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【结 构 式】

【分子编号】59124

【品名】tert-butyl (3S)-3-[(acetyloxy)methyl]-6-(benzyloxy)-5-{[(E)-3-methoxy-3-oxo-1-propenyl]amino}-2,3-dihydro-1H-indole-1-carboxylate

【CA登记号】

【 分 子 式 】C27H32N2O7

【 分 子 量 】496.56036

【元素组成】C 65.31% H 6.5% N 5.64% O 22.55%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(III)

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.

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

合成路线2

该中间体在本合成路线中的序号:(IIIa)

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).

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
Extended Information