Methods of manufacturing benzoquinoline compounds

Patent metadata

Field	Value
Publication number	US-12077487-B2
Application number	US-202217879600-A
Country	US
Kind code	B2
Filing date	Aug 2, 2022
Priority date	Dec 3, 2013
Publication date	Sep 3, 2024
Grant date	Sep 3, 2024

Abstract

The present invention relates to new methods of manufacturing benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), and intermediates thereof.

First claim

The invention claimed is:

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%.

Assignees

• Auspex Pharmaceuticals Inc

Inventors

• Zhang Chengzhi

Classifications

• C07B59/002 Primary

  Heterocyclic compounds · CPC title

• C07B59/001

  Acyclic or carbocyclic compounds · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• C07C221/00

  Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton · CPC title

• C07D217/04

  with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom · CPC title