反应详情

温度

35 °C

A stirred suspension of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (7.76 g, 15 mmol, containing about 9 wt % TBME) in acetone (15 ml) is warmed to 35° C. To the mixture is added a solution of methanesulfonic acid (1.43 g, 14.85 mmol) in water (3.33 g) over 20 min. After 15 min, the solution is warmed to 45° C. and clear filtered into a warm flask (about 45° C.). The filter is rinsed with acetone/water 9:1 (v/v, 12 ml). The 45° C. warm filtrate is diluted with acetone (53 ml) over 30 min and seeded with 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide methanesulfonic acid salt (4 mg) whereupon crystallization begins. After 1 h at 45° C. acetone (30 ml) is added. The suspension is stirred at 45° C. for 1 h before it is cooled to 24° C. over 90 min. TBME (20 ml) is added, and the suspension is stirred at about 24° C. for 15 h. Two more portions of TBME (20 ml each) are added followed by 2 h stirring each time. Thereafter, the suspension is cooled to 0-5° C. and stirred for 3 h before it is filtered. The filter cake is washed with acetone/tert-butyl methyl ether 3:1 (v/v) and dried under reduced pressure at 50° C. for about 17 h to give 7.18 g (85%) of the title compound as a white, crystalline powder.

1. temperaturethe solution is warmed to 45° C.
2. filtrationclear filtered into a warm flask (about 45° C.)
3. washThe filter is rinsed with acetone/water 9:1 (v/v, 12 ml)
4. temperatureThe 45° C. warm filtrate
5. additionis diluted with acetone (53 ml) over 30 min
6. customseeded with 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide methanesulfonic acid salt (4 mg) whereupon crystallization
7. additionAfter 1 h at 45° C. acetone (30 ml) is added
8. temperatureis cooled to 24° C. over 90 min
9. additionTBME (20 ml) is added
10. stirringthe suspension is stirred at about 24° C. for 15 h
11. additionTwo more portions of TBME (20 ml each) are added
12. waitfollowed by 2 h
13. stirringstirring each time
14. temperatureThereafter, the suspension is cooled to 0-5° C.
15. stirringstirred for 3 h before it
16. filtrationis filtered
17. washThe filter cake is washed with acetone/tert-butyl methyl ether 3:1 (v/v)
18. customdried under reduced pressure at 50° C. for about 17 h