title: Daring the Challenge and Thinking Big: The Value of Early Process R&D.
abstract: The production of the L/T channel blocker ACT-280778 required the enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (1) as key building block. As the published routes towards 1 are very low yielding (<0.5% yield) and comprise many steps that are not acceptable for scale-up, a series of processes to 1 was developed to match the increasing requirements from first kg-batches to clinical supplies. The three routes are characterized by an individual asset. (1) The first route contains a scale-up of a Diels-Alder reaction with highly reactive reagents and afforded 90 kg enantiomerically pure 1. To mitigate safety risks, a flow reactor was developed for the high-temperature Diels-Alder reaction. This route relied on an efficient enantiomer separation on a ¼-ton scale by HPLC. (2) A Crystallization Induced Diastereomer Transformation (CIDT) during an intramolecular aldol reaction was the pivotal step of a first enantioselective route that starts with the Shibasaki reaction. (3) The 2(nd) enantioselective route represents a rare example of organocatalysis on scale and allowed to skip six out of nine steps with a significant impact on the cost of goods. This simple way to 1 opened up a short synthesis of Hayashi's chiral diene ligands (bod*) that were so far lacking an affordable access. Some of these novel C1-symmetrical dienes have shown very high enantioselectivities in Rh-catalyzed additions of arylboronates.
authors: Chemistry Process R&D Actelion Pharmaceuticals Ltd Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. stefan.abele@actelion.com.
authors: Stefan
authors: S
authors: Abele
authors: Chemistry Process R&D Actelion Pharmaceuticals Ltd Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors: Jacques-Alexis
authors: JA
authors: Funel
authors: Chemistry Process R&D Actelion Pharmaceuticals Ltd Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors: Gunther
authors: G
authors: Schmidt
authors: Chemical Development and Catalysis Solvias AG Römerpark 2, CH-4303 Kaiseraugst, Switzerland; Pharmaceuticals Division Chemical Development & Supply F. Hoffmann-La Roche AG.
authors: Christian
authors: C
authors: Moessner
authors: Swissi Process Safety GmbH Schwarzwaldallee 215, CH-4002 Basel, Switzerland.
authors: Mischa
authors: M
authors: Schwaninger
authors: HES-SO Haute école spécialisée de Suisse occidentale Haute école d'ingénierie et d'architecture de Fribourg Institut ChemTech, Bd Pérolles 80, CH-1700 Fribourg, Switzerland.
authors: Roger
authors: R
authors: Marti
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D002384:Catalysis; D017321:Clinical Trials, Phase I as Topic; D003460:Crystallization; D061565:Cycloaddition Reaction; D004339:Drug Compounding; D007202:Indicators and Reagents; D012107:Research Design; D013237:Stereoisomerism
chemical_list: D001562:Benzimidazoles; D001643:Bridged Bicyclo Compounds; D002121:Calcium Channel Blockers; D007202:Indicators and Reagents; C000592016:isobutyric acid 2-(2-((3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)propyl)methylamino)ethyl)-5-phenylbicyclo(2.2.2)oct-5-en-2-yl ester