反应详情

A mixture of mycophenolic acid (192 g, 0.6 mol) and 4-(2-hydroxyethyl)-morpholine (440 ml, 6 molar equivalents) was stirred at 150-155° C. for 4 hours in the presence of tin(II) chloride dihydrate (20.4 g, 0.15 molar equivalents) under nitrogen atmosphere. After the completion of the reaction, the reaction mixture was allowed to cool to room temperature. The obtained dark liquid was poured into isobutyl acetate (4.0 l). The solution was extracted with 2% of aqueous sodium bicarbonate solution (1.2 l, then 2×0.4 l). After the first addition of sodium bicarbonate solution the formed two-phase system was treated with charcoal (40 g) and filtrated (an emulsion was filtered off). The solution was extracted with water (1 l). -After phase separation the organic phase was washed with water (1 l) and evaporated to dryness at 40-50° C. under vacuum. To the solid material acetone (400 ml) and isopropanol (3.8 l) were added and the mixture was warmed to 40-45° C. (the material was dissolved). The solution was cooled to −5° C. during 6 hours and it was stirred at this temperature for 10-12 hours. After filtration, the crystals were washed with 2:19 acetone/isopropanol mixture (420 ml). The crude compound was dried in vacuum at 60° C. The yield was 169-195 g (65-75%). HPLC impurity profile: MPA=0.1%. Assay: 99.85%.

1. customAfter the completion of the reaction
2. extractionThe solution was extracted with 2% of aqueous sodium bicarbonate solution (1.2 l
3. additionAfter the first addition of sodium bicarbonate solution the formed two-phase system
4. additionwas treated with charcoal (40 g)
5. filtrationfiltrated (an emulsion
6. filtrationwas filtered off)
7. extractionThe solution was extracted with water (1 l)
8. custom-After phase separation the organic phase
9. washwas washed with water (1 l)
10. customevaporated to dryness at 40-50° C. under vacuum
11. additionTo the solid material acetone (400 ml) and isopropanol (3.8 l) were added
12. temperaturethe mixture was warmed to 40-45° C. (the material
13. dissolutionwas dissolved)
14. temperatureThe solution was cooled to −5° C. during 6 hours
15. filtrationAfter filtration
16. washthe crystals were washed with 2:19 acetone/isopropanol mixture (420 ml)
17. dry with materialThe crude compound was dried in vacuum at 60° C