Use of DOE for rapid development of a red-Al reduction process for the synthesis of 3,4-isopropylidenedioxypyrrolidine hydrotosylate

Organic Process Research and Development

Volumn 8, Issue 6, 2004, Pages 834-837

  Alimardanov, Asaf R ^a   Barrila, Mark T ^b   Busch, Frank R ^b   Carey, James J ^a   Couturier, Michel A ^b   Cui, Curtis ^a  

^a DSM Pharmaceutical Products   (Netherlands)

^b PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3,4 ISOPROPYLIDENEDIOXYPYRROLIDINE HYDROTOSYLATE; CP 368296; INGLIFORIB; PYRROLIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; DEPROTECTION REACTION; DISTILLATION; DRUG SYNTHESIS; ECONOMICS; REDUCTION; STATISTICAL ANALYSIS;

EID: 10044262124     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op040204q     Document Type: Article

References (18)

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3. (b) Hoover, D. J. Manuscript in preparation,
4. Hoover, D. J.; Hulin, B.; Martin, W. H.; Treadway, J. L. (see example no. 31) in WO 96/39385, 1996.
5. (a) Barrila, M. T.; Busch, F. R.; Couturier, M. A.; Orrill, S. L.; Rose, P. R.; Tickner, D. L.; Tobiassen, H. O.; Withbroe, G. J. WO 03/059910 Al,-2003.
6. (b) Barrila, M. T.; Busch, F. R.; Couturier, M. A.; Orrill, S. L.; Rose, P. R.; Tickner, D. L.; Tobiassen, H. O.; Withbroe, G. J. U.S. Pat. Appl. 2003/ 0187051 Al, 2003.
7. Barrila, M. T.; Busch, F. R.; Couturier, M. A.; Orrill, S. L.; Rose, P. R.; Tickner, D. L.; Tobiassen, H. O.; Withbroe, G. J. U.S. Patent 6,696,574 B2, 2004.
8. Couturier, M. A.; Andresen, B. M.; Jorgensen, J. B.; Tucker, J. L.; Busch, F. R.; Brenek, S. J.; Dubé, P.; am Ende, D. J.; Negri, J. T. Org. Process Res. Dev. 2002, 6, 42-48.
9. (e) Couturier, M. A.; Tucker, J. L.; Andresen, B. M.; Dubé, P.; Negri, J. T. Org. Lett. 2001, 3, 465-467.
10. (a) For the general hazards of borane/THF, please refer to MSDS provided from vendors such as Aldrich Chemical.
11. (b) Reisch, M. Chem. Eng. News 2002, 80, 7.
12. For borane/THF stability at 0 °C vs ambient temperature, see: Nettles, S. M.; Matos, K.; Burkhardt, E. R.; Rouda, D. R.; Corella, J. A. J. Org. Chem. 2002, 67, 2970-2976.
13. For safety warning, see: am Ende, D. J.; Vogt, P. F. Org. Process Res. Dev. 2003, 7, 1029-1033.
14. Seyden-Penne, J. Reductions by Alumina- and Borohydrides in Organic Synthesis; Wiley: New York, 1997.
15. Theoretically, 2 equiv of Red-Al is necessary for the reduction. However, excess reagent was necessary to drive the reaction to completion.
16. Investigation of the structure of the partial reduction product supported the amide or hydroxypyrrolidine; in either case, the excess Red-Al continues the reduction to the desired product.
17. Evaluation of the bulk cost of borane/THF and Red-Al in toluene showed that the cost per hydride equivalent was 4-5 times higher with borane/ THF.
18. Due to the relative size of the reaction vessels, two lots of compound 3 were prepared and combined for use in this procedure.