反应详情

温度

22 °C

Crystalline 3′-amino-2′-hydroxybiphenyl-3-carboxylic acid form II (50 g, 218 mmol, PXRD pattern at FIG. 34) (Supplier: Topharman Shangai Co., Ltd; Batch No: BPCA: 090921BPCA) was added to a solvent mixture of methanol (1 L) and hydrochloric acid, 4 M (137 mL) in a 1 L reactor with stirring at room temperature (cca 22° C.). The resulting solution was stirred for ½ h and then cooled to 0-5° C. A refrigerated solution of sodium nitrite (15 g, 217 mmol) in water (50 mL) was added to the reaction mixture over 20 min (maintaining the reaction temperature below 10° C.) and the stirring was continued for 1 h. A Solution of sulfamic acid (2.22 g, 23 mmol) in water (50 mL) was added to the reaction mixture and stirred for 1 h at 5° C. The resulting reaction mixture was heated to room temperature and triethylamine (cca 80 mL) was added to adjust to pH 7-8. Crystalline 1-(3,4-dimethylphenyl)-3-methyl-1H-pyrazol-5-ol (“pyrazole”) form II (44 g, 218 mmol, PXRD pattern at FIG. 33) (Supplier: Topharman Shangai Co., Ltd; Batch No: 090805PYRAZOL) was added in one portion to the reaction mixture and stirred for 2 h at room temperature, maintaining the pH 7-8. Hydrochloric acid (4 M, cca 40 mL) was added to adjust the pH to 1.8 over 20 minutes with stirring. The precipitated solid was filtered, washed with mixture of MeOH:water (1:1, 60 mL) and dried at 40° C./5 bar for about 18 h to yield 100 g (90%) of EBP as a bright orange powder. PXRD analysis provided the diffractogram as shown in FIG. 20. DSC analysis provided the thermogram as shown in FIG. 21

1. stirringThe resulting solution was stirred for ½ h
2. temperaturecooled to 0-5° C
3. temperaturemaintaining the reaction temperature below 10° C.) and the stirring
4. stirringstirred for 1 h at 5° C
5. customThe resulting reaction mixture
6. temperaturewas heated to room temperature
7. stirringstirred for 2 h at room temperature
8. temperaturemaintaining the pH 7-8
9. customover 20 minutes
10. stirringwith stirring
11. filtrationThe precipitated solid was filtered
12. washwashed with mixture of MeOH:water (1:1, 60 mL)
13. customdried at 40° C./5 bar for about 18 h
14. customto yield 100 g (90%) of EBP as a bright orange powder
15. customPXRD analysis provided the diffractogram
16. customDSC analysis provided the thermogram