Investigation into the acidification process of zafirluskast nitroacid leads to a surprising improvement in product quality

Organic Process Research and Development

Volumn 8, Issue 5, 2004, Pages 808-813

  Ancell, Claire L ^a   Derrick, Ian ^a   Moseley, Jonathan D ^a   Stott, Jeffery A ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ZAFIRLUKAST;

ACIDIFICATION; ADDITION REACTION; ARTICLE; DILUTION; DRUG DEVELOPMENT; DRUG SYNTHESIS; PH; REACTION ANALYSIS; TEMPERATURE DEPENDENCE;

EID: 5144225778     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op049911+     Document Type: Article

References (11)

1. Formerly ICI 204219; AstraZeneca trade name Accolate.
2. Krell, R. D.; Aharony, D.; Buckner, C. K.; Keith, R. A.; Kusner, E. J.; Snyder, D. W.; Bernstein, P. R.; Matassa, V. G.; Yee, Y. K.; Brown, F. J., Hesp, B.; Giles, R. E. Am. Rev. Respir. Dis. 1990, 141, 978-987. Smith, L. J.; Geller, S.; Ebright, L.; Glass, M.; Thyrum, P. T. Am. Rev. Respir. Dis. 1990, 141, 988-992.
3. Krell, R. D.; Aharony, D.; Buckner, C. K.; Keith, R. A.; Kusner, E. J.; Snyder, D. W.; Bernstein, P. R.; Matassa, V. G.; Yee, Y. K.; Brown, F. J., Hesp, B.; Giles, R. E. Am. Rev. Respir. Dis. 1990, 141, 978-987. Smith, L. J.; Geller, S.; Ebright, L.; Glass, M.; Thyrum, P. T. Am. Rev. Respir. Dis. 1990, 141, 988-992.
4. Matassa, V. G.; Maduskuie, T. P.; Shapiro, H. S.; Hesp, B.; Snyder, D. W.; Aharony, D.; Krell, R. D.; Keith, R. A. J. Med. Chem. 1990, 33, 1781-1790.
5. No effect on the yield could usefully be discerned for these samples due to the small size of the aliquots, but we were confident that the isolation procedure was reliable for quality on this scale; wash sizes were between 5 and 8 mL for 10-mL aliquots isolated on a small sinter.
6. Nitroester batch 103, which had a C2C3-diester level of 0.82% w/w, was used for much of the initial work. Later, batch 108 was used, which had a C2C3-diester level right on the specification limit at 1.04% w/w, which provided the most exacting test for the new methodology.
7. It is not known to what the lab rpm rates are equivalent on the plant, and no further work was conducted in this area, mainly because there was little scope to change the plant agitation.
8. The effect of the shape of the plant vessel and the use of a modified spray ring was considered in this work, but not further investigated.
9. For an initial trial, the use of 2 M HCl was considered on plant scale since this could be purchased diluted. The most dilute acid that could have been used without increasing the overall water charge was 1.3 M HCl. This would have required dilution from concentrated HCl in a suitable make-up vessel, which was not readily available in the manufacturing facility.
10. Other batches are not shown because more than one parameter had been changed, but the improvements were significant in each case.
11. We observed no change in the polymorph of nitroacid throughout these investigations.