CKD-602, Camtobell, -Drug Synthesis Database

【结构式】

【药物名称】CKD-602, Camtobell

【化学名称】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

【CA登记号】213819-48-8, 256411-32-2 (free base)

【分子式】C₂₅H₂₈ClN₃O₄

【分子量】469.97261

【开发单位】Chong Kun Dang Pharm. (Originator)

【药理作用】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

合成路线1 合成路线2

合成路线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.

参考文献中间体

【1】 Hong, C.I.; Kim, J.K.; Ahn, S.K.; CKD-602. Drugs Fut 2000, 25, 12, 1243.
【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.
【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.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	42500	ethyl 2,4-dioxopentanoate	615-79-2	C₇H₁₀O₄	详情	详情
(II)	42501	ethyl (Z)-4-ethoxy-2-oxo-3-pentenoate		C₉H₁₄O₄	详情	详情
(III)	15637	ethyl 5-cyano-4-methyl-6-oxo-1,6-dihydro-2-pyridinecarboxylate		C₁₀H₁₀N₂O₃	详情	详情
(IV)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(V)	15639	methyl 6-cyano-1-hydroxy-7-methyl-5-oxo-3,5-dihydro-2-indolizinecarboxylate		C₁₂H₁₀N₂O₄	详情	详情
(VI)	15642	2-[6'-Cyano-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]acetic acid ethyl ester		C₁₅H₁₆N₂O₅	详情	详情
(VII)	15644	2-[6'-(Acetamidomethyl)-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]butyric acid ethyl ester		C₁₉H₂₆N₂O₆	详情	详情
(VIII)	42502			C₁₅H₁₇NO₅	详情	详情
(IX)	42503			C₁₅H₁₇NO₄	详情	详情
(X)	42504			C₁₅H₁₉NO₆	详情	详情
(XI)	10841	(4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione		C₁₃H₁₃NO₅	详情	详情
(XII)	42505	benzyl 3-(2-aminophenyl)-3-oxopropyl(isopropyl)carbamate		C₂₀H₂₄N₂O₃	详情	详情

合成路线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.

参考文献中间体

【1】 Hong, C.I.; Kim, J.K.; Ahn, S.K.; CKD-602. Drugs Fut 2000, 25, 12, 1243.
【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.
【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.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	10816	Camptothecin; (4S)-4-Ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 4-et-4-hydroxy-1,12-dihydro-4h-2-oxa-6,12a-diaza-dibenzo(b,h)fluorene-3,13-dione	7689-03-4	C₂₀H₁₆N₂O₄	详情	详情
(XII)	42506	(4S)-4-ethyl-4-hydroxy-11-methyl-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione		C₂₁H₁₈N₂O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)