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【结 构 式】 
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【药物名称】Dopropidil hydrochloride, Org-30701, CERM-4205 【化学名称】1-[1-(Isobutoxymethyl)-2-[[1-(1-propynyl)cyclohexyl]oxy]ethyl]pyrrolidine hydrochloride 【CA登记号】117241-47-1, 79700-61-1 (free base) 【 分 子 式 】C20H36ClNO2 【 分 子 量 】357.96842 |
【开发单位】Riom (Originator) 【药理作用】Angina pectoris, Treatment of, CARDIOVASCULAR DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Calcium Channel Blockers |
合成路线1
This compound can be obtained in a simple way: Under nitrogen, borontrifluoride etherate solution is added to heated 2-methyl-1-propanol (II), and 1-chloro-2,3-epoxypropane (I) is added. When the reaction is completed, pyrrolidine (IV) is added to obtain alpha-[2-methyl-propoxymethyl]-1-pyrrolidine-ethanol (V). 1-[2-Chloro-3-(2-methylpropoxy)propyl]pyrrolidine (VI) is obtained by chlorination with thionyl chloride of the subsequent amino alcohol. The condensation of 1-propynyl-1-cyclohexanol (VII) with 1-[2-chloro-3-(2-methylpropoxy)propyl]pyrrolidine (VI) in toluene and sodium hydroxide in water affords dopropidil. Due to the pyrrolidine shift mechanism, the reaction yields the correct structure, confirmed by 1H and 13C NMR as well as by mass spectra and X-ray analysis. The pyrrolidine shift mechanism is explained by the assumption of an intermediate aziridinium ion (VIII), which is opened regiospecifically at the less hindered C-N bond by the nucleophile ion.
| 【1】 Carlier, P.; Montell, A.J.-C.; Simond, J.A.L. (Riom Laboratoires); Ethers of 1-(2-propynyloxy)-2-amino-3-propanol, their preparation and their application in therapeutic. EP 0031771; US 4430332 . |
| 【2】 Dupont, L.; Dideberg, O.; Simond, J.; X-ray analysis of CERM 4205. Acta Cryst Sect C 1986, 42, 864. |
| 【3】 Massingham, R.; Monteil, A.; DOPROPIDIL HYDROCHLORIDE. Drugs Fut 1990, 15, 5, 453. |
| 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) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (II) | 12982 | 2-Methyl-1-propanol | 78-83-1 | C4H10O | 详情 | 详情 |
| (III) | 12983 | 2-(Isobutoxymethyl)oxirane; Isobutyl 2-oxiranylmethyl ether | C7H14O2 | 详情 | 详情 | |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (V) | 12985 | 1-Isobutoxy-3-(1-pyrrolidinyl)-2-propanol | C11H23NO2 | 详情 | 详情 | |
| (VI) | 12986 | 2-Chloro-3-(1-pyrrolidinyl)propyl isobutyl ether; 1-(2-Chloro-3-isobutoxypropyl)pyrrolidine | C11H22ClNO | 详情 | 详情 | |
| (VII) | 12987 | 1-Propynyl-1-cyclohexanol; 1-(1-Propynyl)cyclohexanol | 697-37-0 | C9H14O | 详情 | 详情 |
| (VIII) | 12988 | 1-(Isobutoxymethyl)-3-azoniaspiro[2.4]heptane | C11H22NO | 详情 | 详情 |