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【结 构 式】

【分子编号】52531

【品名】2,4-dinitrobenzenesulfonyl chloride

【CA登记号】

【 分 子 式 】C6H3ClN2O6S

【 分 子 量 】266.6184

【元素组成】C 27.03% H 1.13% Cl 13.3% N 10.51% O 36.01% S 12.03%

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:(XIX)

The (S)-methyl tryptamine (XIII) was protected as the N-Boc derivative (XIV), and its ethyl ester group was then hydrolyzed with KOH to provide acid (XV). Coupling of (XV) with isoquinuclidine (XVI) in the presence of PyBOP gave amide (XVII). Cleavage of the N-Boc group of (XVII) was carried out employing trifluoroacetic acid in anisole. The resultant amine (XVIII) was condensed with 2,4-dinitrobenzenesulfonyl chloride (XIX) under modified Schotten-Baumann conditions to afford the sulfonamide (XX). Mitsunobu coupling of sulfonamide (XX) with 4-(2-hydroxyethyl)pyridine (XXI) gave adduct (XXII). The sulfonyl group of (XXII) was finally removed by treatment with neat propylamine to yield the title secondary amine.

1 Ashton, W.T.; et al.; Orally, bioavailable, indole-based nonpeptide GnRH receptor antagonists with high potency and functional activity. Bioorg Med Chem Lett 2001, 11, 19, 2597.
2 Chu, L.; Wyvratt, M.J.; Ponpipom, M.M.; Lin, P.; Ashton, W.T.; Goulet, M.; Young, J.; Girotra, N.N.; Fisher, M.H. (Merck & Co., Inc.); Antagonists of gonadotropin releasing hormone. EP 1095038; WO 0004013 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 52525 ethyl 2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropanoate C25H32N2O2 详情 详情
(XIV) 52526 ethyl 2-[3-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-methylethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropanoate C30H40N2O4 详情 详情
(XV) 52527 2-[3-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-methylethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropanoic acid C28H36N2O4 详情 详情
(XVI) 52528 2-azabicyclo[2.2.2]octane C7H13N 详情 详情
(XVII) 52529 1,1-dimethylethyl 2-[5-[2-(2-azabicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]propylcarbamate C35H47N3O3 详情 详情
(XVIII) 52530 2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-(2-azabicyclo[2.2.2]oct-2-yl)-2-methyl-1-propanone C30H39N3O 详情 详情
(XIX) 52531 2,4-dinitrobenzenesulfonyl chloride C6H3ClN2O6S 详情 详情
(XX) 52532 N-{2-[5-[2-(2-azabicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]propyl}-2,4-dinitrobenzenesulfonamide C36H41N5O7S 详情 详情
(XXI) 52533 2-(4-Pyridinyl)-1-ethanol; 2-Pyridin-4-ylethanol C7H9NO 详情 详情
(XXII) 52534 N-{2-[5-[2-(2-azabicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]propyl}-2,4-dinitro-N-[2-(4-pyridinyl)ethyl]benzenesulfonamide C43H48N6O7S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IX)

The reaction of 2(R)-methylcyclopropanecarboxylic acid (I) with (COCl)2 gives the corresponding acyl chloride (II), which is treated with N,O-dimethylhydroxylamine (III) and TEA to yield the amide (IV). The condensation of (IV) with 3,5-dimethylphenyl bromide (V) by means of BuLi in THF affords the benzoylcyclopropane (VI), which is cyclized with 2-(4-hydrazinophenyl)-2-methylpropionic acid ethyl ester (VII) in refluxing ethanol to provide the indole derivative (VIII) (1). The reaction of the amino group of (VIII) with 2,4-dinitrophenylsulfonyl chloride (IX) and collidine in dichloromethane gives the corresponding sulfonamide (X), which is condensed with 2-(1,2,3-benzotriazol-5-yl)ethanol (XI) by means of PPh3, DEAD and propylamine in benzene to yield the secondary amine (XII). The hydrolysis of the ester group of (XII) by means of KOH in methanol/THF affords the propionic acid derivative (XIII), which is finally condensed with 2-azabicyclo[2,2,2]octane (XIV) by means of PyBOP and TEA in dichloromethane to provide the target indole derivative.

1 Young, J.R.; et al.; 2-Arylindoles as gonadotropin releasing hormone (GnRH) antagonists: Optimization of the tryptamine side chain. Bioorg Med Chem Lett 2002, 12, 5, 827.
2 Chu, L.; Wyvratt, M.J.; Ponpipom, M.M.; Lin, P.; Ashton, W.T.; Goulet, M.; Young, J.; Girotra, N.N.; Fisher, M.H. (Merck & Co., Inc.); Antagonists of gonadotropin releasing hormone. EP 1095038; WO 0004013 .
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) 55763 (2R)-2-methylcyclopropanecarboxylic acid C5H8O2 详情 详情
(II) 55764 (2R)-2-methylcyclopropanecarbonyl chloride C5H7ClO 详情 详情
(III) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(IV) 55765 (2R)-N-methoxy-N,2-dimethylcyclopropanecarboxamide C7H13NO2 详情 详情
(V) 52517 5-Bromo-1,3-dimethylbenzene; 5-Bromo-m-xylene; 1-Bromo-3,5-dimethylbenzene; 3,5-Dimethylbromobenzene 556-96-7 C8H9Br 详情 详情
(VI) 55766 (3,5-dimethylphenyl)[(2R)-2-methylcyclopropyl]methanone C13H16O 详情 详情
(VII) 52523 ethyl 2-(4-hydrazinophenyl)-2-methylpropanoate C12H18N2O2 详情 详情
(VIII) 52525 ethyl 2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropanoate C25H32N2O2 详情 详情
(IX) 52531 2,4-dinitrobenzenesulfonyl chloride C6H3ClN2O6S 详情 详情
(X) 55767 ethyl 2-[2-(3,5-dimethylphenyl)-3-((1S)-2-{[(2,4-dinitrophenyl)sulfonyl]amino}-1-methylethyl)-1H-indol-5-yl]-2-methylpropanoate C31H34N4O8S 详情 详情
(XI) 55768 2-(1H-1,2,3-benzotriazol-5-yl)-1-ethanol C8H9N3O 详情 详情
(XII) 55769 ethyl 2-[3-((1S)-2-{[2-(1H-1,2,3-benzotriazol-5-yl)ethyl]amino}-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropanoate C33H39N5O2 详情 详情
(XIII) 55770 2-[3-((1S)-2-{[2-(1H-1,2,3-benzotriazol-5-yl)ethyl]amino}-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropanoic acid C31H35N5O2 详情 详情
Extended Information