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【结 构 式】 
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【药物名称】GYKI-46903 【化学名称】(+)-endo-6-(4-Fluorophenyl)-4-(propionyloxy)-1-azabicyclo[3.3.1]non-6-ene hydrochloride 【CA登记号】142999-59-5 【 分 子 式 】C17H21ClFNO2 【 分 子 量 】325.81382 |
【开发单位】Institute for Drug Research (Originator) 【药理作用】Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Muscarinic M1 Agonists |
合成路线1
N-Benzyl-4-piperidone (I) was reacted with a Grignard reagent prepared from 4-fluorobromobenzene (II) to give the carbinol (III). The benzyl group was removed by catalytic hydrogenation and the resulting amine (IV) was alkylated with 3-bromopropionaldehyde ethylene acetal (V) to the alcohol (VI). Ring closure in hydrochloric acid gave the bicyclic endo-alcohol [(±)-VII] along with some of the exo-isomer removed by crystallization. [(±)-VII] was resolved by crystallization with (R,R)-tartaric acid mono-4-chloroanilide (VIII) to give [(+)-VII] of yet unknown absolute configuration. The latter was acylated with propionic anhydride followed by crystallization with hydrogen chloride in ether to furnish the end product.
| 【1】 Sólyom, S.; Abraham, G.; Szölössy, M.; Borsi, J.; Vitális, B.; Karimné Tapfer, M.; Szabóné Bady, E.; Csuzdi, E.; Goldschmidtné Horváth, K.; Máté, G.; Ling, I.; Miklósné Kovács, A. (Gyogyszerkutato Intezet Kft.); New 1-azabicycloalkane derivs., pharmaceutical compsns. containing them and process for preparing same. EP 0556342; JP 1994505706; WO 9207854 . |
| 【2】 Nogradi, M.; GYKI-46903. Drugs Fut 1993, 18, 5, 421. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| ((+/-)-VII | 15726 | (rac)-[(4R*,5S*)-6-(4-fluorophenyl)-1-azabicyclo[3.3.1]non-6-en-4-ol] | C14H16FNO | 详情 | 详情 | |
| ((R,R)-VII) | 15727 | (2R,3R)-4-(4-chloroanilino)-2,3-dihydroxy-4-oxobutyric acid | C10H10ClNO5 | 详情 | 详情 | |
| ((+)-VII) | 64680 | (4R,5S)-6-(4-fluorophenyl)-1-azabicyclo[3.3.1]non-6-en-4-ol | C14H16FNO | 详情 | 详情 | |
| (I) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (II) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (III) | 15722 | 1-benzyl-4-(4-fluorophenyl)-4-piperidinol | C18H20FNO | 详情 | 详情 | |
| (IV) | 15723 | 4-(4-fluorophenyl)-4-piperidinol; 4-(4-Fluorophenyl)-4-hydroxypiperidine | 3888-65-1 | C11H14FNO | 详情 | 详情 |
| (V) | 15724 | 2-(2-bromoethyl)-1,3-dioxolane | 18742-02-4 | C5H9BrO2 | 详情 | 详情 |
| (VI) | 15725 | 1-[2-(1,3-dioxolan-2-yl)ethyl]-4-(4-fluorophenyl)-4-piperidinol | C16H22FNO3 | 详情 | 详情 |