Process improvements for the preparation of kilo quantities of a series of isoindoline compounds

Organic Process Research and Development

Volumn 7, Issue 4, 2003, Pages 521-532

  Watson, Timothy J ^a,b   Ayers, Timothy A ^a,c   Shah, Nik ^a,d   Wenstrup, David ^a,d   Webster, Mark ^a,e   Freund, David ^a,d   Horgan, Stephen ^a,d   Carey, James P ^a,f  

^a SANOFI   (France)

^b PFIZER INC   (United States)

^c Aventis   (United States)

^d Chemical Development Department   (United States)

^e PROCTER AND GAMBLE COMPANY   (United States)

^f MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HMR 2543; HMR 2651; HMR 2934; ISOINDOLE DERIVATIVE; LITHIUM DERIVATIVE; METHYL 3 BENZYLOXY 2 TRIFLUOROMETHANESULFONATOPROPIONATE; PHTHALIMIDE DERIVATIVE; PIPERAZINE DERIVATIVE; PROPIONIC ACID DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; ATTENTION DEFICIT DISORDER; CHIRALITY; DRUG SYNTHESIS; ENANTIOSELECTIVITY; OBSESSIVE COMPULSIVE DISORDER;

EID: 0042244428     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op020225p     Document Type: Article

References (13)

1. For a recent review of isoxazole chemistry, see: Bonnett, R.; North, S. A. The Chemistry of Isoindoles. In Advances in Heterocyclic Chemistry; Katritzky, A. R., Boulton, A. J., Eds.; Academic Press: New York, 1981; Vol 29, p 341.
2. For a description of earlier work done on the indazole synthesis, see: (a) Hendrix, J. A.; Shimshock, S. J.; Shutske, G. M.; Tomer, J. D., IV; Kapples, K. J.; Palermo, M. G.; Corbett, T. J.; Vargas, H. M.; Kafka, S.; Brooks, K. M.; Laws-Ricker, L.; Lee, D. K. H.; de Lannoy, I.; Bordeleau, M.; Rizkalla, G.; Owolabi, J.; Kamboj, R. K. ChemBioChem 2002, 3, 999. (b) Leroy, V.; Lee, G. E.; Lin, J.; Herman, S. H.; Lee, T. B. Org, Process Res. Dev. 2001, 5, 179. (c) Strupczewski, J. T.; Bordeau, K. J. U.S. Patent 4,954,503, 1990.
3. For a description of earlier work done on the indazole synthesis, see: (a) Hendrix, J. A.; Shimshock, S. J.; Shutske, G. M.; Tomer, J. D., IV; Kapples, K. J.; Palermo, M. G.; Corbett, T. J.; Vargas, H. M.; Kafka, S.; Brooks, K. M.; Laws-Ricker, L.; Lee, D. K. H.; de Lannoy, I.; Bordeleau, M.; Rizkalla, G.; Owolabi, J.; Kamboj, R. K. ChemBioChem 2002, 3, 999. (b) Leroy, V.; Lee, G. E.; Lin, J.; Herman, S. H.; Lee, T. B. Org, Process Res. Dev. 2001, 5, 179. (c) Strupczewski, J. T.; Bordeau, K. J. U.S. Patent 4,954,503, 1990.
4. For a description of earlier work done on the indazole synthesis, see: (a) Hendrix, J. A.; Shimshock, S. J.; Shutske, G. M.; Tomer, J. D., IV; Kapples, K. J.; Palermo, M. G.; Corbett, T. J.; Vargas, H. M.; Kafka, S.; Brooks, K. M.; Laws-Ricker, L.; Lee, D. K. H.; de Lannoy, I.; Bordeleau, M.; Rizkalla, G.; Owolabi, J.; Kamboj, R. K. ChemBioChem 2002, 3, 999. (b) Leroy, V.; Lee, G. E.; Lin, J.; Herman, S. H.; Lee, T. B. Org, Process Res. Dev. 2001, 5, 179. (c) Strupczewski, J. T.; Bordeau, K. J. U.S. Patent 4,954,503, 1990.
5. Tetrazene 9 becomes the major product if the mode of addition is reversed. The amount of tetrazene 9 formed was not typically quantified, as it readily precipitates during sample preparation for analyses.
6. 3N has been described to promote tetrazene formation; see: Shawali, A. S.; Fahmi, A.-G. A. J. Heterocycl. Chem. 1977, 14, 1089.
7. For leading references for the oxidation of isoindolines to isoindoles, see: Kreher, R. P.; Herd, K. J. Chem. Ber., 1988, 121, 1827. Kreher, R.; Kohl, N.; Use, G. Angew. Chem.; GE 1982, 94, 634-635.
8. For leading references for the oxidation of isoindolines to isoindoles, see: Kreher, R. P.; Herd, K. J. Chem. Ber., 1988, 121, 1827. Kreher, R.; Kohl, N.; Use, G. Angew. Chem.; GE 1982, 94, 634-635.
9. The use of the soluble LAH•2THF species in scale-up is our preferred reducing agent. It is easy to handle, and issues with slurries are avoided. In addition, the workup to remove the aluminum salts is easily accomplished.
10. The extent of aziridinium formation in this process will be discussed in a subsequent publication describing an alternative synthesis involving an aziridinium approach for the preparation of compounds 2 and 3.
11. For a recent review of isoxazole chemistry, see: Guartieri, F.; Gianella, M. 1,2-Benzisoxazoles. In The Chemistry of Heterocycles; Grunanger, P., Vita-Finzi, P., Eds.; Isoxazoles, Vol. 49 Part 2; John Wiley & Sons: New York, 1999; Chapter 1.
12. Strupczewski, J. T.; Allen, R. C.; Gardner, B. A.; Schmid, B. L.; Stache, U.; Glamkowski, E. J.; Jones, M. C.; Ellis, D. B.; Huger, F. P.; Dunn, R. W. J. Med. Chem. 1985, 28, 761. Strupczewski, J. T.; Gardner, B. A.; Allen, R. C. U.S. Patent 4,355,037, 1982.
13. Strupczewski, J. T.; Allen, R. C.; Gardner, B. A.; Schmid, B. L.; Stache, U.; Glamkowski, E. J.; Jones, M. C.; Ellis, D. B.; Huger, F. P.; Dunn, R. W. J. Med. Chem. 1985, 28, 761. Strupczewski, J. T.; Gardner, B. A.; Allen, R. C. U.S. Patent 4,355,037, 1982.