Carzelesin, NSC-619029, U-80244, -Drug Synthesis Database

【结构式】

【药物名称】Carzelesin, NSC-619029, U-80244

【化学名称】(S)-N-[2-[1-(Chloromethyl)-8-methyl-5-(N-phenylcarbamoyloxy)-1,2,3,6-tetrahydrobenzo[1,2-b:4,3-b']dipyrrol-3-ylcarbonyl]-1H-indol-5-yl]-6-(diethylamino)benzofuran-2-carboxamide

【CA登记号】119813-10-4

【分子式】C₄₁H₃₇ClN₆O₅

【分子量】729.24224

【开发单位】Pfizer (Originator), National Institutes of Health (Codevelopment)

【药理作用】Oncolytic Drugs, DNA-Damaging Drugs

合成路线1 合成路线2

合成路线1

By condensation of (S)-N-[2-[1-(chloromethyl)-5-hydroxy-8-methyl-1,2,3,6-tetrahydrobenzo [1,2-b:4,3-b']dipyrrol-3-ylcarbonyl]-1H-indol-5-yl]-6-(diethylamino) benzofuran-2-carboxamide (I) with phenyl isocyanate (II) by means of triethylamine in THF.

参考文献中间体

【1】 Mealy, N.; Castaner, J.; Carzelesin. Drugs Fut 1996, 21, 3, 245.
【2】 Kelly, R.C.; Martin, D.G.; Aristoff, P.A. (Pharmacia Corp.); Novel CC-1065 analogs. AU 8812290; EP 0340243; WO 8804659 .

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)	13352	N-(2-[[(1S)-1-(Chloromethyl)-5-hydroxy-8-methyl-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl]carbonyl]-1H-indol-5-yl)-6-(diethylamino)-1-benzofuran-2-carboxamide		C₃₄H₃₂ClN₅O₄	详情	详情
(II)	11289	1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate	103-71-9	C₇H₅NO	详情	详情

合成路线2

The reaction of indoline (I) with propynoic acid methyl ester (II) in methanol gives the acrylic acid derivative (III), which is cyclized by means of Pd(OAc)2 in DMA to yield the pyrroloindole (IV). The reduction of the ester group of (IV) by means of BH3/Me2S in refluxing THF affords intermediate (V), which is treated with CCl4 and PPh3 to provide the chloromethyl derivative (VI). The O-deprotection in (VI) by means of HCOONH4 and Pd/C in THF gives the hydroxy compound (VII), which is N-deprotected by means of HCl in ethyl acetate to yield the pyrroloindole (VIII). The condensation of (VIII) with the known indole carboxylic acid (IX) by means of EDC in DMF affords the carboxamide (X), which is treated with phenyl isocyanate (XI) and TEA in THF to provide the target Carzelesin.

参考文献中间体

【1】 Fukuda, Y.; et al.; Novel syntheses of optically active CC-1065, U-73,975 (adozelesin), U-80,244 (carzelesin), U-77,779 (bizelesin), KW-2189, and DU-86. Heterocycles 1997, 45, 12, 2303.

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)	59123	tert-butyl (3S)-3-[(acetyloxy)methyl]-5-amino-6-(benzyloxy)-2,3-dihydro-1H-indole-1-carboxylate		C₂₃H₂₈N₂O₅	详情	详情
(II)	19588	methyl propiolate	922-67-8	C₄H₄O₂	详情	详情
(III)	59124	tert-butyl (3S)-3-[(acetyloxy)methyl]-6-(benzyloxy)-5-{[(E)-3-methoxy-3-oxo-1-propenyl]amino}-2,3-dihydro-1H-indole-1-carboxylate		C₂₇H₃₂N₂O₇	详情	详情
(IV)	59126	6-(tert-butyl) 1-methyl (8S)-8-[(acetyloxy)methyl]-4-(benzyloxy)-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate		C₂₇H₃₀N₂O₇	详情	详情
(V)	59127	tert-butyl (1S)-5-(benzyloxy)-1-(hydroxymethyl)-8-methyl-1,6-dihydropyrrolo[3,2-e]indole-3(2H)-carboxylate		C₂₄H₂₈N₂O₄	详情	详情
(VI)	59128	tert-butyl (1S)-5-(benzyloxy)-1-(chloromethyl)-8-methyl-1,6-dihydropyrrolo[3,2-e]indole-3(2H)-carboxylate		C₂₄H₂₇ClN₂O₃	详情	详情
(VII)	59129	tert-butyl (1S)-1-(chloromethyl)-5-hydroxy-8-methyl-1,6-dihydropyrrolo[3,2-e]indole-3(2H)-carboxylate		C₁₇H₂₁ClN₂O₃	详情	详情
(VIII)	59130	(8S)-8-(chloromethyl)-1-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indol-4-ol		C₁₂H₁₃ClN₂O	详情	详情
(IX)	61765	5-{[6-(diethylamino)-1-benzofuran-2-yl]carbonyl}-1H-indole-2-carboxylic acid		C₂₂H₂₀N₂O₄	详情	详情
(X)	61766	[(1S)-1-(chloromethyl)-5-hydroxy-8-methyl-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl](5-{[6-(diethylamino)-1-benzofuran-2-yl]carbonyl}-1H-indol-2-yl)methanone		C₃₄H₃₁ClN₄O₄	详情	详情
(XI)	11289	1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate	103-71-9	C₇H₅NO	详情	详情

Extended Information