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【结 构 式】 
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【分子编号】26887 【品名】3-([(11S,11aS)-11-hydroxy-7-methoxy-5-oxo-10-[(2,2,2-trichloroethoxy)carbonyl]-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy)propionic acid 【CA登记号】 |
【 分 子 式 】C19H21Cl3N2O8 【 分 子 量 】511.74252 【元素组成】C 44.59% H 4.14% Cl 20.78% N 5.47% O 25.01% |
合成路线1
该中间体在本合成路线中的序号：(IX)Reaction of vanillic acid (I) with 3-bromopropanol gave ether (II). Subsequent nitration of (II) with simultaneous oxidation of the primary alcohol employing nitric acid afforded the nitro diacid (IV), which by chemoselective esterification in the presence of a catalytic amount of p-toluenesulfonic acid yielded monoester (IV). After conversion of (IV) to the acid chloride upon treatment with oxalyl chloride, coupling with (S)-2-(hydroxymethyl)pyrrolidine (V) gave amide (VI). Catalytic hydrogenation of the nitro group of (VI), followed by protection of the intermediate aniline with 2,2,2-trichloroethyl chloroformate provided carbamate (VII). Further Swern oxidation of the alcohol group of (VII) with concomitant cyclization generated the pyrrolobenzodiazepine (VIII). The methyl ester of (VIII) was then hydrolyzed to carboxylic acid (IX).
| 【1】 Baraldi, P.G.; Cacciari, B.; Guiotto, A.; Leoni, A.; Romagnoli, R.; Spalluto, G.; Mongelli, N.; Howard, P.W.; Thurston, D.E.; Bianchi, N.; Gambari, R.; Design, synthesis and biological activity of a pyrrolo[2,1-c][1,4]benzodiazepine (PBD)-distamycin hybrid. Bioorg Med Chem Lett 1998, 8, 21, 3019. |
| 【2】 Cacciari, B.; Baraldi, P.G.; Balboni, G.; et al.; Synthesis, in vitro antiproliferative activity, and DNA-binding properties of hybrid molecules containing pyrrolo[2,1-c][1,4]benzodiazepine and minor-groove-binding oligopyrrole carriers. J Med Chem 1999, 42, 25, 5131. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 | |
| (I) | 17786 | 4-hydroxy-3-methoxybenzoic acid; Vanillic acid | 121-34-6 | C8H8O4 | 详情 | 详情 |
| (II) | 26881 | 4-(3-hydroxypropoxy)-3-methoxybenzoic acid | C11H14O5 | 详情 | 详情 | |
| (III) | 26882 | 4-(2-carboxyethoxy)-5-methoxy-2-nitrobenzoic acid | C11H11NO8 | 详情 | 详情 | |
| (IV) | 26883 | 5-methoxy-4-(3-methoxy-3-oxopropoxy)-2-nitrobenzoic acid | C12H13NO8 | 详情 | 详情 | |
| (V) | 21347 | (2S)pyrrolidinylmethanol | 23356-96-9 | C5H11NO | 详情 | 详情 |
| (VI) | 26884 | methyl 3-(4-[[(2S)-2-(hydroxymethyl)pyrrolidinyl]carbonyl]-2-methoxy-5-nitrophenoxy)propanoate | C17H22N2O8 | 详情 | 详情 | |
| (VII) | 26885 | methyl 3-(4-[[(2S)-2-(hydroxymethyl)pyrrolidinyl]carbonyl]-2-methoxy-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]phenoxy)propanoate | C20H25Cl3N2O8 | 详情 | 详情 | |
| (VIII) | 26886 | 2,2,2-trichloroethyl (11S,11aS)-11-hydroxy-7-methoxy-8-(3-methoxy-3-oxopropoxy)-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate | C20H23Cl3N2O8 | 详情 | 详情 | |
| (IX) | 26887 | 3-([(11S,11aS)-11-hydroxy-7-methoxy-5-oxo-10-[(2,2,2-trichloroethoxy)carbonyl]-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy)propionic acid | C19H21Cl3N2O8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The coupling of (IX) with deformyl distamycin (X) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide as the condensing reagent to yield amide (XI). Finally, deprotection of the trichloroethyl carbamate of (XI) with Cd/Pb couple in aqueous NH4OAc furnished the target compound.
