|
【结 构 式】 
|
【药物名称】CRA-1000 【化学名称】N-Ethyl-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridinyl]-N-[4-isopropyl-2-(methylsulfanyl)phenyl]-6-methylpyrimidin-2-amine 【CA登记号】 【 分 子 式 】C28H33FN4S 【 分 子 量 】476.66441 |
【开发单位】Taisho (Originator) 【药理作用】Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, CRF1 Antagonists |
合成路线1
The Grignard reaction of 1-(tert-butoxycarbonyl)piperidin-4-one (I) with 3-fluorophenylmagnesium bromide (II) in THF gives the tertiary alcohol (III), which is dehydrated with TFA or HCl in dioxane yielding the tetrahydropyridine (IV). The condensation of (IV) with 2,4-dichloro-6-methylpyrimidine (V) by means of DIEA in ethanol affords 2-chloro-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-6-methylpyrimidine (VI), which is further condensed with 4-isopropyl-2-(methylsulfanyl)aniline (VII) by means of DIEA in refluxing ethylene glycol to give the secondary amine (VIII). Finally, this compound is alkylated with ethyl iodide and NaH in DMF.
| 【1】 Chaki, S.; Nakazato, A.; Okubo, T.; Kumagai, T.; Tomisawa, K.; Okuyama, S.; CRF1 receptor antagonists: Aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives. Symp Med Chem 1998, Abst 1-P-26. |
| 【2】 Okubo, T.; Tanaka, H.; Chaki, S.; Okuyama, S.; Tomisawa, K.; Kumagai, T.; Nakazato, A.; Design, synthesis and structure-affinity relationships of 4-methylidenepiperidine and 4-aryl-1,2,3,6-tetrahydropyridine derivatives as corticotropin-releasing factor1 receptor antagonists. Bioorg Med Chem 2000, 8, 5, 1183. |
| 【3】 Okubo, T.; Okuyama, S.; Nakazato, A.; Tomisawa, K.; Aibe, I.; Chaki, S.; Kumagai, T.; Tanaka, H. (Taisho Pharmaceutical Co., Ltd.); 4-Tetrahydropyridylpyrimidine derivs.. EP 0976745; JP 1999228568; WO 9842699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10925 | Iodoethane;ethyl iod | 75-03-6 | C2H5I | 详情 | 详情 | |
| (I) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (II) | 35384 | bromo(3-fluorophenyl)magnesium | C6H4BrFMg | 详情 | 详情 | |
| (III) | 35385 | tert-butyl 4-(3-fluorophenyl)-4-hydroxy-1-piperidinecarboxylate | C16H22FNO3 | 详情 | 详情 | |
| (IV) | 35386 | 4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridine | C11H12FN | 详情 | 详情 | |
| (V) | 35387 | 2,4-dichloro-6-methylpyrimidine | 5424-21-5 | C5H4Cl2N2 | 详情 | 详情 |
| (VI) | 35388 | 2-chloro-4-[4-(3-fluorophenyl)-3,6-dihydro-1(2H)-pyridinyl]-6-methylpyrimidine | C16H15ClFN3 | 详情 | 详情 | |
| (VII) | 35389 | 4-isopropyl-2-(methylsulfanyl)phenylamine; 4-isopropyl-2-(methylsulfanyl)aniline | C10H15NS | 详情 | 详情 | |
| (VIII) | 35390 | N-[4-[4-(3-fluorophenyl)-3,6-dihydro-1(2H)-pyridinyl]-6-methyl-2-pyrimidinyl]-N-[4-isopropyl-2-(methylsulfanyl)phenyl]amine; 4-[4-(3-fluorophenyl)-3,6-dihydro-1(2H)-pyridinyl]-N-[4-isopropyl-2-(methylsulfanyl)phenyl]-6-methyl-2-pyrimidinamine | C26H29FN4S | 详情 | 详情 |