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药物详细合成路线

Name Cefixime;FK-027;CL-284635;FR-17027;Suprax;Oroken;Denvar;Necopen;Tricef;Cephoral;Suprax;Cefspan
Chemical Name (6R,7R)-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 7(2)-(Z)-[O-(carboxymethyl)oxime];7beta-[2-(2-Aminothiazol-4-yl)-2(Z)-(carboxymethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid
CAS 79350-37-1
Related CAS
Formula C16H15N5O7S2
Structure
Formula Weight 453.45525
Stage 上市-1987
Company Aventis Pharma (Not Determined), Fujisawa (Not Determined), Wyeth Pharmaceuticals (Not Determined), AstraZeneca (Licensee), Esteve (Licensee), Lupin (Licensee), Merck KGaA (Licensee)
Activity/Mechanism Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins
Syn. Route 2
Route 1
the reaction of 7-(5-amino-5-carboxypentanamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid (i), first with benzoyl chloride in acetone-water, and then with diphenyldiazomethane, gives benzhydryl 7-[5-benzamido-5-(benzhydryloxycarbonyl)pentanamido]-3-hydroxymethyl-3-cephem-4-carboxylate (ii), which by reaction with pcl5 is converted into the corresponding chloromethyl derivative (iii). the reaction of (iii) with triphenyl phosphine and nai in dmf yields the phosphonium iodide (iv), which by a wittig condensation with formaldehyde in methylene chloride affords benzhydryl-7-[5-benzamido-5-(benzhydryloxycarbonyl)pentanamido]-3-vinyl-3-cephem-4-carboxylate (v). the cleavage of (v) with pcl-pyridine in methylene chloride gives benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate (vi), which is condensed with 2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (vii) [prepared from 2-formamidothiazol-4-yl)oxoacetic acid (viii) and tert-butyl aminooxyacetate (ix)] yielding benzhydryl 7-[2-tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido-3-vinyl-3-cephem-4-carboxylate (x). the hydrolysis of (x) with hcl in methanol affords the 2-amino derivative (xi), which is finally fully deprotected by treatment with trifluoroacetic acid in anisole.
List of intermediates No.
ethyl 4-nitro-1,3-dioxo-1,3-dihydro-2h-isoindole-2-carboxylate (vi)
n,n,n-tributyl-1-butanaminium (2r)-3-(3-chloro-4-methoxyphenyl)-2-([(e,5s,6s)-5-hydroxy-6-[(2r,3s)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate (vii)
(6ar,6br,12ar)-6a-(hydroxymethyl)-2,2,6b,9,9,12a-hexamethyl-10-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydro-4a(2h)-picenecarboxylic acid (viii)
methyl (2r,3s)-2-amino-3-hydroxy-4-methylpentanoate (i)
(4s,5s)-5-isopropyl-4-methyl-2-phenyl-4,5-dihydro-1,3-oxazole (ii)
methyl (4s,5s)-4-(hydroxymethyl)-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate (iii)
methyl (4r,5s)-4-formyl-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate (iv)
(e)-2-butenyl[bis[(1s,2r,3s,5s)-1,2,5,6,6-pentamethylbicyclo[3.1.1]hept-3-yl]]borane (v)
methyl (4s,5s)-4-[(1s,2s)-1-hydroxy-2-methyl-3-butenyl]-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate (ix)
(2r,3s)-3-hydroxy-3-[(4s,5s)-5-isopropyl-4-(methoxycarbonyl)-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl]-2-methylpropionic acid (x)
(2s,3s,4r)-3-hydroxy-2-[(1s)-1-hydroxy-2-methylpropyl]-4-methyl-5-oxo-2-pyrrolidinecarboxylic acid (xi)
Reference 1:
    takaya, t.; tagasuki, h.; masugi, t.; yamanaka, h.; kawabata, k. (fujisawa pharmaceutical co., ltd.); starting compounds for 7-acylamino-3-vinylcephalosporanic acid derivatives and processes for their preparation. ep 0030630; ep 0123024; ep 0244637; jp 6279452; us 4409214; us 4423213 .
Reference 2:
    serradell, m.n.; blancafort, p.; castaner, j.; fr-17,027. drugs fut 1983, 8, 8, 682.

Route 2
the reaction of 7-(5-amino-5-carboxypentanamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid (i), first with benzoyl chloride in acetone-water, and then with diphenyldiazomethane, gives benzhydryl 7-[5-benzamido-5-(benzhydryloxycarbonyl)pentanamido]-3-hydroxymethyl-3-cephem-4-carboxylate (ii), which by reaction with pcl5 under stronger conditions than before gives benzhydryl-7-amino-3-chloromethyl-3-cephem-4-carboxylate (xii), which is condensed with (vii) by means of pocl3 in dmf as before, yielding the chloromethyl compound (xiii). the reaction of (xiii) with triphenyiphosphine and nai affords the phosphonium salt (xiv), which is finally submitted to a wittig condensation with formaldehyde giving (x). the hydrolysis of (x) with hcl in methanol affords the 2-amino derivative (xi), which is finally fully deprotected by treatment with trifluoroacetic acid in anisole.
List of intermediates No.
n,n,n-tributyl-1-butanaminium (2r)-3-(3-chloro-4-methoxyphenyl)-2-([(e,5s,6s)-5-hydroxy-6-[(2r,3s)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate (vii)
methyl (2r,3s)-2-amino-3-hydroxy-4-methylpentanoate (i)
(4s,5s)-5-isopropyl-4-methyl-2-phenyl-4,5-dihydro-1,3-oxazole (ii)
(2r,3s)-3-hydroxy-3-[(4s,5s)-5-isopropyl-4-(methoxycarbonyl)-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl]-2-methylpropionic acid (x)
(2s,3s,4r)-3-hydroxy-2-[(1s)-1-hydroxy-2-methylpropyl]-4-methyl-5-oxo-2-pyrrolidinecarboxylic acid (xi)
allyl (2r)-2-(acetamido)-3-sulfanylpropanoate (xii)
allyl (2r)-2-(acetamido)-3-[([(2s,3s,4r)-3-hydroxy-2-[(1s)-1-hydroxy-2-methylpropyl]-4-methyl-5-oxopyrrolidinyl]carbonyl)sulfanyl]propanoate (xiii)
(3s,7ar)-6-methyl-3-phenyl-1,7a-dihydro-5h-pyrrolo[1,2-c][1,3]oxazol-5-one (xiv)
Reference 1:
    takaya, t.; tagasuki, h.; masugi, t.; yamanaka, h.; kawabata, k. (fujisawa pharmaceutical co., ltd.); starting compounds for 7-acylamino-3-vinylcephalosporanic acid derivatives and processes for their preparation. ep 0030630; ep 0123024; ep 0244637; jp 6279452; us 4409214; us 4423213 .
Reference 2:
    serradell, m.n.; blancafort, p.; castaner, j.; fr-17,027. drugs fut 1983, 8, 8, 682.

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克肟;英文名Cefixime;FK-027;CL-284635;FR-17027;Suprax;Oroken;Denvar;Necopen;Tricef;Cephoral;Suprax;Cefspan;CAS[79350-37-1]

 
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