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

Efficient, practical syntheses of sorafenib and regorafenib have been achieved in a manner that is free from the problems associated with previously reported methods. The process involved preparation of 4-(4-aminophenoxy)- N -methylpicolinamide (sorafenib intermediate) and 4-(4-amino-3-fluorophenoxy)- N -methylpicolinamide (regorafenib intermediate) using only a single base and did not require the use of an inert atmosphere. The reaction of intermediates with phenyl 4-chloro-3-(trifluoromethyl)phenyl carbamate, prepared using water-assisted synthesis of carbamates, was used to install the main urea functionality in these molecules.

Kinase-regulated biochemical pathways play crucial roles in the formation, progression, and maintenance of cancer, and therefore are targets for the development of novel, efficient, and targeted anticancer therapies. 1VEGFR, EGFR, RAF, and aurora kinases are abundantly expressed in various cancers, and their almost perfect interactions with pharmacophores containing diaryl urea makes these kinase receptors ideal targets for developing anticancer drug molecules.The urea oxygen atom is a superior acceptor and the urea NH moiety is a favoured hydrogen-bond donor, making urea an attractive drug candidate. 2Sorafenib, the first diaryl urea-based oral multikinase inhibitor approved for the treatment of cancer in humans, appeared to be a land-mark discovery in the development of anticancer drugs. 3ince then, several medicinal chemistry initiatives have improved the pharmacological and pharmacokinetic properties of sorafenib and also explored its activity against other types of cancers.As stated earlier, the urea moiety has appeared as a core scaffold in many kinase inhibitors that have now been approved as anti-cancer drugs. 3orafenib was discovered as an emerging drug aimed at the Ras-Raf-MEK-ERK oncogenic pathway, 4 from evaluation of a large library of compounds against Raf1 (or c-Raf) kinase.This study resulted in the identification of 3-thienyl urea, which was chosen for further development; 5 however, no substantial improvement in therapeutic efficacy was achieved.Then, Bayer and Onyx Pharmaceuticals synthesized another new library of bis-aryl ureas using a parallel synthesis approach in order to quickly extend the earlier SAR studies. 6The essential role of the urea moiety in the Raf1 kinase inhibition was established and Sorafenib, with a c-Raf IC50 of 6 nM, was discovered through modification of the heterocyclic moiety and distal pyridine ring of the molecule.This drug has been demonstrated to be effective in both preclinical and clinical investigations against many types of human cancer. 7egorafenib, 8 a fluorinated analogue of sorafenib, exhibited a pharmacodynamic profile similar to that of sorafenib, but with improved clinical performance mainly due to the presence of the fluorine atom on the middle ring of the molecule.Regorafenib was first approved for the treatment of metastatic colorectal cancer in 2012, 9 and later used for advanced hepatocarcinoma in 2017. 10This was followed by an exploration of sorafenib to improve and expand its activity.

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The FDA took over a decade to approve sorafenib for advanced RCC treatment from its selection as a lead molecule in 1994.Regorafenib's Phase I dose escalation trial was conducted when sorafenib was approved, and it took nearly seven years for the FDA to approve it for the treatment of metastatic colorectal cancer. 11A review of the literature revealed that the preparation of sorafenib involved reaction of 4-aminophenol with 4-chloro-N-methyl picolinamide to form 4-(4-aminophenoxy)-N-methylpicolinamide intermediate, which then reacted with an isocynate to give the product (Scheme 1); [12][13][14][15] the analogous use of 4-amino-3fluorophenol gave regorafenib.These methods have drawbacks such as: (a) use of toxic haloformates and isocyanates, which are typically prepared using phosgene gas; (b) com-plex reaction operations; (c) generation of impurities during the synthesis, and (d) inert reaction rendering the processes hazardous, costly, and unsafe.Therefore, there is a need to develop a facile, safe, and practical synthesis of sorafenib and regorafenib with an objective of curtailing the cost of manufacturing of these molecules.Herein, we report a practical and an efficient synthesis of sorafenib and regorafenib. 16,17hree possible routes to sorafenib were envisaged, as depicted in Scheme 2. Route 1 involved the synthesis of diaryl ether from 4-chloro-N-methylpicolinamide and p-aminophenol, followed by reaction with the intermediate (4chloro-3-(trifluoromethyl)phenyl)carbamate.Route 2 involved the synthesis of diaryl ether from reaction of phenyl
Route 1 was explored by reacting picolinic acid with SO-Cl 2 to produce 4-chloropicolinyl chloride, which, upon insitu reaction with methylamine, produced 4-chloro-Nmethylpicolinamide (1); 13 optimization of reaction conditions is summarised in Table 1.Use of DMF, THF, and toluene as solvents, SOCl 2 (2 equivalents) in the chlorination step, and 2 M solution of methylamine in THF did not lead to product formation (entries 1-4), but reaction in chlorobenzene with a catalytic amount of NaBr/DMF at 85 °C and use of 40% aq.methylamine gave 80% yield of 4-chloro-Nmethylpicolinamide (1).Further improvement of the yield to 95% was observed when 3.5 equivalents of thionyl chloride were used in THF, along with a catalytic amount of DMF and 40% aq.methylamine.
Route 2 was explored by synthesizing phenyl (4-hydroxyphenyl) carbamate (5) from the reaction of diphenyl carbonate (2.0 equiv) and amine (1.0 equiv) in aqueous organic medium in the presence of ammonium acetate under reflux reaction conditions, and this was followed by reaction with 4-chloro-N-methylpicolinamide (1) to synthesize the diaryl ether intermediate.This approach was to eliminate the formation of impurities arising from the aromatic nucleophilic substitution reactions of the free amino group present in 4-aminophenol molecule (Route 1).Different reaction conditions were explored such as use of a range of organic and inorganic bases (e.g., KOtBu, Cs 2 CO 3 , NaH and K 2 CO 3 ) in different solvents (e.g., acetone, DMF, THF) in a temperature range of 60 °C to 130 °C for 2-24 h to synthesize phenyl 4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl carbamate, but all failed to yield the desired product (Scheme 3), which was planned to react with 4-chloro-3trifluoromethyl aniline to afford sorafenib.
Finally, Route 3 (Scheme 4) was explored and instead of phenyl (4-hydroxyphenyl) carbamate ( 5), the reaction between phenyl 4-chloro-3-(trifluoromethyl)phenyl carbamate (3) and p-aminophenol in the presence of 1,4-diazabicyclo[2.4), which was reacted further with 4chloro-N-methylpicolinamide in the presence of KOtBu, and K 2 CO 3 , at different reaction temperatures, under Cu catalysed conditions, using TMEDA as ligand in the presence of DMF as a solvent, but to no avail and there was no sign of the desired product.

Scheme 5 A model reaction to understand diaryl ether formation
In all of the above reactions, diaryl ether synthesis was the bottleneck, and either no diaryl ether was formed or a low yield of ether was accompanied by the formation of a large amount of impurities.
Thereafter, it was decided to conduct a model reaction with 4-chloro-N-methylpicolinamide and 2-naphthol (Scheme 5) to prepare the diaryl ether.Different organic and inorganic bases (e.g., Cs 2 CO 3 , K 2 CO 3 , NaOH, Et 3 N, DBU) in different solvents were examined, and caesium carbonate in DMF was found to give the desired product within 2 h refluxing at 110 °C with complete consumption of starting     R. Prachi, M. S. Gill

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material and an isolated yield of ca.80%.The use of DBU or K 2 CO 3 gave a trace amount of the desired product after 48 h of refluxing and no reaction was observed in NaOH or Et 3 N.
Ultimately, phenyl 4-chloro-3-(trifluoromethyl)phenyl carbamate (3) and 4-(4-aminophenoxy)-N-methylpicolinamide (2) reacted in the presence of a catalytic amount of DABCO in acetonitrile at 60 °C for a duration of 1-2 h to afford sorafenib (8) in 54% isolated yield for the final step and overall yield of 45%.Likewise, reaction of phenyl 4-chloro-3-(trifluoromethyl)phenyl carbamate (3) with 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (7) afforded regorafenib (9) in 60% isolated yield and an overall yield of 41% for the process (Table 5) In conclusion, practical and efficient processes to access both sorafenib and regorafenib have been developed that avoid the use of hazardous and moisture-sensitive reagents such as phosgene, isocyanates, chroformates and carbonyldiimidazole.No inert environment was used during the process and in place of two bases, only one base was used.Overall yields for the synthesis of sorafenib and regorafenib were excellent considering the chemistry involved in the synthesis.
All reagents and starting materials were supplied by commercial sources and were used as such without purification unless otherwise noted.All reactions were performed in round-bottom flasks under reflux conditions and also in screw-capped vials.The progress of reactions were monitored by thin-layer chromatography (TLC).TLC plates were visualized under UV light and also in an iodine chamber.The 1 H and 13 C NMR spectra were obtained in DMSO-d 6 as a solvent using 500, 600 and 125, 151 MHz spectrometer, respectively, with internal reference standard of SiMe 4 .High-resolution mass spectra (HRMS) were obtained in electron spray ionization (ESI) mode and LC-MS/LTQ was obtained in APCI mode.Chemical shifts () are reported in parts per million (ppm), and coupling constants (J) are reported in Hz.The abbreviations used to characterize the signals are: s = singlet, d = doublet, dd = double of doublet, t = triplet, m = multiplet. 18solution of picolinic acid (5 g, 41.0 mmol) in anhydrous THF (8 mL) containing DMF (6.0 mmol) was heated to 50 °C, and to this mixture was added, dropwise, thionyl chloride (SOCl 2 ) (10.0 mL, 140.0 mmol), and the temperature of the reaction mixture was raised to 70 °C and kept at this temperature for 16 h.After cooling to room temperature, the reaction mixture was diluted and washed with toluene (twice) and dried under reduced pressure to obtain a dark-purple liquid.To this crude material (4.24 g) was added, portionwise, an aqueous solution containing 40% (w/w) methylamine (20 mL, 0.6 mol) and the above mixture was stirred at 0-10 °C for 4 h.Upon completion of the reaction, the reaction mixture was taken up in water and extracted with EtOAc (three times).The organic phase was dried with anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a dark-brown oil.Further purification of the crude material using column chromatography (dichloromethane/acetone) afforded 4-chloro-N-methylpicolinamide (1).

4-Chloro-N-methylpicolinamide (1)
a stirred solution of 4-aminophenol (3.0 mmol) in N,N-dimethyl formamide at room temperature was added caesium carbonate (3.0 mmol) and the reaction mixture was further stirred for 10 min.4-Chloro-N-methylpicolinamide (1) (3.0 mmol) was then added and the mixture was heated at 110 °C for 2 h.Upon completion of the reaction, the mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (4 × 20 mL).The combined organic layer was washed with water (2 × 15 mL), dried over anhydrous Na 2 SO 4 , and evaporated under reduced pressure to afford a red-brown oil, which was recrystallized from diethyl ether to give 4-(4-aminophenoxy)-N-methylpicolinamide (2).A suspension of diphenyl carbonate (5.0 mmol) and ammonium acetate (5.0 mmol) in a mixture of THF/H 2 O (10:90) was stirred at room temperature, and to this suspension was added 4-chloro-3-(trifluoromethyl)aniline (2.5 mmol), portionwise.The resulting reaction mixture was heated at reflux at 80 °C and, upon completion of the reaction as monitored by thin-layer chromatography, the product was extracted with EtOAc.The combined EtOAc fractions were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (hexane/EtOAc, 5-15%) to afford phenyl 4-chloro-3-(trifluoromethyl)phenyl carbamate (3).
To a dry round-bottom flask were added 10% Pd/C (1.5 mmol), 3-fluoro-4-nitrophenol (1.02 g, 6.5 mmol), water (5 mL), and sodium borohydride (13.0 mmol).The mixture was stirred at 25 °C for 30 min, then filtered through a filter paper and the solvent was evaporated under reduced pressure to afford the desired product.solution of 4-amino-3-fluorophenol (6) (1.0 mmol) in N,N-dimethyl sulfoxide at room temperature was treated with potassium tert-butoxide (1.0 mmol) and stirred for 10 min at room temperature.4-Chloro-N-methylpicolinamide (1) (1.0 mmol) was added and the mix-ture was then heated at 120 °C for 6 h.The mixture was cooled to room temperature, quenched with water (10 mL), and extracted with EtOAc (4 × 5 mL).The combined organics were washed with water (2 × 10 mL), dried over anhydrous MgSO 4 , and evaporated to afford a red-brown oil.The oil was taken up in diethyl ether (10 mL), washed with brine (5 × 10 mL), and the ether layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure to afford a darkbrown solid, which was recrystallized from diethyl ether to give 4-(4amino-3-fluorophenoxy)-N-methylpicolinamide (7).

Scheme 1
Summary of reported synthetic approaches to sorafenib and regorafenib

Table 5
Synthesis of Sorafenib and Regorafenib a Isolated yield.