Decernotinib

753-90-2

1417421-82-9

944842-54-0

Example 4a: Procedure for the synthesis of (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (Ia): 1. to a solution of (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a) (3.5 kg, 11.24 mol, 1.0 eq.) dissolved in 7 vol. (32.6 kg) of dichloromethane (DCM) at <30°C was added diisopropylethylamine (DIEA) (3.61 kg, 28.1 moles, 2.5 equivalents). 2. The total water content of the reaction system was adjusted to 5.5 ± 0.5% by addition of water (0.103 kg) and stirred at <30°C for at least 30 minutes. 3. cool the reaction mixture to 0±5°C and slowly add propylphosphonic anhydride solution (17.9 kg, 28.1 moles, 2.5 eq.), keeping the temperature below 20°C. 4. after stirring at 20±5°C for at least 1 hour, 2,2,2-trifluoroethylamine (1.68 kg, 16.86 mol, 1.5 eq.) was added, keeping the temperature below 20°C. 5. the reaction mixture was warmed to 25±5°C and stirred for 5 hours until the reaction was complete (confirmed by HPLC). 6. add water (17.5 kg, 5 v/v) and stir at <30°C for at least 30 min. 7. Concentrate the mixture under vacuum at <45°C using a rotary evaporator. 8. Add isopropyl acetate (1.55 kg, 0.5 v/v) and adjust pH to 7.5-8.0 with 6N NaOH solution at < 35°C. 9. Cool to 10±5°C and stir for at least 1 h. Re-adjust pH to 7.5-8.0 with 6N HCl if necessary. 10. Filter the slurry, wash the filter cake with water (10.5 kg, 3 v/v) and keep under positive nitrogen pressure for at least 30 minutes. 11. Dissolve the wet filter cake in methanol (44.7 kg, 12 v/v), add PL-BnSH MP-Resin (0.235 kg, 5% w/w) and treat for at least 12 hours at 25±5°C. 12. The mixture was filtered and the solids were washed with methanol (2.77 kg, 1 volume). 13. The filtrate is concentrated under vacuum at <50°C without drying and allowed to stand at room temperature for about 2.5 days with stirring. 14. Heat to 40°C, slowly add preheated water (56.1 kg, 45°C), keep at 45±5°C, rotate for 1 hour and further concentrate methanol. 15. Cool to 5±5°C, stir for at least 2 h. Filter the product and wash with water (10.5 kg, 3 v/v). 16. The filter cake was kept under positive pressure of nitrogen for at least 30 minutes and dried under vacuum to constant weight to give the target product (4.182 kg, white powder). [0412] The resulting (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butyramide (Ia) was analyzed by XRPD, TGS, and DSC, and the results are shown in Figures 5-7.