Investigation of an alternative route to ZD3638 and cost-benefit analysis comparison of raw materials with the previous route

Organic Process Research and Development

Volumn 5, Issue 5, 2001, Pages 491-497

  Moseley, Jonathan D ^a   Moss, William O ^a   Welham, Matthew J ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0035537539     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op0000935     Document Type: Article

References (21)

1. Sunagawa, M.; Sato, H.; Katsube, J.; Yamamoto, H. Chem. Pharm. Bull. 1979, 27, 1806. Zeneca modifications to this route on scale-up to be reported in this journal in due course.
2. For reviews see: Zhao, S. H.; Samuel, O.; Kagan, H. B. Tetrahedron 1987, 43, 5135-5144. Kagan, H. B. Asymmetric Oxidation of Sulphides. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; pp 203-226.
3. For reviews see: Zhao, S. H.; Samuel, O.; Kagan, H. B. Tetrahedron 1987, 43, 5135-5144. Kagan, H. B. Asymmetric Oxidation of Sulphides. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; pp 203-226.
4. Moss, W. O. Zeneca internal 6-monthly report, January-July, 1997.
5. Robinson, G. E. Zeneca internal 6-monthly reports (three), July, 1993, to December, 1994.
6. Gungor, T.; Marsais, F.; Queguiner, G. J. Organomet. Chem. 1981, 215, 139.
7. Weidmann, B.; Widler, L.; Olivero, A. G.; Maycock, C. D.; Seebach, D. Helv. Chim. Acta 1981, 64, 357.
8. Dimitrov, V.; Kostova, K.; Genov, M. Tetrahedron Lett. 1996, 37, 6787 and references therein.
9. The Research Department had investigated the use of this intermediate and had indeed encountered problems with removal of the benzyl group later in the synthesis.
10. CBz piperidone had been required for a previous compound (ZD7944) and was potentially available from Ubichem on the scale required.
11. The figures were put through Zeneca's in-house "Procost" system, an Excel-based software package, to generate the predicted raw material production costs.
12. Gribble, G. W.; Saulnier, M. G. Tetrahedron Lett. 1980, 21, 4137.
13. Encyclopaedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; John Wiley and Sons; Chichester, 1995.
14. Bradlee, M. J.; Helquist, P. Org. Synth. 1997, 74, 137.
15. Marsais, F.; Granger, P.; Queguiner, G. J. Org. Chem. 1981, 46, 4494.
16. Trecourt, F.; Marsais, F.; Gungor, T.; Queguiner, G. J. Chem. Soc., Perkin Trans. 1 1990, 2409.
17. Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35, 151.
18. Comins, D. L.; Myoung, Y. C. J. Org. Chem. 1990, 55, 292.
19. For example, 3-alkoxypyridines have been successfully ortho-lithiated, but the results were poor for a limited study on the comparable 2-substituted series: Marsais, F.; Queguiner, G. Tetrahedron 1983, 39, 2009.
20. There was some evidence that ZD3638 fluoropyridine sublimed under reduced pressure (e.g., on concentration), and this may have led to mechanical losses that would have been exaggerated on the small scale.
21. Ramp rate 5 °C /min. Actual mp in the range 131-134 °C as determined by slow ramp (<1 °C /min) on hot-stage melting point apparatus; see Experimental Section.