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【结 构 式】 
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【分子编号】32986 【品名】4-fluorophenyl (2S)oxiranylmethyl ether; (2S)-2-[(4-fluorophenoxy)methyl]oxirane 【CA登记号】108648-25-5 |
【 分 子 式 】C9H9FO2 【 分 子 量 】168.1676632 【元素组成】C 64.28% H 5.39% F 11.3% O 19.03% |
合成路线1
该中间体在本合成路线中的序号：(V)The reaction of 4-fluorophenol (I) with epichlorohydrin (II) by means of K2CO3 in refluxing acetone gives 2-(4-fluorophenoxymethyl)oxirane (III), which is submitted to an enantioselective ring opening with the Jacobsen (R,R)-catalyst yielding a mixture of the (R)-diol (IV) and unaltered epoxide (V), easily separated by column chromatography. The reaction of (IV) with tosyl chloride and pyridine in dichloromethane affords the primary monotosylate (VI), which is converted into the chiral epoxide (VII) by reaction with NaH in THF/DMF. The reaction of (VII) with allylmagnesium bromide (VIII) in ethyl ether gives the 2-hexenol derivative (IX), which is treated with benzenesulfonyl chloride and DMAP yielding the sulfonate (X). The ozonolysis of (X) with ozone in dichloromethane affords the aldehyde (XI), which is condensed with ethoxycarbonylmethylene(triphenyl)phosphorane (XII) yielding the 2-heptenoic ester (XIII). The reduction of (XIII) with diisobutylaluminum hydride (DIBAL) in toluene/dichloromethane provides the 2-hepten-1-ol (XIV), which is epoxidized with cumene hydroperoxide in the presence of diisopropyl (+)-tartrate and Ti(Oi-Pr)4 in dichloromethane to give the chiral epoxyalcohol (XV). The reaction of (XV) with triphenylphosphine/CCl4 in chloroform affords the corresponding chloride (XVI).
| 【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 |
|---|---|---|---|---|---|---|
| 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 | |
| (I) | 19639 | 4-fluorophenol | 371-41-5 | C6H5FO | 详情 | 详情 |
| (II) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (III) | 22150 | 2-[(4-fluorophenoxy)methyl]oxirane; 4-fluorophenyl 2-oxiranylmethyl ether | 18123-82-5 | C9H9FO2 | 详情 | 详情 |
| (IV) | 32985 | (2R)-3-(4-fluorophenoxy)-1,2-propanediol | C9H11FO3 | 详情 | 详情 | |
| (V) | 32986 | 4-fluorophenyl (2S)oxiranylmethyl ether; (2S)-2-[(4-fluorophenoxy)methyl]oxirane | 108648-25-5 | C9H9FO2 | 详情 | 详情 |
| (VI) | 32987 | (2S)-3-(4-fluorophenoxy)-2-hydroxypropyl 4-methylbenzenesulfonate | C16H17FO5S | 详情 | 详情 | |
| (VII) | 22150 | 2-[(4-fluorophenoxy)methyl]oxirane; 4-fluorophenyl 2-oxiranylmethyl ether | 18123-82-5 | C9H9FO2 | 详情 | 详情 |
| (VIII) | 10386 | Allyl(bromo)magnesium | 1730-25-2 | C3H5BrMg | 详情 | 详情 |
| (IX) | 32988 | (2R)-1-(4-fluorophenoxy)-5-hexen-2-ol | C12H15FO2 | 详情 | 详情 | |
| (X) | 32989 | (1R)-1-[(4-fluorophenoxy)methyl]-4-pentenyl benzenesulfonate | C18H19FO4S | 详情 | 详情 | |
| (XI) | 32990 | (1R)-1-[(4-fluorophenoxy)methyl]-4-oxobutyl benzenesulfonate | C17H17FO5S | 详情 | 详情 | |
| (XII) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XIII) | 32991 | ethyl (E,6R)-7-(4-fluorophenoxy)-6-[(phenylsulfonyl)oxy]-2-heptenoate | C21H23FO6S | 详情 | 详情 | |
| (XIV) | 32992 | (1R,4E)-1-[(4-fluorophenoxy)methyl]-6-hydroxy-4-hexenyl benzenesulfonate | C19H21FO5S | 详情 | 详情 | |
| (XV) | 32993 | (1R)-1-[(4-fluorophenoxy)methyl]-3-[(2R,3S)-3-(hydroxymethyl)oxiranyl]propyl benzenesulfonate | C19H21FO6S | 详情 | 详情 | |
| (XVI) | 32994 | (1R)-3-[(2R,3R)-3-(chloromethyl)oxiranyl]-1-[(4-fluorophenoxy)methyl]propyl benzenesulfonate | C19H20ClFO5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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 |