Improved asymmetric synthesis of 3,4-dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]-alpha-(trifluoromethyl)-1(2H)-quinolineethanol, a potent cholesteryl ester transfer protein inhibitor.
The asymmetric synthesis of 3,4-dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]-alpha-(trifluoromethyl)-1(2H)-quinolineethanol (compound 11), a cholesteryl ester transfer protein inhibitor, is accomplished. The asymmetric center is established via the chiral reduction of ketone 4 employing Corey's (R)-Me CBS oxazaborolidine reagent. The tetrahydroquinoline core of the molecule is established via a Cu-mediated intramolecular amination reaction. The preparation of the prochiral ketone 4 has also been improved by eliminating the use of a hazardous aryltin reagent.
Rano
Thomas A
TA
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 1000 Route 202, P.O. Box 300, Raritan, New Jersey 08869, USA. trano@its.jnj.com
Kuo
Gee-Hong
GH
D000818:Animals; D002384:Catalysis; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000097:blood; D003300:Copper / Q000737:chemistry; D006801:Humans; D007202:Indicators and Reagents; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D009947:Organotin Compounds / Q000737:chemistry / Q000633:toxicity; D010084:Oxidation-Reduction; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
C539971:3,4-dihydro-2-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-5-(3-(trifluoromethoxy)phenyl)-alpha-(trifluoromethyl)-1(2H)-quinolineethanol; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D007202:Indicators and Reagents; D007659:Ketones; D009947:Organotin Compounds; D011804:Quinolines; D003300:Copper