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-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate)
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.
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) having an impurity profile comprising total impurities in an amount that is no greater than about 5% by weight.
2. The VMAT2 inhibitor of claim 1 , wherein the impurity profile comprises total impurities in an amount that is no greater than about 3% by weight.
3. The VMAT2 inhibitor of claim 1 , wherein the impurity profile comprises total impurities in an amount that is no greater than about 2.5% by weight.
4. The VMAT2 inhibitor of claim 1 , wherein the impurity profile comprises total impurities in an amount that is no greater than about 2% by weight.
5. The VMAT2 inhibitor of claim 1 , wherein the impurity profile comprises total impurities in an amount that is no greater than about 1.5% by weight.
6. The VMAT2 inhibitor of claim 1 , 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 1 , 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 1 , 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 1 , 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 1 , 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 1 , wherein the impurity profile comprises 6,7-dimethoxy-3,4-dihydroisoquinoline.
12. The VMAT2 inhibitor of claim 1 , 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 1 , having an impurity profile comprising one or more impurities chosen from metal-based impurities.
14. The VMAT2 inhibitor of claim 1 , 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 (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) 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 9 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 14 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.