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

Organic Process Research and Development

Volumn 11, Issue 3, 2007, Pages 341-345

  Beutler, Ulrich ^a   Fuenfschilling, Peter C ^a   Steinkemper, Andreas ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

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EID: 39049143903     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op060244p     Document Type: Article

References (21)

1. Boehm, M.; Fuenfschilling, P. C.; Krieger, M.; Kuesters, E.; Struber, F. Org. Process Res. Dev. 2007, 11, 336-340.
2. The fixed-dose combination contains 20 mg of 1 and 120 mg of 2.
3. For details, see Experimental Section.
4. As the main by-product, 3-chloroacetyl-2,7-fluorene can be detected in the mother liquor. At higher reaction temperature, bichloroacylated products are formed also.
5. With the increase in temperature, a strong release of hydrogen takes place.
6. If pure 2 is heated at 70 °C in the reaction media of the condensation reaction, the equilibrium is reached within a few hours.
7. (a) Rao, D. R.; Kankan, R. N.; Phull, M. S. Patent Application CN 1009-3724 20060424, 2005.
8. (b) Deng, R.; Zhong, J.; Zhao, D.; Wang, J.; Yaoxue, X. 2000, 35 (1), 22.
9. (c) Allmendinger, Th.; Wernsdorfer, W. H. PCT WO 99/67197.
10. The yield of the chlorination can be increased up to 90% when the reaction is ran at high concentration in acetonitrile and NCS and hydrochloric acid are used. Perrumattam, J.; Shao, Ch.; Confer, W. L. Synthesis 1994, 1181.
11. When monitoring the progress of the conversion of 6 to 8, maximal 1-2% of epoxide b could be detected in reaction mixture.
12. When drastically reducing the amount of solvent, an oily mass rather than a crystalline product is formed, leading to subsequent crust formation; only an increase of concentration of 8 from 5% to 6% was feasible.
13. To suppress the formation of by-products (see section 3.3), prolonged heating at 70 °C has to be avoided.
14. The higher concentration of sodium hydroxide has its beneficial effect on the crystallization only in combination with the higher temperature. At 38 °C, no rate-enhancing effect was observed when the amount of sodium hydroxide was increased from 0.86 to 2 equiv.
15. In addition to some minor compounds, the E-isomer 9 at 1 -3% is the major by-product in crude 2.
16. For 1 kg of crude 2, 25 L of 2-propanol are required.
17. When carefully checking the crude reaction mixture of the milder current process, compound 12 can be detected also; however, it is completely removed into the mother liquor during the crystallization process that leads to crude 2. With the new conditions, more of 12 is formed, and its complete removal occurs in the recrystallization of 2.
18. In the p-chlorobenzaldehyde we used for these experiments, compound 11 was not detectable by GC or HPLC analytics.
19. This is in sharp contrast to the formation of fluorenone 10. Compound 10 can be made to the dominant product if during the conversion of 8 → 2 air is bubbled through the reaction mixture.
20. Fuenfschilling, P. C.; Hoehn P.; Mutz J.-P. Organic Process Res. Dev. 2007, 11, 13.
21. For lithium enolate of acetaldehyde as the reducing agent for nonenolizable aldehydes, see: Di Nunno, L.; Scilimati, A. Tetrahedron 1988, 44, 3639.