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【结 构 式】 
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【药物名称】SU-11925 【化学名称】4-(3-Chloro-4-fluorophenylamino)-5(Z)-[5-[3(R),5(S)-dimethylpiperazin-1-ylcarbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-6-one 【CA登记号】346600-13-3 (cis-isomer) 【 分 子 式 】C25H25ClFN7O2 【 分 子 量 】509.9751 |
【开发单位】Sugen (Originator) 【药理作用】Oncolytic Drugs, EGFR (erbB1) Inhibitors, HER2 (erbB2) Inhibitors, Inhibitors of Signal Transduction Pathways |
合成路线1
Condensation of cyano ester (I) with formamidine in the presence of NaOEt afforded the pyrimidinone derivative (II). Acetal hydrolysis of (II) with concomitant intramolecular cyclization under acidic conditions produced the pyrrolopyrimidinone (III), which was further chlorinated to (IV) in refluxing POCl3. Displacement of the 4-chloro of (IV) with 3-chloro-4-fluoroaniline (V) in the presence of silver triflate in hot DMF afforded the anilino pyrrolopyrimidine (VI). Oxidation of (VI) using pyridinium bromide perbromide furnished the alpha,alpha-dibromo lactam (VII). Reductive debromination of (VII) by means of zinc dust in AcOH gave intermediate (VIII).
| 【1】 Wei, C.C.; Tang, P.C.; McMahon, G.; Sun, L.; Hirth, K.P.; Liang, C.; Cui, J. (Sugen, Inc.); 4-Substd. 7-aza-indolin-2-ones and their use as protein kinase inhibitors. EP 1244672; WO 0146196 . |
| 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) | 14789 | ethyl 2-cyano-4,4-diethoxybutanoate | C11H19NO4 | 详情 | 详情 | |
| (II) | 60644 | 2-[4-bromo-2-(2-fluorobenzoyl)anilino]-2-oxoethyl 4-methylbenzenesulfonate | C22H17BrFNO5S | 详情 | 详情 | |
| (III) | 60045 | 3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one | C6H5N3O | 详情 | 详情 | |
| (IV) | 60046 | 4-chloro-7H-pyrrolo[2,3-d]pyrimidine；6-Chloro-7-deazapurine；4-chloropyrrolo[2,3-d]pyrimidine；4-Chloro-1H-pyrrolo[2,3-d]pyrimidine | 3680-69-1 | C6H4ClN3 | 详情 | 详情 |
| (V) | 18688 | 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline | 367-21-5 | C6H5ClFN | 详情 | 详情 |
| (VI) | 60850 | N-(3-chloro-4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; N-(3-chloro-4-fluorophenyl)-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine | C12H8ClFN4 | 详情 | 详情 | |
| (VII) | 60851 | 5,5-dibromo-4-(3-chloro-4-fluoroanilino)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one | C12H6Br2ClFN4O | 详情 | 详情 | |
| (VIII) | 60852 | 4-(3-chloro-4-fluoroanilino)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one | C12H8ClFN4O | 详情 | 详情 |
合成路线2
Vilsmeier-Haack formylation of ethyl 4-methylpyrrole-2-carboxylate (IX) using POCl3 in DMF furnished the pyrrole aldehyde (X). Subsequent basic hydrolysis of the ethyl ester group of (X) gave 5-formyl-4-methylpyrrole-2-carboxylic acid (XI), which was further coupled to cis-2,6-dimethylpiperazine (XII) producing amide (XIII). The title compound was finally prepared by aldol condensation between the pyrrole aldehyde (XIII) and lactam (VIII) in the presence of piperidine.
| 【1】 Wei, C.C.; Tang, P.C.; McMahon, G.; Sun, L.; Hirth, K.P.; Liang, C.; Cui, J. (Sugen, Inc.); 4-Substd. 7-aza-indolin-2-ones and their use as protein kinase inhibitors. EP 1244672; WO 0146196 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 60852 | 4-(3-chloro-4-fluoroanilino)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one | C12H8ClFN4O | 详情 | 详情 | |
| (IX) | 60049 | ethyl 4-methyl-1H-pyrrole-2-carboxylate | C8H11NO2 | 详情 | 详情 | |
| (X) | 60050 | ethyl 5-formyl-4-methyl-1H-pyrrole-2-carboxylate | C9H11NO3 | 详情 | 详情 | |
| (XI) | 60051 | 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid | C7H7NO3 | 详情 | 详情 | |
| (XII) | 20848 | (2R,6S)-2,6-dimethylpiperazine | C6H14N2 | 详情 | 详情 | |
| (XIII) | 60853 | 5-{[(3R,5S)-3,5-dimethylpiperazinyl]carbonyl}-3-methyl-1H-pyrrole-2-carbaldehyde | C13H19N3O2 | 详情 | 详情 |