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Name Irinotecan hydrochloride;U-101440E(hydrate);NSC-616348;DQ-2805;CPT-11;Camptosar;Topotecin;Campto
Chemical Name [1,4-Bipiperidine]-1-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3,4:6,7]indolizino[1,2-b]quinolin-9-yl ester hydrochloride
      (+)-7-Ethyl-10-[4-(1-piperidinyl)piperidin-1-ylcarbonyloxy]camptothecin hydrochloride
CAS 100286-90-6
Related CAS 97682-44-5 (free base)
Formula C33H39ClN4O6
Structure
Formula Weight 623.15498
Stage 上市-1994
Company Yakult Honsha (Originator), Almirall Prodesfarma (Licensee), Aventis Pharma (Licensee), Daiichi Pharmaceutical (Licensee), Pfizer (Licensee), National Cancer Institute (Codevelopment)
Activity/Mechanism Brain Cancer Therapy, Colorectal Cancer Therapy, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Pancreatic Cancer Therapy, Solid Tumors Therapy, Camptothecins, DNA Topoisomerase I Inhibitors
Syn. Route 3
Route 1
a more complete synthesis for cpt-11 has been reported:the reaction of camptothecin (i) with propionaldehyde and feso4 in water gives 7-ethylcamptothecin (ii), which is oxidized with h2o2 in hot acetic acid yielding 7-ethylcamptothecin 1-oxide (iii). the isomerization of (iii) with uv light (high-pressure hg lamp) in dioxane-1 n h2so4 affords 7-ethyl-10-hydroxycamptothecin (iv), which is treated with phosgene and triethylamine in dioxane to give the corresponding chlorocarbonyl derivative (v). finally, this compound is condensed with 4-piperidinopiperidine (vi) by means of pyridine in dichloromethane.
List of intermediates No.
(10s,11r,12s)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2h,6h,10h-dipyrano[2,3-f:2,3-h]chromen-2-one (i)
5-hydroxy-6-[(2r,3s)-3-hydroxy-2-methylbutanoyl]-2,2-dimethyl-10-propyl-2h,8h-pyrano[2,3-f]chromen-8-one (ii)
5-hydroxy-6-[(2s,3r)-3-hydroxy-2-methylbutanoyl]-2,2-dimethyl-10-propyl-2h,8h-pyrano[2,3-f]chromen-8-one (iii)
(1r,2s)-3-(5-hydroxy-2,2-dimethyl-8-oxo-10-propyl-2h,8h-pyrano[2,3-f]chromen-6-yl)-1,2-dimethyl-3-oxopropyl acetate (iv)
(s)-(4-chlorophenyl)(2-pyridinyl)methyl 4-piperidinyl ether (v)
ethyl 4-(4-[[(s)-(4-chlorophenyl)(2-pyridinyl)methyl]oxy]-1-piperidinyl)butanoate (vi)
Reference 1:
    nokata, k.-i.; furuta, t.; yokokura, t.; okajima, s.; sawada, s.; sugino, e.; miyasaka, t.; aiyama, r.; yamaguchi, k.; synthesis and antitumor activity of 20(s)-camptothecin derivatives: carbamate-linked, water-soluble derivatives of 7-ethyl-10-hydroxycamptothecin. chem pharm bull 1991, 39, 6, 1446-54.

