【结 构 式】 |
【分子编号】28361 【品名】2-(3,5-difluorophenyl)acetic acid 【CA登记号】105184-38-1 |
【 分 子 式 】C8H6F2O2 【 分 子 量 】172.1312464 【元素组成】C 55.82% H 3.51% F 22.07% O 18.59% |
合成路线1
该中间体在本合成路线中的序号:(I)The reaction of 3,5-difluorophenylacetic acid with SOCl2 gives the corresponding acyl chloride (II), which is cyclized with ethylene (III) by means of AlCl3 in dichloromethane yielding the tetralone (IV). The stereoselective reduction of (IV) with LiAlH4 catalyzed by (1R,2S)-N-methylephedrine affords 5,7-difluoro-1,2,3,4-tetrahydro-2(R)-naphthol (V). The reaction of (V) with methanesulfonyl chloride and triethylamine gives the expected mesylate (VI), which is treated with LiN3 in DMF yielding the 2(S)-azide (VII). The reduction of (VII) with H2 over Pd/C in ethyl acetate affords the corresponding amine (VIII), which is treated with formaldehyde and KCN to give the 2-aminoacetonitrile (IX). The acylation of (IX) with butyl formate in refluxing acetonitrile yields the formamide (X), with is treated with ethyl formate and potassium tert-butoxide in THF to afford the hydroxyvinyl derivative (XI). The cyclization of (XI) with potassium thiocyanate in hot ethanol gives 1-(5,7-difluoro-1,2,3,4-tetrahydro naphthalen-2(S)-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-carbonitrile (XII), which is finally reduced with LiAlH4 in THF.
【1】 Martinez, G.R.; Repke, D.B.; Teitelbaum, P.J.; Walker, K.A.M.; Gooding, O.W.; Whiting, R.L.; Bansal, R.P.; Muehldorf, A.V. (Syntex (USA), Inc.); Benzocycloalkylazolethione derivs.. JP 1997512269; US 5438150; WO 9529165 . |
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) | 28361 | 2-(3,5-difluorophenyl)acetic acid | 105184-38-1 | C8H6F2O2 | 详情 | 详情 |
(II) | 28362 | 2-(3,5-difluorophenyl)acetyl chloride | C8H5ClF2O | 详情 | 详情 | |
(III) | 28363 | ethylene | 9002-88-4 | C2H4 | 详情 | 详情 |
(IV) | 28364 | 5,7-difluoro-3,4-dihydro-2(1H)-naphthalenone | C10H8F2O | 详情 | 详情 | |
(V) | 28365 | (2R)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenol | C10H10F2O | 详情 | 详情 | |
(VI) | 28366 | (2R)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl methanesulfonate | C11H12F2O3S | 详情 | 详情 | |
(VII) | 28367 | (2S)-2-azido-5,7-difluoro-1,2,3,4-tetrahydronaphthalene | C10H9F2N3 | 详情 | 详情 | |
(VIII) | 18416 | (2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenylamine; (2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenamine | C10H11F2N | 详情 | 详情 | |
(IX) | 28368 | 2-[[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]amino]acetonitrile | C12H12F2N2 | 详情 | 详情 | |
(X) | 28369 | cyanomethyl[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]formamide | C13H12F2N2O | 详情 | 详情 | |
(XI) | 28370 | (Z)-1-cyano-2-hydroxyethenyl[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]formamide | C14H12F2N2O2 | 详情 | 详情 | |
(XII) | 28371 | 3-[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-2-thioxo-2,3-dihydro-1H-imidazole-4-carbonitrile | C14H11F2N3S | 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 3,5-difluorophenylacetic acid (I) with oxalyl chloride and DMF in dichloromethane gives the corresponding acyl chloride (II), which is condensed with L-alanine (III) by means of aqueous NaOH, yielding N-(3,5-difluorophenylacetyl)-L-alanine (IV). Finally, this compound is condensed with L-phenylglycine tert-butyl ester (V) by means of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester (EEDQ) and NMM in THF.
【1】 Methods and cpds. for inhibiting beta-amyloid peptide release and/or its synthesis. JP 2001503782; WO 9822494 . |
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) | 28361 | 2-(3,5-difluorophenyl)acetic acid | 105184-38-1 | C8H6F2O2 | 详情 | 详情 |
(II) | 28362 | 2-(3,5-difluorophenyl)acetyl chloride | C8H5ClF2O | 详情 | 详情 | |
(III) | 10141 | D-Alanine; D-2-Aminopropionic Acid | 338-69-2 | C3H7NO2 | 详情 | 详情 |
(IV) | 46287 | (2S)-2-[[2-(3,5-difluorophenyl)acetyl]amino]propionic acid | C11H11F2NO3 | 详情 | 详情 | |
(V) | 46288 | tert-butyl (2S)-2-amino-2-phenylethanoate | C12H17NO2 | 详情 | 详情 |