Preparation of pharmaceutical salts of piperazine compounds
a technology of pharmaceutical salts and compounds, which is applied in the field of preparation of pharmaceutical salts of piperazine compounds, can solve the problems of high cost of process and inability to yield the desired salt in decent yields, and achieve the effect of high yields
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example 1
Preparation of the benzenesulfonic acid salt of the compound of Formula I (1:99)
[0109]A solution of amine compound of Formula I in isopropyl acetate (350 mL, 100 g active, 159 mmol) was diluted with ethanol (300 mL). To this solution was added benzenesulfonic acid (26.5 g, 1.05 eq) dissolved in isopropyl acetate (300 mL) at 0-10° C. The reaction mixture was heated at reflux for 3 hours and cooled slowly to room temperature. After a 2 hour hold, the slurry was filtered and the solids were washed 30% ethanol / isopropyl acetate and dried under vacuum. The isolated yield was 85%. The rotamer ratio was 1:99 by HPLC. m.p.: 257.7° C. (dec., DSC onset). 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 10.66 (br, s, 1H), 8.91 (s, 1H), 7.53 (m, 2H), 7.29 (m, 4H), 6.95 (t, J=8.2 Hz, 1H), 6.89 (d, J=7.5 Hz, 1H), 6.82 (d, J=9.2 Hz, 1H), 4.93 (br d, J=13.2 Hz, 1H), 3.84 (d, J=10.5 Hz, 1H), 3.64 (m, 2.5H), 3.53 (d, J=10.6 Hz, 0.5H), 3.41 (t, J=13.1 Hz, 1H), 3.32 (d, J=11.2 Hz, 0.5H), 3.22 (d, J=10.2 ...
example 2
Preparation of the d-10-camphorsulfonic acid salt of the compound of Formula I (98:2):
[0110]The solution of d-10-camphorsulfonic acid (12.4 g, 53 mmol) in ethyl acetate (68 mL) was slowly added to a solution of compound of Formula I (34.0 g, 1.02 eq) in ethyl acetate (136 mL). The resulting solution was warmed to 65° C. and held at this temperature overnight. The heterogeneous mixture was cooled slowly to 0° C. and filtered. The solids were washed with ethyl acetate and dried in a vacuum oven to give a white solid (38.2 g, 81% yield). The rotamer ratio was 98:2 by HPLC. m.p.: 260.6° C. (dec., DSC onset). 1H NMR (400 MHz, CDCl3): δ 8.9 (s, 1H), 7.3 (br s, 1H), 7.0 (m, 3H), 5.0 (br d, 1H), 4.0 (br d, 1H), 3.3-3.7 (m, 4H), 3.3 (br d, 1H), 3.1 (m, 1H), 2.7-3.0 (m, 7H), 2-2.6 (m, 15H), 1.9 (m, 5H), 1.8 (m, 2H), 1.6 (m, 4H), 1.0-1.5 (m, 14H), 88 (s, 3H).
example 3
Glutaric acid salt of the compound of Formula I (3:97)
[0111]Compound of Formula I (2.6 g, 4.2 mmol) and glutaric acid (0.51 g, 1 eq) were mixed in 2.5 mL acetonitrile. The mixture was heated at 75-80° C. for 2 hours. After cooled slowly to room temperature, it was stirred overnight. The resulting slurry was filtered, washed with acetonitrile, and dried under vacuum to give a white solid (2.2 g, 70% yield). m.p.: 106.8° C. (DSC onset). Rotamer ratio was 3:97 by HPLC. 1H NMR (400 MHz, CDCl3): δ 8.91 (s, 1H), 7.29 (dd, J1=14.0 Hz, J2=7.8 Hz, 1H), 6.97 (dt, J1=8.4 Hz, J2=1.9 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 6.80 (d, J=10.1 Hz, 1H), 3.94 (br d, J=14.1 Hz, 1H), 3.85 (br d, J=12.0 Hz, 1H), 3.68 (br d, J=12.3 Hz, 1H), 3.63 (d, J=10.4 Hz, 1H), 3.50 (m, 1H), 3.23 (m, 1H), 2.79 (m, 1H), 2.72 (m, 2H), 2.63 (d, J=10.5 Hz, 2H), 2.43 (s, 3H), 2.40 (t, J=6.9 Hz, 4H), 2.36 (s, 3H), 2.22 (m, 5H), 2.00 (m, 7H), 1.74 (br d, J=13.2 Hz, 1H), 1.20-1.48 (m, 5H), 1.12 (m, 6H), 0.94 (m, 5H).
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