Example 2: Synthesis of (R)-5-methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-chloro-phenyl)-amido]5-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amido}
Step 1. Synthesis of (3aS,6R,7aR)-1-methacryloyl-8,8-dimethylhexahydro-3a,6-methylene-2,1-benzisothiazole-2,2-dioxide (1S)-(-)-2,10-camphorsulfonate
To a solution of (1S)-(-)-2,10-camphorsulfonamide (1.160 g, 5.388 mmol) in toluene (10 ml) was added sodium hydride (60% oil, 0.323 g, 8.08 mmol). After stirring for 1.5 h, methacryloyl chloride (1.126 g, 10.78 mmol) was added directly to the reaction mixture. The mixture was stirred overnight at room temperature, followed by evaporation of the solvent. The residue was extracted into ethyl acetate, washed with 1N HCl, dried with MgSO4, evaporated in vacuum and purified by chromatography (0-20% EtOAc in hexane solution) to afford the target compound (1.240 g, 81%).
1H NMR (400MHz, DMSO-D6) δ ppm: 0.90 (s, 3H), 1.08 (s, 3H), 1.23 (m, 1H), 1.42 (m, 1H), 1.78 (m, 5H), 1.81 (m, 3H), 3.26 (s, 4H), 3.56 (d, J = 14.04Hz, 1H), 3.77 (d , J = 14.04Hz, 1H), 3.91 (m, 1H), 5.48 (s, 1H), 5.60 (s, 1H).
