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【结 构 式】 
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【药物名称】 【化学名称】5-Methoxy-3-[1-methylpyrrolidin-2(R)-ylmethyl]-1H-indole 【CA登记号】 【 分 子 式 】C15H20N2O 【 分 子 量 】244.33945 |
【开发单位】Pfizer (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Antidepressants, Antimigraine Drugs, Anxiolytics, Mood Disorders, Treatment of, PHARMACOLOGICAL TOOLS, PSYCHOPHARMACOLOGIC DRUGS, 5-HT1A Receptor Agonists, 5-HT1D Agonists, 5-HT2 Agonists |
合成路线1
The title compound has been prepared by two related procedures. Treatment of N-carbobenzoxy-D-proline (I) with oxalyl chloride provided the corresponding acid chloride (II). This was condensed with 5-methoxyindolyl magnesium bromide, generated from 5-methoxyindole (III) and ethylmagnesium bromide, to afford the indolyl ketone (IV). Reduction of both keto and carbamate groups of (IV) by means of LiAlH4 in refluxing THF then furnished the target compound.
| 【1】 Schmidt, A.W.; Macor, J.E.; Blake, J.; Ryan, K.; Fox, C.B.; Zorn, S.H.; Morrone, J.M.; Koe, B.K.; Johnson, C.; Schulz, D.W.; Lebel, L.A.; Synthesis and serotonergic pharmacology of the enantiomers of 3-[(N-methylpyrrolidin-2-yl)methyl]-5-methoxy-1H-indole: Discovery of stereogenic differentiation in the aminoethyl side chain of the neurotransmitter serotonin. J Med Chem 1992, 35, 23, 4503. |
| 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) | 17005 | (2R)-1-[(benzyloxy)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid | C13H15NO4 | 详情 | 详情 | |
| (II) | 17006 | benzyl (2R)-2-(chlorocarbonyl)tetrahydro-1H-pyrrole-1-carboxylate | C13H14ClNO3 | 详情 | 详情 | |
| (III) | 25902 | 1H-Indol-5-yl methyl ether; 5-Methoxy-1H-indole; 5-Methoxyindole | 1006-94-6 | C9H9NO | 详情 | 详情 |
| (IV) | 31540 | benzyl (2R)-2-[(5-methoxy-1H-indol-3-yl)carbonyl]-1-pyrrolidinecarboxylate | C22H22N2O4 | 详情 | 详情 |
合成路线2
Alternatively, 5-methoxyindole (III) was N-silylated employing tert-butyldimethylsilyl chloride and n-BuLi, and the resulting silyl derivative (V) was brominated with N-bromosuccinimide at -78 C to afford the 3-bromoindole (VI). After lithium-bromine exchange in (VI) with n-BuLi at -78 C, the 3-lithio compound was condensed with N-methyl-D-proline methyl ester (VII) to give the indolyl ketone (VIII). The ketone function of (VIII) was finally reduced employing LiAlH4 in boiling THF.
| 【1】 Qandil, A.M.; Marona-Lewicka, D.; Gerasimov, M.; Kurrasch-Orbaugh, D.M.; Nichols, D.E.; Further studies on oxygenated tryptamines with LSD-like activity incorporating a chiral pyrrolidine moiety into the side chain. J Med Chem 1999, 42, 20, 4257. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 25902 | 1H-Indol-5-yl methyl ether; 5-Methoxy-1H-indole; 5-Methoxyindole | 1006-94-6 | C9H9NO | 详情 | 详情 |
| (V) | 31541 | 1-[tert-butyl(dimethyl)silyl]-1H-indol-5-yl methyl ether; 1-[tert-butyl(dimethyl)silyl]-5-methoxy-1H-indole | C15H23NOSi | 详情 | 详情 | |
| (VI) | 31542 | 3-bromo-1-[tert-butyl(dimethyl)silyl]-5-methoxy-1H-indole; 3-bromo-1-[tert-butyl(dimethyl)silyl]-1H-indol-5-yl methyl ether | C15H22BrNOSi | 详情 | 详情 | |
| (VII) | 31538 | methyl (2R)-1-methyl-2-pyrrolidinecarboxylate | C7H13NO2 | 详情 | 详情 | |
| (VIII) | 31543 | (5-methoxy-1H-indol-3-yl)[(2R)-1-methylpyrrolidinyl]methanone | C15H18N2O2 | 详情 | 详情 |