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Organic Process Research & Development
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6 Zeng, X.; Gao, J.; Song, J. J.; Ma, S.; Desrosiers, J.ꢀN.; Mulder, J. A.; Rodriguez, S.; Herbage, M. A.; Haddad, N.; Qu, B.;
Fandrick, K. R.; Grinberg, N.; Lee, H.; Wei, X.; Yee, N. K.; Senanayake, C. H. Angew. Chem., Int. Ed. 2014, 53, 12153–
12157.
7 Fandrick, K. R.; Patel, N. D.; Mulder, J. A.; Gao, J.; Konrad, M.; Archer, E.; Buono, F. G.; Duran, A.; Schmid, R.;
Daeubler, J.; Fandrick, D. R.; Ma, S.; Grinberg, N.; Lee, H.; Busacca, C. A.; Song, J. J.; Yee, N. K.; Senanayake, C. H. Org.
Lett. 2014, 16, 4360–4363.
8 The following referenced book chapter tells the larger story of the development of FLAP inhibitor 1: Fandrick, K.; Mulder,
J.; Desrosiers, J.ꢀN.;Patel, N.; Zeng, X.; Fandrick, D.; Busacca, C. A.; Song, J. J.; Senanayake, C. H. Development of an
Efficient Asymmetric Synthesis of the Chiral Quaternary 5ꢀLipoxygenase Activating Protein Inhibitor. In Comprehensive
Accounts of Pharmaceutical Research and Development: From Discovery to LateꢀStage Process Development Volume 1;
AbdelꢀMagid, A. F.; Pesti, J.; Vaidyanathan, R., Ed.; ACS Symposium Series; American Chemical Society: Washington,
DC, 2016; Chapter 5; pp 121–146.
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9 Fandrick, K. R.; Mulder, J. A.; Patel, N. D.; Gao, J.; Konrad, M.; Archer, E.; Buono, F. G.; Duran, A.; Schmid, R.;
Daeubler, J.; Desrosiers, J.ꢀN.; Zeng, X.; Rodriguez, S.; Ma, S.; Qu. B.; Li, Z.; Fandrick, D.; Grinberg, N.; Lee, H.; Bosanac,
T.; Takahashi, H.; Chen, Z.; Bartollozi, A.; Nemeto, P.; Busacca, C.; Song, J. J.; Yee, N. K.; Mahaney, P. E.; Senanayake, C.
H. J. Org. Chem. 2015, 80, 1651–1660.
10 Takahashi, H; Bartolozzi, A.; Simpson, T. Discovery of the Novel OxadiazoleꢀContaining 5ꢀLipoxygenase Activating
Protein (FLAP) Inhibitor BI 665915. In Comprehensive Accounts of Pharmaceutical Research and Development: From
Discovery to LateꢀStage Process Development Volume 1; AbdelꢀMagid, A. F.; Pesti, J.; Vaidyanathan, R., Ed.; ACS
Symposium Series; American Chemical Society: Washington, DC, 2016; Chapter 4; pp 101–119.
11 White, C.; Burnett, J. Journal of Chromatography A 2005, 1074, 175–185.
12 Bretherick, L. Bretherick's Handbook of Reactive Chemical Hazards, 4th ed.; Butterworths: Boston, 1990; 1233ꢀ1234.
13 a) Miyaura, N.; Yamada, K. ; Suzuki, A. Tetrahedron Letters 1979, 20 (36), 3437–3440; b) Miyaura, N.; Suzuki, A. Chem.
Rev. 1995, 95, 2457–2483.
14 Grignard, V. C. R. Acad. Sci. 1900, 130, 1322–1324.
15 a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333–3336; b) Bao, R.; Zhao, R.; Shi, L. Chem. Commun.
2015, 51, 6884–6900.
16 Rajagopal, G.; Kim, S.ꢀS. Tetrahedron Lett. 2009, 65, 4351–4355.
17 The use of pressure reduced the reaction time to 10ꢀ12 h from 24ꢀ72 h. While the nitrile consumption was complete after
24 h at atmospheric pressure, the conversion of the last 5ꢀ10% of intermediate primary amide to acid 9 typically required
extended reaction times.
18
The typical purity of crude 9 was ~85 LCAP. The majority of the impurities were nonꢀpolar and the DCA salt
crystallization was quite powerful leading to isolated 9ꢀDCA in >98.5 LCAP.
19 a) Liu, K.ꢀC.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45, 3916–3918; b) Menzel, K.; Machrouhi, F.; Bodenstein,
M.; Alorati, A.; Cowden, C.; Gibson, A.; Bishop, B.; Ikemoto, N.; Nelson, T. D.; Kress, M. H.; Frantz, D. E. Org. Process
Res. Dev. 2009, 13, 519–524.
20 For an optimized synthesis of the free boronic acid see: Patel, N. D.; Zhang, Y.; Gao, J.; Sidhu, K.; Lorenz, J.; Fandrick, K.
R.; Mulder, J. A.; Herbage, M. A; Li, Z.; Ma, S.; Lee; H. Grinberg, N., Song, J. J.; Busacca, C. A., Yee, N. K.; Senanayake,
C. H. Org. Process Res. Dev. 2016, 20, 95−99.
21 0.20 mol% was used for scaleꢀup. (compared with ~10 mol% required for the first strategy).
22 a) Villa, M.; Cannata, V. PCT Int. Appl. WO 1998/051646. b) Königsberger, K.; Chen, G.ꢀP.; Wu, R. R.; Girgis, M. J.;
Prasad, K.; Repič, O.; Blacklock, T. J.Org. Process Res. Dev. 2003, 7, 733–742.
23 No backꢀextractions were required; however, four water washes were needed to remove residual imidazole and DMF from
the organic layer.
24 Despite being an alkylating agent, alkyl chloride 19 did not raise a flag during the initial in silico genotoxicity assessment.
Because of its high water solubility and reactivity it should not remain with the product after the aqueous workꢀup, and any
carryꢀover should be removed in the EtOH/water recrystallization.
25 Olah, G. A.; Prakash, K. S.; Liang, G. J. Org. Chem. 1977, 46, 2666–2671.
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