The manufacture of ZD6021 cyano acid (1) using a new project approach is described. Research Department processes were scaled up to 100 L if process safety and robustness were not compromised; other factors were treated according to the new approach. By using this strategy, we were able to manufacture a key intermediate on sufficient scale to support delivery of 1 kg quantities of bulk drug within 6 months of the start of lab work.

The manufacture of ZD2249 methoxy sulfoxide (1) using a new project approach is described. Research department processes were scaled up to 100 L if process safety and robustness were not compromised; other factors were treated according to the new approach. Using this strategy, we were able to manufacture a key intermediate on sufficient scale to support delivery of 1 kg quantities of bulk drug within 6 months of the start of lab work.

Four neurokinin antagonists were assembled using a rapid parallel development approach. Research Department processes were scaled up if process safety and robustness were not compromised. Using this approach, 1 kg of each compound was rapidly delivered for clinical trials.

Manufacture of ZD9331 pivaloyloxymethyl (POM) quinacetate, was progressively scaled up from large-scale lab to pilot plant to full-scale production. The specific surface area of the potassium carbonate used for the deprotonation was found to be critical as successive increases in the mass transfer area were counteracted by the reduced mass transfer efficiency, linked to the reactor size and impeller effectiveness. Furthermore, a change from a pressure filter to a centrifuge meant that the washing efficiency was similarly limited by mass transfer, with the rate of dissolution of the undesired regioisomer on the centrifuge being too low for the shorter wash time. These problems were overcome, resulting in two successful manufacturing campaigns with over 1 tonne of POM quinacetate produced well within specification in eight batches.

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