新产品编号:619071
Chemical Name: N-[3-[3,5-Difluoro-4-[4-(hydroxyacetyl)piperazin-1-yl]phenyl]-4,5-dihydroisoxazol-5(R)-ylmethyl]acetamide
CAS No. 238743-18-5 ((-)-enantiomer), 194350-87-3 ((S)-isomer)
项目整合开发状态: Preclinical
项目研究机构: Pfizer (Originator)
合成路线:3,4,5-Trifluorobenzaldehyde (I) is converted into oxime (II) upon treatment with hydroxylamine in aqueous EtOH.Subsequent oxidation of oxime (II) with N-chlorosuccimide produces the hydroximinoyl chloride (III).In situ conversion of (III) to the corresponding nitrile oxide,followed by cycloaddition with N-allyl acetamide (IV) generates the racemic isoxazoline (V).After resolution of (V) by means of chiral HPLC,displacement of the para-fluoride group with piperazine in hot DMSO furnishes (VI).Acylation of piperazine (VI) by means of acetoxyacetyl chloride (VII) gives rise to amide (VIII).Finally,methanolysis of the acetoxy group of (VIII) in the presence of K2CO3 leads to the target hydroxyacetylpiperazine derivative.(1,2)
📌 参考资料/链接：
参考文献标题:Substd.aminophenyl isoxazoline derivs.useful as antimicrobials
文献作者:Thomas,R.C.; Barbachyn,M.R.; Morris,J.; Wishka,D.G.; Cleek,G.J.(Pfizer Inc.)
参考来源:JP 2002503655; US 6069141; WO 9941244
📄 详细内容
合成路线:3,4,5-Trifluorobenzaldehyde (I) is converted into oxime (II) upon treatment with hydroxylamine in aqueous EtOH.Subsequent oxidation of oxime (II) with N-chlorosuccimide produces the hydroximinoyl chloride (III).In situ conversion of (III) to the corresponding nitrile oxide,followed by cycloaddition with N-allyl acetamide (IV) generates the racemic isoxazoline (V).After resolution of (V) by means of chiral HPLC,displacement of the para-fluoride group with piperazine in hot DMSO furnishes (VI).Acylation of piperazine (VI) by means of acetoxyacetyl chloride (VII) gives rise to amide (VIII).Finally,methanolysis of the acetoxy group of (VIII) in the presence of K2CO3 leads to the target hydroxyacetylpiperazine derivative.(1,2)
参考文献标题:Identification of phenylisoxazolines as novel and viable antibacterial agents active against Gram-positive pathogens
文献作者:Barbachyn,M.R.; Cleek,G.J.; Dolak,L.A.; Garmon,S.A.; Morris,J.; Seest,E.P.; Thomas,R.C.; Toops,D.S.; Watt,W.; Wishka,D.G.; Ford,C.W.; Zurenko,G.E.; Hamel,J.C.; Schaadt,R.D.; Stapert,D.; Yagi,B.H.; Adams,W.J.; Friis,J.M.; et al.
参考来源:J Med Chem 2003,46(2),284