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【结 构 式】 
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【分子编号】19645 【品名】4-[(2S,5S)-5-[(4-fluorophenoxy)methyl]tetrahydro-2-furanyl]-3-butyn-1-ol 【CA登记号】 |
【 分 子 式 】C15H17FO3 【 分 子 量 】264.2965832 【元素组成】C 68.17% H 6.48% F 7.19% O 18.16% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Ether (III) was prepared by condensation of (S)-4-(hydroxymethyl)butyrolactone (I) and 4-fluorophenol (II) in the presence of diisopropylazodicarboxylate (DIAD) and triphenylphosphine under Mitsunobu conditions. Then, reduction of lactone (III) with DIBAL-H in toluene at -78 C gave lactol (IV), which was converted to silyl ether (V) by treatment with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole. Subsequent reaction of (V) with TBDMS-Br in CH2Cl2 at -78 C, followed by condensation with the lithium acetylide derived from acetylene (VI), yielded compound (VII) as a mixture of isomers. Chromatographic separation of the mixture provided the desired trans isomer, which was deprotected by treatment with tetra-n-butylammonium fluoride to give alcohol (VIII). This was then condensed with N,O-bis(phenoxycarbonyl)hydroxylamine (IX) in the presence of DIAD and Ph3P to furnish the hydroxamic acid derivative (X). Finally, concomitant deprotection of the O-phenoxycarbonyl group and substitution of the remaining phenoxy group for an amino group by treatment with methanolic ammonia in a pressure tube, provided the title compound.
| 【1】 Cai, X.; Grewal, G.; Hussoin, S.; Fura, A.; Scannell, R.; Biftu, T.; Qian, C. (CytoMed, Inc.); Cpds. and methods for the treatment of cardiovascular, inflammatory and immune disorders. JP 1998506096; US 5703093; US 5792776; WO 9600212 . |
| 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) | 46090 | (5R)-5-(hydroxymethyl)dihydro-2(3H)-furanone | C5H8O3 | 详情 | 详情 | |
| (II) | 19639 | 4-fluorophenol | 371-41-5 | C6H5FO | 详情 | 详情 |
| (III) | 19640 | (5S)-5-[(4-fluorophenoxy)methyl]dihydro-2(3H)-furanone | 175212-40-5 | C11H11FO3 | 详情 | 详情 |
| (IV) | 19641 | (5S)-5-[(4-fluorophenoxy)methyl]tetrahydro-2-furanol | C11H13FO3 | 详情 | 详情 | |
| (V) | 19642 | tert-butyl(dimethyl)silyl (5S)-5-[(4-fluorophenoxy)methyl]tetrahydro-2-furanyl ether; tert-butyl([(5S)-5-[(4-fluorophenoxy)methyl]tetrahydro-2-furanyl]oxy)dimethylsilane | C17H27FO3Si | 详情 | 详情 | |
| (VI) | 19643 | tert-butyl(dimethyl)silyl 3-butynyl ether; tert-butyl(3-butynyloxy)dimethylsilane | C10H20OSi | 详情 | 详情 | |
| (VII) | 19644 | tert-butyl(dimethyl)silyl 4-[(5S)-5-[(4-fluorophenoxy)methyl]tetrahydro-2-furanyl]-3-butynyl ether; tert-butyl[(4-[(5S)-5-[(4-fluorophenoxy)methyl]tetrahydro-2-furanyl]-3-butynyl)oxy]dimethylsilane | C21H31FO3Si | 详情 | 详情 | |
| (VIII) | 19645 | 4-[(2S,5S)-5-[(4-fluorophenoxy)methyl]tetrahydro-2-furanyl]-3-butyn-1-ol | C15H17FO3 | 详情 | 详情 | |
| (IX) | 19646 | 1-[([[(phenoxycarbonyl)oxy]amino]carbonyl)oxy]benzene | C14H11NO5 | 详情 | 详情 | |
| (X) | 19647 | (2S,5S)-2-[(4-fluorophenoxy)methyl]-5-(4-[(phenoxycarbonyl)[(phenoxycarbonyl)oxy]amino]-1-butynyl)tetrahydrofuran | C29H26FNO7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)Intermediate (XVI) is treated with BuLi and diisopropylamine in THF giving the chiral acetylenic tetrahydrofuran (XVII). The addition of ethylene oxide (XVIII) to the terminal acetylene of (XVII) by means of BF3/Et2O in THF gives the 3-butyl-1-ol derivative (XIX), which is condensed with N,O-bis(phenoxy- carbonyl)hydroxylamine (XX) by means of PPh3 and diisopropylazodicarboxylate (DIAD) in THF yielding the final intermediate (XXI). Finally, this compound is treated with ammonia in methanol to obtain the target urea derivative.
