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【结 构 式】 
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【药物名称】 【化学名称】2(S)-[5-[2-(2-Azabicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-N-[2-(4-pyridyl)ethyl]propan-1-amine 【CA登记号】255863-81-1 【 分 子 式 】C37H46N4O 【 分 子 量 】562.80537 |
【开发单位】Merck & Co. (Originator) 【药理作用】ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Oncolytic Drugs, GnRH (LHRH) Antagonists |
合成路线1
The intermediate ketone (VI) was prepared as follows: 2-Methylcyclopropanecarboxylic acid (I) was converted to the Weinreb amide (III) via activation as the corresponding acid chloride (II) followed by reaction with N,O-dimethylhydroxylamine. The organolithium reagent (V), prepared by metalation of 5-bromo-m-xylene (IV) with n-BuLi, was then added to the methoxy amide (III), producing the target aryl cyclopropyl ketone (VI).
| 【1】 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) | 52514 | 2-Methylcyclopropanecarboxylic acid | 29555-02-0 | C5H8O2 | 详情 | 详情 |
| (II) | 52515 | 2-methylcyclopropanecarbonyl chloride | C5H7ClO | 详情 | 详情 | |
| (III) | 52516 | N,2-dimethyl-N-(methyloxy)cyclopropanecarboxamide | C7H13NO2 | 详情 | 详情 | |
| (IV) | 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 |
| (V) | 52518 | (3,5-dimethylphenyl)lithium | C8H9Li | 详情 | 详情 | |
| (VI) | 52519 | (3,5-dimethylphenyl)(2-methylcyclopropyl)methanone | C13H16O | 详情 | 详情 |
合成路线2
Ethyl 2-(4-nitrophenyl)propionate (VIII), obtained by acid-catalyzed esterification of carboxylic acid (VII), was alkylated by means of iodomethane and NaH to furnish the 2-methylpropionate (IX). Subsequent nitro group hydrogenation over Pd/C gave aniline (X). Diazotization of (X), followed by SnCl2 reduction of the intermediate diazonium salt, afforded the aryl hydrazine (XI). Cyclization between hydrazine (XI) and ketone (VI) under Fischer indolization conditions occurred with concomitant cyclopropyl group rearrangement to generate the racemic beta-methyl tryptamine derivative (XII), which was further separated into the enantiomers.
| 【1】 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 |
|---|---|---|---|---|---|---|
| (VI) | 52519 | (3,5-dimethylphenyl)(2-methylcyclopropyl)methanone | C13H16O | 详情 | 详情 | |
| (VII) | 52520 | 2-(4-nitrophenyl)propanoic acid | C9H9NO4 | 详情 | 详情 | |
| (VIII) | 33983 | ethyl 2-(4-nitrophenyl)propanoate | C11H13NO4 | 详情 | 详情 | |
| (IX) | 52521 | ethyl 2-methyl-2-(4-nitrophenyl)propanoate | C12H15NO4 | 详情 | 详情 | |
| (X) | 52522 | ethyl 2-(4-aminophenyl)-2-methylpropanoate | C12H17NO2 | 详情 | 详情 | |
| (XI) | 52523 | ethyl 2-(4-hydrazinophenyl)-2-methylpropanoate | C12H18N2O2 | 详情 | 详情 | |
| (XII) | 52524 | ethyl 2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropanoate | C25H32N2O2 | 详情 | 详情 |
合成路线3
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4
In an alternative procedure, tryptamine (XIII) was acylated with 4-pyridylacetic acid (XXIII) to afford amide (XXIV), which was further reduced to the secondary amine (XXV) with borane in THF. Ester group hydrolysis in (XXV), followed by coupling of the resultant acid (XXVI) with isoquinuclidine (XVI), furnished the target amide.
| 【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. |
| 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 | |
| (XVI) | 52528 | 2-azabicyclo[2.2.2]octane | C7H13N | 详情 | 详情 | |
| (XXIII) | 17883 | 2-(4-pyridinyl)acetic acid | 28356-58-3 | C7H7NO2 | 详情 | 详情 |
| (XXIV) | 52537 | ethyl 2-[2-(3,5-dimethylphenyl)-3-(1-methyl-2-{[2-(4-pyridinyl)acetyl]amino}ethyl)-1H-indol-5-yl]-2-methylpropanoate | C32H37N3O3 | 详情 | 详情 | |
| (XXV) | 52535 | ethyl 2-[2-(3,5-dimethylphenyl)-3-(1-methyl-2-{[2-(4-pyridinyl)ethyl]amino}ethyl)-1H-indol-5-yl]-2-methylpropanoate | C32H39N3O2 | 详情 | 详情 | |
| (XXVI) | 52536 | 2-[2-(3,5-dimethylphenyl)-3-(1-methyl-2-{[2-(4-pyridinyl)ethyl]amino}ethyl)-1H-indol-5-yl]-2-methylpropanoic acid | C30H35N3O2 | 详情 | 详情 |