7.35 g |
In ethanol at 20 - 70℃; for 6h; |
9A
2-((5-chloro-2-((4-((4-methylpiperazin- 1 -yl)methyl)phenyl)amino)pyrimidin-4- yl)amino)-N,N-dimethylbenzenesulfonamide (5 g, 9.69 mmol) was dissolved in anisole (75 g) and EtOH (30 g) at 70 °C. Tartaric acid (2.91 g, 19.38 mmol) dissolved in EtOH (30 g) was added to the mixture over 1 h, then small amount of seed crystal* was added to the solution to initiate the precipitation. The mixture was stirred for 1 h and cooled to 20 °C over 5 h. The solid was collected by filtration, washed with EtOH and dried to afford 2-((5-chloro-2-((4- ((4-methylpiperazin-l-yl)methyl)phenyl)amino)pyrimidin-4-yl)amino)-N,N- dimethylbenzenesulfonamide di-tartrate salt as a white solid (7.35 g, 9.01 mmol). (0232) [223] The purity of the desired product was assessed to be 99.5% by HPLC. (0233) [224] NMR (400 MHz, DMSO-riri) d = 9.56 (s, 1H), 9.33 (s, 1H), 8.58 (s, J = 8.0 Hz, (0234) 1H), 8.29 (s, 1H), 7.83 (dd, J = 8.0, 1.6 Hz, 1H), 7.71 (td, J = 7.2, 1.4 Hz), 7.57 (d, J = 8.4 Hz, 2H), 7.38 (td, J = 7.2 Hz, J = 1.0 Hz), 7.18 (d, J = 8.4 Hz, 2H), 4.19 (s, 4H), 3.51 (s, 2H), 2.86 (bs, 3H),2.65 (s, 6H), 2.60-2.50 (m, 8H) (0235) [225] Proton signals at 4.19 and 3.51 ppm correspond to tartaric acid. Based on the integration of those peaks, tartaric acid to Compound 1 was consistently 2:1. (0236) [226] * Note: Seed crystals of Form A were obtained by combining 2-((5-chloro-2-((4-((4- methylpiperazin-l-yl)methyl)phenyl)amino)pyrimidin-4-yl)amino)-N,N- dimethylbenzenesulfonamide and tartaric acid in anisole/ethanol under the conditions specified above, followed by initiation of crystal formation using one or more techniques such as (1) cooling the solution (e.g., to room temperature, or in a freezer), (2) concentrating the solution (e.g., by slow evaporation, or with a rotary evaporator), and/or (3) scratching the interior of the flask containing the solution. Crystals obtained in this manner were confirmed to be of Form A by 1HNMR and XRPD analysis. |