| 【1】 Adhikari, S.S.; Hymavathi, L.; Sadalapure, K.; Sharma, G.V.M.; Sreenivas, P.; Mhaskar, S.V.; Lalitha, S.V.S.; Chorghade, M.S.; Murugaiah, A.M.S.; Prasad, T.R.; Reddy, B.S.; Gurjar, M.K.; Reddy, V.G.; Krishna, P.R. (LeukoSite, Inc.); Substd. oxygen alicyclic cpds., including methods for synthesis thereof. WO 0001381 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 32994 | (1R)-3-[(2R,3R)-3-(chloromethyl)oxiranyl]-1-[(4-fluorophenoxy)methyl]propyl benzenesulfonate | C19H20ClFO5S | 详情 | 详情 | |
| (XVII) | 32995 | [(2S,5S)-5-ethynyltetrahydro-2-furanyl]methyl 4-fluorophenyl ether; (2S,5S)-2-ethynyl-5-[(4-fluorophenoxy)methyl]tetrahydrofuran | C13H13FO2 | 详情 | 详情 | |
| (XVIII) | 10393 | Oxirane; Ethylene oxide | 75-21-8 | C2H4O | 详情 | 详情 |
| (XIX) | 19645 | 4-[(2S,5S)-5-[(4-fluorophenoxy)methyl]tetrahydro-2-furanyl]-3-butyn-1-ol | C15H17FO3 | 详情 | 详情 | |
| (XX) | 19646 | 1-[([[(phenoxycarbonyl)oxy]amino]carbonyl)oxy]benzene | C14H11NO5 | 详情 | 详情 | |
| (XXI) | 19647 | (2S,5S)-2-[(4-fluorophenoxy)methyl]-5-(4-[(phenoxycarbonyl)[(phenoxycarbonyl)oxy]amino]-1-butynyl)tetrahydrofuran | C29H26FNO7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)The reaction of oxirane (I) with vinylmagnesium bromide in THF gives 1-(4-fluorophenoxy)-4-penten-2(S)-ol (II), which is treated with ethyl vinyl ether and mercuric trifluoroacetate to yield the vinyl ether (III). The cyclization of (III) by means of Grubb's catalyst in refluxing benzene affords the dihydrofuran (IV), which is treated with benzenesulfinic acid in dichloromethane to give the sulfone (V). The reaction of (V) with the acetylenic tetrahydropyranyl ether (VI) by means of isopropylmagnesium bromide in THF yields the expected addition product (VII), which is treated with TsOH to eliminate the tetrahydropyranyl group and provide the alcohol (VIII). The condensation of (VIII) with N,O-bis (phenoxycarbonyl)hydroxylamine (IX) by means of PPh3 and DEAD in THF affords the protected carbamate derivative (X), which is finally treated with ammonia in methanol.
| 【1】 Gurjar, M.K.; et al.; A versatile approach to anti-asthmatic compound CMI-977 and its six-membered analogue. Synthesis 2000, 4, 557. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 | |
| 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 | |
| 40726 | dioxo(phenyl)-lambda(6)-sulfane | C6H6O2S | 详情 | 详情 | ||
| (I) | 32986 | 4-fluorophenyl (2S)oxiranylmethyl ether; (2S)-2-[(4-fluorophenoxy)methyl]oxirane | 108648-25-5 | C9H9FO2 | 详情 | 详情 |
| (II) | 38536 | (2S)-1-(4-fluorophenoxy)-4-penten-2-ol | C11H13FO2 | 详情 | 详情 | |
| (III) | 38537 | (1S)-1-[(4-fluorophenoxy)methyl]-3-butenyl vinyl ether; 1-fluoro-4-[[(2S)-2-(vinyloxy)-4-pentenyl]oxy]benzene | C13H15FO2 | 详情 | 详情 | |
| (IV) | 38538 | (2S)-2-[(4-fluorophenoxy)methyl]-2,3-dihydrofuran; (2S)-2,3-dihydro-2-furanylmethyl 4-fluorophenyl ether | C11H11FO2 | 详情 | 详情 | |
| (V) | 38539 | (2S,5R)-2-[(4-fluorophenoxy)methyl]-5-(phenylsulfonyl)tetrahydrofuran; (2R,5S)-5-[(4-fluorophenoxy)methyl]tetrahydro-2-furanyl phenyl sulfone | C17H17FO4S | 详情 | 详情 | |
| (VI) | 38540 | 2-(4-pentynyloxy)tetrahydro-2H-pyran; 4-pentynyl tetrahydro-2H-pyran-2-yl ether | 62992-46-5 | C10H16O2 | 详情 | 详情 |
| (VII) | 38541 | 5-[(2S,5S)-5-[(4-fluorophenoxy)methyl]tetrahydro-2-furanyl]-4-pentynyl tetrahydro-2H-pyran-2-yl ether; 2-[(5-[(2S,5S)-5-[(4-fluorophenoxy)methyl]tetrahydro-2-furanyl]-4-pentynyl)oxy]tetrahydro-2H-pyran | C21H27FO4 | 详情 | 详情 | |
| (VIII) | 19645 | 4-[(2S,5S)-5-[(4-fluorophenoxy)methyl]tetrahydro-2-furanyl]-3-butyn-1-ol | C15H17FO3 | 详情 | 详情 | |
| (IX) | 19646 | 1-[([[(phenoxycarbonyl)oxy]amino]carbonyl)oxy]benzene | C14H11NO5 | 详情 | 详情 | |
| (X) | 19647 | (2S,5S)-2-[(4-fluorophenoxy)methyl]-5-(4-[(phenoxycarbonyl)[(phenoxycarbonyl)oxy]amino]-1-butynyl)tetrahydrofuran | C29H26FNO7 | 详情 | 详情 |