An efficient and high-yielding protocol for the production of Regorafenib via a new synthetic strategy

Abstract

An improved, high-yielding, and efficient protocol for the production of Regorafenib (1), a novel diaryl urea inhibitor of multiple protein kinases, is described. The highlight of the process chemistry design and development is an optimization of the route for preparing key intermediate 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (7) by O-alkylation, nitration and reduction reactions. The developed process avoids using column chromatography to isolate 7, reduces the reaction requirements and is cost-saving, resulting in an increased overall yield from 35.0 to 57.0 % and purity from 97.0 to 99.8 %.

Regorafenib analogues and their ferrocenic counterparts: synthesis and biological evaluation

“…PET/EtOAc (60:40 to 40:60) with 3% of NEt3 to give the title product which was triturated in an Et2O/pentane mixture to afford 6 as a white solid (1.11 g, 21% over 2 steps). Analytical data analogous to those reported previously 4. Mp137-139 °C.…”

“…Analytical data analogous to those reported previously. 4 Mp 80-82 °C. νmax (film)/cm −1 3331, 1657,1589,1567,1529,1483,1462,1447,1413,1290,1250,1224,1157,1138,1117,961, 900, 884, 758, 732.…”

A Practical and Efficient Method for the Synthesis of Sorafenib and Regorafenib

“…16,17 Scheme 1 Summary of reported synthetic approaches to sorafenib and regorafenib and in all the reactions listed in Table 1. 7) 20 in isolated yield of 80% (Table 1.4) and to our surprise, no product (7) was formed when reaction was carried out in DMF containing cesium carbonate base. 2) In conclusion, a practical and efficient processes both for sorafenib and regorafenib have been developed and those an use of any hazardous and moisture sensitive reagents such as phosgene, isocyanates, chroformates and carbonyldiimidazole.…”

“…In the next step, 4-aminophenol was reacted with 4chloro-N-methylpicolinamide (1) to yield 4-(4-aminophenoxy)-N-methylpicolinamide (2) under different reaction conditions (Table 2). The best yield obtained was very low (25%; entry 6) and, under all the reaction conditions detailed in Table 2, N-methyl-4-(4-( (2-(methylcarbamoyl)pyridin-4-yl)amino)phenoxy)picolinamide 18 was formed as 2) and formation of an impurity in the reaction, further in situ reaction with phenyl 4-chloro-3-(trifluoromethyl)phenyl carbamate to afford sorafenib was not performed and Route 1 was abandoned at this stage.…”

“…Therefore, instead of urea, reaction of 4-amino-3-fluorophenol ( 6) with 4-chloro-N-methylpicolinamide (1) in the presence of KOtBu in DMF at 120 °C after 6 h gave the regorafenib intermediate 4-(4-amino-3-fluorophenoxy)-Nmethylpicolinamide (7) 18 in an isolated yield of 80% (Table 4); however, to our surprise, no product 7 was formed when reaction was carried out in DMF containing caesium carbonate base.…”