Claims for Patent: 9,120,727

Summary for Patent: 9,120,727

Title:	Process for the preparation of pleuromutilins
Abstract:	Process for the preparation of a compound of formula I ##STR00001## in the form of a single stereoisomer in crystalline form, comprising deprotecting the amine group in a compound of formula IIa ##STR00002## or in a mixture of a compound of formula IIa with a compound of formula IIb ##STR00003## 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.
Inventor(s):	Riedl; Rosemarie (Vienna, AT), Heilmayer; Werner (Zillingtal, AT), Spence; Lee (Vienna, AT)
Assignee:	NABRIVA THERAPEUTICS AG (Vienna, AT)
Application Number:	13/699,589
Patent Claims:	1. A compound of formula I ##STR00050## 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 ##STR00051## or in a mixture of a compound of formula IIa with a compound of formula IIb ##STR00052## 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.