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【结 构 式】

【分子编号】44381

【品名】methyl (3S,4aR,10aR)-6-methoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylate

【CA登记号】

【 分 子 式 】C16H21NO3

【 分 子 量 】275.34768

【元素组成】C 69.79% H 7.69% N 5.09% O 17.43%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XI)

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

该中间体在本合成路线中的序号:(XI)

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
Extended Information