U.S. patent application number 15/152705 was filed with the patent office on 2016-11-17 for (s)-csa salt of s-ketamine, (r)-csa salt of s-ketamine and processes for the preparation of s-ketamine.
This patent application is currently assigned to Janssen Pharmaceutica NV. The applicant listed for this patent is Janssen Pharmaceutica NV. Invention is credited to Cheng Yi Chen, Oliver Floegel, Michael Justus, Adrian Maurer, Karl Reuter, Tobias Strittmatter, Tobias Wedel.
Application Number | 20160332962 15/152705 |
Document ID | / |
Family ID | 56068863 |
Filed Date | 2016-11-17 |
United States Patent
Application |
20160332962 |
Kind Code |
A1 |
Chen; Cheng Yi ; et
al. |
November 17, 2016 |
(S)-CSA SALT OF S-KETAMINE, (R)-CSA SALT OF S-KETAMINE AND
PROCESSES FOR THE PREPARATION OF S-KETAMINE
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.
Inventors: |
Chen; Cheng Yi;
(Schaffhausen, CH) ; Floegel; Oliver; (Zurich,
CH) ; Justus; Michael; (Schaffhausen, CH) ;
Maurer; Adrian; (Schaffhausen, CH) ; Reuter;
Karl; (Gundelfingen, DE) ; Strittmatter; Tobias;
(Kussaberg, CH) ; Wedel; Tobias; (Karlsruhe,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Pharmaceutica NV |
Beerse |
|
BE |
|
|
Assignee: |
Janssen Pharmaceutica NV
Beerse
BE
|
Family ID: |
56068863 |
Appl. No.: |
15/152705 |
Filed: |
May 12, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62160659 |
May 13, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 9/12 20180101; A61P
11/00 20180101; C07C 225/20 20130101; C07B 2200/07 20130101; A61P
25/04 20180101; A61P 25/24 20180101; C07B 2200/13 20130101; C07C
309/19 20130101; C07C 2601/14 20170501; C07C 2602/42 20170501; A61P
25/00 20180101; H05K 999/99 20130101; C07C 309/23 20130101 |
International
Class: |
C07C 309/23 20060101
C07C309/23; C07C 225/20 20060101 C07C225/20 |
Claims
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: TABLE-US-00011 position [.degree.2.theta.]
d-spacing [.ANG.] 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: TABLE-US-00012 position [.degree.2.theta.]
d-spacing [.ANG.] 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 ##STR00037##
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.degree. 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.degree. C. to about 100.degree. C.
14. A process as in claim 6, wherein the ketamine is reacted with
(S)-camphorsulfonic acid at a temperature of about 50.degree. C. to
about 80.degree. 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 ##STR00038##
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.degree. 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 ##STR00039## 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.degree. 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: ##STR00040## 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.degree. 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: ##STR00041## 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: ##STR00042## 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.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application 62/160,659, filed on May 13, 2015, which is
incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to processes for the
preparation of (S)-ketamine. 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.
BACKGROUND OF THE INVENTION
[0003] Ketamine (a racemic mixture of the corresponding S- and
R-enantiomers) is an NMDA receptor antagonist, with a wide range of
effects in humans, including analgesia, anesthesia, hallucinations,
dissociative effects, elevated blood pressure and bronchodilation.
Ketamine is primarily used for the induction and maintenance of
general anesthesia. Other uses include sedation in intensive care,
analgesia (particularly in emergency medicine and treatment of
bronchospasms. Ketamine has also been shown to be efficacious in
the treatment of depression (particularly in those who have not
responded to current anti-depressant treatment). In patients with
major depressive disorders, ketamine has additionally been shown to
produce a rapid antidepressant effect, acting within hours.
[0004] The S-ketamine enantiomer (or S-(+)-ketamine or esketamine)
has higher potency or affinity for the NMDA receptor and thus
potentially allowing for lower effective dosages; and is available
for medical use, administered either IV (intravenously) or IM
(intramuscularly), under the brand name KETANEST S.
[0005] HUDYMA, T. W., et al., in DE 2062620 A published Jul. 15,
1971 describe resolution of ketamine with natural L-tartaric acid.
Hudyma et al further disclose that attempts at resolution of
ketamine with camphorsulfonic acid (CSA) were unsuccessful. STEINER
K., et al., in DE 19619665 C2 published Mar. 8, 2001 (US Equiv.
U.S. Pat. No. 6,040,479) describe a process for resolution of
ketamine using L-tartaric acid in water or a mixture of water and
an alcohol and/or ketone, ether or ester. RUSSO, T., et al., in PCT
Publication WO2001/098265 (US Equiv. Patent Publication No.
20030212143 A1), published Aug. 15, 2002 describe chiral resolution
of ketamine using L-tartaric acid in a mixture of solvent and
water.
[0006] There remains a need for a method for the resolution of the
S-ketamine enantiomer from racemic ketamine, wherein (a) the
process does not use chiral tartaric acid; (b) the process
comprises one to three, preferably one to two crystallization steps
(for example, to avoid loss of yield); (c) the process results in a
yield of greater than about 25%; (d) the process uses solvents
which are non-toxic and/or do not require special handling; and/or
(e) the process is suitable for large scale or commercial
manufacture.
SUMMARY OF THE INVENTION
[0007] The present invention is directed to a process for the
preparation of a monohydrate form of (S)-camphorsulfonic acid salt
of S-ketamine (preferably a crystalline monohydrate form), a
compound of formula (I-CSA)
##STR00001##
[0008] (also known by its IUPAC name of
(S)-2-(2-chlorophenyl)-2-(methylammonium)cyclohexanone
(+)-camphorsulfonate monohydrate), comprising
##STR00002##
[0009] reacting ketamine (preferably racemic ketamine) with
(S)-camphorsulfonic acid, a known compound, 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
moles of ketamine);
[0010] in the presence of water; wherein the water is present in an
amount in the range of from about 3.5% to about 15%;
[0011] in an organic solvent; at a temperature in the range of from
about 20.degree. C. to about solvent reflux temperature;
[0012] to yield the monohydrate form of (S)-CSA salt of
S-ketamine;
[0013] wherein the monohydrate form of (S)-CSA salt of S-ketamine
is present in an enantiomeric excess in the range of from about 50%
to about 100%.
[0014] The present invention is further directed to a process for
the preparation of S-ketamine hydrochloride (also known as
esketamine), a compound of formula (I-HCl)
##STR00003##
[0015] comprising the steps of
[0016] (a) reacting the monohydrate form of (S)-camphorsulfonic
acid salt of S-ketamine (prepared for example as described above)
with an inorganic base; in a solvent or mixture of solvents;
preferably in the presence of water; to yield S-ketamine as a free
base; and
[0017] (b) reacting the S-ketamine free base with HCl; to yield the
corresponding S-ketamine hydrochloride salt.
[0018] The present invention is directed to a process for the
preparation of (R)-camphorsulfonic acid salt of R-ketamine
(preferably a crystalline form), a compound of formula (II-CSA)
##STR00004##
[0019] comprising
##STR00005##
[0020] reacting ketamine (preferably racemic ketamine) with
(R)-camphorsulfonic acid, a known compound, 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
moles of ketamine);
[0021] in the presence of water; wherein the water is present in an
amount in the range of from about 3.5% to about 15%;
[0022] in an organic solvent; at a temperature in the range of from
about 20.degree. C. to about solvent reflux temperature;
[0023] to yield a product mixture comprising an (R)-CSA salt of
R-ketamine, preferably as a solid, more preferably as a hydrate
(for example as a monohydrate), and S-ketamine; wherein the
S-ketamine remains in solution;
[0024] wherein the (R)-CSA salt of R-ketamine is present in an
enantiomeric excess in the range of from about 50% to about
100%.
[0025] The present invention is further directed to a process for
the preparation of S-ketamine hydrochloride (also known as
esketamine), a compound of formula (I-HCl)
##STR00006##
[0026] comprising the steps of
Step 1:
##STR00007##
[0028] reacting ketamine (preferably racemic ketamine) with
(R)-camphorsulfonic acid, a known compound, 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
moles of ketamine);
[0029] 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.degree. C.
to about solvent reflux temperature;
[0030] to yield a product mixture comprising an (R)-CSA salt of
R-ketamine, preferably as a hydrate (for example, as a
monohydrate), preferably as a solid, and S-ketamine, wherein the
S-ketamine remains in solution; and wherein the (R)-CSA salt of
R-ketamine is present in an enantiomeric excess in the range of
from about 50% to about 100%
Step 2:
[0031] filtering the product mixture (of Step 1) to yield the
(R)-camphorsulfonic acid salt of R-ketamine as a solid and a
filtrate comprising S-ketamine;
Step 3:
[0032] reacting the S-ketamine (in the filtrate or optionally,
isolated from the filtrate, by, for example, reacting with a
suitably selected inorganic base and extracting with a suitably
selected organic solvent) with HCl; to yield the corresponding
S-ketamine hydrochloride salt.
