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【结 构 式】 
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【分子编号】26888 【品名】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 【CA登记号】 |
【 分 子 式 】C21H27N9O3 【 分 子 量 】453.50424 【元素组成】C 55.62% H 6% N 27.8% O 10.58% |
合成路线1
该中间体在本合成路线中的序号：(X)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2
该中间体在本合成路线中的序号：(I)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 |
合成路线3
该中间体在本合成路线中的序号：(IV)Reaction of 4-mercaptocinnamic acid (I) with 2-chloroethanol in the presence of NaOH afforded the hydroxyethyl sulfide (II), which was converted into the chloroethyl derivative (III) upon treatment with mesyl chloride and 37% HCl in hot pyridine. Coupling of carboxylic acid (III) with desformyldistamycin (IV) by means of DCC and HOBt gave rise to the title amide.
| 【1】 Ragg, E.; Beria, I.; Caldarelli, M.; Geroni, C.; Capolongo, L.; Cozzi, P.; Mazzini, S.; Phenyl sulfur mustard derivatives of distamycin A. Bioorg Med Chem Lett 2000, 10, 15, 1653. |
| 【2】 Beria, I.; Caldarelli, M.; Capolongo, L.; Geroni, M.C.; Cozzi, P. (Pharmacia & Upjohn SpA); Sulfurated distamycin derivs., process for preparing them, and their use as antitumor agents. WO 0006541 . |
| 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) | 43911 | (E)-3-(4-sulfanylphenyl)-2-propenoic acid | C9H8O2S | 详情 | 详情 | |
| (II) | 43912 | (E)-3-[4-[(2-hydroxyethyl)sulfanyl]phenyl]-2-propenoic acid | C11H12O3S | 详情 | 详情 | |
| (III) | 43913 | (E)-3-[4-[(2-chloroethyl)sulfanyl]phenyl]-2-propenoic acid | C11H11ClO2S | 详情 | 详情 | |
| (IV) | 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 |
合成路线4
该中间体在本合成路线中的序号：(IV)The pyrazoledicarboxylic acid mono-methyl ester (I) was converted to the methyl benzyl diester (II) by treatment with benzyl bromide in the presence of DBU. Selective hydrolysis of the methyl ester function with KOH then provided the carboxylic acid (III). Coupling of acid (III) with deformyl distamycin A (IV) using EDC and HOBt gave amide (V). The protecting benzyl ester group of (V) was cleaved by catalytic hydrogenation over Pd/C to yield acid (VI). Amine (VIII) was obtained by acid cleavage of the Boc group from the protected precursor (VII). Subsequent coupling of amine (VIII) with carboxylic acid (VI) furnished the title compound.
| 【1】 Baraldi, P.G.; et al.; Design, synthesis, DNA binding, and biological evaluation of water-soluble hybrid molecules containing two pyrazole analogues of the alkylating cyclopropylpyrroloindole (CPI) subunit of the antitumor agent CC-1065 and polypyrrole minor groove binders. J Med Chem 2001, 44, 16, 2536. |
| 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) | 51295 | 5-(methoxycarbonyl)-1-methyl-1H-pyrazole-3-carboxylic acid | C7H8N2O4 | 详情 | 详情 | |
| (II) | 51296 | 3-benzyl 5-methyl 1-methyl-1H-pyrazole-3,5-dicarboxylate | C14H14N2O4 | 详情 | 详情 | |
| (III) | 51297 | 3-[(benzyloxy)carbonyl]-1-methyl-1H-pyrazole-5-carboxylic acid | C13H12N2O4 | 详情 | 详情 | |
| (IV) | 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 | |
| (V) | 51298 | benzyl 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-pyrazole-3-carboxylate | C34H37N11O6 | 详情 | 详情 | |
| (VI) | 51299 | 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-pyrazole-3-carboxylic acid | C27H31N11O6 | 详情 | 详情 | |
| (VII) | 51300 | tert-butyl 8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydropyrrolo[3,2-e]indazole-6(3H)-carboxylate | C16H20ClN3O3 | 详情 | 详情 | |
| (VIII) | 51301 | 8-(chloromethyl)-1-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indazol-4-ol | C11H12ClN3O | 详情 | 详情 |