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药物详细合成路线

Name Annamycin LF(lipid formulation);Annamycin;AR-522
Chemical Name 3-Deamino-4-demethoxy-4-epi-3-hydroxy-2-iododoxorubicin
      (7S,9S)-4-Demethoxy-7-O-(2,6-dideoxy-2-iodo-alpha-L-manno-hexopyranosyl)adriamycinone
      (7S-cis)-7-(2,6-Dideoxy-2-iodo-alpha-L-mannopyranosyloxy]-6,9,11-trihydroxy-9-(hydroxyacetyl)-7,8,9,10-tetrahydro-5,12-naphthacenedione
CAS 92689-49-1
Related CAS
Formula C26H25IO11
Structure
Formula Weight 640.38695
Stage II 期临床
Company Ohio State University (Originator), Antigenics (Licensee)
Activity/Mechanism Antibiotics and Alkaloids, Antineoplastic Antibiotics, Breast Cancer Therapy, DRUG DELIVERY, Leukemia Therapy, Liposomes, Lymphoma Therapy, Non-Hodgkins Lymphoma Therapy, Oncolytic Drugs, Prostate Cancer Therapy, Renal Cancer Therapy, Anthracyclines
Syn. Route 2
Route 1
the reaction of racemic 4-demethoxydaunomycinone (i) with br2 followed by hydrolysis in basic medium gives 4-demethoxyadriamycinone (ii), which is treated with tert-butyldimethylsilyl chloride and imidazole in dmf to yield the monoprotected compound (iii). the condensation of (iii) with 3,4-di-o-acetyl-2,6-dideoxy-2-iodo-alpha-l-mannopyranose (iv) by means of n-iodosuccinimide (nis), followed by chromatographic separation of the diastereomers affords (7s,9s)-14-o-(tert-butyldimethylsilyl)-4-demethoxy-7-o-(3,4-di-o-acetyl-2,6-dideoxy-2-iodo-alpha-l-mannopyranosyl)adriamycinone (v). the hydrolysis of (v) with sodium methoxide in methanol gives the silylated compound (vi), which is finally desilylated with tetrabutylammonium fluoride (tbaf) in dichloromethane/thf/pyridine.
List of intermediates No.
tert-butyl (2s)-1-[(2s)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-2-pyrrolidinecarboxylate (i)
(2s)-1-[(2s)-2-amino-3-methylbutanoyl]-2-pyrrolidinecarboxylic acid (ii)
(2s)-1-[(2s)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-2-pyrrolidinecarboxylic acid (iii)
(2r,3s)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol (iv)
(2s)-1-[(2s)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-n-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)-2-pyrrolidinecarboxamide (v)
(2s)-1-[(2s)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-n-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)-2-pyrrolidinecarboxamide (vi)
Reference 1:
    graul, a.; prous, j.; castaner, j.; annamycin. drugs fut 1997, 22, 9, 948.
Reference 2:
    horton, d.; priebe, w. (ohio state university); 4-demethoxy-3-desamino-2-haloanthracycline and pharmaceutical compsn. us 4537882 .
Reference 3:
    horton, d.; priebe, w.; varela, o.; synthesis of antitumor-active (7s,9s)-4-demethoxy-7-o-(2,6-dideoxy-2-iodo-alpha-l-mannopyranosyl) adriamycinone: preparative resolution of a racemic anthracyclinone by alkoxyhalogenation of a glycal. carbohydr res 1984, 130, c1-3.

Route 2
the diels-alder cyclization of butadiene (vii) with 1,4-benzoquinone (viii) in thf gives the naphthalenetrione (ix), which is acylated with acetic anhydride and tea to yield the tetralone derivative (x). the grignard reaction of (x) with vinylmagnesium bromide (xi) and cecl3, followed by acylation with acetic anhydride, affords the tetraline derivative (xii), which is treated with nabh4 and oxidized with cerium ammonium nitrate to provide the tetrahydronaphthoquinone (xiii). the cyclization of (xiii) with 4-acetoxy-3,4-dihydro-1h-2-benzopyran-1,3-dione (xiv) by means of nah in thf gives the intermediate (xv), which rearranges to the tetracyclic dione (xvi). the palladium-catalyzed (pdcl2(mecn)2) rearrangement of (xvi) in toluene yields the allyl acetate derivative (xvii), which is oxidized with peracetic acid and rucl3 in water/acetonitrile/dichloromethane to afford the protected intermediate (xviii). finally, this compound is deprotected and simultaneously epimerized by a treatment with hcl in refluxing isopropanol/water to provide the desired target intermediate (ii).
List of intermediates No.
2-(aminomethyl)pyrrrolidine dichloroplatinum complex (viii)
benzhydryl (6r,7r)-7-[((2r,3s)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-3-hydroxybutanoyl)amino]-3-[[(1-methyl-1h-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (xi)
(2s,4e)-2-[(4-methoxybenzyl)oxy]-6-(trityloxy)-4-hexen-1-ol (vii)
(2s,4e)-2-[(4-methoxybenzyl)oxy]-6-(trityloxy)-4-hexenal (ix)
(e)-3-(tributylstannyl)-2-propenal (x)
(xii)
(1e)-5-methyl-1-(tributylstannyl)-1,5-hexadien-3-ol (xiii)
[(1e)-3-(allyloxy)-5-methyl-1,5-hexadienyl](tributyl)stannane; allyl 3-methyl-1-[(e)-2-(tributylstannyl)ethenyl]-3-butenyl ether (xiv)
bromo{(e)-2-[(2s)-4-methyl-3,6-dihydro-2h-pyran-2-yl]ethenyl}magnesium (xv)
(2s)-2-[(e)-2-iodoethenyl]-4-methyl-3,6-dihydro-2h-pyran (xvi)
tributyl{(e)-2-[(2s)-4-methyl-3,6-dihydro-2h-pyran-2-yl]ethenyl}stannane (xvii)
(1e,3s,4s,6e)-4-[(4-methoxybenzyl)oxy]-1-[(2s)-4-methyl-3,6-dihydro-2h-pyran-2-yl]-8-(trityloxy)-1,6-octadien-3-ol (xviii)
tert-butyl(dimethyl)silyl (1s,2s,4e)-2-[(4-methoxybenzyl)oxy]-1-{(e)-2-[(2s)-4-methyl-3,6-dihydro-2h-pyran-2-yl]ethenyl}-6-(trityloxy)-4-hexenyl ether; tert-butyl{[(1s,2s,4e)-2-[(4-methoxybenzyl)oxy]-1-{(e)-2-[(2s)-4-methyl-3,6-dihydro-2h-pyran-2-yl]ethenyl}-6-(trityloxy)-4-hexenyl]oxy}dimethylsilane (ii)
Reference 1:
    hottop, t.; et al.; synthesis of 4-demethoxyadriamycinone utilizing ruthenium-catalyzed oxidation of allyl acetates. tetrahedron lett 2001, 42, 19, 3343.

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(7S,9S)-7-[(2R,3R,4R,5R,6S)-4,5-二羟基-3-碘-6-甲基氧杂环己-2;英文名Annamycin LF(lipid formulation);Annamycin;AR-522;CAS[92689-49-1]

 
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