Development of a practical synthesis of the progesterone receptor antagonist 4-{[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-2,6- dimethylbenzo-nitrile

Organic Process Research and Development

Volumn 13, Issue 5, 2009, Pages 848-853

  Bradley, Paul A ^a   De Koning, Pieter D ^a   Johnson, Patrick S ^a   Lecouturier, Yann C ^a   McManus, David J ^a   Robin, Aurelie ^a   Underwood, Toby J ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 70449432692     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op900110k     Document Type: Article

References (12)

1. Bradley, P. A.; Dack, K. N.; Johnson, P. S.; Skerratt, S. E. U.S. Patent Application US 2007/0105909 A1, 2007.
2. Dack, K. N.; Gibson, K. R.; Skerratt, S. E. Patent Application WO 2008/047224 A1, 2008.
3. Moguilewsky, M.; Philibert, D. J. Steroid Biochem. 1984, 20, 271.
4. Teutsch, G.; Ojasoo, T.; Raynaud, J. P. J. Steroid Biochem. 1988, 31, 549.
5. Song, L.-N.; Coghlan, M.; Gelmann, E. P. Mol. Endocrinol. 2004, 18,70.
6. Cannon, G. W.; Whidden, H. L. J. Org. Chem. 1952, 17, 685.
7. Dabbagh, H. A.; Bagheri, A. J. Chem. Res. 2005, 202.
8. Janzen, A. F.; Lypka, G. N.; Wasylishen, R. E. Can. J. Chem. 1980, 58, 60.
9. A literature search indicated that pyrazole salts with strong acids were known, so the following acids were screened in a selection of solvents: hydrochloric, hydrobromic, sulfuric, phosphoric, p-toluenesulfonic, benzenesulfonic, methanesulfonic, and ethylenedisulfonic.
10. McCarthy, J. R.; Matthews, D. P.; Paolini, J. P. Organic Syntheses; Wiley: New York, 1998; Collect. Vol.9, p 446.
11. The Oxone was added portionwise to a solution of the free base 6 in aqueous methanol, and a thick slurry comprising a mixture of the starting material 6, product 8, and Oxone salts was formed. The risk of product entrainment and thus incomplete reaction was considered too high for the process to be practical. Addition of an aqueous Oxone solution to a methanol solution of 6 resulted in immediate precipitation of a slurry, posing the same risks.
12. Hirt, H.; Haenggi, R.; Reyes, J.; Seeger-Weibel, M.; Gallou, F. Org. Process Res. Dev. 2008, 12, 111.