SC-795
Chemical Name: (+)-1,1,1-Trifluoro-3-[N-(3-phenoxyphenyl)-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]amino]propan-2(R)-ol
CAS No. 263264-30-8
项目整合开发状态: Preclinical
项目研究机构: Pfizer (Originator)
合成路线:Radical bromination of 3-(1,1,2,2-tetrafluoroethoxy)toluene (I) by means of N-bromosuccinimide in the presence of AIBN provided benzyl bromide (II),which was then condensed with 3-phenoxyaniline (III) in refluxing cyclohexane to afford (IV).Alternatively,(IV) was obtained by reductive condensation of 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (A) with 3-phenoxyaniline (III) in the presence of sodium triacetoxyborohydride.The condensation of the secondary amine (IV) with commercially available trifluoromethyloxirane (V) of unspecified enantiomeric composition in the presence of ytterbium triflate furnished a 1:7 mixture of enantiomeric amino alcohols (VI).The title compound was then isolated from (VI) as the minor enantiomer by means of preparative chiral HPLC.
合成路线:The chiral (R)-(+)-epoxide (X) was synthesized by asymmetric reduction of 3-bromotrifluoroacetone (VII) using (+)-B-chlorodiisopinocampheylborane (VIII),followed by intramolecular cyclization of the resulting (R)-bromohydrin (VIII) in aqueous NaOH.Finally,reaction of amine (IV) with the chiral epoxide (X) furnished the desired enantiomer.
📌 参考资料/链接：
参考文献标题:(R)-Chiral halogenated 1-substd.amino-(n+1)-alkanols useful for inhibiting cholesteryl ester transfer protein activity
文献作者:Vernier,W.F.; Wang,L.; Mischke,D.A.; Hamme,A.T.; Promo,M.A.; Sikorski,J.A.; Spangler,D.P.; Grapperhaus,M.L.; Massa,M.A.; Durley,R.C.; Reinhard,E.J.; Fobian,Y.M.; Hickory,B.S.; Tollefson,M.B.; Norton,M.B.; Rueppel,M.L.(Pharmacia Corp.)
参考来源:WO 0018721; WO 0018724
📄 详细内容
合成路线:The chiral (R)-(+)-epoxide (X) was synthesized by asymmetric reduction of 3-bromotrifluoroacetone (VII) using (+)-B-chlorodiisopinocampheylborane (VIII),followed by intramolecular cyclization of the resulting (R)-bromohydrin (VIII) in aqueous NaOH.Finally,reaction of amine (IV) with the chiral epoxide (X) furnished the desired enantiomer.
参考文献标题:New simple class of potent cholesteryl ester transfer protein inhibitors
文献作者:Grapperhaus,M.L.; Hickory,B.S.; Sikorski,J.A.; Wang,L.J.; Massa,M.A.; Mischke,D.A.; Honda,D.D.
参考来源:220th ACS Natl Meet (Aug 20 2000,Washington DC) 2000,Abst MEDI 283
合成路线:Radical bromination of 3-(1,1,2,2-tetrafluoroethoxy)toluene (I) by means of N-bromosuccinimide in the presence of AIBN provided benzyl bromide (II),which was then condensed with 3-phenoxyaniline (III) in refluxing cyclohexane to afford (IV).Alternatively,(IV) was obtained by reductive condensation of 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (A) with 3-phenoxyaniline (III) in the presence of sodium triacetoxyborohydride.The condensation of the secondary amine (IV) with commercially available trifluoromethyloxirane (V) of unspecified enantiomeric composition in the presence of ytterbium triflate furnished a 1:7 mixture of enantiomeric amino alcohols (VI).The title compound was then isolated from (VI) as the minor enantiomer by means of preparative chiral HPLC.
合成路线:The chiral (R)-(+)-epoxide (X) was synthesized by asymmetric reduction of 3-bromotrifluoroacetone (VII) using (+)-B-chlorodiisopinocampheylborane (VIII),followed by intramolecular cyclization of the resulting (R)-bromohydrin (VIII) in aqueous NaOH.Finally,reaction of amine (IV) with the chiral epoxide (X) furnished the desired enantiomer.
参考文献标题:Discovery of chiral N,N-disubstituted trifluoro-3-amino-2-propanols as potent inhibitors of cholesteryl ester transfer protein
文献作者:Durley,R.C.; Grapperhaus,M.L.; Massa,M.A.; Mischke,D.A.; Parnas,B.L.; Fobian,Y.M.; Rath,N.P.; Honda,D.D.; Zeng,M.; Connolly,D.T.; Heuvelman,D.M.; Witherbee,B.J.; Glenn,K.C.; Krul,E.S.; Smith,M.E.; Sikorski,J.A.
参考来源:J Med Chem 2000,43(24),4575
合成路线:The chiral (R)-(+)-epoxide (X) was synthesized by asymmetric reduction of 3-bromotrifluoroacetone (VII) using (+)-B-chlorodiisopinocampheylborane (VIII),followed by intramolecular cyclization of the resulting (R)-bromohydrin (VIII) in aqueous NaOH.Finally,reaction of amine (IV) with the chiral epoxide (X) furnished the desired enantiomer.
参考文献标题:Chiral N,N-disubstituted trifluoro-3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein
文献作者:Durley,R.C.; Grapperhaus,M.L.; Hickory,B.S.; Massa,M.A.; Wang,J.L.; Spangler,D.P.; Mischke,D.A.; Parnas,B.L.; Fobian,Y.M.; Rath,N.P.; Honda,D.D.; Zeng,M.; Connolly,D.T.; Heuvelman,D.M.; Witherbee,B.J.; Melton,M.A.; Glenn,K.C.; et al.
参考来源:J Med Chem 2002,45(18),3891