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药物详细合成路线

Name Idarubicin hydrochloride;NSC-256439;IMI-30;DMDR;Idamycin;Zavedos
Chemical Name (1S,3S)-3-Acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-6,11-dioxo-1-naphthacenyl 3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside hydrochloride;(7S,9S)-9-Acetyl-7-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxy-5,12-naphthacenedione hydrochloride;4-Demethoxydaunomycin hydrochloride;4-Demethoxydaunorubicin hydrochloride
CAS 58957-92-9
Related CAS
Formula C26H28ClNO9
Structure
Formula Weight 533.96736
Stage 上市-1990
Company Pfizer (Originator)
Activity/Mechanism Oncolytic Drugs, Anthracyclines
Syn. Route 2
Route 1
the condensation of chiral tetraline (i) with phthalic anhydride (ii) by means of alcl3 at 180 c gives the naphthacenedione (iii), which is ketalized at the acetyl group with ethylene glycol and p-toluenesulfonic acid yielding the dioxolane (iv). the hydroxylation of (iv) with br2 and aibn in ccl4/chcl3 affords the 4-demethoxy-7-epidaunomycinone (v), which is isomerized with tfa yielding 4-demethoxydaunomycinone (vi) . the condensation of (vi) with the acylated hexopyranosyl chloride (vii) by means of cf3so3ag of br2hg affords the trifluoroacetylated 4-demethoxydaunomycin (viii), which is finally treated with naoh in order to eliminate the trifluoroacetyl groups
List of intermediates No.
(1r,4as,10ar)-7-isopropyl-1,4a-dimethyl-6-sulfo-1,2,3,4,4a,9,10,10a-octahydro-1-phenanthrenecarboxylic acid
2-isopropoxy-1-ethanol (ii)
(3s,6r,7s,8s)-11-(benzyloxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxoundecanoic acid (i)
methyl (3s,6r,7s,8s)-11-(benzyloxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxoundecanoate (iii)
methyl (3s,6r,7s,8s)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-4,4,6,8-tetramethyl-5-oxoundecanoate (iv)
methyl (3s,6r,7s,8s)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-11-[(2-nitrophenyl)selanyl]-5-oxoundecanoate (v)
methyl (3s,6r,7s,8s)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate (vi)
1,2-dimethyl-1h-benzimidazole-5-carbaldehyde (vii)
(1s,5r)-4-acetyl-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione (viii)
Reference 1:
    arcamone, f.; et al.; synthesis and antitumour activity of new daunorubicin and adriamycin analogues. experientia 1978, 34, 1255.
Reference 2:
    bernardi, l.; arcamone, f.; patelli, b.; di marco, a. (pharmacia corp.); daunomycin analogues, their preparation and use. de 2525633; us 4046878 .

Route 2
the reaction of daunomycinone (ix) with alcl3 in dichloromethane gives 4-demethyldaunomycinone (x), which is ketalized with ethylene glycol as before yielding the dioxolane (xi). the selective sulfonation of (xi) with tscl, diea and dmap in pyridine affords the 4-tosyloxy derivative (xii), which is treated with 4-methoxybenzylamine (xiii) in pyridine providing the secondary benzylamine (xiv). elimination of the benzyl protecting group of (xiv) with tfa gives 4-amino-4-demethoxydaunomycinone ethylene ketal (xv), which is deaminated by reaction with tfa, nano2 and h3po2 to give 4-demethoxydaunomycinone (xvi). finally, this compound is submitted to fermentation with streptomyces peucetius corneus, s. peucetius caesius, s. caeruleus, s. peucetius, s. coeruleorubidus, and other chemical or radio-induced mutants thereof.
List of intermediates No.
(1r,4as,10ar)-7-isopropyl-1,4a-dimethyl-6-sulfo-1,2,3,4,4a,9,10,10a-octahydro-1-phenanthrenecarboxylic acid
(3s,5r,8r,9s,10s,13r,17r)-17-(3-furyl)-10,13-dimethylhexadecahydro-14h-cyclopenta[a]phenanthrene-3,14-diol (xiii)
methyl (3s,6r,7s,8s)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate (xvi)
(1s,5r)-4-[(3s)-3-(1,2-dimethyl-1h-benzimidazol-5-yl)-3-hydroxypropanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione (ix)
(1s,5r)-4-[(3s)-3-[[tert-butyl(dimethyl)silyl]oxy]-3-(1,2-dimethyl-1h-benzimidazol-5-yl)propanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione (x)
(3s)-3-[[tert-butyl(dimethyl)silyl]oxy]-3-(1,2-dimethyl-1h-benzimidazol-5-yl)propanal (xi)
5-((1s,3z)-1-[[tert-butyl(dimethyl)silyl]oxy]-4-iodo-3-pentenyl)-1,2-dimethyl-1h-benzimidazole; tert-butyl(dimethyl)silyl (1s,3z)-1-(1,2-dimethyl-1h-benzimidazol-5-yl)-4-iodo-3-pentenyl ether (xii)
methyl (3s,6r,7s,8s)-10-(9-borabicyclo[3.3.1]non-9-yl)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxodecanoate (xiv)
methyl (2r,5r,6s,7s,11z,14s)-2,6,14-tris[[tert-butyl(dimethyl)silyl]oxy]-14-(1,2-dimethyl-1h-benzimidazol-5-yl)-3,3,5,7,11-pentamethyl-4-oxo-11-tetradecenoate (xv)
Reference 1:
    francalanci, f.; martinengo, t.; de bernardinis, s.; cabri, w. (pharmacia corp.); process for the preparation of 4-demethoxydaunomycinone, the aglycone of 4-demethoxy-daunorubicin. ep 0328399 .
Reference 2:
    mitscher, l.a.; lednicer, d. (pharmacia corp.); biosynthesis of simplified anthracyclines. us 4471052 .

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依达比星;英文名Idarubicin hydrochloride;NSC-256439;IMI-30;DMDR;Idamycin;Zavedos;CAS[58957-92-9]

 
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