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【结 构 式】 
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【药物名称】 【化学名称】5-(4-Aminobutylamino)-4-chloro-N-[5-[N-[5-[N-[5-[N-[3-(dimethylamino)propyl]carbamoyl]-1-methyl-1H-pyrrol-3-yl]carbamoyl]-1-methyl-1H-pyrrol-3-yl]carbamoyl]-1-methyl-1H-pyrrol-3-yl]isothiazole-3-carboxamide 【CA登记号】365211-10-5 【 分 子 式 】C31H42ClN11O4S 【 分 子 量 】700.26869 |
【开发单位】GeneSoft (Originator) 【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY |
合成路线1
Friedel-Crafts acylation of N-methylpyrrole (I) with trichloroacetyl chloride (II) affords the pyrrolyl ketone (III), which is subsequently subjected to electrophilic nitration with in situ generated acetyl nitrate, producing nitropyrrole (IV). Cleavage of the trichloroketone group of (IV) under alkaline conditions, followed by Fischer esterification leads to methyl ester (V). The nitro group of (V) is then reduced to amine (VI) by catalytic hydrogenation over Pd/C. After protection of amine (VI) as the corresponding N-Boc derivative (VII), saponification of the methyl ester group of (VII) yields acid (VIII). Coupling between the pyrrolecarboxylic acid (VIII) and amino ester (VI) provides the amide adduct (IX). After alkaline ester hydrolysis in (IX), the resultant carboxylic acid (X) is coupled with a further moiety of methyl 4-amino-1-methylpyrrole-2-carboxylate (VI) to furnish the tripyrrolyl compound (XI). Subsequent methyl ester saponification in (XI) provides acid (XII).
| 【1】 Ge, Y.; Taylor, M.J.; Baird, E.E.; Moser, H.E.; Burli, R.W. (GeneSoft, Inc.); Charged cpds. comprising a nucleic acid binding moiety and uses therefor. JP 2003529609; WO 0174898 . |
| 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) | 11285 | 1-Methyl-1H-pyrrole; Methylpyrrole | 96-54-8 | C5H7N | 详情 | 详情 |
| (II) | 47015 | 2,2,2-trichloroacetyl chloride | 76-02-8 | C2Cl4O | 详情 | 详情 |
| (III) | 47020 | 2,2,2-trichloro-1-(1-methyl-1H-pyrrol-2-yl)-1-ethanone | C7H6Cl3NO | 详情 | 详情 | |
| (IV) | 47021 | 2,2,2-trichloro-1-(1-methyl-4-nitro-1H-pyrrol-2-yl)-1-ethanone | C7H5Cl3N2O3 | 详情 | 详情 | |
| (V) | 58474 | methyl 1-methyl-4-nitro-1H-pyrrole-2-carboxylate | C7H8N2O4 | 详情 | 详情 | |
| (VI) | 53511 | methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate | 180258-45-1 | C7H10N2O2 | 详情 | 详情 |
| (VII) | 58475 | methyl 4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylate | C12H18N2O4 | 详情 | 详情 | |
| (VIII) | 53510 | 4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid | 77716-11-1 | C11H16N2O4 | 详情 | 详情 |
| (IX) | 53512 | methyl 4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylate | n/a | C18H24N4O5 | 详情 | 详情 |
| (X) | 53513 | 4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid | n/a | C17H22N4O5 | 详情 | 详情 |
| (XI) | 53514 | methyl 4-[({4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylate | n/a | C24H30N6O6 | 详情 | 详情 |
| (XII) | 53515 | 4-[({4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid | n/a | C23H28N6O6 | 详情 | 详情 |
合成路线2
The tripyrrolyl acid (XII) is coupled with N,N-dimethyl-1,3-propanediamine (XIII) to afford amide (XIV). After acidic Boc group cleavage in (XIV), the resultant amino compound (XV) is acylated by 4,5-dichloroisothiazole-3-carboxylic acid (XVI) to furnish the tetra-heterocyclic amide (XVII). Finally, selective displacement of the 5-chloro group of (XVII) with 1,4-butanediamine (XVIII) gives rise to the title compound.
| 【1】 Ge, Y.; Taylor, M.J.; Baird, E.E.; Moser, H.E.; Burli, R.W. (GeneSoft, Inc.); Charged cpds. comprising a nucleic acid binding moiety and uses therefor. JP 2003529609; WO 0174898 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 53515 | 4-[({4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid | n/a | C23H28N6O6 | 详情 | 详情 |
| (XIII) | 25248 | N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine | 109-55-7 | C5H14N2 | 详情 | 详情 |
| (XIV) | 58476 | tert-butyl 5-({[5-({[5-({[3-(dimethylamino)propyl]amino}carbonyl)-1-methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H-pyrrol-3-ylcarbamate | C28H40N8O5 | 详情 | 详情 | |
| (XV) | 58477 | 4-{[(4-{[(4-amino-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-N-[3-(dimethylamino)propyl]-1-methyl-1H-pyrrole-2-carboxamide | C23H32N8O3 | 详情 | 详情 | |
| (XVI) | 53577 | ((3aR,4R,6R,6aS)-2,2-dimethyl-6-{6-[(3R)tetrahydro-3-furanylamino]-9H-purin-9-yl}tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl methylcarbamate | n/a | C19H26N6O6 | 详情 | 详情 |
| (XVII) | 58478 | 4,5-dichloro-N-[5-({[5-({[5-({[3-(dimethylamino)propyl]amino}carbonyl)-1-methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H-pyrrol-3-yl]-3-isothiazolecarboxamide | C27H31Cl2N9O4S | 详情 | 详情 | |
| (XVIII) | 42070 | 1,4-butanediamine; 4-aminobutylamine | 110-60-1 | C4H12N2 | 详情 | 详情 |