Bizelesin, NSC-615291, U-77779, -Drug Synthesis Database

【结构式】

【药物名称】Bizelesin, NSC-615291, U-77779

【化学名称】(S,S)-6,6'-[Carbonylbis(5-imino-1H-indole-2-carbonyl)]bis[8-(chloromethyl)-1-methyl-3,6,7,8-tetrahydrobenzo[1,2-b:4,3-b']dipyrrol-4-ol]
　　　　　　(S,S)-1,3-Bis[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]urea

【CA登记号】129655-21-6

【分子式】C₄₃H₃₆Cl₂N₈O₅

【分子量】815.72297

【开发单位】Pfizer (Originator), National Cancer Institute (Codevelopment)

【药理作用】DERMATOLOGIC DRUGS, Oncolytic Drugs, Solid Tumors Therapy, Ultraviolet Light Absorbers, DNA Alkylating Drugs

合成路线1 合成路线2

合成路线1

The intermediate pyrroloindole (VIII) was prepared from the previously reported (S)-aminoindoline (I). Michael addition of methyl propiolate (II) to aminoindoline (I) in MeOH provided the aminoacrylate (IIIa-b). Oxidative cyclization of (IIIa-b) was effected with Pd(OAc)2 in DMA to afford the 3-(methoxycarbonyl)pyrroloindole (IV). Simultaneous reduction of both the methyl ester and acetate groups of (IV) with borane-dimethyl sulfide complex gave rise to alcohol (V). Chlorination of (V) to give the chloromethyl derivative (VI) was carried out by treatment with triphenylphosphine and carbon tetrachloride. The O-benzyl protecting group of (VI) was subsequently removed by transfer hydrogenolysis yielding phenol (VII). The N-Boc group of (VII) was then cleaved under acidic conditions to furnish (VIII).

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.
【2】 Kelly, R.C.; Aristoff, P.A. (Pharmacia Corp.); Novel CC-1065 analogs having two CPI subunits. EP 0359454; JP 1992500664; WO 9002746 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IIIa)	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
(IIIb)	59125	tert-butyl (3S)-3-[(acetyloxy)methyl]-6-(benzyloxy)-5-{[(Z)-3-methoxy-3-oxo-1-propenyl]amino}-2,3-dihydro-1H-indole-1-carboxylate		C₂₇H₃₂N₂O₇	详情	详情
(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
(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

合成路线2

Condensation of 5-aminoindole-2-carboxylic acid ethyl ester (IX) with phosgene at very low temperature furnished the N,N'-bis(indolyl)urea (X). Subsequent basic hydrolysis of the ethyl ester groups of (X) gave diacid (XI). This was finally coupled with the intermediate pyrroloindole (VIII) by means of EDC to provide the title diamide.

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.
【2】 Kelly, R.C.; Aristoff, P.A. (Pharmacia Corp.); Novel CC-1065 analogs having two CPI subunits. EP 0359454; JP 1992500664; WO 9002746 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIII)	59130	(8S)-8-(chloromethyl)-1-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indol-4-ol	C₁₂H₁₃ClN₂O	详情	详情
(IX)	59131	methyl 5-amino-1H-indole-2-carboxylate	C₁₀H₁₀N₂O₂	详情	详情
(X)	59132	methyl 5-[({[2-(methoxycarbonyl)-1H-indol-5-yl]amino}carbonyl)amino]-1H-indole-2-carboxylate	C₂₁H₁₈N₄O₅	详情	详情
(XI)	59133	5-({[(2-carboxy-1H-indol-5-yl)amino]carbonyl}amino)-1H-indole-2-carboxylic acid	C₁₉H₁₄N₄O₅	详情	详情

Extended Information