[0033] The present invention is further directed to a monohydrate
form of (S)-CSA salt of S-ketamine, preferably a crystalline
monohydrate form of (S)-CSA salt of S-ketamine, as described in
detail hereinafter.
[0034] The present invention is further directed to an (R)-CSA salt
of R-ketamine, preferably a crystalline form of (R)-CSA salt of
R-ketamine, as described in detail hereinafter.
[0035] The present invention is further directed to a product
prepared according to any of the processes described herein.
[0036] Illustrative of the invention is a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and a
product prepared according to any of the process(es) described
herein. An illustration of the invention is a pharmaceutical
composition made by mixing a product prepared according to any of
the process(es) described herein and a pharmaceutically acceptable
carrier. Illustrating the invention is a process for making a
pharmaceutical composition comprising mixing a product prepared
according to any of the process(es) described herein and a
pharmaceutically acceptable carrier.
[0037] Exemplifying the invention are methods of treating a
disorder mediated treatment resistant depression comprising
administering to a subject in need thereof a therapeutically
effective amount of a product prepared according to any of the
process(es) described herein.
[0038] In an embodiment, the present invention is directed to a
product prepared according to any of the process(es) described
herein for use as a medicament. In another embodiment, the present
invention is directed to a product prepared according to any of the
process(es) described herein for use in the treatment of treatment
resistant depression. In another embodiment, the present invention
is directed to a composition comprising a product prepared
according to any of the process(es) described herein for the
treatment of treatment resistant depression.
[0039] Another example of the invention is the use of a product
prepared according to any of the process(es) described herein in
the preparation of a medicament for treating treatment resistant
depression, in a subject in need thereof. In another example, the
present invention is directed to a product prepared according to
any of the process(es) described herein for use in a methods for
treating treatment resistant depression, in a subject in need
thereof.
BRIEF DESCRIPTIONS OF THE FIGURES
[0040] FIG. 1 illustrates a pXRD spectra for a representative
sample of the crystalline, monohydrate form of the (S)-CSA salt of
S-ketamine.
DETAILED DESCRIPTION OF THE INVENTION
[0041] The present invention is directed to process(es) for the
preparation of S-ketamine, S-ketamine hydrochloride,
S-ketamine.(S)-CSA salt (the (S)-CSA salt of S-ketamine) and a
monohydrate (preferably crystalline) form of S-ketamine.(S)-CSA
salt. The present invention is directed to process(es) for the
preparation of R-ketamine.(R)-CSA salt (the (R)-CSA salt of
R-ketamine), preferably a crystalline form of R-ketamine.(R)-CSA
salt. The present invention is further directed to process(es) for
the resolution of S-ketamine from a racemic (or enantiomerically
enriched mixture) of ketamine.
[0042] The present invention is further directed to an (S)-CSA salt
of S-ketamine, preferably, a monohydrate (S)-CSA salt of
S-ketamine, more preferably, a crystalline monohydrate (S)-CSA salt
of S-ketamine. The present invention is further directed to an
(R)-CSA salt of R-ketamine, preferably, a crystalline (R)-CSA salt
of R-ketamine. The present invention is further directed to any CSA
salt as described herein.
[0043] As used herein, unless otherwise noted, the term "ketamine"
shall mean a racemic or enantiomerically enriched mixture of
ketamine, a compound of the following structure
##STR00008##
[0044] also known as
2-(2-chlorophenyl)-2-(methylamino)cyclohexanone. As used herein,
unless otherwise noted, the term "enantiomerically enriched
mixture" shall mean a mixture of the corresponding (S)- and
(R)-enantiomers, wherein one of said enantiomers is present in an
enantiomeric excess of greater than about 50%, preferably present
in an enantiomeric excess in the range of from about 50% to about
95%, or any amount or range therein, preferably, in an enantiomeric
excess in the range of from about 75% to about 95%.
[0045] In an embodiment of the present invention, the ketamine is
racemic. In another embodiment of the present invention, the
ketamine is an enantiomerically enriched mixture, wherein the (S)-
or (R)-enantiomer is present in an enantiomeric excess of greater
than about 50%, preferably, in an enantiomeric excess in the range
of from about 50% to about 99%, or any amount or range therein, for
example, in an enantiomeric excess of about 51%, 55%, 60%, 60%,
65%, 70%, 75%, 80%, 85%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%,
93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%
or 99%.
[0046] As used herein, unless otherwise noted, the term
"S-ketamine" shall mean the (S)-enantiomer of ketamine, as a free
base, a compound of formula (I)
##STR00009##
[0047] also known as
(S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone. In an
embodiment, S-ketamine is present in an enantiomeric excess of
greater than about 50%, or any amount or range therein, more
preferably in an enantiomeric excess of greater than about 75%,
more preferably in an enantiomeric excess of greater than about
85%, more preferably in an enantiomeric excess in the range of from
about 90% to about 100%, or any amount or range therein, more
preferably in an enantiomeric excess in the range of from about 95%
to about 99%, for example, in an enantiomeric excess of about 90%,
90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%,
96%, 96.5%, 97%, 97.5%, 98%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%,
98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%,
99.6%, 99.7%, 99.8%, 99.9% or 100%.
[0048] As used herein, unless otherwise noted, the term
"esketamine" shall mean the hydrochloric acid salt of
(S)-enantiomer of ketamine, a compound of formula (I-HCl)
##STR00010##
[0049] also known as
(S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone
hydrochloride.
[0050] As used herein, unless otherwise noted, the term
"R-ketamine" shall mean the (R)-enantiomer of ketamine, as a free
base, a compound of formula
##STR00011##
[0051] also known as
(R)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone. In an
embodiment, R-ketamine is present in an enantiomeric excess of
greater than about 50%, or any amount or range therein, more
preferably in an enantiomeric excess of greater than about 75%,
more preferably in an enantiomeric excess of greater than about
85%, more preferably in an enantiomeric excess in the range of from
about 90% to about 100%, or any amount or range therein, more
preferably in an enantiomeric excess in the range of from about 95%
to about 99%, for example, in an enantiomeric excess of about 90%,
90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%,
96%, 96.5%, 97%, 97.5%, 98%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%,
98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%,
99.6%, 99.7%, 99.8%, 99.9% or 100%.
[0052] As used herein, unless otherwise noted the term "S-CSA"
shall mean (+)-camphorsulfonic acid, also known as (1
S,4R)-camphorsulfonic acid. As used herein, unless otherwise noted,
the term "R-CSA" shall mean (-)-camphorsulfonic acid, also known as
(1R,4S)-camphorsulfonic acid. (Camphorsulfonic acid is also known
by its IUPAC name
(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic
acid.)
[0053] In an embodiment, the present invention is directed to
methods for the treatment of treatment-refractory or
treatment-resistant depression, wherein a product prepared
according to any of the process(es) described herein is
administered at a dosage amount in the range of from about 0.01 mg
to about 1000 mg, or any amount or range therein, preferably from
about 0.01 mg to about 500 mg, or any amount or range therein,
preferably from about 0.1 mg to about 250 mg, or any amount or
range therein. In another embodiment, the present invention is
directed to methods for the treatment of treatment-refractory or
treatment-resistant depression, wherein a product prepared
according to any of the process(es) described herein is
administered at a dosage amount in the range of from about 0.01 mg
to about 1000 mg, preferably selected from the group consisting of
0.01 mg, 0.025 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 25
mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg and 500 mg.
[0054] As used herein, the notation "*" shall denote the presence
of a stereogenic center.
[0055] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. It is to be understood that
all such isomers and mixtures thereof are encompassed within the
scope of the present invention. Preferably, wherein the compound is
present as an enantiomer, the enantiomer is present at an
enantiomeric excess of greater than or equal to about 80%, more
preferably, at an enantiomeric excess of greater than or equal to
about 90%, more preferably still, at an enantiomeric excess of
greater than or equal to about 95%, more preferably still, at an
enantiomeric excess of greater than or equal to about 98%, most
preferably, at an enantiomeric excess of greater than or equal to
about 99%. Similarly, wherein the compound is present as a
diastereomer, the diastereomer is present at an diastereomeric
excess of greater than or equal to about 80%, more preferably, at
an diastereomeric excess of greater than or equal to about 90%,
more preferably still, at an diastereomeric excess of greater than
or equal to about 95%, more preferably still, at an diastereomeric
excess of greater than or equal to about 98%, most preferably, at
an diastereomeric excess of greater than or equal to about 99%.
