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【结 构 式】 
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【药物名称】MLN-977, LDP-977, CMI-977 【化学名称】(2S,5S)-1-[4-[5-(4-Fluorophenoxymethyl)tetrahydrofuran-2-yl]-3-butynyl]-1-hydroxyurea 【CA登记号】175212-04-1 【 分 子 式 】C16H19FN2O4 【 分 子 量 】322.33923 |
【开发单位】Millennium (Originator), Taisho (Licensee) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, 5-Lipoxygenase Inhibitors, Leukotriene Synthesis Inhibitors |
合成路线1
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
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3
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4
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 |