Identification of a Manufacturing Route of Novel CRF-1 Antagonists Containing a 2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine Moiety

Abstract

A case study on the synthesis of novel CRF-1 antagonists containing the 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine moiety is presented. The development of ever more efficient synthetic routes allowed the progression of three candidates at the same time. A manufacturing route was identified and successfully demonstrated on a pilot-plant scale to prepare 100 kg of the CRF-1 antagonist GW876008.

Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals

“…Ribecai and co-workers at GlaxoSmithKline in Italy prepared compounds 653 − 655 as novel corticotropin releasing factor antagonists for the treatment of stress-related conditions such as anxiety and depression (Scheme ) . The final synthetic step to 653 entailed the Cu-catalyzed coupling of iodide 650 and pyrazole 651 .…”

Highly Chemoselective O-Ethylation of N-Boc Amino Alcohols Using Phase Transfer Catalysis

“…Variants of the Williamson reaction using phase-transfer catalysis (PTC) have also been known for decades, including conditions that allow selective formation of mono ether from diols or triols . In continuation of our interest in the application of PTC in the pharmaceutical industry, and due to the fact that poor selectivity was observed above with NaH/DMF conditions which also posed significant safety hazard, we reasoned that under PTC conditions the reactivity difference of the hydroxyl group and the BocNH group might be sufficient enough to allow preferential deprotonation of the hydroxyl group for its ethylation. We investigated the ethylation of N -Boc- d -leucinol ( 1 ) in heptanes using 50% aqueous NaOH as the base and diethyl sulfate as the alkylating agent in the presence of 1.5 mol % of tetrabutylammonium chloride (TBAC).…”

Ausgewählte Kupfer‐katalysierte Reaktionen für die Bildung von C‐N‐, C‐O‐, C‐S‐ und C‐C‐Bindungen

“…Die Reaktion wird bei 110 °C in DMSO mit DBU als Base durchgeführt. Das Kupplungsprodukt wird dann im gleichen Reaktionsgefäß mit MeOH behandelt, um die Acetylschutzgruppe abzuspalten und GW876008 in 85–90 % Ausbeute freizusetzen (Schema ) . Es ist bemerkenswert, dass N , N ‐Dimethylglycin auch ein preiswerter und leicht verfügbarer Cu‐Fänger ist und so das Problem der Verunreinigung des Produkts mit Kupfer gelöst werden konnte.…”