Scalable, efficient process for the synthesis of (R)-3,5- bistrifluoromethylphenyl ethanol via catalytic asymmetric transfer hydrogenation and isolation as a DABCO inclusion complex

Tetrahedron Asymmetry

Volumn 14, Issue 22, 2003, Pages 3581-3587

  Hansen, Karl B ^a   Chilenski, Jennifer R ^a   Desmond, Richard ^a   Devine, Paul N ^a   Grabowski, Edward J J ^a   Heid, Richard ^a   Kubryk, Michele ^a   Mathre, David J ^a   Varsolona, Richard ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,4 DIAZABICYCLO[2.2.2]OCTANE; 3,5 BIS(TRIFLUOROMETHYLPHENYL)ETHANOL; ALCOHOL DERIVATIVE; KETONE; LIGAND; RUTHENIUM; UNCLASSIFIED DRUG;

ARTICLE; ASYMMETRIC SYNTHESIS; CATALYSIS; CHIRALITY; ENANTIOSELECTIVITY; HYDROGENATION; PRIORITY JOURNAL; REDUCTION;

EID: 0242710808     PISSN: 09574166     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetasy.2003.08.043     Document Type: Article

References (23)

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2. Brands K.M.J., Payack J.F., Rosen J.D., Nelson T.D., Candelario A., Huffman M.A., Zhao M.M., Li J., Craig B., Song Z.J., Tschaen D.M., Hansen K., Devine P.N., Pye P.J., Rossen K., Dormer P.G., Reamer R.A., Welch C.J., Mathre D.J., Tsou N.N., McNamara J.M., Reider P.J. J. Am. Chem. Soc. 125:2003;2129-2135.
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6. Borane based reductants and hydrogen are classified at Merck as highly toxic and/or hazardous materials and require additional safety considerations when used on large scale.
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16. cis-Aminoindanol is the one of the key chiral building blocks used in the manufacturing of indinavir sulfate, a Merck product. See: Senanayake, C. H. ; Roberts, F. E.; DiMichele, L. M.; Ryan, K. M.; Liu, J.; Fredenburgh, L. E.; Foster, B. S.; Douglas, A. W.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1995, 23, 3993-3996.
17. The reactions were performed by adding the ligand and metal complex to the isopropanol reaction solvent. Following a 1 h age, 3 was added and the entire solution was degassed by bubbling a stream of nitrogen through the solution for 5 min. KOH was then added under nitrogen and the reaction was aged. Conversion and enantiomeric excess were monitored by chiral GC.
18. Toda F., Tanaka K. Chem. Lett. 1986;1905-1908.
19. a of the two conjugate acids of DABCO are 8.8 and 3.0 for the singly and doubly protonated species, respectively.
20. 10-15% of 2 is lost to the aqueous cut. A better recovery of product can be obtained via an extraction with methyl tert-butyl ether, albeit with significant contamination with dissolved Ru.
21. Small amounts of water or IPA can have a drastic increasing effect on the solubility of 7. Typically the IPA level was <0.5 v/v% and water was less than 1000 PPM.
22. The yield for the isolation from the crude stream of 2 was typically 88-90% prior to the formation of 13.
23. This is based on an ee of 90% for alcohol 2 contained in the system. A lower ee of 2 in the starting system would require more solvent to dissolve all of 13.