(S)-CSA salt of S-ketamine, (R)-CSA salt of S-ketamine and processes for the preparation of S-ketamine

Patent metadata

Field	Value
Publication number	US-10815196-B2
Application number	US-201815997267-A
Country	US
Kind code	B2
Filing date	Jun 4, 2018
Priority date	May 13, 2015
Publication date	Oct 27, 2020
Grant date	Oct 27, 2020

Abstract

The present invention is directed to processes for the preparation of esketamine. The present invention is further directed to processes for the resolution of S-ketamine from a racemic or enantiomerically enriched mixture of ketamine. The present invention is further directed to an (S)-CSA salt of S-ketamine, more particularly a monohydrate form of the (S)-CSA salt of S-ketamine; and to an (R)-CSA salt of R-ketamine.

First claim

What is claimed:

1. A process for the preparation of a monohydrate form of (S)-camphorsulfonic acid salt of S-ketamine comprising

reacting ketamine with (S)-camphorsulfonic acid, wherein the (S)-camphorsulfonic acid is present in an amount in the range of from about 0.5 to about 2.0 molar equivalents (relative to the molar amount of ketamine);
in the presence of water, wherein the water is present in an amount in the range of from about 3.5% to about 15%;
in an organic solvent selected from the group consisting of an ether, a ketone, and mixtures thereof; at a temperature in the range of from about 20° C. to about solvent reflux temperature;
to yield the corresponding monohydrate form of (S)-camphorsulfonic acid salt of S-ketamine;
wherein the monohydrate form of (S)-camphorsulfonic acid salt of S-ketamine is present in an enantiomeric excess in the range of from about 50% to about 100%.

2. The process of claim 1 , wherein the (S)-camphorsulfonic acid is present in an amount in the range of from about 0.75 to about 1.2 molar equivalents.

3. The process of claim 1 , wherein the (S)-camphorsulfonic acid is present in an amount in the range of from about 0.9 to about 1.1 molar equivalents.

4. The process of claim 1 , wherein the water is present in an amount in the range of from about 5% to about 10%.

5. The process of claim 1 , wherein the water is present in an amount in the range of from about 6% to about 8%.

6. The process of claim 1 , wherein the organic solvent is selected from the group consisting of methyl ethyl ketone and 2-methyl-THF.

7. The process of claim 1 , wherein the organic solvent is 2-methyl-THF.

8. The process of claim 1 , wherein the ketamine is reacted with (S)-camphorsulfonic acid at a temperature in the range of from about 30° C. to about 100° C.

9. The process of claim 1 , wherein the ketamine is reacted with (S)-camphorsulfonic acid at a temperature of about 50° C. to about 80° C.

10. The process of claim 1 , wherein the monohydrate form of (S)-camphorsulfonic acid salt of S-ketamine is present in an enantiomeric excess in the range of from about 75% to about 100%.

11. The process of claim 1 , wherein the monohydrate form of (S)-camphorsulfonic acid salt of S-ketamine is present in an enantiomeric excess in the range of from about 90% to about 100%.

12. The process of claim 1 , wherein the monohydrate form of (S)-camphorsulfonic acid salt of S-ketamine is present in an enantiomeric excess of greater than or equal to about 96%.

13. A process for the preparation of a monohydrate form of (S)-camphorsulfonic acid salt of S-ketamine comprising

reacting racemic ketamine with (S)-camphorsulfonic acid, wherein the (S)-camphorsulfonic acid is present in an amount of about 1 molar equivalents (relative to the molar amount of ketamine);
in the presence of water, wherein the water is present in an amount in the range of from about 6% to about 8%;
in 2-methyl-THF; at a temperature of about 70° C.;
to yield the corresponding monohydrate form of (S)-camphorsulfonic acid salt of S-ketamine;
wherein the monohydrate form of (S)-camphorsulfonic acid salt of S-ketamine is present in an enantiomeric excess in the range of from about 80% to about 100%.

14. The process of claim 1 , further comprising
(a) reacting the monohydrate form of (S)-camphorsulfonic acid salt of S-ketamine with a base; in a solvent or mixture of solvents; to yield S-ketamine as a free base; and
(b) reacting the S-ketamine free base with HCL; to yield the corresponding S-ketamine hydrochloride salt.

15. The process of claim 1 , wherein the organic solvent is selected from the group consisting of THF, 2-methyl-THF, methyl ethyl ketone, acetone, methyl isobutyl ketone, and mixtures thereof.

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Chen Cheng Yi
• Floegel Oliver
• Justus Michael
• Maurer Adrian
• Reuter Karl
• Strittmatter Tobias
• Wedel Tobias

Classifications

• C07C309/19 Primary

  of a saturated carbon skeleton containing rings · CPC title

• A61P9/12

  Antihypertensives · CPC title

• C07C2602/42

  the bicyclo ring system containing seven carbon atoms · CPC title

• C07B2200/07

  Optical isomers · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title