Plenary Session, Award- or Invited Lecture
Daring the Challenge and Thinking Big: the Value of Early Process Research (Sandmeyer Award Lecture 2015)
S. Abele1
1Actelion Pharmaceuticals Ltd., Allschwil -
Enantiomerically pure phenylbicyclo[2.2.2]oct-5-en-2-one (1) was required in large quantities for the manufacturing of a L/T calcium channel antagonist ACT-2807781 at Actelion Pharmaceuticals Ltd. Published routes delivered only gram amounts at exorbitant costs.
Two technologies that often defy scale-up have been successfully used to supply material at various stages of drug development: Diels–Alder reactions2 and organocatalysis. Up to 90 kg of enantiomerically pure 1 were produced by a Diels–Alder approach3 followed by a chiral separation of racemic 1. Early, thorough safety assessments enabled the scale-up of inherently hazardous chemistry in a safe manner. More than 14 kg of ACT-280778 were produced over 17 steps, ready for testing in clinical studies. An enantioselective route was required for larger scale. The 2nd generation route features an organocatalytic one-pot Michael addition–aldol reaction with cheap 2-cyclohexenone and phenylacetaldehyde, with L-proline as catalyst, thereby not only reducing the environmental burden but reducing the cost of goods by more than 90%.4
Just two steps were required to synthesize eleven novel chiral diene ligands (c.f. Hayashi’s bod* ligands) from now readily available 1. As an efficient access to bod* ligands was still missing, this protocol should be beneficial for the widespread use of this new authoritative ligand class.5 The courage to apply and safely scale up hazardous, rarely used, novel chemistry, and the use of expert knowhow by tactical outsourcing of special technologies have been crucial for the quick delivery of this Active Pharmaceutical Ingredient and in the quest for shorter routes at lower costs.
(1) J.-A. Funel, S. Brodbeck, Y. Guggisberg, R. Litjens, T. Seidel, M. Struijk, S. Abele, Org. Process Res. Dev. 2014, 18, 1674.
(2) Funel, J.-A.; Abele, S. Angew. Chem. Int. Ed. 2013, 52, 3822.
(3) Funel, J.-A.; Schmidt, G.; Abele, S. Org. Process Res. Dev. 2011, 15, 1420.
(4) Abele, S.; Inauen. R.; Spielvogel, D.; Moessner, C. J. Org. Chem. 2012, 77, 4765.
(5) R. Brönnimann, S. Chun, R. Marti, S. Abele, Helv. Chim. Acta 2012, 95, 1809.