NSC-708298, DB-67, -Drug Synthesis Database

【结构式】

【药物名称】NSC-708298, DB-67

【化学名称】11-(tert-Butyldimethylsilyl)-4(S)-ethyl-4,9-dihydroxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14-dione
　　　　　　(20S)-7-(tert-Butyldimethylsilyl)-10-hydroxycamptothecin

【CA登记号】220913-32-6

【分子式】C₂₆H₃₀N₂O₅Si

【分子量】478.6254

【开发单位】National Cancer Institute (Originator), Tigen Pharmaceuticals (Originator), University of Pittsburgh (Originator), Novartis (Licensee), TaiGen Biotechnology (Codevelopment), TTY Biopharm (Codevelopment)

【药理作用】ONCOLYTIC DRUGS, Camptothecins, DNA Topoisomerase I Inhibitors, DNA-Intercalating Drugs

合成路线1 合成路线2 合成路线3

合成路线1

The reaction of the propargyl tetrahydropyranyl ether (I) with TBDMS-Cl and BuLi in THF gives the silylated acetylene (II), which is treated with Br2 and PPh3 to yield the silylated propargyl bromide (III). The reaction of (III) with the pyranopyridone (IV) by means of NaH and LiBr in DMF/DME affords the alkylated pyranopyridone (V), which is cyclized with 4-acetoxyphenyl isocyanide (VI) by means of hexamethyldistannane in refluxing benzene to provide the silylated acetoxycamptothecin (VII). Finally, this compound is deacetylated with K2CO3 in methanol.

参考文献中间体

【1】 Bom, D.; et al.; The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity. J Med Chem 2000, 43, 21, 3970.
【2】 Bom, D.; Curran, D.P.; Josien, H. (University of Pittsburgh); Camptothecin analogs and methods of preparation thereof. EP 1017399; JP 2001513567; US 6150343; WO 9909996 .
【3】 Bom, D.; Curran, D.P.; Josien, H.; Burke, T.G. (University of Pittsburgh); Camptothecin analogs and methods of preparation thereof. WO 0035924 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	43853	(1S,5S,7R,10S,12S,16S)-3,3-di(tert-butyl)-16-[[tert-butyl(dimethyl)silyl]oxy]-15,18,18-trimethyl-2,4-dioxa-3-silatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-6(11),14-diene-7,10,12-triol	C₃₂H₅₈O₆Si₂	详情	详情
(II)	49254	4,5-dichloro-2-iodoaniline; tert-butyl(dimethyl)[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]silane	C₁₄H₂₆O₂Si	详情	详情
(III)	35102	(3-bromo-1-propynyl)(tert-butyl)dimethylsilane	C₉H₁₇BrSi	详情	详情
(IV)	49255	(4S)-4-ethyl-4-hydroxy-6-iodo-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione	C₁₀H₁₀INO₄	详情	详情
(V)	49256	(4S)-7-[3-[tert-butyl(dimethyl)silyl]-2-propynyl]-4-ethyl-4-hydroxy-6-iodo-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione	C₁₉H₂₆INO₄Si	详情	详情
(VI)	49257		C₉H₇NO₂	详情	详情
(VII)	49258	(4S)-11-[tert-butyl(dimethyl)silyl]-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl acetate	C₂₈H₃₂N₂O₆Si	详情	详情

合成路线2

The reaction of camptothecin (I) with Tbdms-H, (t-BuO)2 and t-BuSH in refluxing dioxane gives the 7-silylcamptothecin (II), which is treated with H2O2 in hot AcOH to give the N-oxide (III). Finally, this compound is isomerized by photolysis in dioxane/H2SO4 to afford the target silylated 10-hydroxycamptothecin.

参考文献中间体

【1】 Du, W.; Kaskar, B.; Blumbergs, P.; Subramanian, P.-K.; Curran, D.P.; Semisynthesis of DB-67 and other silatecans from camptothecin by thiol-promoted addition of silyl radicals. Bioo. & Med. Chem. 2003, 11, 39, 451.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	61733	(7S)-7-ethyl-7-hydroxy-10,13-dihydrobenzo[6,7]indolizino[1,2-b]quinoline-8,11(7H,9H)-dione	C₂₁H₁₈N₂O₃	详情	详情
(II)	61734	(7S)-14-[tert-butyl(dimethyl)silyl]-7-ethyl-7-hydroxy-10,13-dihydrobenzo[6,7]indolizino[1,2-b]quinoline-8,11(7H,9H)-dione	C₂₇H₃₂N₂O₃Si	详情	详情
(III)	61735	(7S)-14-[tert-butyl(dimethyl)silyl]-7-ethyl-7-hydroxy-8,11-dioxo-7,8,9,10,11,13-hexahydrobenzo[6,7]indolizino[1,2-b]quinolin-5-ium-5-olate	C₂₇H₃₂N₂O₄Si	详情	详情

合成路线3

The reaction of 10-hydroxycamptothecin (IV) with Ac2O and pyridine gives the diacetate (V), which is silylated with Tbdms-H, (t-BuO)2 and Tis-SH in refluxing dioxane/TFA to give the silylated diacetate (VI). Finally, this compound is deacetylated by reaction with NaOMe in methanol or HCl in ethanol to afford the target silylated 10-hydroxycamptothecin.

参考文献中间体

【1】 Du, W.; Kaskar, B.; Blumbergs, P.; Subramanian, P.-K.; Curran, D.P.; Semisynthesis of DB-67 and other silatecans from camptothecin by thiol-promoted addition of silyl radicals. Bioo. & Med. Chem. 2003, 11, 39, 451.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IV)	61736	(7S)-7-ethyl-2,7-dihydroxy-10,13-dihydrobenzo[6,7]indolizino[1,2-b]quinoline-8,11(7H,9H)-dione	C₂₁H₁₈N₂O₄	详情	详情
(V)	61737	(7S)-2-(acetyloxy)-7-ethyl-8,11-dioxo-7,8,9,10,11,13-hexahydrobenzo[6,7]indolizino[1,2-b]quinolin-7-yl acetate	C₂₅H₂₂N₂O₆	详情	详情
(VI)	61738	(7S)-2-(acetyloxy)-14-[tert-butyl(dimethyl)silyl]-7-ethyl-8,11-dioxo-7,8,9,10,11,13-hexahydrobenzo[6,7]indolizino[1,2-b]quinolin-7-yl acetate	C₃₁H₃₆N₂O₆Si	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)