(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 . An (S)-camphorsulfonic acid salt of S-ketamine.
2 . An (S)-camphorsulfonic acid salt of S-ketamine as in claim 1 , wherein the salt is a monohydrate.
3 . A crystalline monohydrate form of (S)-camphorsulfonic acid salt of S-ketamine.
4 . A crystalline monohydrate form as in claim 3 comprising the following pXRD peaks:
position [°2θ]
d-spacing [Å]
relative intensity [%]
7.76
11.38
58.03
8.11
10.89
21.58
12.75
6.94
24.89
13.13
6.74
55.99
13.31
6.65
23.96
13.64
6.49
31.52
14.92
5.93
100.00
15.51
5.71
32.12
15.71
5.64
28.46
18.45
4.80
43.84
24.22
3.67
25.66
25.26
3.52
28.46
27.33
3.26
51.32.
5 . A crystalline monohydrate form as in claim 3 comprising the following pXRD peaks:
position [°2θ]
d-spacing [Å]
relative intensity [%]
7.76
11.38
58.03
8.11
10.89
21.58
12.75
6.94
24.89
13.13
6.74
55.99
13.31
6.65
23.96
13.64
6.49
31.52
14.92
5.93
100.00
15.51
5.71
32.12
15.71
5.64
28.46
18.45
4.80
43.84
21.29
4.17
12.49
22.38
3.97
14.87
23.26
3.82
10.45
24.22
3.67
25.66
25.26
3.52
28.46
26.76
3.33
13.93
27.33
3.26
51.32
28.21
3.16
12.32
29.13
3.06
11.05.
6 . 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; 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%.
7 . A process as in claim 6 , wherein the (S)-camphorsulfonic acid is present in an amount in the range of from about 0.75 to about 1.2 molar equivalents.
8 . A process as in claim 6 , wherein the (S)-camphorsulfonic acid is present in an amount in the range of from about 0.9 to about 1.1 molar equivalents.
9 . A process as in claim 6 , wherein the water is present in an amount in the range of from about 5% to about 10%.
10 . A process as in claim 6 , wherein the water is present in an amount in the range of from about 6% to about 8%.
11 . A process as in claim 6 , wherein the organic solvent is selected from the group consisting of methyl ethyl ketone and 2-methyl-THF.
12 . A process as in claim 6 , wherein the organic solvent is 2-methyl-THF.
13 . A process as in claim 6 , wherein the ketamine is reacted with (S)-camphorsulfonic acid at a temperature in the range of from about 30° C. to about 100° C.
14 . A process as in claim 6 , wherein the ketamine is reacted with (S)-camphorsulfonic acid at a temperature of about 50° C. to about 80° C.
15 . A process as in claim 6 , 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%.
16 . A process as in claim 6 , 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%.
17 . A process as in claim 6 , 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%.
18 . 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 of 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%.
19 . A product prepared according to the process of any of claim 6 .
20 . A process according to claim 6 , 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.
21 . An (R)-camphorsulfonic acid salt of R-ketamine.
22 . An (R)-camphorsulfonic acid salt of R-ketamine as in claim 21 , wherein the salt is crystalline.
23 . An (R)-camphorsulfonic acid salt of R-ketamine as in claim 21 , wherein the salt is a hydrate.
24 . An (R)-camphorsulfonic acid salt of R-ketamine as in claim 21 , wherein the salt is a monohydrate.
25 . A process for the preparation of (R)-camphorsulfonic acid salt of R-ketamine comprising
reacting ketamine with (R)-camphorsulfonic acid, wherein the (R)-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; at a temperature in the range of from about 20° C. to about solvent reflux temperature;
to yield a product mixture comprising (R)-camphorsulfonic acid salt of S-ketamine as a solid and S-ketamine;
wherein the (R)-camphorsulfonic acid salt of R-ketamine is present in an enantiomeric excess in the range of from about 50% to about 100%.
26 . A process as in claim 25 , further comprising
(a) filtering the product mixture to yield the (R)-camphorsulfonic acid salt of R-ketamine as a solid and a filtrate comprising S-ketamine;
(b) reacting the S-ketamine with HCl; to yield the corresponding S-ketamine hydrochloride salt.
27 . A process for the preparation of S-ketamine hydrochloride comprising the following steps:
Step 1:
reacting ketamine with (R)-camphorsulfonic acid, wherein the (R)-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; at a temperature in the range of from about 20° C. to about solvent reflux temperature;
to yield a product mixture comprising (R)-camphorsulfonic acid salt of S-ketamine as a solid and S-ketamine in solution; wherein the (R)-camphorsulfonic acid salt of R-ketamine is present in an enantiomeric excess in the range of from about 50% to about 100%;
Step 2:
filtering the product mixture to yield the (R)-camphorsulfonic acid salt of R-ketamine as a solid and a filtrate comprising S-ketamine; and
Step 3:
reacting the S-ketamine with HCl; to yield the corresponding S-ketamine hydrochloride salt.
28 . A product prepared according to the process of claim 25 .
29 . A product prepared according to the process of claim 27 .
30 . A process for the preparation of S-ketamine or S-ketamine hydrochloride as described herein.
31 . A product prepared according to any of the processes described herein.