[0056] Furthermore, it is intended that within the scope of the
present invention, any element, in particular when mentioned in
relation to a compound of formula (I), shall comprise all isotopes
and isotopic mixtures of said element, either naturally occurring
or synthetically produced, either with natural abundance or in an
isotopically enriched form. For example, a reference to hydrogen
includes within its scope .sup.1H, .sup.2H (D), and .sup.3H (T).
Similarly, references to carbon and oxygen include within their
scope respectively .sup.12C, .sup.13C and .sup.14C and .sup.16O and
.sup.18O. The isotopes may be radioactive or non-radioactive.
Radiolabelled compounds of formula (I) may comprise a radioactive
isotope selected from the group of .sup.3H, .sup.11C, .sup.18F,
.sup.122I, .sup.123In, .sup.125I, .sup.131I, .sup.75Br, .sup.76Br,
.sup.77Br and .sup.82Br. Preferably, the radioactive isotope is
selected from the group of .sup.3H, .sup.11C and .sup.18F.
[0057] Abbreviations used in the specification, particularly the
Schemes and Examples, are as follows: [0058] CPME=Cyclopentyl
methyl ether [0059] CSA=Camphorsulfonic acid (IUPAC name
(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid)
[0060] DCM=Dichloromethane [0061] DMF=N,N-Dimethylformamide [0062]
DMSO=Dimethyl sulfoxide [0063] DSC=Dynamic Scanning calorimetry
[0064] DVS=Dynamic Vapor Sorption [0065] ee or % e.e. =Enantiomeric
Excess [0066] .sup.1H NMR=Hydrogen Nuclear Magnetic Resonance
[0067] MeOH=Methanol [0068] MEK=Methyl ethyl ketone [0069]
2-Me-THF=2-Methyl-tetrahydrofuran [0070] ML--Mother Liquor [0071]
2-PrOH or IPA=2-Propanol (Isopropanol) [0072] pXRD=Powder X-Ray
Doffraction [0073] % RH=% Relative Humidity [0074] RT=Room
temperature [0075] TBME or MTBE=tert-Butyl methyl ether [0076]
TG-FTIR=ThermoGravimetric-Fourier Transform InfraRed (Spectroscopy)
[0077] THF=Tetrahydrofuran [0078] v:v=volume:volume ratio
[0079] As used herein, unless otherwise noted, the term "isolated
form" shall mean that the compound is present in a form which is
separate from any solid mixture with another compound(s), solvent
system or biological environment. In an embodiment of the present
invention, a product prepared according to any of the process(es)
described herein is present in an isolated form. In another
embodiment, the (S)-CSA salt of S-ketamine, preferably the
monohydrate form of the (S)-CSA salt of S-ketamine, more preferably
the crystalline monohydrate form of the (S)-CSA salt of S-ketamine,
is present in an isolated form. In another embodiment, the (R)-CSA
salt of R-ketamine, preferably the crystalline form of the (R)-CSA
salt of R-ketamine, is present in an isolated form.
[0080] As used herein, unless otherwise noted, the term
"substantially pure form" shall mean that the mole percent of
impurities in the isolated compound is less than about 5 mole
percent, preferably less than about 2 mole percent, more
preferably, less than about 0.5 mole percent, most preferably, less
than about 0.1 mole percent. In an embodiment of the present
invention, a product prepared according to any of the process(es)
described herein is present as a substantially pure form. In
another embodiment, the (S)-CSA salt of S-ketamine, preferably the
monohydrate form of the (S)-CSA salt of S-ketamine, more preferably
the crystalline monohydrate form of the (S)-CSA salt of S-ketamine,
is present as a substantially pure form. In another embodiment, the
(R)-CSA salt of R-ketamine, preferably a crystalline form of the
(R)-CSA salt of R-ketamine, is present as a substantially pure
form.
[0081] As used herein, unless otherwise noted, the term
"substantially free of a corresponding salt form(s)" when used to
described the compound of formula (I) shall mean that mole percent
of the corresponding salt form(s) in the isolated base of formula
(I) is less than about 5 mole percent, preferably less than about 2
mole percent, more preferably, less than about 0.5 mole percent,
most preferably less than about 0.1 mole percent. In an embodiment
of the present invention, a product prepared according to any of
the process(es) described herein is present in a form which is
substantially free of corresponding salt form(s). In another
embodiment, the (S)-CSA salt of S-ketamine, preferably the
monohydrate form of the (S)-CSA salt of S-ketamine, more preferably
the crystalline monohydrate form of (S)-CSA salt of S-ketamine, is
present in a form which is substantially free of corresponding salt
form(s). In another embodiment, the (R)-CSA salt of R-ketamine,
preferably a crystalline form of the (R)-CSA salt of R-ketamine, is
present in a form which is substantially free of corresponding salt
form(s).
[0082] As used herein, the term "treatment-refractory or
treatment-resistant depression" and the abbreviation "TRD" shall be
defined as major depressive disorder that does not respond to
adequate courses of at least two antidepressants, preferably two or
more antidepressants, more preferably two to three,
antidepressants.
[0083] One skilled in the art will recognize that the failure to
respond to an adequate course of a given antidepressant may be
determined retrospectively or prospectively. In an embodiment, at
least one of the failures to respond to an adequate course of
antidepressant is determined prospectively. In another embodiment,
at least two of the failures to respond to an adequate course of
antidepressant are determined prospectively. In another embodiment,
at least one of the failures to respond to an adequate course of
antidepressant is determined retrospectively. In another
embodiment, at least two of the failures to respond to an adequate
course of antidepressant are determined retrospectively.
[0084] As used herein, unless otherwise noted, the terms
"treating", "treatment" and the like, shall include the management
and care of a subject or patient (preferably mammal, more
preferably human) for the purpose of combating a disease,
condition, or disorder and includes the administration of a
compound of the present invention to prevent the onset of the
symptoms or complications, alleviate the symptoms or complications,
or eliminate the disease, condition, or disorder.
[0085] As used herein, unless otherwise noted, the term
"prevention" shall include (a) reduction in the frequency of one or
more symptoms; (b) reduction in the severity of one or more
symptoms; (c) the delay or avoidance of the development of
additional symptoms; and/or (d) delay or avoidance of the
development of the disorder or condition.
[0086] One skilled in the art will recognize that wherein the
present invention is directed to methods of prevention, a subject
in need of thereof (i.e. a subject in need of prevention) shall
include any subject or patient (preferably a mammal, more
preferably a human) who has experienced or exhibited at least one
symptom of the disorder, disease or condition to be prevented.
Further, a subject in need thereof may additionally be a subject
(preferably a mammal, more preferably a human) who has not
exhibited any symptoms of the disorder, disease or condition to be
prevented, but who has been deemed by a physician, clinician or
other medical profession to be at risk of developing said disorder,
disease or condition. For example, the subject may be deemed at
risk of developing a disorder, disease or condition (and therefore
in need of prevention or preventive treatment) as a consequence of
the subject's medical history, including, but not limited to,
family history, pre-disposition, co-existing (comorbid) disorders
or conditions, genetic testing, and the like.
[0087] The term "subject" as used herein, refers to an animal,
preferably a mammal, most preferably a human, who has been the
object of treatment, observation or experiment. Preferably, the
subject has experienced and/or exhibited at least one symptom of
the disease or disorder to be treated and/or prevented.
[0088] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation of
the symptoms of the disease or disorder being treated.
[0089] Optimal dosages to be administered may be readily determined
by those skilled in the art, and will vary with the particular
compound or compounds used, the mode of administration, the
strength of the preparation and the advancement of the disease
condition. In addition, factors associated with the particular
patient being treated, including patient's sex, age, weight, diet,
time of administration and concomitant diseases, will result in the
need to adjust dosages.
[0090] One skilled in the art will recognize that, both in vivo and
in vitro trials using suitable, known and generally accepted cell
and/or animal models are predictive of the ability of a test
compound to treat or prevent a given disorder.
[0091] One skilled in the art will further recognize that human
clinical trials including first-in-human, dose ranging and efficacy
trials, in healthy patients and/or those suffering from a given
disorder, may be completed according to methods well known in the
clinical and medical arts.
[0092] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0093] To provide a more concise description, some of the
quantitative expressions given herein are not qualified with the
term "about". It is understood that whether the term "about" is
used explicitly or not, every quantity given herein is meant to
refer to the actual given value, and it is also meant to refer to
the approximation to such given value that would reasonably be
inferred based on the ordinary skill in the art, including
approximations due to the experimental and/or measurement
conditions for such given value.
[0094] To provide a more concise description, some of the
quantitative expressions herein are recited as a range from about
amount X to about amount Y. It is understood that wherein a range
is recited, the range is not limited to the recited upper and lower
bounds, but rather includes the full range from about amount X
through about amount Y, or any amount or range therein.
