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Name 9-Aminocamptothecin;IDEC-132;NSC-603071;NSC-629971((R;S)-isomer);9-AC
Chemical Name (S)-10-Amino-4-ethyl-4-hydroxy-3,4,12,14-tetrahydro-1H-pyrano[3,4:6,7]indolizino[1,2-b]quinoline-3,14-dione
      9-Amino-20(S)-camptothecin
CAS 91421-43-1
Related CAS
Formula C20H17N3O4
Structure
Formula Weight 363.37619
Stage III 期临床
Company Biogen Idec (Proprietary), Research Triangle Institute (Originator), National Cancer Institute (Codevelopment), Pfizer (Bulk Supplier)
Activity/Mechanism AIDS Medicines, ANTIINFECTIVE THERAPY, Bladder Cancer Therapy , Breast Cancer Therapy, Colorectal Cancer Therapy, Leukemia Therapy, Lymphoma Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Treatment of AIDS-Associated Malignancies, Camptothecins, DNA Topoisomerase I Inhibitors
Syn. Route 3
Route 1
9-amino-20(s)-camptothecin is obtained by nitration of camptothecin (i) with fuming nitric acid in concentrated sulfuric acid yielding the intermediate 9-nitrocamptothecin (ii), which is then reduced with h2 over pto2 in absolute ethanol.
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)
4-[1-(2,3-dimethylphenyl)vinyl]-1h-imidazole (ii)
Reference 1:
    robinson, c.; robinson, k.; castaner, j.; 9-aminocamptothecin. drugs fut 1996, 21, 9, 881.
Reference 2:
    wani, m.c.; nicholas, a.w.; wall, m.e.; plant antitumor agents. 23. synthesis and antileukemic activity of camptothecin analogues. j med chem 1986, 29, 11, 2358.

Route 2
9-amino-20(rs)-camptothecin is obtained as follows:the cyclization of cyanoacetamide (i) with 2-ethoxy-4-oxo-2-pentenoic acid ethyl ester (ii) by means of k2co3 in hot dmf gives the intermediate pyridone (iii), which without isolation is cyclized again with methyl acrylate (iv) in the same conditions affording the indolizinone (v). the treatment of (v) with concentrated hcl in refluxing acetic acid gives the indolizinedione (vi), which is treated with ethylene glycol and trimethylsilyl chloride in dichloromethane to yield the ethylene ketal (vii). the carboxylation of (vii) with diethyl carbonate and kh in refluxing toluene affords the acetic ester derivative (viii), which is alkylated with ethyl iodide and potassium tert-butoxide in anhydrous dme to the corresponding butyric ester derivative (ix). the reductive acetylation of (ix) with h2 over rani in acetic anhydride gives the acetamide derivative (x), which is treated with nano2 in acetic acid to yield the corresponding n-nitroso compound (xi). thermal degradation of (xi) in refluxing ccl4 affords the acetoxymethyl compound (xii), which is submitted to a oxidative cyclization with o2 in methanol/k2co3 to give the tetracyclic ketal (xiii). hydrolysis of the ketal group of (xiii) with 2n h2so4 in hot dme yields the tricyclic triketone (xiv), which is further cyclized with 2-amino-6-nitrobenzaldehyde (xv) by heating at 160 c to afford 9-nitro-20(rs)-camptothecin (xvi). finally, this compound is hydrogenated with h2 over pd/c in ethanol.the title product can also be obtained by direct cyclization of tricyclic triketone (xiv) with 2,6-diaminobenzaldehyde (xvii) in the same conditions.
List of intermediates No.
1-(2-chlorophenyl)-2-(2-phenyl-1-pyrrolidinyl)-1-ethanol (i)
1-methyl-2-oxo-1,2-dihydro-4-pyridinecarbaldehyde (iv)
3-fluorobenzenethiol (ii)
5-chloro-2-iodobenzoic acid (iii)
5-chloro-2-[(3-fluorophenyl)sulfanyl]benzoic acid (v)
2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]acetonitrile (vi)
2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]acetic acid (vii)
1-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]-1-ethanone (viii)
2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]-1-(4-morpholinyl)-1-ethanethione (ix)
2-chloro-7-fluorodibenzo[b,f]thiepin-10(11h)-one (x)
2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-ol (xi)
2,10-dichloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepine (xii)
ethyl 4-(2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazinecarboxylate (xiii)
3-(1-piperazinyl)propanamide (xv)
cyanic bromide (xvi)
2-(chlorosulfanyl)benzoyl chloride (xvii)
Reference 1:
    sinai, b.k.; palmer, k.h.; mcphail, a.t.; sim, g.a.; topoisomerase inhibitors. a review of their therapeutic potential in cancer. drugs 1995, 49, 11-19.
Reference 2:
    wall, m.e.; wani, m. (research triangle institute); camptothecin analogs as potent inhibitors of colorectal cancer. ep 0497910; jp 1993508619; us 5106742; wo 9105556 .
Reference 3:
    wall, m.e.; wani, m.c.; nicholas, a.w.; manikumar, g. (research triangle institute); synthesis of camptothecin and analogs thereof. wo 9003169 .
Reference 4:
    wall, m.e.; wani, m.c.; nicholas, a.w.; manikumar, g. (res. triangle inst.); camptothecin and analogues thereof and pharmaceutical compsns and method using them. us 5122526 .

Route 3
the hydroxylation of camptothecin (i) with h2o2 in hoac gives 10-hydroxycamptothecin (ii), which is nitrated with hno3/h2so4 to yield 10-hydroxy-9-nitrocamptothecin (iii). the sulfonation of (iii) with tscl, dea and dmap affords 9-nitro-10-p-toluenesulfonyloxy)camptothecin (iv), which is finally desulfonated and reduced by means of ammonium formate and a pd(oac)3/bidentate phosphine ligand catalyst. other sulfonates such as 1-naphthyl-, phenyl-, 4-fluorophenyl-, 4-nitrophenyl-, 4-methoxyphenyl- or methylsulfonate can be used instead of the reported p-toluenesulfonate.
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)
[2,6-diamino-5-(2,3,5-trichlorophenyl)-4-pyrimidinyl]methanol (ii)
1-benzyl 4-(2,2,2-trichloroethyl) (2r)-2-nonylbutanedioate (iii)
2,2,2-trichloroethyl (3r)-3-(chlorocarbonyl)dodecanoate (iv)
Reference 1:
    cabri, w.; et al.; a new high yield semisynthetic approach to (20s)-9-nh2-camptothecin based on a sequence of palladium-catalysed reductions. tetrahedron lett 1995, 36, 50, 9197.

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9-氨基喜树碱;英文名9-Aminocamptothecin;IDEC-132;NSC-603071;NSC-629971((R;S)-isomer);9-AC;CAS[91421-43-1]

 
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