The general procedure for the synthesis of N-((S)-1-amino-3-(3-fluorophenyl)propan-2-yl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)thiophene-2-carboxamide as a hydrochloride salt was as follows: 5 mL of methyl tert-butyl ether (MTBE) was added to 213.9 mg (0.500 mmol) of the amorphous free base and the mixture was heated under magnetic The mixture was heated to 40 °C under magnetic stirring and maintained for 1 hour. Subsequently, a 1,4-dioxane solution of 4 M HCl was added in four additions (totaling 1 equiv, 125.1 μL). After the first addition of 0.25 equivalents of HCl solution, the mixture was heated to 42 °C and 1 mL of acetonitrile was added to completely dissolve the solid. After the remaining HCl solution was added, solid precipitation was observed. The slurry was stirred at 42°C for 4 hours, then held sequentially at 35°C, 30°C, and 25°C for 90 minutes each at a rate of 5°C per hour, and finally cooled slowly to 22°C overnight. The white solid was collected by filtration and dried under vacuum at 50 °C while slowly purged by passing nitrogen overnight. The yield of the resulting hydrochloride was 73.6% (0.3685 mmol, 170.90 mg). The product was confirmed to be HCl salt with stoichiometric ratio of 1:1 by ion chromatography analysis, and the powder X-ray diffraction (PXRD) pattern (Figure 1) showed it to be in the crystalline state, with the following characteristic diffraction peaks, and a melting point of 211 °C. The characteristic PXRD peaks (2θ values, with d-spacing in parentheses): 7.2° (12.20 ) , 14.4° (6.16 ) , 17.9° (4.94 ) , 18.5° (4.79 ) , 20.8° (4.26 ) , 21.5° (4.12 ) , 22.4° (3.96 ) , 22.9° (3.88 ) , 23.7° (3.75 ) , 24.5° (3.63 ) , 24.7° (3.61 ) , 25.1° (4.12 ) , 25.7° (3.46 ) , 27.3° (3.26 ) , 28.2° (3.16 ) , 28.8° (3.10 ) , 30.4° (2.94 ) , 32.4° (2.76 ) , 32.7° (2.73 ) , 35.2° (2.55 ) , 36.1° (2.48 ) , 40.0° (2.25 ) , 41.3° (2.18 ) , 41.7° (2.16 ) The Measuring instrument: Panaco X'Pert-Pro MPD diffractometer with Johansson monochromator (Cu Kα1 radiation, wavelength 1.540598 ) and X'Celerator detector. Key test parameters: voltage 45 kV, current 40 mA, start angle 2.0° 2θ, end angle 52.0° 2θ, step size 0.02°, counting time per step 40.0 s, scanning speed 0.05°/sec. Incident beam configuration: 2° fixed anti-scattering slit, programmable divergence slit; diffraction beam configuration: 0.02 rad Soller slit, programmable anti-scattering slit. Samples were prepared on a silicon zero background sample holder.