[0095] Wherein the enantiomeric excess expressions recited herein
state that the % ee is greater than about X %, said expression is
understood to mean a range from an enantiomeric excess of greater
than about X % to about 100%, or any amount or range therein.
[0096] Examples of suitable solvents, bases, reaction temperatures,
and other reaction parameters and components are provided in the
detailed description which follows herein. One skilled in the art
will recognize that the listing of said examples is not intended,
and should not be construed, as limiting in any way the invention
set forth in the claims which follow thereafter.
[0097] As more extensively provided in this written description,
terms such as "reacting" and "reacted" are used herein in reference
to a chemical entity that is any one of: (a) the actually recited
form of such chemical entity, and (b) any of the forms of such
chemical entity in the medium in which the compound is being
considered when named.
[0098] One skilled in the art will recognize that, where not
otherwise specified, the reaction step(s) is performed under
suitable conditions, according to known methods, to provide the
desired product. One skilled in the art will further recognize
that, in the specification and claims as presented herein, wherein
a reagent or reagent class/type (e.g. base, solvent, etc.) is
recited in more than one step of a process, the individual reagents
are independently selected for each reaction step and may be the
same of different from each other. For example wherein two steps of
a process recite an organic or inorganic base as a reagent, the
organic or inorganic base selected for the first step may be the
same or different than the organic or inorganic base of the second
step. Further, one skilled in the art will recognize that wherein a
reaction step of the present invention may be carried out in a
variety of solvents or solvent systems, said reaction step may also
be carried out in a mixture of the suitable solvents or solvent
systems. One skilled in the art will further recognize that wherein
two consecutive reaction or process steps are run without isolation
of the intermediate product (i.e. the product of the first of the
two consecutive reaction or process steps), then the first and
second reaction or process steps may be run in the same solvent or
solvent system; or alternatively may be run in different solvents
or solvent systems following solvent exchange, which may be
completed according to known methods.
[0099] One skilled in the art will further recognize that the
reaction or process step(s) as herein described (or claimed) are
allowed to proceed for a sufficient period of time until the
reaction is complete, as determined by any method known to one
skilled in the art, for example, chromatography (e.g. HPLC). In
this context a "completed reaction or process step" shall mean that
the reaction mixture contains a significantly diminished amount of
the starting material(s)/reagent(s) and a significantly reduced
amount of the desired product(s), as compared to the amounts of
each present at the beginning of the reaction.
[0100] Chiral HPLC against a standard may be used to determine
percent enantiomeric excess (% ee). The enantiomeric excess may be
calculated as follows
[(Rmoles-Smoles)/(Rmoles+Smoles)].times.100%
[0101] where Rmoles and Smoles are the R and S mole fractions in
the mixture such that Rmoles+Smoles=1. The enantiomeric excess may
alternatively be calculated from the specific rotations of the
desired enantiomer and the prepared mixture as follows:
ee=([.alpha.-obs]/[.alpha.-max]).times.100.
[0102] For use in medicine, the salts of the compounds of this
invention refer to non-toxic "pharmaceutically acceptable salts."
Other salts may, however, be useful in the preparation of compounds
according to this invention or of their pharmaceutically acceptable
salts. Suitable pharmaceutically acceptable salts of the compounds
include acid addition salts which may, for example, be formed by
mixing a solution of the compound with a solution of a
pharmaceutically acceptable acid such as hydrochloric acid,
sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic
acid, benzoic acid, citric acid, tartaric acid, carbonic acid or
phosphoric acid. Furthermore, where the compounds of the invention
carry an acidic moiety, suitable pharmaceutically acceptable salts
thereof may include alkali metal salts, e.g., sodium or potassium
salts; alkaline earth metal salts, e.g., calcium or magnesium
salts; and salts formed with suitable organic ligands, e.g.,
quaternary ammonium salts. Thus, representative pharmaceutically
acceptable salts include, but are not limited to, the following:
acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,
chloride, clavulanate, citrate, dihydrochloride, edetate,
edisylate, estolate, esylate, fumarate, gluceptate, gluconate,
glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,
hydrobromide, hydrochloride, hydroxynaphthoate, iodide,
isothionate, lactate, lactobionate, laurate, malate, maleate,
mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,
mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
oleate, pamoate (embonate), palmitate, pantothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate,
sulfate, subacetate, succinate, tannate, tartrate, teoclate,
tosylate, triethiodide and valerate.
[0103] Representative acids which may be used in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
the following: acids including acetic acid, 2,2-dichloroacetic
acid, acylated amino acids, adipic acid, alginic acid, ascorbic
acid, L-aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic
acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucuronic acid, L-glutamic acid, .alpha.-oxo-glutaric
acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric
acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid, lactobionic acid,
maleic acid, (-)-L-malic acid, malonic acid, (.+-.)-DL-mandelic
acid, methanesulfonic acid, naphthalene-2-sulfonic acid,
naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid,
nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid,
palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid,
salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid,
succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid,
thiocyanic acid, p-toluenesulfonic acid and undecylenic acid.
[0104] Representative bases which may be used in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
the following: bases including ammonia, L-arginine, benethamine,
benzathine, calcium hydroxide, choline, deanol, diethanolamine,
diethylamine, 2-(diethylamino)-ethanol, ethanolamine,
ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole,
L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine,
piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine,
secondary amine, sodium hydroxide, triethanolamine, tromethamine
and zinc hydroxide.
Resolution of Ketamine (General Methods)
[0105] The present invention is directed to a process for the
resolution of ketamine into its enantiomers, and more particularly,
to processes for the preparation of an (S)-CSA salt of S-ketamine
and an HCl salt of S-ketamine, as described in more detail in
Scheme 1, below.
##STR00012##
[0106] Accordingly, ketamine (preferably racemic ketamine) is
reacted with (S)-camphorsulfonic acid (also known as (+)-CSA or
S-CSA)), a known compound; wherein the (S)-CSA is present in an
amount in the range of from about 0.5 to about 2.0 molar
equivalents (relative to the amount of ketamine), or any amount or
range therein, preferably in an amount in the range of from about
0.75 to about 1.2 molar equivalents, more preferably, in an amount
in the range of from about 0.9 to about 1.1 molar equivalents, more
preferably, in an amount of about 1 molar equivalent;
[0107] in the presence of water; wherein the water is present in an
amount in the range of from about 3.5% to about 15% (by weight in
the solvent), or any amount or range therein, preferably in an
amount in the range of from about 3.8% to about 11%, more
preferably in an amount in the range of from about 5% to about 10%,
more preferably in an amount in the range of from about 6% and
about 8% (for example about 6.7%);
[0108] in a suitably selected organic solvent such as a suitably
selected ether (for example a cyclic ether) such as THF,
2-methyl-THF, and the like, or a suitably selected ketone such as
methyl ethyl ketone, acetone, methyl isobutyl ketone, and the like,
preferably methyl ethyl ketone or 2-methyl-THF, more preferably
2-methyl-THF; at a temperature in the range of from about
20.degree. C. to about solvent reflux temperature, or any
temperature or range therein, preferably at a temperature in the
range of from about 30.degree. C. to about 100.degree. C., more
preferably at a temperature in the range of from about 50.degree.
C. to about 80.degree. C. (for example at about 70.degree. C., at
about 75.degree. C., at about 80.degree. C., at about 100.degree.
C.);
[0109] to yield the corresponding monohydrate (S)-CSA salt of
S-ketamine, preferably as a solid, more preferably as a crystalline
solid; wherein the monohydrate (S)-CSA salt of S-ketamine is
preferably present in an enantiomeric excess of greater than about
50%, preferably in an enantiomeric excess in the range of from
about 50% to about 100%, or any amount or range therein, more
preferably, in an enantiomeric excess in the range of from about
75% to about 100%, more preferably, more preferably, in an
enantiomeric excess in the range of from about 80% to about 100%,
more preferably, in an enantiomeric excess in the range of from
about 90% to about 100%, more preferably, in an enantiomeric excess
in the range of from about 98% to about 100%. In an example, the
monohydrate (S)-CSA salt of S-ketamine is prepared in an
enantiomeric excess of greater than or equal to about 90%. In
another example, the monohydrate (S)-CSA salt of S-ketamine is
prepared in an enantiomeric excess of greater than or equal to
about 96%.
[0110] Preferably, the monohydrate (S)-CSA salt of S-ketamine is
isolated by known methods, for example by filtration.
[0111] One skilled in the art will recognize that the product
mixture resulting from the above reaction of ketamine with (S)-CSA
will comprise the monohydrate (S)-CSA salt of S-ketamine (as a
precipitate or suspension) and R-ketamine (protonated, in
solution). Further, one skilled in the art will recognize, that
following filtration of the monohydrate (S)-CSA salt of S-ketamine,
the mother liquor or filtrate will comprise enantiomerically
enriched R-ketamine.
[0112] The monohydrate (S)-CSA salt of S-ketamine is optionally
recrystallized, according to known methods, from a suitably
selected solvent or mixture of solvents, (for example from THF,
methyl ethyl ketone or a mixture of THF and water), preferably in
the presence of (or in a mixture with) water.
[0113] The monohydrate (S)-CSA salt of S-ketamine is further
optionally reacted with a suitably selected base, preferably an
inorganic base such as K.sub.2CO.sub.3, Na.sub.2CO.sub.3,
NaHCO.sub.3, NaOH, KOH, and the like, preferably K.sub.2CO.sub.3;
wherein the base is preferably present in an amount in the range of
from about 1.0 to about 10 molar equivalents (relative to the moles
of the monohydrate (S)-CSA salt of S-ketamine), preferably in the
range of from about 1.0 to about 5.0 molar equivalents, more
preferably in a range of from about 1.0 to about 2.0 molar
equivalents (for example, about 1.2 molar equivalents);
[0114] in a suitably selected solvent such as isopropyl acetate,
ethyl acetate, toluene, and the like, preferably isopropyl acetate;
preferably a solvent which is not miscible with water; to yield the
corresponding S-ketamine, as a free base. One skilled in the art
will recognize that the enantiomeric excess of the S-ketamine base
will be approximately equal to the enantiomeric excess of the
monohydrate (S)-CSA salt of S-ketamine, since the reaction with the
inorganic base would not be expected to affect the stereo-center
(e.g. result in racemization at the stereo-center).
[0115] Preferably, the S-ketamine free base is isolated according
to known methods, for example by filtration.
[0116] The S-ketamine free base is further optionally reacted,
according to known methods, with a suitably selected acid such as
HCl (for example as HCl gas), to yield the corresponding acid
addition salt, preferably the corresponding hydrochloride salt. One
skilled in the art will recognize that the enantiomeric excess of
the S-ketamine salt, preferably the S-ketamine hydrochloride salt
will be approximately equal to or greater than the enantiomeric
excess of the S-ketamine, since the reaction with the suitably
selected acid would not be expected to affect the stereo-center
(e.g. result in racemization at the stereo-center).
[0117] In an embodiment of the present invention, the S-ketamine
free base is reacted with the acid, preferably HCl, wherein the
amount of the acid is in the range of from about 0.8 to about 5.0
molar equivalents (relative to the moles of S-ketamine base), more
preferably in an amount in the range of rom about 1.0 to about 3.0
molar equivalents, more preferably in an amount in the range of
from about 1.0 to about 1.5 molar equivalents (for example about
1.2 molar equivalents).
[0118] The present invention is further directed to a process for
the resolution of ketamine into its enantiomers, and more
particularly, to a process for the preparation of an (R)-CSA salt
of R-ketamine and an HCl salt of S-ketamine, as described in more
detail in Scheme 2, below.
##STR00013##
[0119] Accordingly, ketamine (preferably racemic ketamine) is
reacted with (R)-camphorsulfonic acid (also known as (-)-CSA or
R-CSA)), a known compound; wherein the (R)-CSA is present in an
amount in the range of from about 0.5 to about 2.0 molar
equivalents (relative to the amount of ketamine), or any amount or
range therein, preferably in an amount in the range of from about
0.75 to about 1.5 molar equivalents, for example in an amount of
about 1.0 molar equivalents;
[0120] in the presence of water; wherein the water is present in an
amount in the range of from about 3.5% to about 15% (by weight in
the solvent), or any amount or range therein, preferably in an
amount in the range of from about 7.5% to about 12.5%, for example
in an amount of about 9%;
[0121] in a suitably selected organic solvent such as a suitably
selected ether (for example a cyclic ether) such as THF,
2-methyl-THF, and the like, or a suitably selected ketone such as
methyl ethyl ketone, acetone, methyl isobutyl ketone, and the like,
preferably methyl ethyl ketone or 2-methyl-THF, more preferably
2-methyl-THF; at a temperature in the range of from about
20.degree. C. to about solvent reflux temperature, or any
temperature or range therein, preferably at a temperature in the
range of from about 30.degree. C. to about 100.degree. C.; to yield
a product mixture comprising
[0122] (a) the corresponding (R)-CSA salt of R-ketamine,
preferably, as a hydrate (for example, as a monohydrate),
preferably as a solid, more preferably as a crystalline solid (for
example, as a precipitate); wherein the (R)-CSA salt of R-ketamine
is preferably present in an enantiomeric excess of greater than
about 50%, preferably in an enantiomeric excess in the range of
from about 50% to about 100%, or any amount or range therein, more
preferably, in an enantiomeric excess in the range of from about
75% to about 100%, more preferably, in an enantiomeric excess of
about 96%, more preferably, in an enantiomeric excess in the range
of from about 98% to about 100%; and
[0123] (b) S-ketamine; wherein the S-ketamine remains in solution;
wherein the S-ketamine is preferably present in an enantiomeric
excess of greater than about 50%, preferably in an enantiomeric
excess in the range of from about 50% to about 100%, or any amount
or range therein, more preferably, in an enantiomeric excess in the
range of from about 75% to about 100%, more preferably, in an
enantiomeric excess of about 96%, more preferably, in an
enantiomeric excess in the range of from about 98% to about
100%.
[0124] Although not intended to be limiting or definitive, it is
theorized that the S-ketamine, which remains in solution in the
product mixture described above, may present in a protonated base
form (protonated by any excess (R)-CSA present).
[0125] Preferably, the (R)-CSA salt of R-ketamine is isolated
according to known methods, for example by filtration. One skilled
in the art will recognize that filtration of the product mixture
will yield the (R)-CSA salt of R-ketamine as a solid and a filtrate
or mother liquor comprising S-ketamine.
[0126] The S-ketamine is then further optionally isolated from the
filtrate or mother liquor (according to known methods, for example
by reacting with a suitably selected inorganic base such as
K.sub.2CO.sub.3, Na.sub.2CO.sub.3, NaHCO.sub.3, NaOH, KOH, and the
like, and further extracting with a suitably selected organic
solvent, preferably an organic solvent which is not miscible with
water, such as 2-methyl-THF, isopropyl acetate, and the like,
preferably isopropyl acetate) and/or reacted (according to known
methods), with a suitably selected acid such as HCl (for example as
HCl gas), to yield the corresponding acid addition salt, preferably
the corresponding hydrochloride salt. One skilled in the art will
recognize that the enantiomeric excess of the S-ketamine salt,
preferably the S-ketamine hydrochloride salt will be approximately
equal to or greater than the enantiomeric excess of the S-ketamine,
since the reaction with the suitably selected acid would not be
expected to affect the stereo-center (e.g. result in racemization
at the stereo-center).
[0127] In an embodiment of the present invention, the S-ketamine is
reacted with the acid, preferably HCl, wherein the amount of the
acid is in the range of from about 0.8 to about 5.0 molar
equivalents (relative to the moles of S-ketamine base), more
preferably in an amount in the range of rom about 1.0 to about 3.0
molar equivalents, more preferably in an amount in the range of
from about 1.0 to about 1.5 molar equivalents (for example about
1.2 molar equivalents).
Crystalline Forms
[0128] The crystalline forms of the present invention, for example
the monohydrate form of the (S)-CSA salt of S-ketamine may be
characterized by, for example, powder X-Ray Diffraction (pXRD),
TG-FTIR, DSC, DVS, Karl-Fischer analysis, optical rotation, and
other known methods for determining the physical properties of a
solid or crystal.
[0129] The powder X-ray diffractograms (diffraction spectra, pXRD)
provided herein were measured using on an X-ray diffractometer
using CuK.alpha. radiation. The pestled sample was back-loaded into
a conventional x-ray holder. The sample was scanned from 3 to
40.degree. 2.theta. with a step size of 0.01.degree. 2.theta. and a
time per step of 5.0 seconds. Instrument voltage and current
settings were 40 kV and 30 mA.
[0130] ThermoGravimetric-Fourier Transform InfraRed (TG-FTIR)
measurements, where carried out were measures using a Netzsche
Thermo-Microbalance TG209 with Bruker FT-IR Spectrometer Vector 22,
with aluminum crucible with microhoel, nitrogen atmosphere and
scanning form 25.degree. C. to 300.degree. C. at a heating rate of
10K/min.
[0131] Dynamic Scanning calorimetry (DSC) measurements (where
completed) were measured using either (a) Perkins Elmer DSC 7,
hermetically closed gold crucible, measuring from 20.degree. C. to
270.degree. C. at a heating rate of 10K/min, (b) TA Instruments DSC
Q2000, hermetically closed gold crucible, measuring from 20.degree.
C. to 300.degree. C. at a heating rate of 10K/min.
[0132] Dynamic Vapor Sorption (DVS) measurements (where completed)
were measured using a Projekt Messtechnik Sorptions Prufsystem SPS
11 or Surface Measurement Systems DVS-1 scanning (cycling relative
humidity and hodling the sample at a set relative humidity) as
follow: (a) holding sample at 50% RH for 2 hours; (b) 50% RH to 0%
RH (5%/h); holding at 0% RH for 5 hours; (c) 0% RH to 95% RH
(5%/h); holding at 95% RH for 5 hours; and (d) 95% RH to 50% RH
(5%/h); holding at 50% RH for 2 hours.
[0133] A powder XRD (pXRD) diffractogram was measured for multiple
samples of the crystalline monohydrate form of (S)-CSA salt of
S-ketamine (prepared as described herein), with a representative
example as shown in FIG. 1. The crystalline monohydrate form of
(S)-CSA salt of S-ketamine, may be characterized by its X-ray
diffraction pattern, comprising peaks having a relative intensity
greater than or equal to about 5%, as listed in Table 1, below.
TABLE-US-00001 TABLE 1 pXRD Peaks for Monohydrate (S)-CSA salt of
S-Ketamine position [.degree.2.theta.] d-spacing [.ANG.] 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 17.09 5.18 6.03 17.26 5.13
8.92 18.20 4.87 7.73 18.45 4.80 43.84 19.43 4.56 7.39 20.10 4.41
10.03 21.29 4.17 12.49 22.38 3.97 14.87 22.58 3.93 6.88 22.71 3.91
7.31 23.26 3.82 10.45 23.66 3.76 7.90 24.22 3.67 25.66 25.26 3.52
28.46 25.68 3.47 5.35 25.93 3.43 8.92 26.76 3.33 13.93 27.33 3.26
51.32 28.21 3.16 12.32 29.13 3.06 11.05 29.85 2.99 7.90 31.31 2.86
7.48 32.12 2.78 8.24 32.79 2.73 7.90 33.10 2.70 6.20 33.72 2.66
7.48 34.95 2.56 7.48 36.20 2.48 9.77 37.17 2.42 6.03
[0134] In an embodiment, the crystalline monohydrate form of
(S)-CSA salt of S-ketamine is characterized by its pXRD pattern
which comprises peaks having a relative intensity greater than or
equal to about 10%, as listed in Table 2, below.
TABLE-US-00002 TABLE 2 PXRD Peaks for Monohydrate (S)-CSA salt of
S-Ketamine position [.degree.2.theta.] d-spacing [.ANG.] 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
[0135] In another embodiment, the crystalline monohydrate form of
(S)-CSA salt of S-ketamine is characterized by its pXRD pattern
which comprises peaks having a relative intensity greater than or
equal to about 20%, as listed in Table 3, below.
TABLE-US-00003 TABLE 3 PXRD Peaks for Monohydrate (S)-CSA salt of
S-Ketamine position [.degree.2.theta.] d-spacing [.ANG.] 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
[0136] % Water content was measured under adequate exclusion of
atmospheric moisture using a modified volumetric Karl-Fischer
titration for ketones, as follows. About 500 mg of the sample was
weighed accurately and was dissolved in 40 mL of the
Hydranal.RTM.-KetoSolver from Fluka (pre-titrated with the
Karl-Fischer reagent Hydranal.RTM.-Composite 5K, from Fluka).
Afterwards, the solution was titrated with the Karl-Fischer
reagent. The endpoint was detected voltammetrically and the water
content in percent was calculated according to the following
formula:
Water content[%]=V*F*0.1/S
where S represents Sample weight [g], F represents Factor of
Karl-Fischer reagent [mg/mL], and V represents Consumption of
Karl-Fischer reagent [mL].
[0137] The % water content was determined for multiple samples of
crystalline monohydrate form of (S)-CSA salt of S-ketamine
(prepared as described herein) with measured values ranging between
3.76% and 3.79% (average water content was 3.8%). The calculated
theoretical value for a monohydrate of (S)-CSA salt of S-ketamine
is 3.7%.
[0138] TG-FTIR measurement of a representative sample of the
monohydrate crystalline form of (S)-CSA salt of S-ketamine
exhibited a weight loss of 3.7 wt % in one step between 110.degree.
C. and 190.degree. C. due to evaporation of water (corresponding to
the theoretical 3.69 wt % stoichiometric water content of a
monohydrate) and a chemical decomposition above 230.degree. C.
[0139] The absolute optical rotation of multiple samples of
monohydrate form of (S)-CSA salt of S-ketamine (prepared as
described herein) was determined to range between 66.8.degree. and
67.4.degree.. Average absolute optical rotation was
[.alpha.].sup.20.sub.D=+67.8.degree. (c=1.0, methanol).
[0140] Optical microscopy on the crystalline form of the
monohydrate (S)-CSA salt of S-ketamine showed 1000-50 .mu.M large
equant crystals, appearing as fractured blocks. .sup.1H NMR of a
representative sample of the monohydrate (S)-CSA salt of S-ketamine
confirmed the 1:1 salt stoichiometry.
[0141] DSC measured for a representative sample of the monohydrate
(S)-CSA salt of S-ketamine exhibited a melting point of about
144.degree. C., and a melting enthalpy of 121 J/g. DVS measurement
of a representative sample of the monohydrate (S)-CSA salt of
S-ketamine exhibited no hygroscopicity, and physical stability at
elevated relative humidity.
[0142] The approximate solubility of the monohydrate crystalline
form of the (S)-CSA salt of S-ketamine was measured by stepwise
dilution of a suspension of about 10 mg of the sample in 0.05 mL
solvent. Table 4 below lists the approximate solubility, denoted
"S". If a sample was not dissolved by addition of a total of 10-12
mL of solvent, the solubility is indicated as <1 mg/mL in the
Table 4, below.
TABLE-US-00004 TABLE 4 Approximate Solubility of Crystalline,
Monohydrate Form of (S)-CSA salt of S-Ketamine Solvent or Mixture
Solubility (mg/mL) acetone 5 < S < 6 anisole S < 1 DCM 67
< S < 101 1,4-dioxane 5 < S < 6 DMF 91 < S < 185
DMSO 106 < S < 212 ethyl acetate S < 1 ethanol 67 < S
< 100 heptane S < 1 acetonitrile 22 < S < 24 methanol
226 < S 2-methyl-THF 5 < S < 7 2-propanol 22 < S <
25 isopropyl acetate S < 1 TBME S < 1 THF 5 < S < 7
toluene S < 1 water 20 < S < 24 1:1 acetone:water 58 <
S < 77 10:1 aectobne:water 20 < S < 24 2-methyl THF
saturated with water 6 < S < 8 1:1 2-propanol:water 93 < S
< 189 10:1 2-propanol:water 24 < S < 28 1:1
2-propanol:isopropyl acetate 10 < S < 11
[0143] Additionally, the solubility of the monohydrate crystalline
form of the (S)-CSA salt of S-ketamine in select solvents was
determined as follows: 21 g of (S)-CSA salt of S-ketamine was
dissolved in 100 mL of solvent (as listed in Table 5 below). After
24 hours, the solutions were analyzed visually. If the compound was
completely dissolved, solubility was above 20 g/100 mL. If the
compound was not completely dissolved, any remaining precipitate
was filtered off, the filtrate was diluted 400-fold with HPLC
dilution solvent (or acetonitrile/HPLC dilution solvent) and
analyzed by HPLC, with results as listed in Table 5, below.
TABLE-US-00005 TABLE 5 Solubility Measurements
(S)-Ketamine-(+)-10-camphorsulfonate-monohydrate Solubility Solvent
[g/100 mL] at 23.6.degree. C. demineralized water 5.344 methanol
18.457 ethanol 18.297 2-propanol 7.275 acetone (2-propanone) 0.578
N,N-dimethylacetamide 18.200 N,N-dimethylformamide 18.267 acetic
acid 18.209 dichloromethane/methanol (50/50 v/v) 18.589
[0144] The present invention is further directed to an amorphous
form of the (S)-CSA salt of S-ketamine. In an embodiment of the
present invention, the amorphous form of the (S)-CSA salt of
S-ketamine is anhydrous.
[0145] The amorphous, anhydrous form of the (S)-CSA salt of
S-ketamine may be prepared by dehydrating the monohydrate form at
an elevated temperature, for example at a temperature greater than
about 120.degree. C. In an example, a sample of the monohydrate
crystalline form of (S)-CSA salt of S-ketamine was maintained at
160.degree. C. under dry nitrogen flow for 30 min. pXRD analysis
carried out several hours later showed a mixture of the crystalline
monohydrate and amorphous anhydrous forms of (S)-CSA salt of
S-ketamine. The amorphous anhydrous form of (S)-CSA salt of
S-ketamine was also obtained (in a mixture with the monohdrate
form) by slurrying the crystalline monohydrate form of (S)-CSA salt
of S-ketamine in 2-methyl THF or isopropyl acetate at about
80.degree. C. for about 4 days.
[0146] The amorphous, anhydrous form of (S)-CSA salt of S-ketamine
is hygroscopic and rapidly converts to the monohydrate form of
(S)-CSA salt of S-ketamine on storage at ambient conditions.
[0147] The present invention further comprises pharmaceutical
compositions containing a product prepared according to any of the
process(es) described herein with a pharmaceutically acceptable
carrier. Pharmaceutical compositions containing one or more of the
compounds of the invention described herein as the active
ingredient can be prepared by intimately mixing the compound or
compounds with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques. The carrier may take a wide
variety of forms depending upon the desired route of administration
(e.g., oral, parenteral). Thus for liquid oral preparations such as
suspensions, elixirs and solutions, suitable carriers and additives
include water, glycols, oils, alcohols, flavoring agents,
preservatives, stabilizers, coloring agents and the like; for solid
oral preparations, such as powders, capsules and tablets, suitable
carriers and additives include starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and
the like. Solid oral preparations may also be coated with
substances such as sugars or be enteric-coated so as to modulate
major site of absorption. For parenteral administration, the
carrier will usually consist of sterile water and other ingredients
may be added to increase solubility or preservation. Injectable
suspensions or solutions may also be prepared utilizing aqueous
carriers along with appropriate additives.
[0148] To prepare the pharmaceutical compositions of this
invention, one or more compounds of the present invention as the
active ingredient is intimately admixed with a pharmaceutical
carrier according to conventional pharmaceutical compounding
techniques, which carrier may take a wide variety of forms
depending of the form of preparation desired for administration,
e.g., oral or parenteral such as intramuscular. In preparing the
compositions in oral dosage form, any of the usual pharmaceutical
media may be employed. Thus, for liquid oral preparations, such as
for example, suspensions, elixirs and solutions, suitable carriers
and additives include water, glycols, oils, alcohols, flavoring
agents, preservatives, coloring agents and the like; for solid oral
preparations such as, for example, powders, capsules, caplets,
gelcaps and tablets, suitable carriers and additives include
starches, sugars, diluents, granulating agents, lubricants,
binders, disintegrating agents and the like. Because of their ease
in administration, tablets and capsules represent the most
advantageous oral dosage unit form, in which case solid
pharmaceutical carriers are obviously employed. If desired, tablets
may be sugar coated or enteric coated by standard techniques. For
parenterals, the carrier will usually comprise sterile water,
through other ingredients, for example, for purposes such as aiding
solubility or for preservation, may be included. Injectable
suspensions may also be prepared, in which case appropriate liquid
carriers, suspending agents and the like may be employed. The
pharmaceutical compositions herein will contain, per dosage unit,
e.g., tablet, capsule, powder, injection, teaspoonful and the like,
an amount of the active ingredient necessary to deliver an
effective dose as described above.
[0149] The pharmaceutical compositions herein will contain, per
unit dosage unit, e.g., tablet, capsule, powder, injection,
suppository, teaspoonful, and the like, of from about 0.01 mg to
about 1000 mg or any amount or range therein, and may be given at a
dosage of from about 0.01 mg/kg to about 1.5 mg/kg, or any amount
or range therein, preferably from about 0.01 mg/kg/day to about
0.75 mg/kg, or any amount or range therein, preferably from about
0.05 mg/kg to about 0.5 mg/kg, or any amount or range therein,
preferably from about 0.1 mg/kg to about 0.5 mg/kg, or any amount
or range therein, of each active ingredient. The dosages, however,
may be varied depending upon the requirement of the patients, the
severity of the condition being treated and the compound being
employed. The use of either daily administration or post-periodic
dosing may be employed.
[0150] Preferably these compositions are in unit dosage forms from
such as tablets, pills, capsules, powders, granules, sterile
parenteral solutions or suspensions, metered aerosol or liquid
sprays, drops, ampoules, autoinjector devices or suppositories; for
oral parenteral, intranasal, sublingual or rectal administration,
or for administration by inhalation or insufflation. Alternatively,
the composition may be presented in a form suitable for once-weekly
or once-monthly administration; for example, an insoluble salt of
the active compound, such as the decanoate salt, may be adapted to
provide a depot preparation for intramuscular injection. For
preparing solid compositions such as tablets, the principal active
ingredient is mixed with a pharmaceutical carrier, e.g.
conventional tableting ingredients such as corn starch, lactose,
sucrose, sorbitol, talc, stearic acid, magnesium stearate,
dicalcium phosphate or gums, and other pharmaceutical diluents,
e.g. water, to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention, or a
pharmaceutically acceptable salt thereof. When referring to these
preformulation compositions as homogeneous, it is meant that the
active ingredient is dispersed evenly throughout the composition so
that the composition may be readily subdivided into equally
effective dosage forms such as tablets, pills and capsules. This
solid preformulation composition is then subdivided into unit
dosage forms of the type described above containing from about 0.01
mg to about 1,000 mg, or any amount or range therein, of the active
ingredient of the present invention. The tablets or pills of the
novel composition can be coated or otherwise compounded to provide
a dosage form affording the advantage of prolonged action. For
example, the tablet or pill can comprise an inner dosage and an
outer dosage component, the latter being in the form of an envelope
over the former. The two components can be separated by an enteric
layer which serves to resist disintegration in the stomach and
permits the inner component to pass intact into the duodenum or to
be delayed in release. A variety of material can be used for such
enteric layers or coatings, such materials including a number of
polymeric acids with such materials as shellac, cetyl alcohol and
cellulose acetate.
[0151] The liquid forms in which the novel compositions of the
present invention may be incorporated for administration orally or
by injection include, aqueous solutions, suitably flavoured syrups,
aqueous or oil suspensions, and flavoured emulsions with edible
oils such as cottonseed oil, sesame oil, coconut oil or peanut oil,
as well as elixirs and similar pharmaceutical vehicles. Suitable
dispersing or suspending agents for aqueous suspensions, include
synthetic and natural gums such as tragacanth, acacia, alginate,
dextran, sodium carboxymethylcellulose, methylcellulose,
polyvinyl-pyrrolidone or gelatin.
[0152] The method of treating treatment resistant depression
described in the present invention may also be carried out using a
pharmaceutical composition comprising any of the compounds as
defined herein and a pharmaceutically acceptable carrier. The
pharmaceutical composition may contain between about 0.01 mg and
about 1000 mg of the compound, or any amount or range therein;
preferably from about 0.05 mg to about 500 mg of the compound, or
any amount or range therein, and may be constituted into any form
suitable for the mode of administration selected. Carriers include
necessary and inert pharmaceutical excipients, including, but not
limited to, binders, suspending agents, lubricants, flavorants,
sweeteners, preservatives, dyes, and coatings. Compositions
suitable for oral administration include solid forms, such as
pills, tablets, caplets, capsules (each including immediate
release, timed release and sustained release formulations),
granules, and powders, and liquid forms, such as solutions, syrups,
elixirs, emulsions, and suspensions. Forms useful for parenteral
administration include sterile solutions, emulsions and
suspensions.
[0153] Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times daily.
Furthermore, compounds for the present invention can be
administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to
those of ordinary skill in that art. To be administered in the form
of a transdermal delivery system, the dosage administration will,
of course, be continuous rather than intermittent throughout the
dosage regimen.
[0154] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic pharmaceutically acceptable inert carrier such
as ethanol, glycerol, water and the like. Moreover, when desired or
necessary, suitable binders; lubricants, disintegrating agents and
coloring agents can also be incorporated into the mixture. Suitable
binders include, without limitation, starch, gelatin, natural
sugars such as glucose or beta-lactose, corn sweeteners, natural
and synthetic gums such as acacia, tragacanth or sodium oleate,
sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar, bentonite,
xanthan gum and the like.
[0155] The liquid forms in suitably flavored suspending or
dispersing agents such as the synthetic and natural gums, for
example, tragacanth, acacia, methyl-cellulose and the like. For
parenteral administration, sterile suspensions and solutions are
desired. Isotonic preparations which generally contain suitable
preservatives are employed when intravenous administration is
desired.
