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【结 构 式】 
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【分子编号】41269 【品名】2-(2-fluoro-4'-hydroxy[1,1'-biphenyl]-4-yl)acetic acid 【CA登记号】 |
【 分 子 式 】C14H11FO3 【 分 子 量 】246.2379432 【元素组成】C 68.29% H 4.5% F 7.72% O 19.49% |
合成路线1
该中间体在本合成路线中的序号：(I)By condensation of 2-(2-fluoro-4'-hydroxybiphenyl-4-yl)acetic acid (I) with 2-(chloromethyl)quinoline (II) by means of NaH in DMF.
| 【1】 Marshall, L.A.; Wong, A.; Kreft, A.F.; Structure -activity relationships in the quinoline- containing class of inhibitors of 5-lipoxygenase (5-LO) enzyme translocation and activation. Drugs Fut 1994, 19, 3, 255. |
| 【2】 Kreft, A.F.; Failli, A.; Musser, J.H.; et al.; Conversion of a cyclooxygenase (CO) inhibitor into a 5-lipoxygenase (LO) inhibitor - A general route to novel antiinflammatory and antiallergy drugs. Drugs Exp Clin Res 1991, 17, 381-387. |
合成路线2
该中间体在本合成路线中的序号：(VI)The enantioselective condensation of the silylated 4-hydroxy-2-butanone (I) with the silylated enol ester (II) by means of Sn(OTf)2 and the chiral pyrrolidine (III) gives the chiral benzylated trihydroxyester (IV), which is partially dehydroxylated with thiocarbonyl diimidazole (TCDI) and tributyltin hydride in refluxing toluene to yield the protected dihydroxy ester (V). The reduction of (V) with DIBAL in dichloromethane affords the corresponding alcohol (VI), which is oxidized with oxalyl chloride and TEA in DMSO/dichloromethane to provide the aldehyde (VII). The condensation of (VII) with the enol ether (IX) and 2-methoxyaniline (VIII) by means of Yb(OTf)3 in THF/water gives the beta aminoketone (X), which is cyclized by means of HF, PPh3, CBr4 and cerium ammonium nitrate (CAN) in acetonitrile/water to yield the chiral piperidine (XI). The bromination of (XI) with Br2 and HBr in HOAc affords the bromo derivative (XII), which is treated with Boc2O to provide the N-protected piperidine (XIII). The condensation of (XIII) with quinazolin-4(3H)-one (XIV) by means of KOH gives the adduct (XV), which is finally deprotected and cyclized by treatment with refluxing 6N HCl to afford the target isofebrifugine.
| 【1】 Wataya, Y.; Ueno, M.; Suzuki, R.; Kim, H.-S.; Kobayashi, S.; Ishitani, H.; Catalytic asymmetric synthesis of antimalarial alkaloids febrifubine and isofebrifugine and their biological actvity. J Org Chem 1999, 64, 18, 6833. |
| 【2】 Kobayashi, S.; Kim, H.-S.; Wataya, Y. (Japan Science and Technology Corp.); Febrifugine and isofebrifugine and processes for the preparation of both. EP 1076057; WO 0052005 . |
| 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) | 44768 | 4-[[tert-butyl(dimethyl)silyl]oxy]-2-butanone | C10H22O2Si | 详情 | 详情 | |
| (II) | 44769 | benzyl (Z)-2-phenoxy-2-[(trimethylsilyl)oxy]ethenyl ether; [[(Z)-2-(benzyloxy)-1-phenoxyethenyl]oxy](trimethyl)silane | C18H22O3Si | 详情 | 详情 | |
| (III) | 51268 | N-(1-naphthyl)-N-[(2S)pyrrolidinylmethyl]amine; N-[(2S)pyrrolidinylmethyl]-1-naphthalenamine | C15H18N2 | 详情 | 详情 | |
| (IV) | 44771 | phenyl (2S,3R)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxypentanoate | C24H34O5Si | 详情 | 详情 | |
| (V) | 44773 | phenyl (2S)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]pentanoate | C24H34O4Si | 详情 | 详情 | |
| (VI) | 41269 | 2-(2-fluoro-4'-hydroxy[1,1'-biphenyl]-4-yl)acetic acid | C14H11FO3 | 详情 | 详情 | |
| (VII) | 44774 | (2S)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]pentanal | C18H30O3Si | 详情 | 详情 | |
| (VIII) | 25193 | 2-methoxyphenylamine; 2-methoxyaniline | 517-28-2 | C7H9NO | 详情 | 详情 |
| (IX) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (X) | 41270 | 8-(acetamido)-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid | C11H11NO5 | 详情 | 详情 | |
| (XI) | 51271 | 1-[(2S,3S)-3-(benzyloxy)piperidinyl]acetone | C15H21NO2 | 详情 | 详情 | |
| (XII) | 51272 | 1-[(2S,3S)-3-(benzyloxy)piperidinyl]-3-bromoacetone | C15H20BrNO2 | 详情 | 详情 | |
| (XIII) | 51273 | tert-butyl (2S,3S)-3-(benzyloxy)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate | C20H28BrNO4 | 详情 | 详情 | |
| (XIV) | 14634 | 4(3H)-quinazolinone | C8H6N2O | 详情 | 详情 | |
| (XV) | 51274 | tert-butyl (2S,3S)-3-(benzyloxy)-2-[2-oxo-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate | C28H33N3O5 | 详情 | 详情 |