【结 构 式】 |
【药物名称】CI-201678(HCl), Cpd-201678, 201678 【化学名称】(-)-(4S,5aR)-5-Ethyl-9,10-dihydroxy-4-propyl-4,5,5a,6-tetrahydrodibenz[cd,f]indole 【CA登记号】82166-77-6, 82188-32-7 ((4S)-trans-isomer, HBr), 82188-33-8 ((4S)-trans-isomer, HCl), 82122-86-9 (rac-trans-isomer) 【 分 子 式 】C20H23NO2 【 分 子 量 】309.41181 |
【开发单位】Novartis (Originator) 【药理作用】Antiparkinsonian Drugs, Extrapyramidal Disorders, Treatment of, NEUROLOGIC DRUGS, Treatment of Alcohol Dependency, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, Treatment of Substance Dependency, Dopamine Receptor Agonists |
合成路线1
The acylation of 9-ethylamino-8-bromo-3,4-dimethoxyphenanthrene (I) with butyryl chloride (II) in CH2Cl2 gives 9-(N-ethyl-N-butyrylamino)-8-bromo-3,4-dimethoxyphenanthrene (III), which is cyclized by means of butyllithium in THF yielding 5-ethyl-4,5-dihydro-9,10-dimethoxy-4-n-propyldibenz[cd,f]indole-4-ol (IV). The reduction of (IV) with Zn-HgCl2 in refluxing ethanol water affords 5-ethyl-4,5,5a,6-tetrahydro-9,10-diethoxy-4-n-propyldibenz[cd,f]indole (V), which is finally demethylated by means of refluxing aqueous 47% HBr.
【1】 Giger, R.K.A. (Novartis AG); Nouveaux derives du dibenz[cd,f]indole, leur preparation et leur application comme medicaments. DE 3124086; FR 2485530; FR 2510996; WO 8200143 . |
【2】 Castaner, J.; Serradell, M.N.; 201678. Drugs Fut 1985, 10, 2, 99. |
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) | 28983 | 8-bromo-N-ethyl-3,4-dimethoxy-9-phenanthrenamine | C18H18BrNO2 | 详情 | 详情 | |
(II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
(III) | 28984 | N-(8-bromo-3,4-dimethoxy-9-phenanthryl)-N-ethylbutanamide | C22H24BrNO3 | 详情 | 详情 | |
(IV) | 28985 | (4R)-5-ethyl-9,10-dimethoxy-4-propyl-4,5-dihydrodibenzo[cd,f]indol-4-ol | C22H25NO3 | 详情 | 详情 | |
(V) | 28986 | (4S,5aR)-5-ethyl-10-methoxy-4-propyl-4,5,5a,6-tetrahydrodibenzo[cd,f]indol-9-yl methyl ether | C22H27NO2 | 详情 | 详情 |
合成路线2
The reaction of 3,4-dimethoxyphenanthrene-9-carboxylic acid (VI) first with trifluoroacetic anhydride and then with sodium azide gives 9-amino-3,4-dimethoxyphenanthrene (VII), which is acetylated with acetyl chloride in CH2Cl2 yielding 9-acetylamino-3,4-dimethoxyphenanthrene (VIII). The reduction of (VIII) with diborane in THF affords 9-ethylamino-3,4-dimethoxyphenanthrene (IX), which is cyclized with CO2 by means of n-butyllithium in THF affording 5-ethyl-4,5-dihydro-9,10-dimethoxy-4-oxodibenz[cd,f]indole (X). Finally, this compound is submitted to a Grignard synthesis with propylmagnesium bromide (A) in THF to give (IV), already obtained.
【1】 Giger, R.K.A. (Novartis AG); Nouveaux derives du dibenz[cd,f]indole, leur preparation et leur application comme medicaments. DE 3124086; FR 2485530; FR 2510996; WO 8200143 . |
【2】 Castaner, J.; Serradell, M.N.; 201678. Drugs Fut 1985, 10, 2, 99. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(A) | 10790 | Bromo(propyl)magnesium;bromopropylMagnesium;4-propylbutyrolactone;propylmagnesiumbromide;n-propylmagnesium bromide;Bromopropylmagnesium; | 927-77-5 | C3H7BrMg | 详情 | 详情 |
(IV) | 28985 | (4R)-5-ethyl-9,10-dimethoxy-4-propyl-4,5-dihydrodibenzo[cd,f]indol-4-ol | C22H25NO3 | 详情 | 详情 | |
(V) | 28986 | (4S,5aR)-5-ethyl-10-methoxy-4-propyl-4,5,5a,6-tetrahydrodibenzo[cd,f]indol-9-yl methyl ether | C22H27NO2 | 详情 | 详情 | |
(VI) | 28987 | 3,4-dimethoxy-9-phenanthrenecarboxylic acid | C17H14O4 | 详情 | 详情 | |
(VII) | 28988 | 3,4-dimethoxy-9-phenanthrenamine | C16H15NO2 | 详情 | 详情 | |
(VIII) | 28989 | N-(3,4-dimethoxy-9-phenanthryl)acetamide | C18H17NO3 | 详情 | 详情 | |
(IX) | 28990 | N-(3,4-dimethoxy-9-phenanthryl)-N-ethylamine | C18H19NO2 | 详情 | 详情 | |
(X) | 28991 | 5-ethyl-9,10-dimethoxydibenzo[cd,f]indol-4(5H)-one | C19H17NO3 | 详情 | 详情 |