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【结 构 式】

【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%

与该中间体有关的原料药合成路线共 2 条

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.
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) 41269 2-(2-fluoro-4'-hydroxy[1,1'-biphenyl]-4-yl)acetic acid C14H11FO3 详情 详情
(II) 13162 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine 4377-41-7 C10H8ClN 详情 详情

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
Extended Information