【结 构 式】 |
【药物名称】Brofaromine hydrochloride, CGP-11305A, Consonar 【化学名称】4-(7-Bromo-5-methoxy-2-benzofuranyl)piperidine hydrochloride 【CA登记号】63638-90-4, 63638-91-5 (free base) 【 分 子 式 】C14H17BrClNO2 【 分 子 量 】346.65409 |
【开发单位】Novartis (Originator) 【药理作用】Antidepressants, Cognition Disorders, Treatment of, Mood Disorders, Treatment of, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, MAO-A Inhibitors |
合成路线1
Bromination of 2-hydroxy-5-methoxybenzaldehyde (I) in acetic acid / sodium acetate mixture gives bromoaldehyde (II). Condensation to the benzofuranylpyridine (IV) is achieved by heating a solution of (II) and 4-(chloromethyl)pyridine hydrochloride (III) in polyethylene glycol-400 in the presence of potassium carbonate. Quaternization of (IV) with dimethylsulfate in dichloromethane affords (V), which upon reduction with sodium borohydride gives intermediate (VI). Reduction of (VI) with platinum on charcoal in methanol/HBr solution yields the N-methylpiperidine (VII). Degradation of the N-methyl group with ethylchloroformate in toluene affords the carbamate (VIII). Final treatment of (VIII) with potassium hydroxide in n-butanol yields the free base of brofaremine, which is converted to its hydrochloride salt by treatment with hydrochloric acid in methanol.
【1】 Schenker, K.; Bernasconi, R. (Novartis AG); Tetrahydropyridine and piperidine derivatives and processes for the preparation thereof. DE 2653147; ES 453582; FR 2332754; GB 1565055; JP 52065277 . |
【2】 Waldmeier, P.C.; Schilling, W.; Brofaremine Hydrochloride. Drugs Fut 1985, 10, 5, 371. |
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) | 29301 | 2-hydroxy-5-methoxybenzaldehyde | 672-13-9 | C8H8O3 | 详情 | 详情 |
(II) | 29302 | 3-bromo-2-hydroxy-5-methoxybenzaldehyde | C8H7BrO3 | 详情 | 详情 | |
(III) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
(IV) | 29303 | 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)pyridine | C14H10BrNO2 | 详情 | 详情 | |
(V) | 29304 | 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-methylpyridinium (sulfonatooxy)methane | C16H16BrNO6S | 详情 | 详情 | |
(VI) | 29305 | 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine | C15H16BrNO2 | 详情 | 详情 | |
(VII) | 29306 | 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-methylpiperidine | C15H18BrNO2 | 详情 | 详情 | |
(VIII) | 29307 | ethyl 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-piperidinecarboxylate | C17H20BrNO4 | 详情 | 详情 | |
(IX) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |