Asymmetric synthesis of the cholesteryl ester transfer protein inhibitor torcetrapib

Organic Process Research and Development

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

  Damon, David B ^a   Dugger, Robert W ^a   Hubbs, Stephen E ^a   Scott, Jill M ^a   Scott, Robert W ^a  

^a PFIZER INC   (United States)

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EID: 33745748824     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op060013i     Document Type: Article

References (18)

1. Damon, D. B.; Dugger, R. W.; Magnus-Aryitey, G.; Ruggeri, R. B.; Wester, R. T.; Tu, M. Abramov, Y. Org. Process Res. Dev. 2006, 10, 464-471.
2. Tickner, D.; Kasthurikrishnan Org. Process Rev. Dev. 2001, 5, 270-271.
3. DeNinno, M. P.; Eller, C. Tetrahedron Lett. 1997, 38, 6545-6548.
4. This material was purchased from Fisher Scientific.
5. The main impurity is (R)-4-ethyloxazolidin-2-one formed from cyclization of the BOC-protected mesylate.
6. In time, other vendors were identified to provide this key raw material using variations of the described method or alternate technologies.
7. For overviews of the literature coupling conditions, see: (a) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144-1157.
8. (b) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158-1174.
9. 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. 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.
11. (a) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N. Tetrahedron 1975, 31, 1437-1441.
12. (b) Dijkink, J.; Speckamp, W. N. Tetrahedron Lett. 1975, 46, 4047-4050.
13. Kollonitsch, J.; Fuchs, O.; Gabor, V. Nature 1955, 346.
14. 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. 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. 2, and releasing pyridine.
17. 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. Anhydrous ethanol denatured with 0.5% toluene was used.