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【结 构 式】 
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【药物名称】ER-127528 【化学名称】(+)-2-Fluoro-2-[1-(3-fluorobenzyl)piperidin-4-ylmethyl]-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one hydrochloride 【CA登记号】290308-82-6 (undefined isomer), 290308-83-7 (undefined isomer, free base) 【 分 子 式 】C24H28ClF2NO3 【 分 子 量 】451.94546 |
【开发单位】Eisai (Originator) 【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Acetylcholinesterase Inhibitors |
合成路线1
The lithium enolate of the indanone derivative (I) is fluorinated by treatment with N-fluorobenzenesulfonimide, to afford the corresponding fluoro ketone, which is finally isolated as the corresponding hydrochloride salt.
| 【1】 Sugimoto, H.; Yamanishi, Y.; Shibata, T.; Kosaka, T.; Suzuki, E.; Takeuchi, Y.; Imura, Y. (Eisai Co., Ltd.); Fluorides of 4-substd. piperidine derivs.. EP 1157989; JP 2000319258; WO 0051985 . |
| 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) | 57509 | 2-{[1-(3-fluorobenzyl)-4-piperidinyl]methyl}-5,6-dimethoxy-1-indanone | C24H28FNO3 | 详情 | 详情 |
合成路线2
The title compound is also prepared by a related method. Indanone (I) is fluorinated by means of N-fluorobenzenesulfonimide in the presence of lithium hexamethyldisilazide, to afford the corresponding fluoro ketone (II). Subsequent dealkylation of the N-benzyl group of (II) is accomplished by treatment with 1-chloroethyl chloroformate, to produce the intermediate carbamate (III), which is then decarboxylated to the secondary amine (IV) in boiling MeOH. Finally, piperidine (IV) is reductively alkylated with 3-fluorobenzaldehyde (V) in the presence of NaBH(OAc)3.
| 【1】 Takeuchi, Y.; Yamanishi, Y.; Sugimoto, H.; Suzuki, N.; Iimura, Y.; Kawakami, Y.; Inoue, A.; Kuriya, Y.; Kosasa, T.; Recent advances in the study of acetylcholinesterase inhibitor "donepezil" (1): Synthesis and structure-activity relationships of fluorine-introduced donepezil and related compounds. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 67. |
| 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) | 57510 | 2-[(1-benzyl-4-piperidinyl)methyl]-5,6-dimethoxy-1-indanone | C24H29NO3 | 详情 | 详情 | |
| (II) | 57511 | 2-[(1-benzyl-4-piperidinyl)methyl]-2-fluoro-5,6-dimethoxy-1-indanone | C24H28FNO3 | 详情 | 详情 | |
| (III) | 57512 | 1-chloroethyl 4-[(2-fluoro-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl]-1-piperidinecarboxylate | C20H25ClFNO5 | 详情 | 详情 | |
| (IV) | 57513 | 2-fluoro-5,6-dimethoxy-2-(4-piperidinylmethyl)-1-indanone | C17H22FNO3 | 详情 | 详情 | |
| (V) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |