A New Approach to Rapid Parallel Development of Four Neurokinin Antagonists. Part 4. Synthesis of ZD2249 Methoxy Sulfoxide

Organic Process Research and Development

Volumn 8, Issue 1, 2004, Pages 33-44

  Bowden, Sharon A ^a   Nigel Burke, J ^b   Gray, Fiona ^a   McKown, Steven ^b   Moseley, Jonathan D ^a   Moss, William O ^a   Murray, Paul M ^a   Welham, Matthew J ^a   Young, Maureen J ^a  

^a ASTRAZENECA   (United Kingdom)

^b Large Scale Laboratory   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ALCOHOL; BLOCKING AGENT; NEUROKININ; PHENOL DERIVATIVE; PROTEIN INHIBITOR; SULFIDE; SULFOXIDE; THIOCARBAMIC ACID DERIVATIVE; UNCLASSIFIED DRUG; ZD 2249;

ARTICLE; DRUG MANUFACTURE; DRUG SYNTHESIS; HYDROGENATION; PROCESS DEVELOPMENT; QUANTUM YIELD; REACTION ANALYSIS;

EID: 0842263634     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op030039z     Document Type: Article

References (24)

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15. 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 at different sites which operate in a similar fashion.
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23. Several other potentially shorter routes to methoxy sulfoxide that were briefly investigated may also be reported at a later date.
24. Manufacture of the methoxy sulfoxide portion required 20 batches in total, being generally three batches per stage for the early stages and one to two for the later ones. No batches were lost from either repeat manufactures of the cyano acid or N-methylamine portions.