Processes for making, and methods of using, glycopyrronium compounds
Provided herein are processes for making and methods of using salts of glycopyrronium, including solid forms and forms suitable for use as topicals. Disclosed here are processes for making salts of glycopyrronium, also processes for making compositions comprising salts of glycopyrronium, and methods of treating hyperhidrosis with salts of glycopyrronium as well as with compositions comprising salts of glycopyrronium such as, but not limited to, topical compositions. Disclosed herein are methods of treating hyperhidrosis including administering salts of glycopyrronium to subjects in need thereof.
1. A process for making a compound of Formula (I):
wherein:
R 1 and R 2 are each, independently in each instance, selected from alkyl and alkyl substituted with alkoxycarbonyl;
the stereochemical configuration about the carbon atom indicated by 2 is R;
the stereochemical configuration about carbon atom indicated by 3′ is R;
X − is an anion;
wherein the process comprises:
contacting compound (1) with pivaldehyde to form compound (2):
contacting compound (2) with LiHMDS and cyclopentyl bromide to form compound (3):
contacting compound (3):
with methanolic potassium hydroxide to form a compound (4):
and contacting compound (4) with a compound of Formula (Ib) under coupling conditions to form a compound of Formula (Ic):
and contacting a compound of Formula (Ic) with a compound of Formula (Id) to make a compound of Formula (I):
2. The process of claim 1 , further comprising:
isolating a stereomerically pure stereoisomer of a compound of Formula (I).
3. The process of claim 2 , wherein isolating a stereomerically pure stereoisomer of a compound of Formula (I) is by column chromatography or by simulated moving bed (SMB) separation.
4. The process of claim 1 , wherein R 1 is alkyl.
5. The process of claim 4 , wherein R 1 is methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, n-pentyl, or i-pentyl.
6. The process of claim 5 , wherein R 1 is methyl or ethyl.
7. The process of claim 1 , wherein R 2 is alkyl.
8. The process of claim 7 , wherein R 2 is methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, n-pentyl, or i-pentyl.
9. The process of claim 8 , wherein R 2 is methyl or ethyl.
10. The process of claim 1 , wherein R 1 is alkyl substituted with alkoxycarbonyl.
11. The process of claim 10 , wherein R 1 —CH 2 C(O)OCH 2 CH 3 .
12. The process of claim 11 , wherein R 2 is methyl.
13. The process of claim 1 , wherein during the contacting of compound (4) with a compound of Formula (Ib) under coupling conditions to form a compound of Formula (Ic), compound (4) and Formula (Ib) are stereomerically pure.
14. The process of claim 1 , wherein the compound of Formula (I) has the following structure (Ia1) or (Ia2):
15. The process of claim 1 , wherein the compound of Formula (I) comprises a compound having the following structure:
16. The process of claim 1 , wherein the compound of Formula (I) comprises a mixture of compounds having the following structures:
17. The process of claim 1 , wherein the compound of Formula (I) is the following:
18. The process of claim 1 , wherein the compound of Formula (I) is the following:
19. The process of claim 1 , wherein the compound of Formula (I) is the following:
20. The process of claim 1 , wherein during the contacting of compound (4) with a compound of Formula (Ib) under coupling conditions to form a compound of Formula (Ic), a compound of Formula (Ib-s) is present:
21. The process of claim 2 , wherein isolating compound (Ic) from a mixture compound (Ic) and its stereoisomers comprises using chiral resolution agents and salts.
22. The process of claim 1 , wherein R 1 and R 2 are both alkyl.
23. The process of claim 1 , wherein X − is halide.
24. The process of claim 23 , wherein X − is selected from the group consisting of F − , Cl − , Br − , I − and combinations thereof.
25. The process of claim 1 , wherein the compound of Formula (Ib) is compound (7):
26. The process of claim 1 , wherein the compound of Formula (Ic) is compound (8):
27. The process of claim 1 , wherein the compound of Formula (I) is the following compound:
28. The process of claim 1 , wherein the compound of Formula (I) is compound (9):
29. The process of claim 1 , wherein the compound of Formula (Id) is the following compound:
30. The process of claim 1 , wherein the compound of Formula (Id) is the following compound:
31. The process of claim 1 , comprising crystallizing the compound (4).
32. The process of claim 1 , wherein the compound of Formula (Ib) is compound (7):
wherein and the process comprises producing compound (7) by contacting compound (6) with a reducing agent:
33. The process of claim 32 , wherein the process comprises producing compound (6) by contacting R(−)-malic acid, compound (5), with methyl amine:
34. A composition comprising a mixture of compounds having following structures (Ia1a) and (Ia1b):
wherein the compounds having structures (Ia1a) and (Ia1b) are prepared by the process of claim 1 .
35. A composition comprising a compound having following structure:
wherein the compound is prepared by the process of claim 1 .
36. A method of treating hyperhidrosis, comprising administering to a subject in need thereof a composition comprising a compound prepared by the process of claim 1 .
37. A method of treating a disease or disorder marked by a need for an anticholinergic agent, comprising administering to a subject in need thereof a composition comprising a compound prepared by the process of claim 1 .