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【结 构 式】 
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【药物名称】LY-341495 【化学名称】2(S)-Amino-2-[2(S)-carboxy-1(S)-cyclopropyl]-3-(9H-xanthen-9-yl)propionic acid 【CA登记号】201943-63-7 【 分 子 式 】C20H19NO5 【 分 子 量 】353.37813 |
【开发单位】Lilly (Originator) 【药理作用】Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, mglu2 Antagonists |
合成路线1
Partial hydrolysis of chiral cyclopropanedicarboxylate (I) with 1 equivalent of NaOH in aqueous isopropanol provided monoester (II), which was converted to acid chloride (III) by treatment with SOCl2. Palladium-mediated coupling of (III) with the organozincate from 9-xanthenylmethyl iodide (IV) and Zn-Cu couple afforded (S,S)-ketone (V). Basic hydrolysis of (V) then provided ketoacid (VI), which was transformed into a mixture of diastereomeric hydantoins (VII) under Bucherer-Berg conditions using an excess of KCN and (NH4)2CO3 in water at 55 C. Subsequent reaction with 4-methoxybenzyl bromide (VIII) and KHCO3 in DMF produced both N- and O-alkylation to provide a diastereomeric mixture, which was separated by column chromatography. Hydrolysis of isomer (IX) with aqueous Ba(OH)2 in a pressure reactor at 200 C gave the target (S,S,S)-amino acid, which was purified by cation-exchange chromatography.
| 【1】 Ornstein, P.L.; Arnold, M.B.; Bleisch, T.J.; Wright, R.A.; Wheeler, W.J.; Schoepp, D.D.; [3H]LY341495, a highly potent, selective and novel radioligand for labeling group II metabotropic glutamate receptors. Bioorg Med Chem Lett 1998, 8, 14, 1919. |
| 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) | 18221 | (1S,2R)-2-[(1S)-1-amino-1-carboxy-2-(9H-xanthen-9-yl)ethyl]cyclopropanecarboxylic acid | C20H19NO5 | 详情 | 详情 | |
| (II) | 18222 | (1S,2R)-2-[(1S)-1-amino-1-carboxy-2-(2,7-dibromo-9H-xanthen-9-yl)ethyl]cyclopropanecarboxylic acid | C20H17Br2NO5 | 详情 | 详情 | |
| (III) | 18223 | trimethylsilyl (1S,2R)-2-[(1S)-1-amino-1-[(2,7-dibromo-9H-xanthen-9-yl)methyl]-2-oxo-2-[(trimethylsilyl)oxy]ethyl]cyclopropanecarboxylate | C26H33Br2NO5Si2 | 详情 | 详情 |
合成路线2
Partial hydrolysis of chiral cyclopropanedicarboxylate (I) with 1 equivalent of NaOH in aqueous isopropanol provided monoester (II), which was converted to acid chloride (III) by treatment with SOCl2. Palladium-mediated coupling of (III) with the organozincate from 9-xanthenylmethyl iodide (IV) and Zn-Cu couple afforded (S,S)-ketone (V). Basic hydrolysis of (V) then provided ketoacid (VI), which was transformed into a mixture of diastereomeric hydantoins (VII) under Bucherer-Berg conditions using an excess of KCN and (NH4)2CO3 in water at 55 C. Subsequent reaction of (VII) with 4-methoxybenzyl bromide (VIII) and KHCO3 in DMF produced both N- and O-alkylation to provide a diastereomeric mixture, which was separated by column chromatography. Hydrolysis of isomer (IX) with aqueous Ba(OH)2 in a pressure reactor at 200 C gave the target (S,S,S)-amino acid, which was purified by cation-exchange chromatography.
| 【1】 Kallman, M.J.; Johnson, B.G.; Bleisch, T.J.; Schoepp, D.D.; Tizzano, J.P.; Wright, R.A.; Kennedy, J.H.; Helton, D.R.; Brian Arnold, M.; Ornstein, P.L.; 2-Substituted (2SR)-2-amino-2-(1SR, 2SR)-2-carboxycycloprop-1-yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability. J Med Chem 1998, 41, 3, 358. |
| 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) | 27483 | bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] (1S,2S)-1,2-cyclopropanedicarboxylate | C25H42O4 | 详情 | 详情 | |
| (II) | 27484 | (1S,2S)-2-([[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]carbonyl)cyclopropanecarboxylic acid | C15H24O4 | 详情 | 详情 | |
| (III) | 27485 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (1S,2S)-2-(chlorocarbonyl)cyclopropanecarboxylate | C15H23ClO3 | 详情 | 详情 | |
| (IV) | 27486 | 9-(iodomethyl)-9H-xanthene | C14H11IO | 详情 | 详情 | |
| (V) | 27487 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (1S,2S)-2-[2-(9H-xanthen-9-yl)acetyl]cyclopropanecarboxylate | C29H34O4 | 详情 | 详情 | |
| (VI) | 27488 | (1S,2S)-2-[2-(9H-xanthen-9-yl)acetyl]cyclopropanecarboxylic acid | C19H16O4 | 详情 | 详情 | |
| (VII) | 27489 | (1S,2S)-2-[(4S)-2,5-dioxo-4-(9H-xanthen-9-ylmethyl)imidazolidinyl]cyclopropanecarboxylic acid | C21H18N2O5 | 详情 | 详情 | |
| (VIII) | 27490 | 1-(bromomethyl)-4-methoxybenzene | C8H9BrO | 详情 | 详情 | |
| (IX) | 27491 | 4-methoxybenzyl (1S,2S)-2-[(4S)-1-(4-methoxybenzyl)-2,5-dioxo-4-(9H-xanthen-9-ylmethyl)imidazolidinyl]cyclopropanecarboxylate | C37H34N2O7 | 详情 | 详情 |