Route 2
a new asymmetric synthesis of irinotecan has been reported:the reaction of 2,6-dihydroxypyridine-4-carboxylic acid (i) with hot pocl3 and trimethylammonium chloride gives 2,6-dichloropyridine-4-carboxylic acid (ii), which by a grignard condensation with ethylmagnesium bromide in thf is converted into the propanone (iii). the ketalization of (iii) with ethylene glycol and trimethylsilyl chloride (tms-cl) affords the dioxolane (iv), which by reaction with sodium methoxide in refluxing methanol gives the monomethoxy-pyridine derivative (v). the carbonylation of (v) with butyllithium and dmf affords the pyridine-carbaldehyde (vi), which is reduced to the methanol (vii) with nabh4. the protection of the hydroxy group of (vii) with benzyl bromide and potassium tert-butoxide in thf affords the benzyl ether (viii), which is treated with co, k2co3, palladium acetate and 1,3-bis(diphenylphosphino)propane (dppp) in propanol/dmf giving the propyl ester (ix). the treatment of (ix) with trifluoroacetic acid yields the propanone (x), which is treated with methyltriphenylphosphonium bromide and potassium bis(trimethylsilyl)amide (khmds) in dmf to afford the expected methylene derivative (xi). the oxidation of (xi) with oso4 in tert-butanol gives the racemic diol (xii), which is submitted to optical resolution with ps-30 catalyst (pseudomonas cepaica lipase over celite 521) to give the corresponding (s)-enantiomer (xiii). the oxidation of (xiii) with naocl affords the 2(s)-hydroxybutyraldehyde (xiv), which is submitted to cyclization by debenzylation with h2 over pd/c in methanol giving the cyclized diol (xv). the oxidation of (xv) with naocl in dichloromethane affords the hydroxylactone (xvi), which is treated with trimethylsilyl chloride and nai to give the pyridone (xvii). a new cyclization of (xvii) with tert-butyl acrylate (xviii) by means of cs2co3 in dmso yield the tricyclic tert-butyl ester (xix), which is decarboxylated with trifluoroacetic acid in refluxing toluene to afford the tricyclic trione (xx). the cyclization of (xx) with 2-amino-5-hydroxypropiophenone (xxi) by means of p-toluenesulfonic acid in hot toluene/acetic acid gives the camptothecin derivative (xxii), which is finally acylated with 4-(1-piperidyl)piperidine-1-carbonyl chloride (xxiii) in pyridine.
List of intermediates No.
(1r,2s)-3-(5-hydroxy-2,2-dimethyl-8-oxo-10-propyl-2h,8h-pyrano[2,3-f]chromen-6-yl)-1,2-dimethyl-3-oxopropyl acetate (xxii)
2,5-bis(trifluoromethyl)phenylamine; 2,5-bis(trifluoromethyl)aniline (i)
(8s,9s,10r,13s,14s,17s)-n-[2,5-bis(trifluoromethyl)phenyl]-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthrene-17-carboxamide (ii)
3-((3s,3as,5as,6r,9as,9bs)-3-[[2,5-bis(trifluoromethyl)anilino]carbonyl]-3a,6-dimethyl-7-oxododecahydro-1h-cyclopenta[a]naphthalen-6-yl)propionic acid (iii)
(4ar,4bs,6as,7s,9as,9bs)-n-[2,5-bis(trifluoromethyl)phenyl]-4a,6a-dimethyl-2-oxo-2,3,4,4a,4b,5,6,6a,7,8,9,9a,9b,10-tetradecahydro-1h-indeno[5,4-f]quinoline-7-carboxamide (iv)
(4ar,4bs,6as,7s,9as,9bs,11ar)-n-[2,5-bis(trifluoromethyl)phenyl]-4a,6a-dimethyl-2-oxohexadecahydro-1h-indeno[5,4-f]quinoline-7-carboxamide (v)
(3s,3as,5as,6r,9as,9bs)-6-(2-carboxyethyl)-3a,6-dimethyl-7-oxododecahydro-1h-cyclopenta[a]naphthalene-3-carboxylic acid (vi)
(4ar,4bs,6as,7s,9as,9bs,11ar)-4a,6a-dimethyl-2-oxohexadecahydro-1h-indeno[5,4-f]quinoline-7-carboxylic acid (vii)
2,2-dithiodipyridine; 2-(2-pyridinyldisulfanyl)pyridine; 2,2-dipyridinyl disulfide (viii)
s-(2-pyridinyl) (4as,4bs,6as,7s,9as,9bs,11ar)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1h-indeno[5,4-f]quinoline-7-carbothioate (ix)
4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine (x)
n-[4-(benzyloxy)phenyl]-2,2,2-trifluoroacetamide (xi)
n-[4-(benzyloxy)phenyl]-2,2,2-trifluoroethanimidoyl chloride (xii)
1-[4-(benzyloxy)phenyl]-5-(trifluoromethyl)-1h-1,2,3,4-tetraazole; benzyl 4-[5-(trifluoromethyl)-1h-1,2,3,4-tetraazol-1-yl]phenyl ether (xiii)
4-[5-(trifluoromethyl)-1h-1,2,3,4-tetraazol-1-yl]phenol (xiv)
2-hydroxy-5-[5-(trifluoromethyl)-1h-1,2,3,4-tetraazol-1-yl]benzaldehyde (xv)
2-methoxy-5-[5-(trifluoromethyl)-1h-1,2,3,4-tetraazol-1-yl]benzaldehyde (xvi)
(2s,3s)-2-phenylpiperidinylamine; (2s,3s)-2-phenyl-3-piperidinamine (xvii)
(2s)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(tert-butoxy)phenyl]propionic acid (xix)
tert-butyl 2-[(1-[(2s)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate (xx)
Reference 1:
    ashford, s.w.; sih, j.c.; gu, r.l.; henegar, k.e.; baughman, t.a.; practical asymmetric synthesis of (s)-4-ethyl-7,8-dihydro-4-hydroxy-1h-pyrano[3,4-f]indolizine-3,6,10(4h)-trione, a key intermediate for the synthesis of irinotecan and other camptothecin analogs. j org chem 1997, 62, 19, 6588.

Route 3
the reaction of 7-ethyl-10-hydroxycamptothecin (i) with phosgene gives 7-ethyl-10-(chlorocarbonyloxy)camptothecin (ii), which is then condensed with 4-(1-piperidyl)piperidine.
List of intermediates No.
(1r,2s)-3-(5-hydroxy-2,2-dimethyl-8-oxo-10-propyl-2h,8h-pyrano[2,3-f]chromen-6-yl)-1,2-dimethyl-3-oxopropyl acetate (i)
(s)-(4-chlorophenyl)(2-pyridinyl)methyl 4-piperidinyl ether (ii)
ethyl 4-(4-[[(s)-(4-chlorophenyl)(2-pyridinyl)methyl]oxy]-1-piperidinyl)butanoate (iii)
Reference 1:
    miyasaka, t.; mutai, m.; nokata, k.; sawada, s.; sugino, e. (yakult honsha co., ltd.); new camptothecin derivs. and process for preparing same. ep 0137145; jp 1985019790 .
Reference 2:
    davis, p.d. (angiogene pharmaceuticals ltd.); benzimidazole vascular damaging agents. ep 1140078; wo 0041669 .

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盐酸伊立替康;英文名Irinotecan hydrochloride;U-101440E(hydrate);NSC-616348;DQ-2805;CPT-11;Camptosar;Topotecin;Campto;CAS[100286-90-6]

 
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