Daring the Challenge and Thinking Big: The Value of Early Process R&D.
Chimia (Aarau)
; 70(7-8): 502-11, 2016.
Article
in En
| MEDLINE
| ID: mdl-27561612
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 »-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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Research Design
/
Benzimidazoles
/
Bridged Bicyclo Compounds
/
Calcium Channel Blockers
Language:
En
Journal:
Chimia (Aarau)
Year:
2016
Document type:
Article
Affiliation country:
Switzerland