| 【1】 Baraldi, P.G.; Cacciari, B.; Guiotto, A.; Leoni, A.; Romagnoli, R.; Spalluto, G.; Mongelli, N.; Howard, P.W.; Thurston, D.E.; Bianchi, N.; Gambari, R.; Design, synthesis and biological activity of a pyrrolo[2,1-c][1,4]benzodiazepine (PBD)-distamycin hybrid. Bioorg Med Chem Lett 1998, 8, 21, 3019. |
| 【2】 Cacciari, B.; Baraldi, P.G.; Balboni, G.; et al.; Synthesis, in vitro antiproliferative activity, and DNA-binding properties of hybrid molecules containing pyrrolo[2,1-c][1,4]benzodiazepine and minor-groove-binding oligopyrrole carriers. J Med Chem 1999, 42, 25, 5131. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 26887 | 3-([(11S,11aS)-11-hydroxy-7-methoxy-5-oxo-10-[(2,2,2-trichloroethoxy)carbonyl]-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy)propionic acid | C19H21Cl3N2O8 | 详情 | 详情 | |
| (X) | 26888 | N-(3-amino-3-iminopropyl)-4-[[(4-[[(4-amino-1-methyl-1H-pyrrol-2-yl)carbonyl]amino]-1-methyl-1H-pyrrol-2-yl)carbonyl]amino]-1-methyl-1H-pyrrole-2-carboxamide | C21H27N9O3 | 详情 | 详情 | |
| (XI) | 26889 | (11S,11aS)-8-[2-[N-[5-[N-[5-[N-[5-[N-[2-(Amidinoethyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]etoxy]-11-hydroxy-7-methoxy-5-oxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]-benzodiazepine-10-carboxylic acid 2,2,2-trichloroethyl ester; (11S,11aS)-8-[2-[N-[5-[N-[5-[N-[5-[N-[2-(Amidinoethyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]etoxy]-11-hydroxy-7-methoxy-5-oxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]-benzodiazepine-10-carboxylic acid 2,2,2-trichloroethyl ester | C40H46Cl3N11O10 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The acylation of N-deformyldistamycin (I) with 4-formamido-1-methyl-1H-pyrrole-2-carboxylic acid (II) by means of carbonyldiimidazole (CDI) in DMF gives the tetrapyrrole (III), which is deformylated as usual to yield the aminotetrapyrrole (IV). The condensation of the pyrrolobenzodiazepin-8-yloxypropionic acid (V) with the tetrapyrrole derivative (IV) by means of EDC and DIEA in DMF gives the troc protected target molecule (III), which is finally treated with Cd/Pb in aqueous NH4OAc. The synthesis of the intermediate pyrrolobenzodiazepin-8-yloxypropionic acid (I) has already been described in scheme2700821a, corresponding to the synthesis of the compound with EN 270082.
| 【1】 D'Alessio, R.; et al.; Structure-activity relationship of novel distamycin a derivatives: Synthesis and antitumor activity. Bioorg Med Chem Lett 1994, 4, 12, 1467. |
| 【2】 Cacciari, B.; Baraldi, P.G.; Balboni, G.; et al.; Synthesis, in vitro antiproliferative activity, and DNA-binding properties of hybrid molecules containing pyrrolo[2,1-c][1,4]benzodiazepine and minor-groove-binding oligopyrrole carriers. J Med Chem 1999, 42, 25, 5131. |
| 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) | 26888 | N-(3-amino-3-iminopropyl)-4-[[(4-[[(4-amino-1-methyl-1H-pyrrol-2-yl)carbonyl]amino]-1-methyl-1H-pyrrol-2-yl)carbonyl]amino]-1-methyl-1H-pyrrole-2-carboxamide | C21H27N9O3 | 详情 | 详情 | |
| (II) | 31630 | 4-(formylamino)-1-methyl-1H-pyrrole-2-carboxylic acid | C7H8N2O3 | 详情 | 详情 | |
| (III) | 31631 | N-(5-[[(5-[[(5-[[(3-amino-3-iminopropyl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)-4-(formylamino)-1-methyl-1H-pyrrole-2-carboxamide | C28H33N11O5 | 详情 | 详情 | |
| (IV) | 31632 | N-(5-[[(5-[[(3-amino-3-iminopropyl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)-4-[[(4-amino-1-methyl-1H-pyrrol-2-yl)carbonyl]amino]-1-methyl-1H-pyrrole-2-carboxamide | C27H33N11O4 | 详情 | 详情 | |
| (V) | 26887 | 3-([(11S,11aS)-11-hydroxy-7-methoxy-5-oxo-10-[(2,2,2-trichloroethoxy)carbonyl]-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy)propionic acid | C19H21Cl3N2O8 | 详情 | 详情 | |
| (VI) | 31633 | 2,2,2-trichloroethyl (11S,11aS)-8-[3-[(5-[[(5-[[(5-[[(5-[[(3-amino-3-iminopropyl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)oxy]-3-o | C46H51Cl3N12O12 | 详情 | 详情 |