Development of a multigram asymmetric synthesis of 2-(R)-2-(4,7,10-tris tert-butylcarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)-pentanedioic acid, 1-tert-butyl ester, (R)-tert-Bu 4-DOTAGA 1

Organic Process Research and Development

Volumn 13, Issue 3, 2009, Pages 535-542

  Levy, Stuart G ^c   Jacques, Vincent ^a,b   Zhou, Kevin Li ^a,b   Kalogeropoulos, Shirley ^a,b   Schumacher, Kelly ^a,b   Amedio, John C ^d   Scherer, Jonathan E ^a,b   Witowski, Steven R ^e   Lombardy, Richard ^b   Koppetsch, Karsten ^f  

^a EPX Pharmaceuticals Inc   (United States)

^b Johnson Matthey Pharmaceutical Materials Inc   (United States)

^c Magen Biosciences   (United States)

^d Ziopharm Oncology   (United States)

^e Ironwood Pharmaceuticals   (United States)

^f GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 66249100886     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op8002932     Document Type: Article

References (18)

1. During the preparation of this manuscript, a patent was submitted and issued covering the chemistry described in this publication: (a) Amedio, J. C.; Caravan, P. D.; Jacques, V.; Zhou, K. L.; Levy, S.; Kalogeropoulos, S.; Greenfield, M. WO2005/001415 (AN 2005 14659), 2005.
2. Jacques, V.; Desreux, J. F. Synthesis of MRI Contrast Agents II. Macrocyclic Ligands. In The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging; Merbach, A. E., Toth, E., Eds.; John Wiley and Sons: New York, NY, 2001; pp 157-191.
3. (a) Eisenweiner, K.; Powell, P.; Mäcke, H. R. Bioorg. Med. Chem. Lett. 2000, 2133.
4. Mäcke, H. R.; Eisenweiner, K.; Powell, P. Patent WO 02/024235 A3 (AN 2002 240598), 2002.
5. Kang, S. I.; Ranganathan, R. S.; Emswiler, J. E.; Kumar, K.; Gougoutas, J. Z.; Malley, M. F.; Tweedle, M. F. Inorg. Chem. 1993, 32, 2912.
6. Schmidt, U.; Braun, C.; Sutoris, H. Synthesis 1996, 223.
7. (a) Lactone hydrolysis: Shin, I.; Lee, M.; Lee, M.; Jung, M.; Lee, W.; Yoon, J. J. Org. Chem, 2000, 65, 7667.
8. Benzyl bromide alkylation: Hoffmann, M.; Wasielewski, C. Roczniki Chem. 1975, 49, 151.
9. The motivation for the generation and use of the triflate ester of 11 was based on results reported in ref 2.
10. (a) Doolittle, R. E.; Heath, R. R. J. Org. Chem. 1984, 49, 5041.
11. Vigneron, J. P.; Meric, R.; Larcheveque, M.; Debal, A.; Lallemend, J. Y.; Kunesch, G.; Zagatti, P.; Gallois, M. Tetrahedron 1984, 40, 3521.
12. Gringore, O. H.; Rouessac, F. P. Organic Syntheses 1985, 63, 121.
13. Okabe, M.; Sun, R. C.; Tam, S. Y. K.; Todaro, L. J.; Coffen, D. L. J. Org. Chem. 1988, 53, 4780.
14. Zamzow, M.; Hocker, H. Macromol. Chem. Phys. 1994, 195, 2381.
15. Cai, X.; Chorghade, M. S.; Fura, A.; Grewal, G. S.; Jauregi, K. A.; Lounsbury, H. A.; Scannel, R. T.; Yeh, C. G.; Young, M. A.; Yu, S.; Guo, L.; Moriarty, R. M.; Penmasta, R.; Rao, M. S.; Singhal, R. K.; Song, Z.; Staszewski, J. P.; Tuladhar, S. M.; Yang, S. Org. Process Res. Dev. 1999, 3, 73.
16. Lactone carboxylic acid 6 was chosen as the optically enriched starting material for 9. It was necessary to determine whether stereochemical integrity was maintained throughout the synthesis of 4, starting from 6. Analysis of 4 was done using HPLC, with a chiral stationary phase. The chromatographic resolution of 4 was not sufficient to obtain baseline resolution of the peaks corresponding to the enantiomers of 4 and allow a precise determination of optical purity. An analysis of a diastereomeric derivative of 4 prepared via the triflate ester of 9 using proton NMR was then undertaken. The diastereomer (R,R)-5 was prepared by reacting 4 with (R)-(+)-R-methyl benzylamine in the presence of DIC and HOBt, as shown in Scheme 1 (see Experimental Section).
17. (a) Crossland, R. K.; Wells, W. E.; Shiner, V. J., Jr. J. Am. Chem. Soc. 1971, 93, 4217.
18. Streitweiser, A., Jr.; Wilkins, C. L.; Kiehlman, E. J. Am. Chem. Soc. 1968, 90, 1598.