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【结 构 式】 
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【药物名称】KF-27376 【化学名称】4-[2-[2-(Dimethylamino)-1-methylethoxy]phenyl]-2,6-dimethyl-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-1,3-dione hydrochloride 【CA登记号】 【 分 子 式 】C27H28ClN3O3 【 分 子 量 】477.99551 |
【开发单位】Kyowa Hakko (Originator) 【药理作用】Antithrombocytopenic, Chemoprotective Agents, HEMATOLOGIC DRUGS, Hematopoiesis Disorders Therapy, Hematopoietic Agents, ONCOLYTIC DRUGS |
合成路线1
The condensation of 1-methylindole-2-carbaldehyde (I) with 2-hydroxybenzyl triphenylphosphonium bromide (II) by means of BuLi in THF gives the vinyl derivative (III), which is condensed with (rac)-methyl lactate (IV) by means of DEAD and PPh3 in THF yielding the ether derivative (V). The reduction of the carboxylate group of (V) with DIBAL in THF affords the expected propanol derivative (VI), which is cyclized with N-methylmaleimide (VII) by heating at 180 C and aromatized with DDQ giving the pyrrolocarbazole (VIII). The reaction of the hydroxy group of (VIII) with tosyl chloride and pyridine yields the corresponding tosylate (IX), which is finally condensed with dimethylamine in hot DMF.
| 【1】 Ikuina, Y.; et al.; Synthesis and structure-activity relationships of pyrrolocarbazole derivatives possessing thrombopoietic activity. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 089. |
| 【2】 Ikuina, Y.; Murakata, C.; Saitoh, Y.; Shiotsu, Y.; Iida, T.; Tamaoki, T.; Yamashita, K.; Akinaga, S. (Kyowa Hakko Kogyo Co., Ltd.); Pyrrolocarbazole derivs.. EP 0768311; US 5728709; WO 9628447 . |
| 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) | 30938 | 1-methyl-1H-indole-2-carbaldehyde | C10H9NO | 详情 | 详情 | |
| (II) | 30939 | (2-hydroxybenzyl)(triphenyl)phosphonium bromide | 70340-04-4 | C25H22BrOP | 详情 | 详情 |
| (III) | 30940 | 2-[(E)-2-(1-methyl-1H-indol-2-yl)ethenyl]phenol | C17H15NO | 详情 | 详情 | |
| (IV) | 30946 | methyl 2-hydroxypropanoate | C4H8O3 | 详情 | 详情 | |
| (V) | 30947 | methyl 2-[2-[(E)-2-(1-methyl-1H-indol-2-yl)ethenyl]phenoxy]propanoate | C21H21NO3 | 详情 | 详情 | |
| (VI) | 30948 | 2-[2-[(E)-2-(1-methyl-1H-indol-2-yl)ethenyl]phenoxy]-1-propanol | C20H21NO2 | 详情 | 详情 | |
| (VII) | 30943 | 1-methyl-1H-pyrrole-2,5-dione | 930-88-1 | C5H5NO2 | 详情 | 详情 |
| (VIII) | 30949 | 4-[2-(2-hydroxy-1-methylethoxy)phenyl]-2,6-dimethylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione | C25H22N2O4 | 详情 | 详情 | |
| (IX) | 30950 | 2-[2-(2,6-dimethyl-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-4-yl)phenoxy]propyl 4-methylbenzenesulfonate | C32H28N2O6S | 详情 | 详情 |