Improved asymmetric synthesis of 3,4-dihydro-2-[3-(1,1,2,2- tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]-α- (trifluoromethyl)-1(2H)-quinolineethanol, a potent cholesteryl ester transfer protein inhibitor

Organic Letters

Volumn 11, Issue 13, 2009, Pages 2812-2815

  Rano, Thomas A ^a   Kuo, Gee Hong ^a  

^a JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3,4 DIHYDRO 2 (3 (1,1,2,2 TETRAFLUOROETHOXY)PHENYL) 5 (3 (TRIFLUOROMETHOXY)PHENYL) ALPHA (TRIFLUOROMETHYL) 1(2H) QUINOLINEETHANOL; 3,4-DIHYDRO-2-(3-(1,1,2,2-TETRAFLUOROETHOXY)PHENYL)-5-(3-(TRIFLUOROMETHOXY)PHENYL)-ALPHA-(TRIFLUOROMETHYL)-1(2H)-QUINOLINEETHANOL; CETP PROTEIN, HUMAN; CHOLESTEROL ESTER TRANSFER PROTEIN; COPPER; DYES, REAGENTS, INDICATORS, MARKERS AND BUFFERS; KETONE; ORGANOTIN COMPOUND; QUINOLINE DERIVATIVE;

ANIMAL; ARTICLE; BLOOD; CATALYSIS; CHEMICAL STRUCTURE; CHEMISTRY; DRUG ANTAGONISM; HUMAN; MOUSE; OXIDATION REDUCTION REACTION; STEREOISOMERISM; SYNTHESIS; TRANSGENIC MOUSE;

ANIMALS; CATALYSIS; CHOLESTEROL ESTER TRANSFER PROTEINS; COPPER; HUMANS; INDICATORS AND REAGENTS; KETONES; MICE; MICE, TRANSGENIC; MOLECULAR STRUCTURE; ORGANOTIN COMPOUNDS; OXIDATION-REDUCTION; QUINOLINES; STEREOISOMERISM;

EID: 67649467493     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol900639j     Document Type: Article

References (22)

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8. The sodium salt of dimethyl malonate or di-tert-butyl malonate could also be used with equal efficiency. In the latter case, the monocarboxylic acid could be obtained via the two-step process of tert-butyl ester removal with TFA followed by 6 N HCl heated to reflux.
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10. 4 in approximately 65% yield.
11. Several synthetic routes to 4 were attempted without success. For example, direct alkylation of the lithium, potassium, or sodium enolate of m-tetrafluoroethoxy acetophenone with 1 led to complex mixtures of ketone 4 along with bis-alkylation, starting material, and decomposition products. Halogen-metal exchange of m-tetrafluoroethoxybromobenzene followed by addition to 3-(2,6-dibromopheny)propionaldehyde provided no desired product. It was subsequently determined that the hydrogen atom, of the tetrafluoroethoxy moiety was sufficiently acidic to be deprotonated by strong base, resulting in the splitting out of tetrafluoroethylene and the corresponding phenol.
12. 2O, which afforded the desired amine in 28% yield.
13. Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett 2002, 2, 231.
14. Intramolecular Fukuyama cyclization under identical conditions on the free amine did not produce any desired product.
15. A variety of copper-mediated Buchwald conditions were also attempted with limited success, affording the tetrahydroquinoline core in approximately 25% yield.
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18. Enantiomeric excess determined by chiral HPLC (Chiralcel AS; isocratic elution. 90/10 Hexane/IPA) by area integration at 210 nm). The structure assigned to each new compound is in accord with its 400 MHz NMR spectrum as well as appropriate ion identification by mass spectrometry.
19. Ohtani, I. Kusumi, T. Kashman, Y. Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092-4096. Both the R and S Mosher esters of the R antipode of alcohol 8 were prepared for use in this study. The 400 MHz NMR spectra of these compounds are included in the Supporting Information.
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21. For a detailed report of the biological evaluation of compound 11, please see; Kuo, G. H.; Rano, T.; Pelton, P.; Demarest, K. T.; Gibbs, A. C.; Murray, W. V.; Damiano, B. P.; Connelly, M. A. J. Med. Chem. 2009, 52, 1768-1772.
22. The structures of compound 13 and 14 are as follows: