Development of a Scalable Synthesis of Gastrazole (JB95008):  A Potent CCK₂ Receptor Antagonist

Abstract

A practical and scalable synthesis was developed that was used to prepare multikilogram batches of gastrazole, a selective cholecystokinin-2 receptor antagonist. In addition, evidence was found to indicate an amide bond-forming reaction proceeded via the isoimide of a benzimidazoleamide acid derivative.

Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals

“…This reagent is relatively inexpensive, widely available, and its coupling byproducts (quinoline, EtOH) can be purged by extraction into acidic aqueous media. Despite its longevity, only one example of EEDQ on large scale has been found in the peer-reviewed literature …”

“…EDC is by far the most widely used carbodiimide for the synthesis of drug candidates. ,,,,,,,,,, The fact that the urea byproduct is water-soluble and can be removed during the aqueous workup offers a clear advantage over other carbodiimides such as DCC and DIC. However, the high cost of this reagent is an issue that may disfavor its use over other alternatives on scale, especially in late development.…”

“…As shown in Scheme , Ormerod, Willemsens, and co-workers at Johnson & Johnson reported an amide coupling using EEDQ for the synthesis of cholecystokinin-2 receptor antagonist 91 . The process chemistry team retained EEDQ from the discovery synthesis for the scaled coupling of amino acid 88 and aniline 89 , as alternative reagents induced racemization.…”

Synthesis, Saccharide‐Binding and Anti‐cancer Cell Proliferation Properties of Arylboronic Acid Derivatives of Indoquinolines

“…Tetracyclic conjugated system was accomplished via PPA‐mediated cyclization, followed by chlorinative aromatization and hydrogenation (34–36). Coupling of 3‐aminophenylboronic acid with these carboxylic acids by classic amidation (37) gave arylboronic acid–derived indoloquinolines using EDC/HOBt/DMAP as coupling reagent.…”

Fluorinated phenylalanines: synthesis and pharmaceutical applications

“…Structures of melfufen (179) and melphalan (180) anticancer drugs. Gastrazole (JB95008), a CCK2 receptor antagonist: 2-Fluoro-ʟ-phenylalanine derivatives are required for the synthesis of gastrazole (JB95008, 181), a potent and highly selective cholecystokinin-2 (CCK2) receptor antagonist, originally developed at the James Black Foundation[104][105][106][107][108][109]. Roberts et al demonstrated its inhibitory activity of gastrin-stimulated growth of pancreatic cancer both in vitro and in vivo studies[110] (Figure 4).…”