Process for the preparation of pleuromutilins
Process for the preparation of a compound of formula I in the form of a single stereoisomer in crystalline form, comprising deprotecting the amine group in a compound of formula IIa or in a mixture of a compound of formula IIa with a compound of formula IIb and isolating a compound of formula I from the reaction mixture; compounds and salts of compounds of formula I in crystalline form; pharmaceutical compositions comprising such salts; processes for the preparation of intermediates and intermediates in a process for the preparation of a compound of formula I.
1. A compound of formula I
in the form of a single stereoisomer in crystalline form selected from the group consisting of:
crystalline Form 1, which is characterized by an X-ray powder diffraction pattern having at least two peaks 2-theta at (degrees, ±0.2): 10.6, 11.1, 12.0, 14.3, 15.1, 16.1, or 21.1;
crystalline Form 2, which is an n-butanol solvate characterized by an X-ray powder diffraction pattern having at least two peaks 2-theta at (degrees, ±0.2): 9.8, 11.1, 13.1, 14.1, 17.6, 19.7, or 22.2;
an acetate in crystalline Form A, which is characterized by an X-ray powder diffraction pattern having at least four peaks 2-theta at (degrees, ±0.2): 7.0, 7.7, 11.6, 12.1, 12.6, 13.5, 13.7, 15.4, 15.7, 16.9, 17.3, 19.0, 19.9, 21.1, 23.4, 24.2, or 24.4;
an acetate in crystalline Form B, which is characterized by an X-ray powder diffraction pattern having at least four peaks 2-theta at (degrees, ±0.2): 10.3, 10.7, 12.7, 14.3, 15.5, 16.0, 17.2, 19.5, 20.6, or 22.9;
an L-lactate in crystalline Form 1, which is characterized by an X-ray powder diffraction pattern having at least two peaks 2-theta at (degrees, ±0.2): 7.0, 11.6, 12.0, 12.5, 13.4, 13.6, 13.9, 15.3, 16.8, 18.8, 19.5, 19.8, 20.9, 23.3, 23.9, or 24.2; and
a hydrogenmaleate in crystalline Form 1, which is characterized by an X-ray powder diffraction pattern having at least two peaks 2-theta at (degrees, ±0.2): 7.0, 11.3, 11.7, 12.5, 13.5, 13.8, 15.3, 16.7, 18.3, 19.4, 19.7, 21.1, 22.2, 23.8, or 23.9.
2. A compound according to claim 1 , which is in crystalline Form 1.
3. A compound according to claim 2 , in which the compound in crystalline Form 1 is characterized by an X-ray powder diffraction pattern having peaks 2-theta at (degrees, ±0.2): 10.6, 11.1, 12.0, 14.3, 15.1, 16.1, and 21.1.
4. A compound according to claim 1 , which is in crystalline Form 2.
5. A compound according to claim 4 , in which the compound in crystalline Form 2 is characterized by an X-ray powder diffraction pattern having peaks 2-theta at (degrees, ±0.2): 9.8, 11.1, 13.1, 14.1, 17.6, 19.7, and 22.2.
6. A compound according to claim 1 , which is in the form of a crystalline salt.
7. A compound according to claim 6 , wherein the crystalline salt is an acetate, lactate or hydrogenmaleate.
8. A compound according to claim 1 , which is an acetate in crystalline Form A.
9. A compound according to claim 8 , in which the acetate in crystalline Form A is characterized by an X-ray powder diffraction pattern having peaks 2-theta at (degrees, ±0.2): 7.0, 7.7, 11.6, 12.1, 12.6, 13.5, 13.7, 15.4, 15.7, 16.9, 17.3, 19.0, 19.9, 21.1, 23.4, 24.2, and 24.4.
10. A compound according to claim 1 , which is an acetate in crystalline Form B.
11. A compound according to claim 10 , in which the acetate in crystalline Form B is characterized by an X-ray powder diffraction pattern having peaks 2-theta at (degrees, ±0.2): 10.3, 10.7, 12.7, 14.3, 15.5, 16.0, 17.2, 19.5, 20.6, or 22.9.
12. A compound according to claim 1 , which is an L-lactate in crystalline Form 1.
13. A compound according to claim 12 , in which the L-lactate in crystalline Form 1 is characterized by an X-ray powder diffraction pattern having peaks 2-theta at (degrees, ±0.2): 7.0, 11.6, 12.0, 12.5, 13.4, 13.6, 13.9, 15.3, 16.8, 18.8, 19.5, 19.8, 20.9, 23.3, 23.9, and 24.2.
14. A compound according to claim 1 , which is a hydrogenmaleate in crystalline Form 1.
15. A compound according to claim 14 , in which the hydrogenmaleate in crystalline Form 1 is characterized by an X-ray powder diffraction pattern having peaks 2-theta at (degrees, ±0.2): 7.0, 11.3, 11.7, 12.5, 13.5, 13.8, 15.3, 16.7, 18.3, 19.4, 19.7, 21.1, 22.2, 23.8, or 23.9.
16. A pharmaceutical composition comprising the compound according to claim 1 as an active ingredient in combination with a pharmaceutically acceptable carrier or diluent.
17. A pharmaceutical composition comprising the compound according to any one of claim 2 , 8 , 10 , 12 , or 14 as an active ingredient in combination with a pharmaceutically acceptable carrier or diluent.
18. A process for the preparation of the compound of formula I according to claim 1 , comprising deprotecting the amine group
either in a compound of formula IIa
or in a mixture of a compound of formula IIa with a compound of formula IIb
wherein R is an amine protecting group, and
isolating a compound of formula I obtained in the form of a single diastereomer in crystalline form either directly from the reaction mixture or via recrystallization in organic solvent.
19. A process according to claim 1 , wherein R in the compound of formula IIa is tert-butoxycarbonyl or trifluoroacetyl.
20. A pharmaceutical composition comprising the compound according to any one of claims 3 to 15 as an active ingredient in combination with a pharmaceutically acceptable carrier or diluent.