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药物详细合成路线

Name CKD-602;Camtobell
Chemical Name 4(S)-Ethyl-4-hydroxy-11-[2-(isopropylamino)ethyl]-3,4,12,14-tetrahydro-1H-pyrano[3,4:6,7]indolizino[1,2-b]quinoline-3,14-dione hydrochloride
      (20S)-7-[2-(Isopropylamino)ethyl]camptothecin hydrochloride
CAS 213819-48-8
Related CAS 256411-32-2 (free base)
Formula C25H28ClN3O4
Structure
Formula Weight 469.97261
Stage 上市-2003
Company Chong Kun Dang Pharm. (Originator)
Activity/Mechanism Colorectal Cancer Therapy, Gastric Cancer Therapy, Lung Cancer Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Small Cell Lung Cancer Therapy, Camptothecins, DNA Topoisomerase I Inhibitors, DNA-Intercalating Drugs
Syn. Route 2
Route 1
total synthesis: reaction of ethyl acetopyruvate (i) with triethyl orthoformate gives compound (ii), which is then treated with cyanoacetamide to yield 3-cyano-4-methyl-6-(carbethoxy)-2(1h)-pyridone (iii). the reaction of (iii) with methyl acrylate (a) gives compound (iv), which is sequentially submitted to decarboxylation, ketalization and treatment with diethylcarbonate, giving the functionalized tetrahydroindolizine (v). ethylation of (v) followed by reduction in the presence of acetic anhydride gives the amide (vi), which is reacted with sodium nitrite, refluxed in ccl4, hydrolyzed and acidified to give the tricyclic compound (vii). the dibal reduction of (vii) and subsequent elimination of the hydroxyl group gives the cyclic enol ether (viii). asymmetric dihydroxylation of compound (viii) with (dhqd)2phal, k2oso4 and k3fe(cn)6 in t-buoh gives the diol (ix). the oxidation and deketalization of compound (ix) gives (s)-hydroxylactone (x). finally, friedlander condensation of the lactone (x) with 3-[n-isopropyl-n-(carbobenzyloxy)amino]-1-(2-aminophenyl)propan-1-one (b) followed by deprotection gives ckd-602.
List of intermediates No.
tert-butyl 2-[(1-[(2s)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate (xi)
1-methyl-2-oxo-1,2-dihydro-4-pyridinecarbaldehyde (iv)
5-chloro-2-iodobenzoic acid (iii)
5-chloro-2-[(3-fluorophenyl)sulfanyl]benzoic acid (v)
1-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]-1-ethanone (vi)
2-chloro-7-fluorodibenzo[b,f]thiepin-10(11h)-one (vii)
tert-butyl (2r)-3-(1h-indol-3-yl)-2-{[(4-vinylphenyl)sulfonyl]amino}propanoate (i)
tert-butyl (2r)-2-{[(4-formylphenyl)sulfonyl]amino}-3-(1h-indol-3-yl)propanoate (ii)
benzenesulfonic acid hydrazide; benzenesulfonyl hydrazide (viii)
tert-butyl (2r)-3-(1h-indol-3-yl)-2-{[(4-{[(e)-2-(phenylsulfonyl)hydrazono]methyl}phenyl)sulfonyl]amino}propanoate (ix)
tert-butyl (2r)-3-(1h-indol-3-yl)-2-({[4-(2-phenyl-2h-1,2,3,4-tetraazol-5-yl)phenyl]sulfonyl}amino)propanoate (x)
dimethyl 4-(3-aminophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (xii)
Reference 1:
    hong, c.i.; kim, j.k.; ahn, s.k.; ckd-602. drugs fut 2000, 25, 12, 1243.
Reference 2:
    kim, j.m.; jew, s.; kim, m.g.; kim, h.-j.; hah, j.m.; ok, k.; cho, y.; enantioselective synthesis of 20(s)-camptothecin using sharpless catalytic asymmetric dihydroxylation. tetrahedron asymmetry 1995, 6, 6, 1245.
Reference 3:
    jew, s.-s.; kim, h.-j.; kim, m.g.; et al.; synthesis and antitumor activity of 7-substituted 20(rs)-camptothecin analogues. bioorg med chem lett 1996, 6, 7, 845.

Route 2
semisynthesis: treatment of camptothecin (xi) with tert-butylhydroperoxide in the presence of feso4, conc. h2so4 and acetic acid in water gives (s)-7-methylcamptothecin (xii). mannich reaction of compound (xii) with isopropylamine hydrochloride in dmso as a formaldehyde source gives ckd-602.
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 (xi)
dimethyl 4-{3-[(methoxycarbonyl)amino]phenyl}-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (xii)
Reference 1:
    hong, c.i.; kim, j.k.; ahn, s.k.; ckd-602. drugs fut 2000, 25, 12, 1243.
Reference 2:
    kim, k.k.; kim, j.w.; journ, d.j.; jeong, b.s.; choi, n.s.; hong, c.i.; ahn, s.k.; kim, j.k.; lee, s.j.; jew, s.-s.; practical synthesis of (s)-7-(2-isopropylamino)ethylcamptothecin hydrochloride, potent topoisomerase i inhibitor. j heterocycl chem 2000, 37, 1141.
Reference 3:
    miyasaka, t.; nokata, k.; furuta, t.; yokokura, t.; sawada, s.; chemical modification of an antitumor alkaloid camptothecin: synthesis and antitumor activity of 7-c-substituted camptothecins. chem pharm bull 1991, 39, 10, 2574.

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CKD-602 盐酸盐;英文名CKD-602;Camtobell;CAS[213819-48-8]

 
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