*3.1.1.2.3 Case study 3: synthesis of Dabrafenib [trade name Tafinlar, N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6 difluorobenzenesulfonamide, GSK2118436, (60)]*

Rheault and his colleagues reported the synthesis of Dabrafenib (GSK2118436, (60)) (**Figure 7**). The strategy depends on synthesizing the building blocks starting from the bromobenzoic acid derivative (52) and the sulfonamide (56). The coupling to pyrimidine moiety was performed via a nucleophilic substitution of 2-chloro-4 methylpyrimidine (61) facilitated by lithiation of the 4-methyl using LiHMDS. The yield of this step was recorded as high. The synthesis of the core substituted thiozole (59) was accomplished via bromination of the benzylic/alpha carbon of (58) using NBS and reacting the intermediate with 2,2,2- trimethylthioacetamide either in polar aprotic solvent like DMF or DMA [69].

The second substitution at N2-pyrimidine was accomplished by either concentrated ammonia (7 N NH3) in methanol in sealed tube under heating of 100°C or under acidic facilitated substitution (using HCl in 2,2,2-trifluoroethanol as solvent) when the amine

#### **Figure 6.**

*Synthesis of Spebrutinib (51) [CC-292, AVL2923, (5 N-[3-[[5-fluoro-2-[4-(2-methoxyethoxy)anilino] pyrimidin-4-yl]amino]phenyl]prop-2-enamide]. Reagents and conditions: a) DMA, reflux; b) DMA, reflux; c) TFA, DCM, r.t, acyl halide,TEA, r.t.*

(= R2NH2 amine) and microwave at elevated temperature of 180°C. This step of attaching 2-chloro-4-methylpyrimidine (61) to methyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (57) was reported to proceed (71%) and afforded N-{3- [(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide as title compound that is a mixture of keto-enol **Figures 8**, 58a \$ 58b). The second substitution was performed following the formation of the thiazole central moiety and afforded N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)- 1,3-thiazol-4-yl]-2 fluorophenyl}-2,6-difluorobenzenesulfonamide (60) in 47% yield.

The 2,4-disubstitution regioisomer selectivity around the pyrimidine core was granted by using the 2-methyl-4-chloropyrimidine substrate [65–68, 70]. Other recent report confirmed the feasibility, high yield and regio-selective coupling using 2-methyl-4-chloropyrimidine [65–68].
