Bromide-assisted chemoselective Heck reaction of 3-bromoindazoles under high-speed ball-milling conditions: synthesis of axitinib

Abstract

A mechanically-activated chemoselective Heck coupling for the synthesis of 3-vinylindazoles has been developed with the aid of catalytic amounts of TBAB and NaBr as both dehalogenation restrainer and grinding auxiliary. After tuning of the chemical conditions and mechanical parameters, a series of non-activated 3-bromoindazoles and a broad scope of olefins worked well to give the corresponding coupling products in good to excellent yields. A further application of this protocol was performed in a two-step mechanochemical Heck/Migita cross coupling, which provided a highly efficient route for the synthesis of axitinib.

Liquid‐Assisted Grinding Mechanochemistry in the Synthesis of Pharmaceuticals

“…Nowadays, A firmly established application of modern mechanochemistry is generally in medicinal chemistry which termed as “medicinal mechanochemistry”, [10] dedicating to access active pharmaceutical ingredients (APIs), and pharmaceutically relevant fragments and functionalities in mechanochemical way with reduced environmental impaction [11,6b] . Many elegant mechanosynthesis of APIs have been developed, including teriflunomide [11a] (multiple sclerosis therapy), ftivazide [11c] (anti tuberculosis), axitinib [11f] (for the treatment of renal cell carcinoma), nitrofurantoin (antibacterial agent) and dantrolene (skeletal muscle myorelaxant) [11g] by group of Lamaty, Baltas, Su, Colacino and others. Very recently, Colacina group demonstrated the scalability (25 g scale) of the preparation of nitrofurantoin and dantrolene [6b] by a twin‐screw extrusion (TSE) (Scheme 1).…”

Synthesis and Characterization of Palladium Supported Amino Functionalized Magnetic-MOF-MIL-101 as an Efficient and Recoverable Catalyst for Mizoroki–Heck Cross-Coupling

“…The latter has been extensively reported in the literature along the years [5], while the former version of the Heck reaction was reported much more recently [6]. A variety of reagents such as bromo and chloro derivatives with unactivated alkenes were utilized for synthesizing Heck products, the most industrially relevant studies were conducted with aryl bromides [7]. In most cases, the coupling reactions occur in the presence of palladium as a catalyst [8].…”

Direct Catalytic Functionalization of Indazole Derivatives

“…The desired 3-alkenyl1Hindazole derivatives (58 b) were obtained with moderate to good yields (Scheme 58). [44]…”

“…Indazoles are usually functionalized with the help of cross-coupling reactions in the presence of different kinds of transition-metal catalysts such as palladium, copper, ruthenium, zinc etc. [39][40][41][42][43][44] Moreover, functionalized indazole derivatives are also synthesized in different ways such as metal-catalyzed coupling between diazo compounds and aldehydes, [45][46][47] [3 + 2] type cycloaddition of arynes with sydnones [48][49] and CF 3 CHN 2 , [50] and many other methods. [51][52][53][54][55][56][57] A very recent breakthrough in this field is visible-lightinduced direct organophotocatalytic functionalization strategies.…”