Synthesis of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer's Disease

Organic Letters

Volumn 18, Issue 22, 2016, Pages 5780-5783

  Thaisrivongs, David A ^a   Miller, Steven P ^a   Molinaro, Carmela ^a   Chen, Qinghao ^a   Song, Zhiguo J ^a   Tan, Lushi ^a   Chen, Lu ^b   Chen, Wenyong ^a   Lekhal, Azzeddine ^a   Pulicare, Sarah K ^a   Xu, Yanke ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b WUXI APPTEC   (China)

Author keywords

[No Author keywords available]

Indexed keywords

ASPARTIC PROTEINASE; BACE1 PROTEIN, HUMAN; COPPER; SECRETASE; SULFOXIDE; THIADIAZINE DERIVATIVE; VERUBECESTAT;

ALZHEIMER DISEASE; ANTAGONISTS AND INHIBITORS; CATALYSIS; CHEMICAL STRUCTURE; CHEMISTRY; HUMAN; METABOLISM; SYNTHESIS;

ALZHEIMER DISEASE; AMYLOID PRECURSOR PROTEIN SECRETASES; ASPARTIC ACID ENDOPEPTIDASES; CATALYSIS; CHEMISTRY TECHNIQUES, SYNTHETIC; COPPER; CYCLIC S-OXIDES; HUMANS; MOLECULAR STRUCTURE; THIADIAZINES;

EID: 84996562185     PISSN: 15237060     EISSN: 15237052     Source Type: Journal    
DOI: 10.1021/acs.orglett.6b01793     Document Type: Article

References (13)

1. Duthey, B. Background Paper 6.11 Alzheimer Disease and other Dementias. Report for the European Commission by the World Health Organization; WHO, Feb 20, 2013.
2. Alzheimer's Disease Medications Fact Sheet. https://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-medications-fact-sheet (accessed Jul 11, 2016).
3. Scott, J. D.; Stamford, A. W.; Gilbert, E. J.; Cumming, J. N.; Iserloh, U.; Misiaszek, J. A.; Li, G. PCT Int. Appl. WO 2011/044181 A1, PCT/US2010/051553, 2011.
4. Kennedy, M. E.; Stamford, A. W.; Chen, X.; Cox, K.; Cumming, J. N.; Dockendorf, M. F.; Egan, M.; Ersehefsky, L.; Hodgson, R. A.; Hyde, L. A.; Jhee, S.; Kleijn, H. J.; Kuvelkar, R.; Li, W.; Mattson, B. A.; Mei, H.; Palcza, J.; Scott, J. D.; Tanen, M.; Troyer, M. D.; Tseng, J. L.; Stone, J. A.; Parker, E. M.; Forman, M. S. Sci. Transl. Med. 2016, 8, 363ra150 10.1126/scitranslmed.aad9704
5. Vassar, R.; Bennett, B. D.; Babu-Khan, S. B.; Kahn, S.; Mendiaz, E. A.; Denis, P.; Teplow, D. B.; Ross, S.; Amarante, P.; Leoloff, R.; Luo, Y.; Fisher, S.; Fuller, J.; Edenson, S.; Lile, J.; Jarosinski, M. A.; Biere, A. L.; Curran, E.; Burgess, T.; Louis, J.-C.; Collins, F.; Treanor, J.; Rogers, G.; Citron, M. Science 1999, 286, 735 10.1126/science.286.5440.735
6. Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268 10.1021/ja983217q
7. Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600 10.1021/cr900382t
8. Scott, J. D.; Li, S. W.; Brunskill, A. P. J.; Chen, X.; Cox, K.; Cumming, J. N.; Forman, M.; Gilbert, E. J.; Hodgson, R. A.; Hyde, L. A.; Jiang, Q.; Iserloh, U.; Kazakevich, I.; Kuvelkar, R.; Mei, H.; Meredith, J.; Misiaszek, J.; Orth, P.; Rossiter, L. M.; Slater, M.; Stone, J.; Strickland, C.; Voigt, J. H.; Wang, G.; Wang, H.; Wu, Y.; Greenlee, W. J.; Parker, E. M.; Kennedy, M. E.; Stamford, A. W. J. Med. Chem. 2016, 10.1021/acs.jmedchem.6b00307
9. Fors, B. P.; Watson, D. W.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 13552 10.1021/ja8055358
10. Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727 10.1021/ja016226z
11. Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421 10.1021/ja0260465
12. For a related strategy employing an EDTE-chelate of soluble titanium, see: Reeves, J. T.; Tan, Z.; Han, Z. S.; Li, G.; Zhang, Y.; Xu, Y.; Reeves, D. C.; Gonnella, N. C.; Ma, S.; Lee, H.; Lu, B. Z.; Senanayake, C. H. Angew. Chem., Int. Ed. 2012, 51, 1400 10.1002/anie.201107601
13. 4 to form sulfinyl ketimines simplifies the workup protocol: Reeves, J. T.; Visco, M. D.; Marsini, M. A.; Grinberg, N.; Busacca, C. A.; Mattson, A. E.; Senanayake, C. H. Org. Lett. 2015, 17, 2442 10.1021/acs.orglett.5b00949