Organic Process Research & Development
Article
Z.; Mergott, D. J. J. Neurosci. 2015, 35, 1199−1210. (b) Mergott, D. J.;
Vaught, G. M. BACE Inhibitors, US 2012/8278441.
(2) Use of an oxime to generate a nitrone intermediate via
tautomerization of the OH proton to nitrogen is a variant of the
classical nitrone cycloaddition, see: (a) Noguchi, M.; Okada, H.;
Nishimura, S.; Yamagata, Y.; Takamura, S.; Tanaka, M.; Kakehi, A.;
Yamamoto, H. J. Chem. Soc., Perkin Trans. 1 1999, 185−191. (b) Rincon,
́
J. A.; Mateos, M.; Garcia-Losada, P.; Mergott, D. J. Org. Process Res. Dev.
2015, 19, 347.
(3) Hansen, M. M.; Jarmer, D. J.; Arslantas, E.; DeBaillie, A. C.;
Frederick, A. L.; Harding, M.; Hoard, D. W.; Hollister, A.; Huber, D.;
Kolis, S. P.; Kuehne-Willmore, J. E.; Kull, T.; Laurila, M. E.; Linder, R. J.;
Martin, T.; Martinelli, J. R.; McCulley, M. J.; Richey, R. N.; Ward, J. A.;
Zaborenko, N.; Zweifel, T. Org. Process Res. Dev. 2015, DOI: 10.1021/
(4) (a) Pellisier, H. Tetrahedron 2007, 63, 3235−3285. (b) Jørgensen,
K. A. Chem. Rev. 1998, 98, 863−909. (c) For a review on non-
asymmetric nitrone cycloadditions, see: Confalone, P. N.; Huie, E. M.
Org. React. 1988, 36, 1−173.
(5) (a) Amado, A. F.; Kouklovsky, C.; Yves Langlois, Y. Synlett 2005,
103−106. Phenylglycinol derived chiral nitrones generated from
aldehydes containing a pendant olefin are also known in the literature,
but no examples using ketones as we require were found. See: (b) Zhao,
Q.; Han, F.; Romero, D. L. J. Org. Chem. 2002, 67, 3317−3322.
(c) Hanselmann, R.; Zhou, J.; Ma, P.; Confalone, P. N. J. Org. Chem.
2003, 68, 8739−8741.
(6) The nitrile rather than the orthoester was a suitable precursor to the
nitrone intermediate. Cycloaddition occurred under conditions of the
condensation between the nitrile and hydroxylamine.
removed by distillation at 50 °C until approximately 600 kg of
distillate was collected. 2-Methyltetrahydrofuran was added at
<35 °C and the mixture was transferred to a workup vessel. The
organic layer was washed sequentially with a solution of citric
acid (837 kg) in H2O (1200 kg), KHCO3(246 kg) in H2O (750
kg), and 315 kg of H2O. Solvent was removed by vacuum
distillation at 35−50 °C until approximately 1300 kg of distillate
was collected. Nondenatured EtOH (94%, 1,021 kg) was added
to the mixture, and approximately 900 kg of distillate was
removed. Another 1021 kg of EtOH was added, and
approximately 1243 kg of distillate was removed. The mixture
was cooled to 25 °C over 1 h to afford a slurry. The slurry was
cooled to −10 to −5 °C over 3 h, and held for 2−3 h. The solids
were collected by filtration, washed with −10 °C EtOH (2 × 102
kg) and dried under vacuum to afford a white solid. The average
yield of 19 over eight batches was approximately 69%.
Telescoping over two steps led to some uncertainty in the
solution yield at the ketone stage, so a more accurate 55% average
yield was calculated from the Weinreb amide 2 (990 kg) over two
steps to cycloadduct 19 (1395 kg). HPLC purity ranged from
99.95−100 area %. Assay = 99.4−100.6 wt%. Titanium < 0.05 wt
% (ICP). Mp 92 °C. HPLC Method A tR = 4.74 min, minor
diastereomer = 4.58 min. 1H NMR (DMSO-d6) δ 7.33 (td, J =
3.1, 8.4 Hz, 1H), 7.09−7.03 (m, 1H), 7.06−7.00 (m, 3H), 7.04−
6.99 (m, 2H), 6.94 (dd, J = 2.1, 6.7 Hz, 1H), 4.16 (s, 1H), 4.17−
4.11 (m, 1H), 4.01−3.94 (m, 1H), 3.90 (t, J=8.2 Hz, 1H), 3.71−
3.65 (m, 1H), 3.70−3.64 (m, 1H), 3.67 (br s, 1H), 3.29−3.23 (m,
1H), 2.09−2.00 (m, 1H), 1.61−1.51 (m, 1H), 0.51 (t, J = 7.5 Hz,
3H). 13C NMR (DMSO-d6) δ 159.53 (d, J = 248.1 Hz, 1C),
139.49 (s, 1C), 131.53 (d, J = 9.1 Hz, 1C), 131.25 (d, J = 4.8 Hz,
1C), 130.76 (d, J = 12.0 Hz, 1C), 128.09 (s, 2C), 127.38 (s, 2C),
127.13 (s, 1C), 118.12 (d, J = 25.4 Hz, 1C), 115.69 (d, J = 2.9 Hz,
1C), 77.79 (d, J = 5.3 Hz, 1C), 72.63 (s, 1C), 70.99 (s, 1C), 69.52
(s, 1C), 67.03 (s, 1C), 58.38 (s, 1C), 27.63 (s, 1C), 9.88 (s, 1C) .
