Development of a Process Route to the FAK/ALK Dual Inhibitor TEV-37440

Abstract

The development of a scalable route to TEV-37440, a dual inhibitor of focal adhesion kinase (FAK) and anaplastic lymphoma kinase (ALK), is presented. The medicinal chemistry route used to support this target through nomination is reviewed, along with the early process chemistry route to support IND (inversigational new drug) enabling activities within CMC (Chemistry, Manufacturing, and Controls). The identification and development of an improved route that was performed in the pilot plant to supply early phase clinical supplies are discussed. Details surrounding the use of a novel ring expansion, a selective nitration through a para-blocking group strategy, a single-pot amination–hydrogenation, a diastereomeric salt resolution, a through-process step to avoid a hazardous intermediate, and a practical formation of a trihydrochloride dihydrate salt are disclosed.

Latest perspectives of orally bioavailable 2,4-diarylaminopyrimidine analogues (DAAPalogues) as anaplastic lymphoma kinase inhibitors: discovery and clinical developments

“…To provide early-phase clinical supplies of CEP-37440, Allwein et al, reviewed the previously described medicinal chemistry route of CEP-28122 and presented a scalable route to TEV-CEP-37440 (ref. 171) to obtain 22 kilograms of (19) as trihydrochloride dihydrate. The pilot plant synthesis involve the use of several steps such as a unique ring expansion approach, parablocking group strategy followed by selective nitration, amination-hydrogenation in a single-pot, resolution of diastereomeric salt, a step to avoid a dangerous intermediates, and a large-scale production of trihydrochloride dihydrate salt were the key highlighted features.…”

“…To provide early-phase clinical supplies of CEP-37440, Allwein et al , reviewed the previously described medicinal chemistry route of CEP-28122 and presented a scalable route to TEV-CEP-37440 ( ref. 171 ) to obtain 22 kilograms of (19) as trihydrochloride dihydrate.…”

Minimális fázisjelölés terc-butil csoporttal és alkalmazása Mitsunobu-, és Wittig-reakcióban

“…A Wittig reakció népszerűségét mutatja a napjainkban is megjelenő publikációk nagy száma. [58], [59], [60], [61], [62], [63], [64], [65], [66] Mindenképpen érdemes azonban megje- [69], [70], [71] Savas vagy bázikus funkciós csoportot tartalmazó olefinek esetében sóképzés [72] és/vagy pH változtatással járó extrakció alkalmazható a termék tisztítására. [73], [74], [75], [76], [77] Néhány esetben a Wittig reakció után a nyersterméket tisztítás nélkül alakítják tovább, majd egy későbbi lépésben, mikor a termék könnyebben elválasztható a foszfin-oxidtól végzik el a tisztítást.…”

N,N′-Bisoxalamides Enhance the Catalytic Activity in Cu-Catalyzed Coupling of (Hetero)Aryl Bromides with Anilines and Secondary Amines

“…Biaryl amines and aromatic tertiary amines containing structural motifs are very common in pharmaceuticals and materials (Figure ). As these scaffolds are often utilized for the synthesis of pharmaceuticals and materials, development of efficient and cost-effective methods for their synthesis demand more efforts both in academia and industry. The metal catalyzed cross-coupling reactions − have provided a straightforward and reliable approach for preparing (hetero)­aryl amines.…”