Synthesis of HIV protease inhibitor ABT-378 (lopinavir)

Organic Process Research and Development

Volumn 4, Issue 4, 2000, Pages 264-269

  Stoner, Eric J ^a   Cooper, Arthur J ^a   Dickman, Daniel A ^a   Kolaczkowski, Lawrence ^a   Lallaman, John E ^a   Liu, Jih Hua ^a   Oliver Shaffer, Patricia A ^a   Patel, Ketan M ^a   Paterson Jr , Joseph B ^a   Plata, Daniel J ^a   Riley, David A ^a   Sham, Hing L ^a   Stengel, Peter J ^a   Tien, Jien Heh J ^a  

^a ABBOTT LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0034374764     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op990202j     Document Type: Article

References (29)

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2. Moyle, G.; Gazzard, B. Drugs 1996, 51(5), 701.
3. Also referred to as ABT-538, see: Kempf, D. J.; Marsh, K. C.; Denissen, J. F.; McDonald, E.; Vasavanonda, S.; Flentge, C. A.; Green, B. E.; Fino, L.; Park, C. H.; Kong, X.-P.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati, W. M.; Sham, H. L.; Robins, T.; Stewart, K. D.; Hsu, A.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W. Proc. Natl. Acad. Sci. U.S.A. 1995, 92(7), 2484.
4. (a) Molla, A.; Korneyeva, M.; Gao, Q.; Vasavanonda, S.; Schipper, P. J.; Mo. H.-M.; Markowitz, M.; Chernyavskiy, T.; Niu, P.; Lyonns, N.; Hsu, A.; Granneman, G. R.; Ho. D. D.; Boucher, C. A. B.; Leonard, J. M.; Norbeck, D. W.; Kempf, D. J. Nat. Med. 1996, 2(7), 760.
5. (b) Schmit, J.-C.; Ruiz, L.; Clotet, B.; Raventos, A.; Tor, J.; Leonard, J.; Desmyter, J.; De Clercq, E.; Vandamme, A.-M. AIDS 1996, 10, 995.
6. Sham, H. L.; Chen, X. Exp. Opin. Invest. Drugs 1996, 5(8), 977.
7. Sham, H. L.; Kempf, D. L.; Molla, A.; Marsh, K. C.; Kumar, G. N.; Chen, C.-M.; Kati, W.; Stewart, K.; Lal, R.; Hsu, A.; Betebenner, D.; Korneyeva, M.; Vasavanonda, S.; McDonald, E.; Saldivar, A.; Wideburg, N.; Chen, X.; Niu, P.; Park, C.; Jayanti, V.; Grabowski, B.; Granneman, G. R.; Sun, E.; Japour, A. J.; Leonard, J. M.; Plattner, J. J.; Norbeck, D. W. Antimicrob. Agents Chemother. 1998, 42, 3218.
8. Sham, H. L.; Norbeck, D. W.; Chen, X.; Betebenner, D. A.; Kempf, D. J.; Herrin, T. R.; Kumar, G. N.; Condon, S. L.; Cooper, A. J.; Dickman, D. A.; Hannick, S. M.; Kolaczkowski, L.; Oliver, P. A.; Plata, D. J.; Stengel, P. J.; Stoner, E. J.; Tien, J.-H. J.; Liu, J.-H.; Patel, K. M. U.S. Patent Application 95-57226; Chem. Abstr. 1997, 127: 122001.
9. (a) Molla, A.; Vasavanoda, S.; Kumar, G. N.; Sham, H. L.; Johnson, M.; Grabowski, B.; Denissen, J. F.; Kohlbrenner, W.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W.; Kempf, D. J. Virology 1998 250, 255.
10. (b) Carillo, A.; Stewart, K.; Sham, H.; Norbeck, D.; Kempf, D.; Kohlbrenner, W.; Leonard, J.; Molla, A. J. Virology 1998, 72, 7532.
11. Hayes, N. V.; Branch, G. E. K. J. Am. Chem. Soc. 1943, 65, 1555.
12. (a) Stuk, T. L.; Haight, A. R.; Scarpetti, D.; Allen, M. S.; Menzia, J. A.; Robbins, T. A.; Parekh, S. I.; Langridge, D. C.; Tien, J.-H. J.; Pariza, R. J.; Kerdesky, F. A. J. J. Org. Chem. 1994, 59, 4040.
13. (b) Haight, A. R.; Stuk, T. L.; Allen, M. S.; Bhagavatula, L.; Fitzgerald, M.; Hannick, S. M.; Kerdesky, F. A. J.; Menzia, J. A.; Parekh, S. I.; Robbins, T. A.; Scarpetti, D.; Tien, J.-H., J. Org. Process Res. Dev. 1999, 3, 94.
14. Haight, A. R.; Stuk, T. L.; Menzia, J. A.; Robbins, T. A. Tetrahedron Lett. 1997, 38(24), 4191.
15. While the % de of 4 is determined, the % ee is nol measured. Subsequent processing in the ritonavir synthesis incorporates one additional chiral center; the enantiomer of 4 would be manifested as a ritonavir diastereomer, which is not observed. This suggests that the % ee of 4 is a reflection of the precursor enaminone.
16. Organic Syntheses; Baumgarten, H. E., Ed.; Wiley: New York, 1973; Collect. Vol. 5, p 251.
17. Organic Syntheses; Baumgarten, H. E., Ed.; Wiley: New York, 1973; Collect. Vol. 5, p 251.
18. This compound is used in the manufacturing of ritonavir as well.
19. Wuts, P. G. M.; Pruitt, L. E. Synthesis 1989, 622.
20. High quality 3-chloropropylamine hydrochloride can be obtained by carbon treatment of commercial materials followed by recrystallization or by synthesis from 3-aminopropanol.
21. A more detailed discussion of the optimization of this reaction is available: Stoner, E. J.; Cooper, A. J.; Stengel, P. J. Org. Process Res. Dev. 1999, 3, 145.
22. Racemization of acyl chloride 11 during coupling is observed only when the material is allowed to stand in solution at room temperature for extended periods of time (several hours). If prepared and used immediately, no racemization is detected as the formation of the known (and independently prepared) diastereomer (17) (see ref 20).
23. 2 in the previous step. Although this necessitated a second charge of catalyst to effect complete reaction, it did not otherwise affect the process.
24. Crystallographic studies have shown, to our surprise, that 2 isolated by this crystallization method is not a solvate.
25. 17 Compound 18 can only result from the acylation of the enantiomer of 4 (2R,3R,5R) with 5. The levels of 17/18 observed in 2 are typically <0.1%. Until there is a need for a more definitive assay, we assume this represents an upper limit to the amount of ent-2 present.
26. Enantiomeric excess is determined by HPLC (Chiracel OD column, elution with hexane: ethanol: trifluoroacetic acid (930: 70: 1). The desired L-isomer has a retention time of approximately 14 min; the D-isomer, 11.5 min.
27. Analysis was performed on crude reaction aliquots quenched into methanol.
28. Karl Fischer titration at this point: 0.07% water. Anhydrous conditions facilitate the crystallization.
29. Product crystallized in this matter contains approximately 2% residual ethyl acetate which cannot be removed by further drying.