HRMS (ESI+): calcd. for C20H22O2BrFN [M + H+] 406.0812;
found 406.0804.
(7) Patel, I.; Smith, N. A.; Tyler, S. N. G. Org. Process Res. Dev. 2009, 13,
49−53.
(8) The reaction was complete in ∼5 h using bromoacetonitrile. When
chloroacetonitrile was used, the reaction was <20% complete at 5 h.
(9) (a) The second generation route was developed based on the
following literature precedents: Grundke, G.; Keese, W.; Rimpler, R.
Synthesis 1987, 1115−1116. (b) Wovkulich, P. M.; Uskokovic, M. R.
Tetrahedron 1985, 41, 3455−3462. (c) Polonski, T.; Chimiak, A.
Tetrahedon Lett. 1974, 15, 2453−2456.
(10) (a) Taillier, C.; Hameury, T.; Bellosta, B.; Cossy, J. Tetrahderon
2007, 63, 4472−4490. (b) Hiersemann, M. Synthesis 2000, 1279−1290.
(c) Olier, C.; Azzi, N.; Bil, G.; Gastaldi, S.; Bertrand, M. P. J. Org. Chem.
2008, 73, 8469−8473.
(11) Audia, J. E.; Mergott, D. J.; Shi, C. E.; Vaught, G. M.; Watson, B.
M.; Winneroski, L. L. Preparation of Fused Aminothiazine Derivatives
as BACE Inhibitors and Useful in the Treatment of Alzheimer’s Disease.
WO2011005738, January 13, 2011.
AUTHOR INFORMATION
■
Corresponding Author
Present Address
Lukas Brandli: Arisdorferstrasse 68b, 4410 Liestal, Switzerland;
̈
̈
(12) Jiminez-Gonzalez, C.; Ponder, C. S.; Broxterman, Q. B.; Manley,
Adrienne Hollister: 1314 1/2 6th Ave, Tacoma, WA 98405;
J. B. Org. Process Res. Dev. 2011, 15, 912−917.
Dominique Huber: Gassli 9, 5603 Staufen, Switzerland; Jeffrey
̈
(13) Himer, S.; Kirchner, D. K.; Somfai, P. Eur. J. Org. Chem. 2008, 33,
5583−5589.
Ward: 7274 Eagle Road, Indianapolis, IN 46278, United States.
(14) Koshti, N.; Reddy, G. V.; Jacobs, H.; Gopalan, A. Synth. Commun.
2002, 3779−3790.
Notes
The authors declare no competing financial interest.
(15) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(b) Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008, 3707−3738.
(16) For a general review on Directed Ortho Metalations, see Snieckus,
V. Chem. Rev. 1990, 90, 879−933.
ACKNOWLEDGMENTS
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We thank these individuals for project support at Eli Lilly:
Christopher Doecke, Paul Dodson, Robert Forbes, William J.
Hornback, Adam McFarland, Curtis Miller, Shankarraman
Vaidyaraman, and Shekhar Viswanath. We thank these
(17) Kaku, Y.; Tsuruoka, A.; Kakinuma, H.; Tsukada, I.; Yanagisawa,
M.; Naito, T. Chem. Pharm. Bull. 1998, 46, 1125−1129.
(18) We examined the morpholine amide analog of Weinreb amide 2
as well, but yields were inferior, perhaps due to deprotonation of the
electrophile. These reactions required the use of chromatography to
purify the ketone 3, and yields were low (50%) compared to the typical
yield obtained using 2 (75−80% without chromatography). Potential
safety issues with the use of Weinreb amides are known, but were
deemed acceptable due to the poor behavior of the morpholine amide.
See: Jackson, M. M.; Leverett, C.; Toczko, J. F.; Roberts, J. C. J. Org.
Chem. 2002, 67, 5032−5035.
́
individuals for project support at Dottikon: Andre Aebi.
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Org. Process Res. Dev. XXXX, XXX, XXX−XXX