Synthetic methods for preparation of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1,-a]isoquinolin-2-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate)

Patent metadata

Field	Value
Publication number	US-10906902-B2
Application number	US-202016929694-A
Country	US
Kind code	B2
Filing date	Jul 15, 2020
Priority date	Dec 23, 2015
Publication date	Feb 2, 2021
Grant date	Feb 2, 2021

Abstract

Provided herein are processes for the preparation of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or a solvate, hydrate, or polymorph thereof.

First claim

What is claimed is:

1. A VMAT2 inhibitor that is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) prepared by a method comprising a step of converting (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate dihydrochloride to (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate).

2. The VMAT2 inhibitor of claim 1 , wherein the step of converting (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate dihydrochloride to (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) comprises: (a) reacting (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate dihydrochloride with a base, and (b) reacting the product of (a) with p-toluenesulfonic acid.

3. The VMAT2 inhibitor of claim 1 , wherein (5)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) has an impurity profile comprising total impurities in an amount that is no greater than about 5% by weight.

4. The VMAT2 inhibitor of claim 3 , wherein the impurity profile comprises total impurities in an amount that is no greater than about 3% by weight.

5. The VMAT2 inhibitor of claim 3 , wherein the impurity profile comprises total impurities in an amount that is no greater than about 2% by weight.

6. The VMAT2 inhibitor of claim 3 , wherein the impurity profile comprises total impurities in an amount that is no greater than about 1% by weight.

7. The VMAT2 inhibitor of claim 3 , wherein the impurity profile comprises total impurities in an amount that is no greater than about 0.5% by weight.

8. The VMAT2 inhibitor of claim 3 , wherein the impurity profile comprises total impurities in an amount that is no greater than about 0.1% by weight.

9. The VMAT2 inhibitor of claim 3 , wherein the impurity profile comprises one or more impurities chosen from: (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof, (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-aminopropanoate, and (S)-(2S,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate.

10. The VMAT2 inhibitor of claim 3 , wherein the impurity profile comprises (R)-(2R,3R,11bR)-3-isobutyl-9,10,11b-trimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate.

11. The VMAT2 inhibitor of claim 3 , wherein the impurity profile comprises 6,7-dimethoxy-3,4-dihydroisoquinoline.

12. The VMAT2 inhibitor of claim 3 , wherein the impurity profile comprises (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-7-oxo-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate.

13. The VMAT2 inhibitor of claim 3 , having an impurity profile comprising one or more impurities chosen from metal-based impurities.

14. The VMAT2 inhibitor of claim 3 , having an impurity profile comprising one or more impurities chosen from dimethylamine, formaldehyde, ethyl chloride, and isopropyl chloride.

15. The VMAT2 inhibitor of claim 1 , wherein (5)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) has a weight loss on drying (LOD) of no greater than about 5% by weight.

16. The VMAT2 inhibitor of claim 15 , having a weight loss on drying (LOD) of no greater than about 4% by weight.

17. The VMAT2 inhibitor of claim 15 , having a weight loss on drying (LOD) of no greater than about 3% by weight.

18. The VMAT2 inhibitor of claim 15 , having a weight loss on drying (LOD) of no greater than about 2% by weight.

19. The VMAT2 inhibitor of claim 15 , having a weight loss on drying (LOD) of no greater than about 1% by weight.

20. The VMAT2 inhibitor of claim 15 , having a weight loss on drying (LOD) of no greater than about 0.8% by weight.

21. The VMAT2 inhibitor of claim 15 , having a weight loss on drying (LOD) of no greater than about 0.6% by weight.

22. The VMAT2 inhibitor of claim 15 , having a weight loss on drying (LOD) of no greater than about 0.4% by weight.

23. The VMAT2 inhibitor of claim 15 , having a weight loss on drying (LOD) of no greater than about 0.2% by weight.

24. The VMAT2 inhibitor of claim 15 , having a weight loss on drying (LOD) of no greater than about 0.1% by weight.

25. A pharmaceutical composition comprising (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) of claim 1 and a pharmaceutically acceptable carrier.

26. A pharmaceutical composition comprising (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) of claim 2 and a pharmaceutically acceptable carrier.

27. A pharmaceutical composition comprising (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) of claim 3 and a pharmaceutically acceptable carrier.

28. A pharmaceutical composition comprising (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) of claim 9 and a pharmaceutically acceptable carrier.

29. A pharmaceutical composition comprising (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) of claim 15 and a pharmaceutically acceptable carrier.

30. A pharmaceutical composition comprising (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) of claim 18 and a pharmaceutically acceptable carrier.

Assignees

• Neurocrine Biosciences Inc

Inventors

• Mcgee Kevin
• Li Bin-Feng
• Branum Shawn

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title