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 . The (cis)-d 6 -Tetrabenazine having a diastereomeric purity of at least 99% and having a deuterium enrichment of no less than about 10%.
2 . The (cis)-d 6 -Tetrabenazine of claim 1 having a deuterium enrichment of no less than about 20%.
3 . The (cis)-d 6 -Tetrabenazine of claim 1 having a deuterium enrichment of no less than about 50%.
4 . The (cis)-d 6 -Tetrabenazine of claim 1 having a deuterium enrichment of no less than about 70%.
5 . The (cis)-d 6 -Tetrabenazine of claim 1 having a deuterium enrichment of no less than about 80%.
6 . The (cis)-d 6 -Tetrabenazine of claim 1 having a deuterium enrichment of no less than about 90%.
7 . The (cis)-d 6 -Tetrabenazine of claim 1 having a deuterium enrichment of no less than about 98%.
8 . A pharmaceutical composition comprising the (cis)-d 6 -tetrabenazine of claim 1 and a pharmaceutically acceptable excipient.
9 . The pharmaceutical composition of claim 8 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 20%.
10 . The pharmaceutical composition of claim 8 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 50%.
11 . The pharmaceutical composition of claim 8 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 70%.
12 . The pharmaceutical composition of claim 8 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 80%.
13 . The pharmaceutical composition of claim 8 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 90%.
14 . The pharmaceutical composition of claim 8 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 98%.
15 . A process of preparing a (cis)-d 6 -tetrabenazine having a diastereomeric purity of at least 99% and having a deuterium enrichment of 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:
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 one or more solvents;
for a period of time and at a temperature sufficient to produce the (cis)-d 6 -tetrabenazine having a diastereomeric purity of at least 99%, based on high performance liquid chromatography.
16 . The process of claim 15 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 20%.
17 . The process of claim 15 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 50%.
18 . The process of claim 15 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 70%.
19 . The process of claim 15 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 80%.
20 . The process of claim 15 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 90%.
21 . The process of claim 15 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 98%.
22 . The process of claim 15 , wherein the one or more solvents are selected from the group consisting of water, methanol, and ethanol.
23 . The process of claim 15 , wherein the one or more solvents comprise water.
24 . The process of claim 15 , wherein the one or more solvents comprise water, methanol, or ethanol.
25 . The process of claim 15 , wherein the process is carried out in the presence of a base.
26 . The process of claim 25 , wherein the base is K 2 CO 3 .
27 . The process of claim 15 , wherein the salt form of d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline is d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride.
28 . The process of claim 27 , wherein the process is carried out in the presence of a base.
29 . The process of claim 28 , wherein the base is K 2 CO 3 .
30 . The process of claim 15 , wherein X is halogen.
31 . The process of claim 15 , wherein X is iodide.
32 . The process of claim 15 , wherein the diastereomeric purity of the (cis)-d 6 -tetrabenazine is at least 99.1%.