A mechanistic insight into a simple c-n bond formation via sn2 displacement: A synergistic kinetics and design of experiment approach

Organic Process Research and Development

Volumn 14, Issue 6, 2010, Pages 1364-1372

  Massari, Luca ^a   Panelli, Laura ^a   Hughes, Mark ^b   Stazi, Federica ^a   Maton, William ^a   Westerduin, Pieter ^a   Scaravelli, Federico ^a   Bacchi, Sergio ^a  

^a GSK   (Italy)

^b GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BOND FORMATION; CHEMICAL DEVELOPMENT; DESIGN SPACES; HALIDE DERIVATIVES; KINETIC MODELS; NOVEL SERIES; REACTION CONDITIONS; RECEPTOR ANTAGONISTS; RELIABILITY AND ROBUSTNESS;

CHEMICAL BONDS; HEXANE; ORGANIC POLYMERS;

DESIGN OF EXPERIMENTS;

EID: 78649684441     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op100176u     Document Type: Article

References (25)

1. Micheli, F.; Arista, L.; Bonanomi, G.; Blaney, E. F.; Braggio, S.; Capelli, A. M.; Checchia, A.; Damiani, F.; Di-Fabio, R.; Fontana, S.; Gentile, G.; Griffante, C.; Hamprecht, D.; Marchioro, C.; Mugnaini, M.; Piner, J.; Ratti, E.; Tedesco, G.; Tarsi, L.; Terreni, S.; Worby, A.; Ashby Jr, C. R.; Heidbreder, C. J. Med. Chem. 2010, 53, 374-391
2. Arista, L.; Bonanomi, G.; Capelli, A. M.; Damiani, F.; Di-Fabio, R.; Gentile, G.; Hamprecht, D.; Micheli, F.; Tarsi, L.; Tedesco, G.; Terreni, S. PCT Int. Appl. WO/2005/080382, 2005.
3. Bonanomi, G.; Checchia, A.; Fazzolari, E.; Hamprecht, D.; Micheli, F.; Tarsi, L.; Terreni, S. PCT Int. Appl. WO/2006/108701, 2006.
4. Arista, L.; Cardullo, F.; Cecchia, A.; Hamprecht, D.; Micheli, F.; Tedesco, G.; Terreni, S. PCT Int. Appl. WO/2006/133946, 2006.
5. The ICH Guidance Q8 represents the U.S. Food and Drug Administration (FDA) current thinking on Pharmaceutical Development manufacturing process. This guidance describes the suggested contents to input in a regulatory submission providing an opportunity to present the knowledge gained through the application of scientific approaches and quality risk management to the development of a product and its manufacturing process. This guidance is part of a set of Guidance for Industry developed within the Expert Working Group (Quality) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
6. ICH Q8 Pharmaceutical Development, (R2); U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Rockville, MD, Aug 2009.
7. Iwakubo, M.; Takami, A.; Okada, Y.; Kawata, T.; Tagami, Y.; Sato, M.; Sugiyama, T.; Fukushima, K.; Taya, S.; Amano, M.; Kaibuchi, K.; Iijima, H. Bioorg. Med. Chem. Lett. 2007, 15, 1022-1033
8. Lavrador, K.; Murphy, B.; Saunders, J.; Struthers, S.; Wang, X.; Williams, J. J. Med. Chem. 2004, 47, 6864-6874
9. Kumar, N.; Kaur, K.; Aeron, S.; dharmarajan, S.; Silamkoti, A. D. V.; Metha, A.; Gupta, S.; Chugh, A.; Gupta, J. B.; Salman, M.; Palle, V. P.; Cliffe, I. A. Bioorg. Med. Chem. Lett. 2007, 17, 5256-5260
10. In addition to the four chosen factors, two more parameters can be identified: the amount of DMSO and temperature ramp. The first one was fixed at four volumes to maximize the inter-molecular/intra-molecular ratio considering the restriction due to the minimum stirrable volume in SK233. The temperature ramp was judged influent if compared with the typical 18 h reaction time.
11. The Half-Normal Probability Plot is a graphical tool that helps assess which factors are important and which should not be considered as significant. Such a diagnostic tool that is used to assess whether the coefficient estimates come from a normal distribution with mean = 0 and variance = ς. If it is the case, all the estimations should lie close to a straight line. This means that no coefficient estimation is significantly different from 0. Otherwise, a departure from the straight line might suggest that the coefficient could be different from 0.
12. Derringer, G.; Suich, R. J. Qual. Tech. 1980, 12, 214-219
13. Hunter, J. S. J. Qual. Tech. 1999, 31, 54-57
14. Peterson, J. J. J. Biopharm. Stat. 2008, 18, 959-975
15. Carlson, R.; Axelsson, A. K.; Nordahl, A.; Barth, T. J. Chemom. 1993, 7, 341-367
16. Kanemasa, S.; Nakamura, S.; Kajigaeshi, S. Chem. Lett. 1980, 947-950
17. Barton, D. H. R.; Bushmann, E.; Hauesler, J.; Holzapfel, C. W.; Sheradksy, T.; Taylor, D. A. J. Chem. Soc., Perkin Trans. 1 1977, 9, 1107-1114
18. Gonzales-Rosende, M. E.; Olivar, T.; Castillo, E.; Sepulveda-Arques, J. J. Arch. Pharm. Chem. Life Sci. 2008, 341, 690-695
19. Guliyev, R.; Buyukcakir, O.; Sozmen, F.; Bozdemir, O. A. Tetrahedron Lett. 2009, 50, 5139-5141
20. Tu, C.; Osborne, E. A.; Louie, A. Y. Tetrahedron 2009, 65, 1241-1246
21. Vasse, J. L.; Levacher, V.; Bourguignon, J.; Dupas, G. Tetrahedron 2003, 59, 4911-4921
22. The Advantage Series 3400 process chemistry workstation provided by Argonaut, is a computer-controlled, automated multi-reactor system designed to offer an increased amount of information in respect to standard manual chemistry. Process parameters can be measured, monitored, controlled, and recorded making use of basic reactor automation.
23. DynoChem is a set of software tools for process design, characterisation, optimisation and scale-up based on first principles of chemical engineering and physical organic chemistry. The software contains tools designed for the pharmaceutical chemists and engineers, and it is accessible through a Microsoft Excel interface. For further information visit http://www.scale-up.com.
24. To build the kinetic model, we had to focus on the compounds that had been identified and characterised: starting materials 4 and 5, product 1, and main impurities 6 and 7. The reaction volume was calculated, assuming a density = 1 mg/mL. The response factor of 7 was not measured because an analytical marker was not available; however, considering that 7 is a strictly related isomer of 1, we assumed it had the same response factor as the main product. Finally we observed a 5% mass imbalance, but we did not impose normalisation by attributing the missing mass to 7, that in this way becomes a general indicator of the purity of the reaction.
25. The data relative to the chlorine-mediated pathway resulted in being more accurate because they were directly measured. The equilibrium constant of the halogen exchange was imposed on the base of in-house knowledge. The data relative to the iodine-mediated pathway were less accurate because the input data were obtained by finding the differences between those of the chlorine-mediated pathway. For this reason the absolute value of the kinetic constant and activation energy of the iodine-mediated chemistry was considered as soft data, whereas the ratio between the two was still valid, i.e. the activation energy of the cyclisation of 8 was 20 KJ/mol higher that the activation energy of the reaction of 8 with 5 to give 1, whatever its absolute value was. This lack of accuracy on the rate constant and activation energy of the iodine-mediated chemistry didnt affect the overall output of the kinetics model because these two steps were not rate determining, they were the fastest of the entire set.