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药物详细合成路线

Name Ceftizoxime alapivoxil;AS-924;KY-020
Chemical Name (6R,7R)-7-[2-(2-L-Alanylaminothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester
CAS 135821-54-4
Related CAS
Formula C22H28N6O8S2
Structure
Formula Weight 568.63186
Stage 预注册
Company Kyoto Pharmaceutical (Originator), Asahi Kasei (Licensee)
Activity/Mechanism Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins
Syn. Route 2
Route 1
coupling of ethyl glyoxylate derivative (i) with boc-l-alanine (ii) by means of edc and dmap in dmf provides compound (iii), whose ethyl ester is subjected to saponification by treatment with naoh in etoh to furnish carboxylic acid (iv). condensation of (iv) with methoxyamine (nh2ome) in thf/h2o yields methoxyimino acetic acid derivative (v), which is then coupled to pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (vi) in ch2cl2 by means of phosphorus oxychloride (pocl3) in dmf/etoac and n-trimethylsilylacetamide to give compound (vii). finally, the desired compound is obtained after treatment of (vii) with tfa and anisole in ch2cl2 for boc removal . alternatively, methoxyimino acetic acid derivative (v) can be converted into intermediate (vii) by coupling with 7-amino-3-cephem-4-carboxylic acid (viii) by means of pocl3 in dmf/etoac and n-trimethylsilylacetamide in ch2cl2 to provide derivative (ix), followed by condensation with iodomethyl pivalate (x) by means of potassium acetate in dmf.
List of intermediates No.
diethyl 5-hydroxy-10-methoxybenzo[a]phenazine-6,9-dicarboxylate (x)
methyl (2s)-3-phenyl-2-([[(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)amino]carbonyl]amino)propanoate (ii)
4-acetyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione (i)
4-[(3s)-3-hydroxy-4,4-dimethyl-5-oxoheptanoyl]-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione (iii)
4-((3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-dimethyl-5-oxoheptanoyl)-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione (iv)
(2s,6z,9s,10e)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[(triethylsilyl)oxy]-6,10-undecadienal (v)
4-{(3s,6r,7s,8s,12z,15s,16e)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[(triethylsilyl)oxy]-12,16-heptadecadienoyl}-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione (vi)
4-{(3s,6r,7s,8s,12z,15s,16e)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[(triethylsilyl)oxy]-12,16-heptadecadienoyl}-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione (vii)
(3s,6r,7s,8s,12z,15s,16e)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[(triethylsilyl)oxy]-12,16-heptadecadienoic acid (viii)
[(2r,4r)-2-phenyl-1,3-dioxan-4-yl]methanol (ix)
Reference 1:
    muro, h.; kasai, m.; hatano, s.; nishimura, k.-i.; nishizawa, s.; kakeya, n. (kyoto pharmaceutical industries, ltd.); cephalosporin cpds. and production thereof. ep 0497978; jp 1991204883; us 5389625; wo 9106549 .

Route 2
coupling of pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (vi) and methoxyimino acetic acid derivative (xi) by means of pocl3 and pyridine in ch2cl2 gives compound (xii) (alternatively (xii) can be obtained by condensation of ceftizoxime (czx) (xiii) with iodomethyl pivalate (x) in n,n-dimethylacetamide (dmac) in the presence of dicyclohexylamine). coupling of (xii) with boc-l-alanine (ii) by means of edc and dmap in ch2cl2 gives intermediate (vii), whose boc protecting group is removed by treatment with either hcl/isopropanol in formic acid or tfa and anisole in ch2cl2.yet another strategy can be followed, involving the coupling of pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (vi) with derivative (xiv) by means of et3n in n,n-dimethylacetamide.
List of intermediates No.
diethyl 5-hydroxy-10-methoxybenzo[a]phenazine-6,9-dicarboxylate (x)
1-chloro-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-propanol (xi)
methyl (2s)-3-phenyl-2-([[(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)amino]carbonyl]amino)propanoate (ii)
4-{(3s,6r,7s,8s,12z,15s,16e)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[(triethylsilyl)oxy]-12,16-heptadecadienoyl}-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione (vi)
4-{(3s,6r,7s,8s,12z,15s,16e)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[(triethylsilyl)oxy]-12,16-heptadecadienoyl}-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione (vii)
(2r,4r)-2-phenyl-1,3-dioxane-4-carbaldehyde (xii)
allyl(triphenyl)phosphonium bromide (xiii)
(2r,4r)-4-[(1e)-1,3-butadienyl]-2-phenyl-1,3-dioxane (xiv)
Reference 1:
    shirahase, h.; hatano, s.; yoshimi, a.; kitagawa, m.; kasai, m.; nishimura, k.; kakeya, n.; as-924, a novel bifunctional prodrug of ceftizoxime. j antibiot 1999, 52, 5, 491.
Reference 2:
    kasai, m.; et al.; as-924, a novel orally active bifunctional prodrug of ceftizoxime. synthesis and relationship between physicochemical properties and oral absorption. chem pharm bull 1999, 47, 8, 1081.
Reference 3:
    muro, h.; kasai, m.; hatano, s.; nishimura, k.-i.; nishizawa, s.; kakeya, n. (kyoto pharmaceutical industries, ltd.); cephalosporin cpds. and production thereof. ep 0497978; jp 1991204883; us 5389625; wo 9106549 .

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唑肟丙匹酯;英文名Ceftizoxime alapivoxil;AS-924;KY-020;CAS[135821-54-4]

 
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