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Volumn 10, Issue 3, 2006, Pages 472-480

Asymmetric synthesis of the cholesteryl ester transfer protein inhibitor torcetrapib

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Indexed keywords


EID: 33745748824     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op060013i     Document Type: Article
Times cited : (60)

References (18)
  • 4
    • 33745736972 scopus 로고    scopus 로고
    • note
    • This material was purchased from Fisher Scientific.
  • 5
    • 33745742345 scopus 로고    scopus 로고
    • note
    • The main impurity is (R)-4-ethyloxazolidin-2-one formed from cyclization of the BOC-protected mesylate.
  • 6
    • 33745748234 scopus 로고    scopus 로고
    • note
    • In time, other vendors were identified to provide this key raw material using variations of the described method or alternate technologies.
  • 7
    • 0034712161 scopus 로고    scopus 로고
    • For overviews of the literature coupling conditions, see: (a) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144-1157.
    • (2000) J. Org. Chem. , vol.65 , pp. 1144-1157
    • Wolfe, J.P.1    Buchwald, S.L.2
  • 9
    • 33745750685 scopus 로고    scopus 로고
    • note
    • Comparison of reactions at 85 and 110 °C showed 3 times as much enantiomer by chiral HPLC at the higher temperature. Typically, 0.2-0.6% of enantiomer was detected at the end of reactions at 85 °C.
  • 10
    • 33745741208 scopus 로고    scopus 로고
    • note
    • Cyclohexane can be replaced with hexanes or heptane, but cyclohexane is the solvent of choice based on the consistent physical characteristics of the amide thus obtained.
  • 14
    • 33745758279 scopus 로고    scopus 로고
    • note
    • This material was purchased from Aldrich Chemical Co. Due to lower activity of the pellets, the surface was "preactivated" by stirring the pellets in the solvent for 20 min at room temperature.
  • 15
    • 33745752894 scopus 로고    scopus 로고
    • note
    • To circumvent a final-step alkylation, we also examined the alternate permutation: alkylation of 25 first with bis(trifluoromethyl)benzyl bromide followed by conversion of the tetrahydroquinoline nitrogen to the ethyl carbamate. Although the major product from this sequence was the desired compound, the alkylation step was not completely selective for the desired nitrogen, leading to significant impurities.
  • 16
    • 33745761109 scopus 로고    scopus 로고
    • note
    • 2, and releasing pyridine.
  • 17
    • 33745747853 scopus 로고    scopus 로고
    • note
    • This impurity arises from deprotonation at the benzyl center of 27, which displaces the bromide of a second molecule of 27. The intermediate can then undergo base-catalyzed elimination to provide 29. Formation of this material must be minimized as it is difficult to purge in the final crystallization. (Diagram presented)
  • 18
    • 33745761972 scopus 로고    scopus 로고
    • note
    • Anhydrous ethanol denatured with 0.5% toluene was used.


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.