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 (cis)-d 6 -tetrabenazine having a diastereomeric purity of at least 99%, comprising:
a) 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:
2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium salt
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 water and methanol;
for a period of time and at a temperature sufficient to produce crude (cis)-d 6 -tetrabenazine; and
b) recrystallizing the crude (cis)-d 6 -tetrabenazine from ethanol to produce the (cis)-d 6 -tetrabenazine having a diastereomeric purity of at least 99%.
2. The process of claim 1 , wherein the (cis)-d 6 -tetrabenazine having a diastereomeric purity of at least 99%, has a deuterium enrichment of no less than about 20%.
3. The process of claim 1 , wherein the (cis)-d 6 -tetrabenazine having a diastereomeric purity of at least 99%, has a deuterium enrichment of no less than about 50%.
4. The process of claim 1 , wherein the (cis)-d 6 -tetrabenazine having a diastereomeric purity of at least 99%, has a deuterium enrichment of no less than about 70%.
5. The process of claim 1 , wherein the (cis)-d 6 -tetrabenazine having a diastereomeric purity of at least 99%, has a deuterium enrichment of no less than about 80%.
6. The process of claim 1 , wherein the (cis)-d 6 -tetrabenazine having a diastereomeric purity of at least 99%, has a deuterium enrichment of no less than about 90%.
7. The process of claim 1 , wherein the (cis)-d 6 -tetrabenazine having a diastereomeric purity of at least 99%, has a deuterium enrichment of no less than about 98%.
8. The process of claim 1 , wherein the water and methanol comprise a 3:1 ratio of methanol to water.
9. The process of claim 1 , 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 the salt form of d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline is d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride.
12. The process of claim 11 , wherein the process is carried out in the presence of a base.
13. The process of claim 12 , wherein the base is K 2 CO 3 .
14. The process of claim 1 , wherein X is halogen.
15. The process of claim 1 , wherein X is iodide.
16. The process of claim 1 , wherein in step b), the diastereomeric purity of (cis)-d 6 -tetrabenazine is at least 99.1%.
17. The process of claim 1 , wherein in step b), the diastereomeric purity of (cis)-d 6 -tetrabenazine is about 99.1%-99.9%.
18. The process of claim 1 , wherein in step b), the diastereomeric purity of (cis)-d 6 -tetrabenazine is about 99.2%.
19. The process of claim 1 , wherein in step b), the diastereomeric purity of (cis)-d 6 -tetrabenazine is about 99.5%.
20. The process of claim 1 , wherein in step b), the diastereomeric purity of (cis)-d 6 -tetrabenazine is about 99.6%.
21. The process of claim 1 , wherein in step b), the diastereomeric purity of (cis)-d 6 -tetrabenazine is about 99.9%.