A high-throughput impurity-free process for gatifloxacin

Organic Process Research and Development

Volumn 12, Issue 5, 2008, Pages 900-903

  Villasante, F Javier ^a   Gude, Lourdes ^a   Fernández, Sara P ^a   Alonso, Olga ^a   García, Elena ^a   Cosme, Antonio ^a  

^a NONE

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EID: 58149114900     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op800042a     Document Type: Article

References (20)

1. Mather, R.; Karenchak, L. M.; Romanowski, E. G.; Kowalski, R. P. Am, J. Ophthalmol. 2002, 133 (4), 463.
2. Corey, E. J.; Czakó, B.; Kürti, L. Molecules and Medicine; Wiley: NJ, 2007; p 135.
3. Masuzawa, K.; Suzue, S.; Hirai, K.; Ishizaki, T. 8- Alkoxyquinolonecarboxylic acid and salts thereof excellent in the selective toxicity and process of preparing the same EP 0 230 295 A3, 1987.
4. Niddam-Hildesheim, V.; Dolitzky, B.-Z.; Pilarsky, G.; Steribaum, G. Synthesis of Gatifloxacin WO 2004/069825 Al, 2004.
5. Ruzic, M; Relic, M; Tomsic, Z; Mirtek, M. Process for the preparation of Gatifloxacin and regeneration of degradation products WO 2006/ 004561 Al, 2006.
6. Iwata, M.; Kimura, T.; Fujiwara, Y.; Katsube, T. Quinoline-3-carboxylic acid derivatives, their preparation and use EP 0 241 206 A2, 1987.
7. Sanchez, J. P.; Gogliotti, R. D.; Domagala, J. M.; Garcheck, S. J.; Huband, M. D.; Sesnie, J. A.; Cohen, M. A.; Shapiro, M. A. J. Med. Chem. 1995, 38, 4478.
8. Satyanarayana, C.; Ramanjaneyulu, G. S.; Kumar, I. V. S. Novel crystalline forms of Gatifloxacin WO 2005/009970 Al 2005.
9. 4)bis(acyloxy-O)borates and the salts thereof, and methods for their manufacture EP 0 464 823 Al, 1991.
10. These compounds are known to be irritants and produce a nasty taste in the mouth.
11. We have observed that treating 2 with triethylamine (2.5 equiv) in 1 volume of dimethylacetamide (100°C, 2 h) or acetonitrile (reflux, 2 h), 41% and 37% of 4 were formed, respectively. In addition, when diisopropylethylamine was employed instead of triethylamine, under the same conditions, 4.7% and 5.8% of 4 were formed, respectively.
12. A method for the selective cleavage of primary alkyl aryl ethers with boron trichloride/tetra-n-butylammonium iodide, which uses slightly similar conditions to those used in the synthesis of gatifloxacin through boron chelates, has been reported by Brooks, P. R.; Wirtz, M. C.; Vetelino, M. G.; Rescek, D. M.; Woodworth, G. F.; Morgan, B. P.; Coe, J. W. J. Org. Chem. 1999, 64, 9719.
13. Although the formation of trimethylsilyl ester 9 is probably immediate, reflux is kept for 1 h in order to ensure elimination of all ammonia gas.
14. Palomo, F. E.; Solis, O.; Palomo, A. L. Trimethylsilyl esters and solvates of chelates of quinoline-3-carboxylic acids, and their preparation and use in a process for quinolone antibacterialsES 2 077 490 Al, 1995.
15. Fluorotrimethylsilane (bp: 16°C) is converted into the less volatile methoxytrimethylsilane (bp: 57-58°C) in the subsequent distillation, in which the condensed solvent vapors are treated with a solution of sodium methoxide in methanol. To ensure the complete conversion of all formed fluorotrimethylsilane, solvents and gases that might pass through the pump are bubbled into the same solution. The resulting solution of methoxytrimethylsilane is treated as organic waste.
16. Yields were calculated as the average of three batches. Yields for individual batches were: batch 1, 32.3 kg, 85%; batch 2, 33.2 kg, 87%; batch 3, 31.8 kg, 83%.
17. Samples were diluted in water (1:1; v/v) to carry out the pH measurements.
18. DSC analysis showed two endothermic peaks at 166.2°C (T onset = 164.3°C) and 190.0°C (T onset = 188.2°C) and an exothermic one at 168.1°C. The shape of this DSC curve is characteristic of a monotropic transition between crystalline forms.
19. Although there are several hydrates described for gatifloxacin such as, among others, the hemimydrate, sesquihydrate, and pentahydrate (Raghavan, K. S.; Ranadive, S. A.; Gougoutas, J. Z.; Dimarco, J. D.; Parker, W. L.; Dovich, M.; Neuman, A. Gatifloxacin pentahydrate. WO 2002/22126 Al, 2002), the Gatifloxacin obtained by the present procedure does not seem to form a stoichiometric hydrate, but instead it retains moisture. Thus, the product is usually obtained with a Karl-Fischer value below 1% after drying, but it can absorb moisture until a final content of about 3%. This water content can vary between 2.0% and 3.5%, depending on the relative humidity of the environment. DSC analysis revealed a broad endothermic signal with minimum at 76°C, while TGA analysis showed that the product loses all the water below 80°C. No loss of weight is registered when the product melts, and the weight is constant until the decomposition of the material at about 200°C. On the basis of these results, it can be said that the water content of the gatifloxacin obtained by the present process is retained moisture instead of water belonging to the lattice. The shape of the derivative of the weight curve at the beginning of the analysis shows that the sample has already lost part of the moisture when the register starts. This is probably due to the sample starting to lose weight when makes contact with the dry atmosphere of the TGA oven that could explain the different values obtained for water content of the analyzed sample by TGA (1.90%) and Karl-Fischer (2.64%) methods.
20. The respective boron contents found for batches 2 and 3 were 160 and 300 ppm.