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【结 构 式】 
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【药物名称】Quinagolide hydrochloride, SDZ-205502, CV-205502, Norprolac 【化学名称】(±)-N,N-Diethyl-N'-[(3alpha,4aalpha,10abeta)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-3-yl]sulfamide hydrochloride 【CA登记号】94424-50-7, 87056-78-8 (free base) 【 分 子 式 】C20H34ClN3O3S 【 分 子 量 】432.02928 |
【开发单位】Novartis (Originator) 【药理作用】Contraceptives, Disorders of Sexual Function and Reproduction, Treatment of, ENDOCRINE DRUGS, Male Contraceptives, Pituitary Disorder Therapy, Treatment of Acromegaly, Treatment of Growth Hormone Secretion Disorders, Treatment of Hyperprolactinemia, Dopamine D2 Agonists, Prolactin Secretion Inhibitors |
合成路线1
The reaction of 5-methoxy-2-tetralone (I) with benzenethiosulfonic acid S-phenyl ester and sodium acetate in methanol gives 1,1-bis(phenylsulfanyl)-2-tetralone (II), which is condensed with 2-(bromomethyl)acrylic acid tert-butyl ester (III) by means of n-BuLi and diisopropylamine (DIA) in THF to yield the acrylic acid derivative (IV). Desulfurization of (IV) with Al/Hg in THF/water affords compound (V), which is treated with O-methylhydroxylamine and Na2HPO4 in methanol, providing the methoxyimino compound (VI). The reduction of (VI) with Zn/HOAc provides the methoxyamino compound (VII). The cyclization of (VII) by means of potassium hydrogen phosphate gives 1,6-dimethoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylic acid tert-butyl ester as a diastereomeric mixture that is separated by chromatography to furnish the desired diastereomer (VIII). Hydrolysis of the tert-butoxy ester group of (VIII) by means of TFA yields the carboxylic acid (IX), which is treated with diazomethane to afford the methyl ester (X). Selective demethoxylation of (X) with Zn/HOAc provides the octahydrobenzoquinoline (XI).
| 【1】 Nordmann, R.; Petcher, T.J.; Octahydrobenzo[g]quinolines: Potent dopamine agonists which show the relationship between ergolines and apomorphine. J Med Chem 1985, 28, 3, 367. |
| 【2】 Petcher, T.J.; Nordmann, R. (Novartis AG); Novel pharmaceutically active 1,2,3,4,4a,5,10,10a-octahydrobenzo(g)quinoline derivs.. EP 0077754; ES 8606281; ES 8706120 . |
| 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) | 14647 | 5-methoxy-3,4-dihydro-2(1H)-naphthalenone | 32940-15-1 | C11H12O2 | 详情 | 详情 |
| (II) | 44372 | 5-methoxy-1,1-bis(phenylsulfanyl)-3,4-dihydro-2(1H)-naphthalenone | C23H20O2S2 | 详情 | 详情 | |
| (III) | 44373 | tert-butyl 2-(bromomethyl)acrylate | C8H13BrO2 | 详情 | 详情 | |
| (IV) | 44374 | tert-butyl 2-[[8-methoxy-3-oxo-4,4-bis(phenylsulfanyl)-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]acrylate | C31H32O4S2 | 详情 | 详情 | |
| (V) | 44375 | tert-butyl 2-[(8-methoxy-3-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]acrylate | C19H24O4 | 详情 | 详情 | |
| (VI) | 44376 | tert-butyl 2-[[8-methoxy-3-(methoxyimino)-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]acrylate | C20H27NO4 | 详情 | 详情 | |
| (VII) | 44377 | tert-butyl 2-[[8-methoxy-3-(methoxyamino)-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]acrylate | C20H29NO4 | 详情 | 详情 | |
| (VIII) | 44378 | tert-butyl (3S,4aR,10aR)-1,6-dimethoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylate | C20H29NO4 | 详情 | 详情 | |
| (IX) | 44379 | (3S,4aR,10aR)-1,6-dimethoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylic acid | C16H21NO4 | 详情 | 详情 | |
| (X) | 44380 | methyl (3S,4aR,10aR)-1,6-dimethoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylate | C17H23NO4 | 详情 | 详情 | |
| (XI) | 44381 | methyl (3S,4aR,10aR)-6-methoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylate | C16H21NO3 | 详情 | 详情 |
合成路线2
Free NH group of (XI) is alkylated by reductocondensation with propionaldehyde (XII) and H2 over Pd/C, giving the N-propyl derivative (XIII). The reaction of the ester group of (XIII) with hydrazine yields the corresponding hydrazide (XIV), which is submitted to degradation with nitrosyl chloride in THF to afford the amine (XV). The condensation of (XV) with N,N-diethylsulfamoyl chloride (XVI) by means of TEA in chloroform gives the sulfamide (XVII), which is finally demethylated by a treatment with BBr3 in dichloromethane.
| 【1】 Nordmann, R.; Petcher, T.J.; Octahydrobenzo[g]quinolines: Potent dopamine agonists which show the relationship between ergolines and apomorphine. J Med Chem 1985, 28, 3, 367. |
| 【2】 Petcher, T.J.; Nordmann, R. (Novartis AG); Novel pharmaceutically active 1,2,3,4,4a,5,10,10a-octahydrobenzo(g)quinoline derivs.. EP 0077754; ES 8606281; ES 8706120 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 44381 | methyl (3S,4aR,10aR)-6-methoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylate | C16H21NO3 | 详情 | 详情 | |
| (XII) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (XIII) | 44382 | methyl (3S,4aR,10aR)-6-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylate | C19H27NO3 | 详情 | 详情 | |
| (XIV) | 44383 | (3S,4aR,10aR)-6-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carbohydrazide | C18H27N3O2 | 详情 | 详情 | |
| (XV) | 44384 | (3S,4aS,10aR)-6-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-3-ylamine; (3S,4aS,10aR)-6-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-3-amine | C17H26N2O | 详情 | 详情 | |
| (XVI) | 44385 | 1-[(chlorosulfonyl)(ethyl)amino]ethane | C4H10ClNO2S | 详情 | 详情 | |
| (XVII) | 44386 | N'-[(3S,4aS,10aR)-6-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-3-yl]-N,N-diethylsulfamide | C21H35N3O3S | 详情 | 详情 |