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