Methods of manufacturing benzoquinoline compounds

Patent metadata

Field	Value
Publication number	US-10513488-B2
Application number	US-201715472779-A
Country	US
Kind code	B2
Filing date	Mar 29, 2017
Priority date	Dec 3, 2013
Publication date	Dec 24, 2019
Grant date	Dec 24, 2019

Abstract

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

First claim

What is claimed is:

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.

Assignees

• Auspex Pharmaceuticals Inc

Inventors

• Zhang Chengzhi

Classifications

• C07C221/00

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

• C07D455/06

  containing benzo [a] quinolizine ring systems · CPC title

• C07D217/04

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

• C07C231/02 Primary

  from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines · CPC title

• C07B2200/05

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