Lasofoxifene tartrate, CP-336156

合成路线:The condensation of 6-methoxy-1-tetralone (I) with 1-[2-(4-bromophenoxy)ethyl]pyrrolidine (II) by means of CeCl3 and butyllithium in THF gives 1-[2-[4-(6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine (III),which is brominated with pyridinium bromide perbromide in THF yielding the bromo derivative (IV).The condensation of (IV) with phenylboronic acid (V) by means of tetrakis(triphenylphosphonium) palladium/Na2CO3 in THF affords 1-[2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine (nafoxidene) (VI).Nadoxifene is reduced with H2 over Pd/C in ethanol/methanol giving (?-cis-1-[2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl]-pyrrolidine (VII).The demethylation of (VII) with boron tribromide in dichloromethane or 48% HBr in hot acetic acid yields (?-cis-6-phenyl-5-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol (VIII),which is submitted to optical resolution by chromatography over a Chiralcell OD column in 99.95% (ethanol/heptane 5:95)/0.05% diethylamine,by crystallization with (?-(R)-1,1'- binaphthyl-2,2'-diyl hydrogenphosphate (R-binaph) or by crystallization with D-tartaric acid.

参考文献标题:(?-cis-6(S)-Phenyl-5(R)-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol D-tartrate.
文献作者:Chiu,C.K.; Meltz,M.(Pfizer Inc.)
参考来源:EP 0876359; JP 1999502866; WO 9716434


合成路线:The condensation of 6-methoxy-1-tetralone (I) with 1-[2-(4-bromophenoxy)ethyl]pyrrolidine (II) by means of CeCl3 and butyllithium in THF gives 1-[2-[4-(6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine (III),which is brominated with pyridinium bromide perbromide in THF yielding the bromo derivative (IV).The condensation of (IV) with phenylboronic acid (V) by means of tetrakis(triphenylphosphonium) palladium/Na2CO3 in THF affords 1-[2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine (nafoxidene) (VI).Nadoxifene is reduced with H2 over Pd/C in ethanol/methanol giving (?-cis-1-[2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl]-pyrrolidine (VII).The demethylation of (VII) with boron tribromide in dichloromethane or 48% HBr in hot acetic acid yields (?-cis-6-phenyl-5-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol (VIII),which is submitted to optical resolution by chromatography over a Chiralcell OD column in 99.95% (ethanol/heptane 5:95)/0.05% diethylamine,by crystallization with (?-(R)-1,1'- binaphthyl-2,2'-diyl hydrogenphosphate (R-binaph) or by crystallization with D-tartaric acid.

参考文献标题:Discovery and preclinical pharmacology of a novel,potent,nonsteroidal estrogen receptor agonist/antagonist,CP-336156,a diaryltetrahydronaphthalene
文献作者:Rosati,R.L.; Da Silva Jardine,P.; Cameron,K.O.; Thompson,D.D.; Ke,H.Z.; Toler,S.M.; Brown,T.A.; Pan,L.C.; Ebbinghaus,C.F.; Reinhold,A.R.; Elliott,N.C.; Newhouse,B.N.; Tjoa,C.M.; Sweetnam,P.M.; Cole,M.J.; Arriola,M.W.; et al.
参考来源:J Med Chem 1998,41(16),2928-31


合成路线:The condensation of 6-methoxy-1-tetralone (I) with 1-[2-(4-bromophenoxy)ethyl]pyrrolidine (II) by means of CeCl3 and butyllithium in THF gives 1-[2-[4-(6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine (III),which is brominated with pyridinium bromide perbromide in THF yielding the bromo derivative (IV).The condensation of (IV) with phenylboronic acid (V) by means of tetrakis(triphenylphosphonium) palladium/Na2CO3 in THF affords 1-[2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine (nafoxidene) (VI).Nadoxifene is reduced with H2 over Pd/C in ethanol/methanol giving (?-cis-1-[2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl]-pyrrolidine (VII).The demethylation of (VII) with boron tribromide in dichloromethane or 48% HBr in hot acetic acid yields (?-cis-6-phenyl-5-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol (VIII),which is submitted to optical resolution by chromatography over a Chiralcell OD column in 99.95% (ethanol/heptane 5:95)/0.05% diethylamine,by crystallization with (?-(R)-1,1'- binaphthyl-2,2'-diyl hydrogenphosphate (R-binaph) or by crystallization with D-tartaric acid.

参考文献标题:CP-336156
文献作者:Leeson,P.A.; Castar,J.; Sorbera,L.A.
参考来源:Drugs Fut 1998,23(10),1066-1070


合成路线:The acetylation of racemic cis-lasofoxifene (CP-319609) (I) by conventional methods gives the corresponding acetate (II),which is submitted to an enzymatic hydrolysis with cholesterol lipase (porcine pancreas) in a pH 7 phosphate buffer to yield pure lasofoxifene with an e.e.of 96% at 35% conversion.This optical purity can be improved up to 99% e.e.by crystallization in 95:5 ethanol/water.
参考文献标题:Enzyme-catalyzed asymmetric deacylation for the preparation of lasofoxifene (CP-336156),a selective estrogen receptor modulator
文献作者:Yang,X.; Reinhold,A.R.; Rosati,R.L.; Liu,K.K.-C.
参考来源:Org Lett 2000,2(25),4025