Discodermolide, purification

Figure 21-5. Purification of 101 mg of crude discodermolide on 46 g of YMC-OD-A 5-15 gm (column 250-mm x 20-mm i.d.). The drug substance is dissolved in 31.4 mL of 2-propanol and 220.6 mL of water are added. The feed solution is pumped with a flow rate of lOmL/min onto the column, and the compounds are eluted afterwards with a mixture of acetonitrUe/water = 2/1 (V/V), flow rate 15ml/min UV detection 220 nm.

The compound supply for development cannot be met through the isolation and purification of discodermolide from Discodermia sp. (which must be harvested using manned submersibles). Attempts to reproducibly isolate a discodermolide-producing microorganism for fermentation have not been successful to date. Therefore, all discodermolide used for late preclinical research and development activities as well as for the ongoing... 

The amount of discodermolide produced would equate to around 3000 kg of sponge, a quantity that probably does not exist The total number of steps is 36 with an overall yield of 0.2% (main chain). This is on the low side, but it should be remembered that the yields for each step have not been optimized. The description of the various optimization processes in this article have only related to the various scale-up and reproducibility issues, not to obtaining the maximum possible yield, so there is plenty of scope for increasing the yield. There were, in this second campaign, some 18 chromatographic purifications. This has now been somewhat reduced to 14. The number of crystalline intermediates stands currently at 7. 

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