amino]-4-(9h-fluoren-9-ylmethoxy)-4-oxobutyric acid (xi)
Reference 1:
    sakane, k.; kawabata, k.; ohki, h. (fujisawa pharmaceutical co., ltd.); process for the preparation of cephalosporin cpd. jp 1992173792 .
Reference 2:
    prous, j.; graul, a.; castaner, j.; fk-037. drugs fut 1994, 19, 4, 325.

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硫酸头孢噻利;英文名Cefoselis sulfate;FK-037;Wincef;CAS[122841-12-7]

 
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