Methods of manufacturing benzoquinoline compounds
The present invention relates to new methods of manufacturing benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), and intermediates thereof.
1. A process of preparing a racemic mixture of (RR,SS)-d 6 -tetrabenazine
(RR, SS)-d 6 -tetrabenazine
wherein the deuterium enrichment of the (RR, SS)-d 6 -tetrabenazine is no less than about 10%, comprising:
reacting d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline, or a salt thereof:
d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline
with a salt of 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium:
wherein X is halogen, alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkyloxonium, alkylphosphate, or alkyl carbonate;
and an optional base;
in the presence of a solvent mixture that is a combination of water and an alcohol that is methanol or ethanol;
for a period of time and at a temperature sufficient to produce the (RR,SS)-d 6 -tetrabenazine having a diastereomeric purity of at least 99%, based on high performance liquid chromatography.
2. The process of claim 1 , wherein the solvent mixture is a combination of methanol and water.
3. The process of claim 2 , wherein the ratio of methanol:water is about 5:1 to about 1:1.
4. The process of claim 2 , wherein the ratio of methanol:water is about 3:1.
5. The process of claim 2 , wherein the ratio of methanol:water is about 1:1.
6. The process of claim 1 , wherein the solvent mixture is a combination of ethanol and water.
7. The process of claim 1 , wherein the d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline is a salt form of d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline.
8. The process of claim 7 , wherein the salt form of d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline is d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride.
9. The process of claim 8 , wherein the process is carried out in the presence of a base.
10. The process of claim 9 , wherein the base is K 2 CO 3 .
11. The process of claim 1 , wherein X is halogen.
12. The process of claim 11 , wherein the halogen is iodide.
13. The process of claim 1 , wherein the period of time is about 24 hours to about 63 hours.
14. The process of claim 1 , wherein the temperature is about 40° C. to about 60° C.
15. The process of claim 1 , wherein the diastereomeric purity is at least 99.1%.
16. The process of claim 1 , wherein the diastereomeric purity is at least 99.2%.
17. The process of claim 1 , wherein the diastereomeric purity is at least 99.5%.
18. The process of claim 1 , wherein the diastereomeric purity is at least 99.6%.
19. The process of claim 1 , wherein the diastereomeric purity is at least 99.9%.
20. The process of claim 1 , wherein the deuterium enrichment of the (RR,SS)-d 6 -tetrabenazine is no less than about 50%.
21. The process of claim 1 , wherein the deuterium enrichment of the (RR,SS)-d 6 -tetrabenazine is no less than about 90%.
22. The process of claim 1 , wherein the deuterium enrichment of the (RR,SS)-d 6 -tetrabenazine is no less than about 98%.
23. The process of claim 4 , wherein a salt form of d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline is reacted and the salt form is d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride.
24. The process of claim 23 , wherein the process is carried out in the presence of K 2 CO 3.
25. The process of claim 24 , wherein Xis halogen.
26. The process of claim 25 , wherein the halogen is iodide.
27. The process of claim 26 , wherein the diastereomeric purity is at least 99.1%.
28. The process of claim 4 , wherein Xis halogen.
29. The process of claim 28 , wherein the halogen is iodide.
30. The process of claim 4 , wherein the deuterium enrichment of the (RR,SS)-d 6 -tetrabenazine is no less than about 50%.
31. The process of claim 4 , wherein the deuterium enrichment of the (RR,SS)-d 6 -tetrabenazine is no less than about 90%.
32. The process of claim 4 , wherein the deuterium enrichment of the (RR,SS)-d 6 -tetrabenazine is no less than about 98%.
33. The process of claim 23 , wherein the deuterium enrichment of the (RR,SS)-d 6 -tetrabenazine is no less than about 50%.
34. The process of claim 23 , wherein the deuterium enrichment of the (RR,SS)-d 6 -tetrabenazine is no less than about 90%.
35. The process of claim 23 , wherein the deuterium enrichment of the (RR,SS)-d 6 -tetrabenazine is no less than about 98%.
36. The process of claim 4 , wherein a salt form of d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline is reacted and the salt form is d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride, X is iodide, and the diastereomeric purity is at least 99.1.
37. The process of claim 36 , wherein the process is carried out in the presence of K 2 CO 3.