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【结 构 式】 
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【药物名称】A-318315 【化学名称】N-[2-(Dimethylamino)acetyl]-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide hydrochloride 【CA登记号】312299-92-6 (free base) 【 分 子 式 】C22H28ClN3O6S 【 分 子 量 】498.00196 |
【开发单位】Abbott (Originator) 【药理作用】Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, ONCOLYTIC DRUGS, Antimitotic Drugs, Microtubule-Stabilizing Agents |
合成路线1
The reaction of indoline (I) with formic acid in refluxing toluene gives N-formylindoline (II), which is treated with chlorosulfonic acid to yield 5-(chlorosulfonyl)indoline-1-carbaldehyde (III). The reaction of (III) with 3,4,5-trimethoxyaniline (IV) and pyridine in THF affords the sulfonamide (V), which is deformylated to sulfonamide (VI) with HCl in methanol. The reaction of indoline (VI) with salcomine and O2 in methanol provides the corresponding indole derivative (VII), which is methylated with methyl iodide and NaHMDS in THF to give 1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide (VIII). Finally, this compound is condensed with N,N-dimethylglycine (IX) by means of DCC and 4-(1-pyrrolidinyl)pyridine (pypyr) in dichloromethane.
| 【1】 Li, Q.; Woods, K.W.; Steiner, A.; et al.; Synthesis and biological evaluation of biarylsulfonamides as tubulin polymerization inhibitors. Discovery of A-318315 and A-293620 as orally and intravenously active antimitotic agents. Proc Am Assoc Cancer Res 2002, 43, Abst 1313. |
| 【2】 Barr, K.J.; Steiner, B.A.; Qun, L.; Rosenberg, S.; Sham, H.; Gwaltney, S.L. II; Imade, H.M.; Woods, K.W. (Abbott Laboratories Inc.); Cell proliferation inhibitors. WO 0073264 . |
| 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) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (II) | 55546 | 1-Formylindoline | 2861-59-8 | C9H9NO | 详情 | 详情 |
| (III) | 55547 | 1-formyl-5-indolinesulfonyl chloride | C9H8ClNO3S | 详情 | 详情 | |
| (IV) | 31545 | 3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine；3,4,5-Trimethoxybenzenamine；[3,4,5-Tris(methyloxy)phenyl]amine | 24313-88-0 | C9H13NO3 | 详情 | 详情 |
| (V) | 55548 | 1-formyl-N-(3,4,5-trimethoxyphenyl)-5-indolinesulfonamide | C18H20N2O6S | 详情 | 详情 | |
| (VI) | 55549 | N-(3,4,5-trimethoxyphenyl)-5-indolinesulfonamide | C17H20N2O5S | 详情 | 详情 | |
| (VII) | 55550 | N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide | C17H18N2O5S | 详情 | 详情 | |
| (VIII) | 55569 | 1-methyl-N-[3,4,5-tris(methyloxy)phenyl]-1H-indole-5-sulfonamide | C18H20N2O5S | 详情 | 详情 | |
| (IX) | 16765 | 2-(dimethylamino)acetic acid; N,N-Dimethylglycine | 1118-68-9 | C4H9NO2 | 详情 | 详情 |