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【结 构 式】 
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【药物名称】A-259745 【化学名称】1-Methyl-5-[5-(3,4,5-trimethoxyphenyl)-4,5-dihydrooxazol-2-yl]-1H-indole 【CA登记号】256934-83-5, 256935-04-3 (R-isomer), 256935-03-2 (S-isomer) 【 分 子 式 】C21H22N2O4 【 分 子 量 】366.42049 |
【开发单位】Abbott (Originator) 【药理作用】ONCOLYTIC DRUGS, Antimitotic Drugs, Microtubule-Stabilizing Agents |
合成路线1
Condensation of 3,4,5-trimethoxybenzaldehyde (I) with nitromethane in the presence of KOH produced the nitro alcohol (II), which was subsequently hydrogenated over Pd/C to afford amino alcohol (III). Acylation of (III) with 5-indolecarboxylic acid (IV) gave the corresponding amide (V). Oxazoline (VI) was then obtained by cyclization of (V) in the presence of Burgess reagent. Finally, N-methylation of the indole ring with MeI and KOH furnished the title compound.
| 【1】 Liu, G.; Jae, H.-S.; Szczepankiewicz, B.G.; et al.; New antimitotic agents with activity in multi-drug-resistant cell lines and in vivo efficacy in murine tumor models. J Med Chem 2001, 44, 25, 4416. |
| 【2】 Woods, K.W.; Wang, L.; Kalvin, D.M.; Barr, K.J.; Li, Q.; Liu, G.; Gwaltney, S.L. II; Claiborne, A.K.; Jae, H.-S.; Sham, H.L. (Abbott Laboratories Inc.); Substd. oxazolines as antiproliferative agents. WO 0006556 . |
| 【3】 Sham, H.L.; Jae, H.-S.; Li, Q.; Wang, L.; Woods, K.W.; Liu, G.; Barr, K.J.; Kalvin, D.M.; Gwaltney, S.L. II; Claiborne, A.K. (Abbott Laboratories Inc.); Oxazoline antiproliferative agents. US 6228868 . |
| 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) | 11136 | 3,4,5-Trimethoxybenzaldehyde | 86-81-7 | C10H12O4 | 详情 | 详情 |
| (II) | 48616 | 2-nitro-1-(3,4,5-trimethoxyphenyl)-1-ethanol | C11H15NO6 | 详情 | 详情 | |
| (III) | 48617 | 2-amino-1-(3,4,5-trimethoxyphenyl)-1-ethanol | C11H17NO4 | 详情 | 详情 | |
| (IV) | 48618 | Indole-5-carboxylic acid | 1670-81-1 | C9H7NO2 | 详情 | 详情 |
| (V) | 48619 | N-[2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-1H-indole-5-carboxamide | C20H22N2O5 | 详情 | 详情 | |
| (VI) | 48620 | 5-[5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-indole; 4-[2-(1H-indol-5-yl)-4,5-dihydro-1,3-oxazol-5-yl]-2,6-dimethoxyphenyl methyl ether | C20H20N2O4 | 详情 | 详情 |
合成路线2
In a closely related procedure, amino alcohol (III) was coupled with 1-methyl-5-indolecarboxylic acid (VII) to afford amide (VIII). This was then cyclized to the target oxazoline by using the Burgess reagent.
| 【1】 Liu, G.; Jae, H.-S.; Szczepankiewicz, B.G.; et al.; New antimitotic agents with activity in multi-drug-resistant cell lines and in vivo efficacy in murine tumor models. J Med Chem 2001, 44, 25, 4416. |
| 【2】 Sorensen, B.K.; Liu, G.; Tasker, A.S.; et al.; Antimitotic agents with activity in multidrug-resistant tumor cell lines. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 139. |