A new approach to rapid parallel development for four neurokinin antagonists. Part 1

Organic Process Research and Development

Volumn 7, Issue 1, 2003, Pages 53-57

  Moseley, Jonathan D ^a   Moss, William O ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

NEUROKININ; PROTEIN INHIBITOR; UNCLASSIFIED DRUG; ZD 2249; ZD 374979; ZD 4974; ZD 6021; ZM 374979;

ARTICLE; AUTOMATION; DRUG SYNTHESIS; EXPERIMENTAL DESIGN; PARALLEL DESIGN; SAFETY; SCALE UP;

EID: 0037280518     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op020064p     Document Type: Article

References (20)

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2. Bernstein, P. R.; Aharony, D.; Albert, J. S.; Andisik, D.; Barthlow, H. G.; Bialecki, R.; Davenport, T.; Dedinas, R. F.; Dembofsky, B. T.; Koether, G.; Kosmider, B. J.; Kirkland, K.; Ohnmacht, C. J.; Potts, W.; Rumsey, W. L.; Shen, L.; Shenvi, A.; Sherwood, S.; Stollman, D.; Russell, K. Bioorg. Med. Chem. Lett. 2001, 11, 2769 and references therein. Albert, J. S.; Aharony, D.; Andisik, D.; Barthlow, H.; Bernstein, P.; Bialecki, R. A.; Dedinas, R.; Dembofsky, B. T.; Hill, D.; Kirkland, K.; Koether, G. M.; Kosmider, B. J.; Ohnmacht, C.; Palmer, W.; Potts, W.; Rumsey, W.; Russell, K.; Shen, L.; Shenvi, A.; Sherwood, S.; Warwick, P. J. J. Med. Chem. 2002, 45, 3972.
3. This approach was named "Project Discovery" in ex-Zeneca, but this term has not been used here, in part because the medicinal chemistry departments are now referred to as Discovery Chemistry. To avoid possible confusion, the Medicinal Chemistry/Discovery Department is referred to throughout this paper as the Research Department.
4. Moseley, J. D.; Moss, W. O.; Welham, M. J.; Ancell, C. L.; Banister, J.; Bowden, S. A.; Norton, G.; Young, M. J. Org. Progress Res. Dev,. 2003, 7, pp 58-66.
5. Parker, J. S.; Bowden, S. A.; Firkin, C. R.; Moseley, J. D.; Murray, P. M.; Welham, M. J.; Wisedale, R.; Young, M. J.; Moss, W. O. Org. Process Res. Dev. 2003, 7, pp 67-73.
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7. Bowden, S. A.; Burke, J. N.; Gray, F.; McKown, S.; Moseley, J. D.; Moss, W. O.; Murray, P. M.; Welham, M. J. Org. Process Res. Dev. Manuscript in preparation.
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9. The Macclesfield LSL is a cGMP manufacturing facility for synthesis of bulk drug for clinical studies and uses all glass vessels. It is typically where the first significant scale-up of a process occurs and commonly delivers tens of kilograms of intermediates and kilograms of bulk drug. It consists of a range of glass reactors 10-100 L in scale, fully contained, with other ancillary equipment in fume cupboards. Operating ranges vary from -78 to +130 °C. Atmospheric hydrogenations can be performed, and a 20-L rotary evaporator is available for distillations if required. Product is generally isolated as a solid on Nutsches. AstraZeneca has several other LSLs ar different sites which operate in a similar fashion.
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18. Chromatography was performed on polypropylene Nutsches of 32- or 42-cm diameter, extended to about 70-cm depth and specially manufactured for this purpose. The base of the Nutshche had a paper filter covered in a layer of sand onto which the silica "column" was loaded as a slurry, with another layer of sand on top. Standard flash chromatography silica gel was used (230-400 mesh), with as little as 10-14 times the mass used compared to that of the crude material in some cases, but more if needed, depending on the chromatographic separation. The crude products were loaded in the minimum of solvent, and vacuum was used to pull through aliquots of solvent from below without allowing the column to dry out. Solvents were then removed on a large rotary evaporator.
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