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【结 构 式】 
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【分子编号】38837 【品名】4-nitrophenyl hydrogen carbonate 【CA登记号】 |
【 分 子 式 】C7H5NO5 【 分 子 量 】183.12044 【元素组成】C 45.91% H 2.75% N 7.65% O 43.69% |
合成路线1
该中间体在本合成路线中的序号：(VI)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 |
合成路线2
该中间体在本合成路线中的序号：(II)The title compound was prepared by solid-phase synthesis. Resin (II) was treated with 4-nitrophenyl chloroformate (I), and the activated nitrophenyl carbonate resin (III) was coupled to (R)-N-[2-(4-aminophenyl)ethyl]-2-hydroxy-2-(pyrid-3-yl)ethylamine (IV) to furnish the resine-bound aniline (V). After protection of the hydroxyl group as the triethylsilyl ether (VI), reaction with 4-cyanobenzenesulfonyl chloride (VII) in the presence of pyridine provided the resine-bound sulfonamide (VIII). Addition of hydroxylamine to the cyano group of (VIII) afforded the corresponding amidoxime (IX). The required oxadiazole (XI) was obtained by acylation of (IX) with 4-(trifluoromethoxy)phenylacetic acid (X) in the presence of EDC, followed by heating in diglyme to effect the cyclization. Cleavage from the resin and simultaneous desilylation was achieved by treatment with trifluoroacetic acid in dichloromethane.
| 【1】 Biftu, T.; Liang, G.-B.; Feng, D.D.; et al.; Synthesis and SAR of benzyl and phenoxymethylene oxadiazole benzenesulfonamides as selective beta3 adrenergic receptor agonist antiobesity agents. Bioorg Med Chem Lett 2000, 10, 13, 1431. |
| 【2】 Biftu, T.; Feng, D.D.; Fisher, M.H.; Kuo, C.-H.; Liang, G.-B.; Weber, A.E.; Naylor, E.M. (Merck & Co., Inc.); Oxadiazole benzenesulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. EP 0906310; US 6034106; WO 9746556 . |
| 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) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (II) | 38837 | 4-nitrophenyl hydrogen carbonate | C7H5NO5 | 详情 | 详情 | |
| (III) | 26652 | tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinylcarbamate | C17H26N2O3 | 详情 | 详情 | |
| (IV) | 42097 | 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamic acid | C16H19N3O3 | 详情 | 详情 | |
| (V) | 42098 | 4-aminophenethyl[(2R)-2-(3-pyridinyl)-2-[(triethylsilyl)oxy]ethyl]carbamic acid | C22H33N3O3Si | 详情 | 详情 | |
| (VI) | 29284 | 4-cyanobenzenesulfonyl chloride | 49584-26-1 | C7H4ClNO2S | 详情 | 详情 |
| (VII) | 42099 | 4-[[(4-cyanophenyl)sulfonyl]amino]phenethyl[(2R)-2-(3-pyridinyl)-2-[(triethylsilyl)oxy]ethyl]carbamic acid | C29H36N4O5SSi | 详情 | 详情 | |
| (VIII) | 42100 | 4-[([4-[amino(hydroxyimino)methyl]phenyl]sulfonyl)amino]phenethyl[(2R)-2-(3-pyridinyl)-2-[(triethylsilyl)oxy]ethyl]carbamic acid | C29H39N5O6SSi | 详情 | 详情 | |
| (IX) | 29289 | 2-[4-(trifluoromethoxy)phenyl]acetic acid | 4315-07-5 | C9H7F3O3 | 详情 | 详情 |
| (X) | 42101 | (2R)-2-(3-pyridinyl)-2-[(triethylsilyl)oxy]ethyl(4-[[(4-[5-[4-(trifluoromethoxy)benzyl]-1,2,4-oxadiazol-3-yl]phenyl)sulfonyl]amino]phenethyl)carbamic acid | C38H42F3N5O7SSi | 详情 | 详情 |