Organic Process Research & Development
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Itoh, T.; Xie, C.; Wen, X.; Zhao, D.; Muzzio, D. J.; Bassan, E. M.; Shultz, C. S. Org.
Process Res. Dev. 2012, 16, 1069–1081. (d) Tudhope, S. R.; Bellamy, J. A.; Ball, A.;
Rajasekar, D.; AzadiꢀArdakani, M.; Meera, H. S.; Gnanadeepam, J. M.; Saiganesh, R.;
Gibson, F.; He, L.; Behrens, C. H.; Underiner, G.; Marfurt, J.; Favre, N. Org. Process
Res. Dev. 2012, 16, 635–642. (e) Deerberg, J.; Prasad, S. J.; Sfouggatakis, C.; Eastgate,
M. D.; Fan, Y.; Chidambaram, R.; Sharma, P.; Li, L.; Schild, R.; Müslehiddinoğlu, J.;
Chung, H.ꢀJ.; Leung, S.; Rosso, V. Org. Process Res. Dev. 2016, 20, 1949–1966. (f)
Smith, M. J.; Lawler, M. J.; Kopp, N.; McLeod, D. D.; Davulcu, A. H.; Lin, D.;
Katipally, K.; Sfouggatakis, C. Org. Process Res. Dev. 2017, 21, 1859–1863.
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9. For the use of flow chemistry to derisk process safety liabilities associated with the
Curtius rearrangement, see: (a) Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.;
Wittkamp, B.; Goode, J. G.; Gaunt, N. L. Org. Process Res. Dev. 2010, 14, 393–404. (b)
Filipponi, P.; Ostacolo, C.; Novellino, E.; Pellicciari, R.; Gioiello, A., Org. Process Res.
Dev. 2014, 18, 1345–1353. (c) Marsini, M. A.; Buono, F. G.; Lorenz, J. C.; Yang, B.ꢀS.;
Reeves, J. T.; Sidhu, K.; Sarvestani, M.; Tan, Z.; Zhang, Y.; Li, N.; Lee, H.; Brazzillo, J.;
Nummy, L. J.; Chung, J. C.; Luvaga, I. K.; Narayanan, B. A.; Wei, X.; Song, J. J.;
Roschangar, F.; Yee, N. K.; Senanayake, C. H. Green Chem. 2017, 19 (6), 1454–1461.
1
0. The processing of 5ꢀmethylpyrazineꢀ2ꢀcarboxylic acid (3) to 2ꢀaminoꢀ5ꢀmethylpyrazine
1) using the sequence shown in Scheme 4 was found not to meaningfully reject
(
impurities arising from pyrazineꢀ2ꢀcarboxylic acid in the starting material. This led to an
acceptance criterion (provisionally 0.20 LC area percent) being placed on the level of
pyrazineꢀ2ꢀcarboxylic acid in 5ꢀmethylpyrazineꢀ2ꢀcarboxylic acid (3).
1
1. Taylor, E. C.; Perlman, K. L.; Sword, I. P.; SequinꢀFrey, M.; Jacobi, P. A. J. Am. Chem.
Soc. 1973, 95, 6407−6412.
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2. AlbanezeꢀWalker, J.; Zhao, M.; Baker, M. D.; Dormer, P. G.; McNamara, J. Tet
.
Lett. 2002, 43, 6747 6750.
−
3. Diaz, F.; Farouz, F. S.; Holcomb, R.; Kesicki, E. A.; Ooi, H. C.; Rudolph,
A.; Stappenbeck, F.; Thorsett, E.; Gaudino, J. J.; Fischer, K. L.; Cook, A. W. Heteroaryl
urea derivatives useful for inhibiting chk1. WO 2006105262, Oct 05, 2006.
1
4. Itoh, T.; Maeda, K.; Wada, T.; Tomimoto, K.; Mase, T. Tetrahedron Lett. 2002, 43
,
9287–9290.
15. Craven, A. Inst. Chem. Eng. Symp. Ser. 1982, 102, 97–111.
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6. The DPPA was produced inhouse. Wolff, O.; Waldvogel, S. R. Synthesis 2004,
305.
8, 1303–
1
7. Ende, D. J.; DeVries, K. M.; Clifford, P. J.; Brenek, S. J. Org. Process Res. Dev. 1998,
82–392.
2,
3
8. A protective basis of safety for use with dedicated equipment could have involved
appropriate ventꢀsizing for the vessel feed tank and reactor in order to prevent
overpressurization.
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