An improved manufacturing process for the antimalaria drug coartem. Part I

Organic Process Research and Development

Volumn 11, Issue 3, 2007, Pages 336-340

  Boehm, Matthias ^a   Fuenfschilling, Peter C ^a   Krieger, Matthias ^a   Kuesters, Ernst ^a   Struber, Fritz ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 39049097281     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op0602425     Document Type: Article

References (29)

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2. (b) Klayman, D. L.; Lin, A. J.; Acton, N.; Scovill, J. P.; Hoch, J. M.; Milhous, W. K.; Theoharides, A. D. J. Nat. Prod. 1984, 47, 715.
3. Clinical studies on the treatment of malaria with Qingaosu and its derivatives, J. Tradit. Chin. Med. 1982, 2(1), 45.
4. Haynes, R. K.; Vonwiller S. C. Trans. R. Soc. Trop. Med. Hyg. 1984, 88, Supplement 1, 23.
5. Li, Y.; Yu, P.-L.; Chen, Y.-X.; Li, L.-Q.; Gai, Y.-Z.; Wang, D.-S.; Zheng, Y. Kexue Tonbao 1979, 14, 667.
6. Compared to sodium borohydride, potassium borohydride is less hygroscopic and therefore easier to handle on large scale.
7. The reduction is also described with sodium borohydride without addition of calcium chloride: Sing, C.; Tiwari, P. Ind. J. Chem. 2002, 41B, 2185.
8. In this batch, the isolated yield dropped from an average yield of 79% to only 2%.
9. (a) Idowu, O. R.; Maggs, J. L.; Ward, S. A.; Edwards, G. Tetrahedron 1990, 46. 1871.
10. (b) Yagen, B.; Pu, Y. M.; Yeh, H. J. C.: Ziffer, H. J. Chem. Soc. Perkin Trans. 1 1994, 843.
11. (c) Baker, J. K.; Chi, H. T. Heterocycles, 1994, 38, 1497.
12. (d) Imakura, Y.; Hachiya, K.; Ikemoto, T.; Yamashita, S.; Kihara, M.; Kobayashi, S.; Shingu, T.; Milhous, W. K.; Lee, K. H. Heterocycles 1990, 31, 1011.
13. Large deviations in temperature and amount of acid as applied in these laboratory experiments could be ruled out for batch 35.
14. 2 in methanol at 5 °C.
15. To investigate this hypothesis, potassium borohydride was completely decomposed in methanol (leading to a pH around 9). After adding of artemisinin 3 and calcium chloride, the reduction reaction was run under standard conditions. No influence on the yield was noted.
16. Potassium hydroxide is a "logical" impurity in potassium borohydride. The latter compound is usually obtained by treating sodium borohydride with ethanolic KOH and subsequent washing with ethanol.
17. Besides 4, artemisinin, 3, is also sensitive towards strong base. However, whereas catalytic amounts of a strong base are sufficient to cause significant degradation in the lactol 4, molar quantities of base are needed in the case of lacton 3.
18. The application of a lower reaction temperature leads to a slower decomposition of potassium borohydride by methanol.
19. For details on the analytical specifications of potassium borohydride, see Experimental Section.
20. Sy, L. K.; Hui, S.-M.; Cheung, K. K.; Brown, G. D. Tetrahedron 1997, 53, 7493.
21. (a) Zeng, M. Y.; Li, L. N.; Chen, S. F.; Li, G. Y.; Liang, X. T.; Chen, M.; Clardy, J. Tetrahedron 1983, 39, 2941.
22. (b) Shang, X.; He, C.; Zheng, Q.; Yang, J.; Liang, X. Heterocycles 1989, 28, 421.
23. ( 18) In our plant, some of the first production batches failed to meet specifications due to insufficient depletion of 10α-epimer 5 and 9α-epimer 6. To reach the required quality, a recrystallization procedure had to be developed. Furthermore, the precipitation and washing procedures had to be optimized (for details, see Experimental Section).
24. Pu, Y. M.; Ziffer, H. Heterocydes 1994, 39, 649.
25. Haynes, R. K.; Chan, H.-W.; Cheung, M.-K.; Chung, S. T.; Lam, W.-L.; Tsang, H.-W.; Voerste, A.; Williams, I. D. Eur. J. Org. Chem. 2003, 11, 2098.
26. Precipitation of artemether crude from methanol/water 55:45 mol/mol % leads to >95% depletion of 5, 90% of 7, but only 40% of 6. (22) The feasibility of the conversion 4 → 1 in methyl acetate has been demonstrated on a kilogram scale. Since artemether will in future be produced externally, this process was not implemented at Chemical Production Novartis.
27. With hydroxide-free borohydride, the reaction and gas evolution were vigorous from the beginning.
28. Since four out of the first six batches failed to meet the specifications due to high levels of by-products (up to 2.3% of 5 and up to 0.67% of 7), amount and addition mode of water had to be optimized.
29. In this optimization work we found also that seeding is not necessary.