Organic Letters
Letter
Scheme 4. Bis-deprotection of 18 with Trifluoroacetic Acid
ASSOCIATED CONTENT
Supporting Information
■
*
S
Experimental procedures, compound characterization
data, and NMR spectra (PDF)
reaction, the desired bis-deprotection of 18 delivers 24 in high
yield (Scheme 4).
AUTHOR INFORMATION
■
*
*
The guanidinylation of 11 to 12 with cyanogen bromide
proceeded in only moderate yield (Scheme 1), in part because the
reaction requires 48 h at 85 °C to reach high levels of conversion.
During this time, guanidine 12 that is formed slowly degrades in
solution, reducing the yield obtained after isolation. We explored
other reagents for the guanidinylation of 24 (e.g., 1-cyanato-4-
methoxybenzene, N-cyanoimido-S,S-dimethyldithiocarbonate,
and S-methylisothiourea) without success, and we could not
significantly improve the rate of reaction through higher
temperatures and pressures. However, we serendipitously
discovered as part of a solvent screen that if the process was
conducted in a mixture of isopropyl acetate and acetonitrile the
HBr salt (25) of 1 spontaneously crystallized (Scheme 5). This
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
WethankXiaodongBu, LiZhang, andDanielZewgeforanalytical
chemistry support and Paul Devine and Louis-Charles Campeau
for helpful discussions. All are members of Process Research and
Development, Merck Research Laboratories.
REFERENCES
■
Scheme 5. Synthesis of Verubecestat (1) from 24
(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.
accessed Jul 11, 2016).
3) (a) 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. (b) 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.
crucial observation provided three advantages over the previous
chemistry. First, it allowed for the isolation of 25 simply by a
filtration of the crude reaction stream, obviating the need to
perform an aqueous workup or separate crystallization unit
operation. Second, 25 came out of solution in >99% purity, a
phenomenon that enabled a robust downstream isolation of 1
suitableforclinical studies. Third, thereactive crystallization of 25
phase separates the product from the remaining reaction
components, conferring a remarkable degree of stability over
the prolonged reaction times. This results in a significantly higher
yield of 25 than what was correspondingly obtained in the first-
generation synthesis. Free basing 25 with potassium carbonate
and then crystallization of the API from ethyl acetate and heptane
provides 1 in a purity suitable for clinical studies and manufacture.
The sum of this work represents a viable commercial synthesis
of verubecestat (1). The overall yield of 37% through the longest
linear sequence is over three times the 13% yield of the first-
generation route. This was achieved not only by redesigning the
route to take advantage of a key C−N coupling but also
minimizing protecting group manipulations and avoiding a chiral
salt upgrade. Further improvements were realized by developing
more robust isolations and purifications for several trans-
formations (such as the workup of sulfinyl ketimine 22 and the
guanidinylation of 24). This dramatic increase in efficiency across
theboardhasreducedthesynthesiscostof1bymorethanhalfand
enabled a much greener production going forward, as the waste
generatedinthesecond-generationsynthesisisover70%lessthan
the first.
(4)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.
(5) (a) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268.
(b) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110,
3600.
(6)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.;
(7) Fors, B. P.; Watson, D. W.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 13552.
(8)(a)Klapars, A.;Antilla, J. C.;Huang, X.;Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727. (b) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 7421.
(9) 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)ArecentreportdemonstratesthattheuseofB(OCH CF ) instead
2 3 3
of Ti(OEt) to form sulfinyl ketimines simplifies the workup protocol:
4
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.
D
Org. Lett. XXXX, XXX, XXX−XXX