Process for the preparation of midostaurin with high purity
A process for the preparation of midostaurin with high purity, particularly a process for the preparation of midostaurin with a content of oxidation impurities lower than 0.1% comprising the treatment of crude midostaurin or staurosporine with strong organic or inorganic acids in a water-immiscible solvent and, optionally, also with reducing silanes is described.
1. A process for the preparation of midostaurin with high purity, that is with a content of 3-hydroxymidostaurin impurities (III) and (IV) lower than 0.1%, comprising treating crude midostaurin with strong organic or inorganic acids in a water-immiscible solvent and, optionally, also with reducing silanes.
2. The process according to claim 1 , further comprising treating the crude midostaurin with a reducing silane.
3. A process for the preparation of midostaurin with high purity, that is with a content of 3-hydroxymidostaurin impurities (III) and (IV) lower than 0.1%, comprising treating crude staurosporine with a strong organic or inorganic acid, optionally with the concomitant addition of a reducing silane.
4. The process according to claim 1 , wherein the water-immiscible solvent is an aprotic polar water-immiscible solvent.
5. The process according to claim 4 wherein the water-immiscible solvent is dichloromethane, dichloroethane, methyl tetrahydrofuran or methylethylketone.
6. The process according to claim 1 , wherein the strong acid is trifluoroacetic acid.
7. The process according to claim 1 , wherein the reducing silane is triethylsilane.
8. The process according to claim 3 , further comprising the benzoylation reaction of staurosporine to midostaurin wherein the benzoylation reaction is quenched with an aqueous solution having a slightly acid pH.
9. The process according to claim 8 wherein the aqueous solution having a slightly acid pH is an aqueous ammonium chloride solution.
10. The process of claim 1 , wherein the purified midostaurin is obtained by crystallization from 2-MeTHF and is isolated by:
dissolving the crystallized midostaurin in a water-miscible polar solvent,
adding water
isolating purified midostaurin as an amorphous solid obtained by filtering and drying, with a content of organic solvents <50 ppm.
11. The process for the preparation of purified midostaurin according to claim 10 , wherein the polar solvent is ethanol.
12. The process according to claim 5 , wherein the water-immiscible solvent is dichloromethane.
13. The process according to claim 3 , wherein the water-immiscible solvent is an aprotic polar water-immiscible solvent.
14. The process according to claim 13 wherein the water-immiscible solvent is dichloromethane, dichloroethane, methyl tetrahydrofuran or methylethylketone.
15. The process according to claim 14 , wherein the water-immiscible solvent is dichloromethane.
16. The process according to claim 3 , wherein the strong acid is trifluoroacetic acid.
17. The process according to claim 3 , wherein the reducing silane is triethylsilane.