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【结 构 式】 
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【药物名称】RWJ-314313 【化学名称】4-[2-Chloro-5-[3(R)-pyrrolidinyloxy]pyridin-3-yl]benzonitrile 【CA登记号】259262-24-3 【 分 子 式 】C16H14ClN3O 【 分 子 量 】299.76248 |
【开发单位】R.W. Johnson (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Non-Opioid Analgesics, Drugs Acting on Acetylcholine Receptors (Nicotinic) |
合成路线1
Mitsunobu coupling of N-Boc-3-(S)-hydroxypyrrolidine (I) with 3-bromo-2-chloro-5-hydroxypyridine (II) afforded ether (III). Subsequent introduction of the cyanophenyl group in (III) to give (V) was effected by Suzuki coupling with boronic acid (IV) in the presence of palladium catalyst. Finally, acid deprotection of the Boc group of (V) furnished the title compound.
| 【1】 Shank, R.; Davis, C.; Reiltz, A.; Rivero, R.; Lee, J.; Discovery of novel pyridyl ethers as ligand for nicotinic acetylcholine receptor. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 271. |
| 【2】 Jung, S.L. (Ortho-McNeil Pharmaceutical, Inc.); Pyridyl ethers and thioethers as ligands for nicotinic acetylcholine receptor and its therapeutic application. WO 0010997 . |
| 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) | 16286 | tert-butyl (3S)-3-hydroxytetrahydro-1H-pyrrole-1-carboxylate | C9H17NO3 | 详情 | 详情 | |
| (II) | 38833 | 5-bromo-6-chloro-3-pyridinol | C5H3BrClNO | 详情 | 详情 | |
| (III) | 38834 | tert-butyl (3R)-3-[(5-bromo-6-chloro-3-pyridinyl)oxy]-1-pyrrolidinecarboxylate | C14H18BrClN2O3 | 详情 | 详情 | |
| (IV) | 38835 | 4-cyanophenylboronic acid | 126747-14-6 | C7H6BNO2 | 详情 | 详情 |
| (V) | 38836 | tert-butyl (3R)-3-[[6-chloro-5-(4-cyanophenyl)-3-pyridinyl]oxy]-1-pyrrolidinecarboxylate | C21H22ClN3O3 | 详情 | 详情 |
合成路线2
The compound has also been obtained by solid phase synthesis. Attachment of (S)-3-hydroxypyrrolidine (VII) to p-nitrophenylcarbonate Wang resin (VI) in the presence of diisopropylethylamine provided the resin bound pyrrolidinol (VIII). Coupling of (VIII) with 3-bromo-2-chloro-5-hydroxypyridine (II) under Mitsunobu conditions gave resin (IX). Further Suzuki coupling of (IX) with 4-cyanophenylboronic acid (IV) afforded (X). The title compound was then cleaved from the resin (X) by treatment with trifluoroacetic acid.
| 【1】 Shank, R.; Davis, C.; Reiltz, A.; Rivero, R.; Lee, J.; Discovery of novel pyridyl ethers as ligand for nicotinic acetylcholine receptor. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 271. |
| 【2】 Davis, C.B.; Shank, R.P.; Reitz, A.B.; Lee, J.; Rivero, R.A.; Synthesis and structure-activity relationship of novel pyridyl ethers for the nicotinic acetylcholine receptor. Bioorg Med Chem Lett 2000, 10, 10, 1063. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 38833 | 5-bromo-6-chloro-3-pyridinol | C5H3BrClNO | 详情 | 详情 | |
| (IV) | 38835 | 4-cyanophenylboronic acid | 126747-14-6 | C7H6BNO2 | 详情 | 详情 |
| (VI) | 38837 | 4-nitrophenyl hydrogen carbonate | C7H5NO5 | 详情 | 详情 | |
| (VII) | 38841 | (3R)-3-pyrrolidinol | C4H9NO | 详情 | 详情 | |
| (VIII) | 38838 | (3R)-3-hydroxy-1-pyrrolidinecarboxylic acid | C5H9NO3 | 详情 | 详情 | |
| (IX) | 38839 | (3R)-3-[(5-bromo-6-chloro-3-pyridinyl)oxy]-1-pyrrolidinecarboxylic acid | C10H10BrClN2O3 | 详情 | 详情 | |
| (X) | 38840 | (3R)-3-[[6-chloro-5-(4-cyanophenyl)-3-pyridinyl]oxy]-1-pyrrolidinecarboxylic acid | C17H14ClN3O3 | 详情 | 详情 |