[0156] To prepare a pharmaceutical composition of the present
invention, a product prepared according to any of the process(es)
as described herein as the active ingredient is intimately admixed
with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques, which carrier may take a
wide variety of forms depending of the form of preparation desired
for administration (e.g. oral or parenteral). Suitable
pharmaceutically acceptable carriers are well known in the art.
Descriptions of some of these pharmaceutically acceptable carriers
may be found in The Handbook of Pharmaceutical Excipients,
published by the American Pharmaceutical Association and the
Pharmaceutical Society of Great Britain.
[0157] Methods of formulating pharmaceutical compositions have been
described in numerous publications such as Pharmaceutical Dosage
Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3,
edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral
Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical
Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et
al; published by Marcel Dekker, Inc.
[0158] The following Examples are set forth to aid in the
understanding of the invention, and are not intended and should not
be construed to limit in any way the invention set forth in the
claims which follow thereafter.
[0159] In the Examples which follow, some synthesis products are
listed as having been isolated as a residue. It will be understood
by one of ordinary skill in the art that the term "residue" does
not limit the physical state in which the product was isolated and
may include, for example, a solid, an oil, a foam, a gum, a syrup,
and the like.
Example 1
Preparation of (S)-Ketamine (+)-CSA Monohydrate Salt
##STR00014##
[0161] rac-Ketamine free base (10 g, 42 mmol) and (+)-CSA (10 g, 42
mmol, 98 mass %, 1 eq.) in methyl ethyl ketone (33.3 g) and water
(1.85 g) were stirred at room temperature. The reaction mixture was
then heated 50.degree. C. and stirred for 1 h at this temperature.
The resulting slurry was cooled to room temperature over 1 h. The
resulting suspension stirred overnight and filtered. The wet cake
was washed twice with methyl ethyl ketone (5 g) to yield the title
compound as a white solid (10.15 g of wet product). The material
was dried for 6 h at 50.degree. C., 10 mbar to yield (S)-Ketamine
CSA salt as a white solid.
[0162] Yield: 10.04 g
[0163] Purity: HPLC: 100%,
[0164] Enantiomeric purity: 96.4%
[0165] Assay corrected yield: 49%
Example 2
Recrystallization of (S)-Ketamine (+)-CSA Monohydrate Salt
##STR00015##
[0167] To (S)-ketamine-(+)-CSA monohydrate salt (10.1 g, 41.3 mmol)
were added methyl ethyl ketone (33.3 g) and water (1.85 g). The
reaction mixture was then warmed to 80.degree. C. A clear solution
was observed to form. The reaction mixture was then cooled to
50.degree. C. (a slurry was observed to form). At this temperature,
additional methyl ethyl ketone (33.3 g) was added. The resulting
suspension was cooled to 20.degree. C. over 1 h. The resulting
suspension was stirred overnight and filtered. The wet cake was
washed twice with methyl ethyl ketone (5 g) to yield the title
compound as a white solid (8.84 g of wet product). The material was
dried for 1 h at 50.degree. C., 10 mbar to yield (S)-Ketamine CSA
salt as a white solid.
[0168] Yield: 8.81 g
[0169] Purity: HPLC: 100%
[0170] Enantiomeric purity: 100%
[0171] Assay corrected yield: 86%
Example 3
Preparation of (S)-Ketamine (+)-CSA Monohydrate Salt
##STR00016##
[0173] rac-Ketamine free base (10 g, 42 mmol) and (+)-CSA (9.8 g,
42 mmol, 1 eq.) in 2-methyl-THF (70 g) were stirred at room
temperature. Water (6.3 g) was added to yield a slurry. The slurry
was heated to reflux (T=73.degree. C.), resulting in the formation
of a clear solution. The solution was stirred at reflux temperature
for 1 h, then cooled to 63.degree. C. and seeded with small amounts
(one spatula tip) of (S)-Ketamine-CSA salt. Crystallization was
observed to start. The suspension was maintained at this
temperature for 1 h, cooled in 1 h to 50.degree. C. and then to
20.degree. C., over an additional one hour. The resulting
suspension was stirred overnight and filtered. The wet cake was
washed twice with 2-methyl-THF (10 g) to yield the title compound
as a white solid (9.1 g of wet product). The material is dried
overnight at 50.degree. C., 20 mbar to yield (S)-Ketamine CSA salt
as a white solid.
[0174] Yield: 9.06 g
[0175] Purity: HPLC: 100%,
[0176] Enantiomeric purity: 99.3%
[0177] Assay corrected yield: 45%
Example 4
Preparation of (S)-Ketamine (+)-CSA Monohydrate Salt
##STR00017##
[0179] rac-Ketamine free base (600 g, 2.524 mol) (+)-CSA (588 g,
2.531 mol, 1 eq) in 2-Me-THF (4200 g) were stirred at room
temperature. Then water (378 g) was added (formation of a slurry
was observed). The slurry was heated to reflux (T=72-73.degree.
C.). A clear solution was observed to form. The solution was
stirred at this temperature for about 10 minutes. The mixture was
cooled to 63.degree. C. within 20 min and seeded with
(S)-Ketamine-(+)-CSA monohydrate salt (2 g). Crystallization was
observed to start. The resulting suspension was maintained at this
temperature for 1 h. Then the following cooling profile was
applied: cooling to 59.degree. C. in 1 h, cooling to 52.degree. C.
in 1 h, cooling to 38.degree. C. in 1 h, cooling to 20.degree. C.
in 40 min, cooling to 0.degree. C. in 20 min. The suspension was
stirred for 6 h-16 h and filtered. The wet cake was washed with
2-Me-THF (a total of 2150 g) containing 2% of water (2107 g
2-Me-THF, 43 g water) in 3 portions and wet product were obtained
as white solid (654 g). The material was dried overnight at
50.degree. C. at 20 mbar and (S)-Ketamine CSA salt monohydrate (573
g) was obtained as white solid.
[0180] Enantiomeric purity: 99.21
[0181] Assay corrected yield: 47%
[0182] Water content: 3.84%
Example 6
Recrystallization of (S)-Ketamine (+)-CSA Monohydrate Salt
##STR00018##
[0184] (S)-Ketamine-(+)-CSA monohydrate (50.0 g, 102.46 mmol) was
suspended in THF (375 g) and water (25 g). The resulting mixture
was heated to reflux (clear solution, T=64.degree. C.). The clear
solution was cooled to 50.degree. C. and seeded with crystals of
(S)-Ketamine-(+)-CSA monohydrate (0.25 g). Crystallization was
observed to start and a suspension was formed, which was stirred
for 1 h at this temperature. The suspension was cooled to 0.degree.
C. within 8 h and stirred for overnight at this temperature. The
product was filtered off and washed with THF (3.times.25 g). The
wet product (45.8 g) was dried overnight at 50.degree. C. at 20
mbar to yield (S)-Ketamine-(+)-CSA monohydrate are isolated as
white solid (45.4 g).
[0185] Enantiomeric Purity: 100.00
[0186] Assay Corrected Yield: 91%
[0187] Water Content: 3.84%
Example 7
Preparation of (R)-Ketamine (-)-CSA Monohydrate Salt
##STR00019##
[0189] rac-Ketamine free base (10 g, 42 mmol) and (-)-CSA (9.8 g,
42 mmol, 1 eq.) in 2-methyl-THF (70 g) were stirred at room
temperature. Water (6.3 g) was added to yield a slurry. The slurry
was heated to reflux (T=72.degree. C.), resulting in the formation
of a clear solution. The solution was stirred at reflux temperature
for 1 h, then cooled to 63.degree. C. 0.5 ml of a suspension
prepared from 100 mg (R)-ketamine, and 98 mg
(-)-camphor-10-sulfonic acid dissolved in 1.5 g of THF and 8 .mu.g
of water (spontaneous crystallization) was added. The reaction
mixture became turbid. The formed suspension was cooled to
59.degree. C. within 1 h, then further cooled in 1 h to 52.degree.
C., in 1 h to 38.degree. C., in 2 h to 20.degree. C., and in 2 h to
0.degree. C. The formed suspension was further stirred at 0.degree.
C. overnight. The resulting suspension was filtered, and the wet
cake was washed twice with a mixture of 2-methyl-THF (9.6 g) and
water (0.4 g) to yield the title compound as a white solid (10.5 g
of wet product). The material was dried overnight at 50.degree. C.,
20 mbar to yield (R)-Ketamine (-)-CSA salt as a white solid.
[0190] Yield: 9.3 g; Assay corrected yield: 43%
[0191] Purity: HPLC: 100%;
[0192] Enantiomeric purity: 99.38%, purity 100%, assay 95.23%
Example 8
Preparation of (S)-Ketamine Hydrochloride Salt from the Mother
Liquor of
Example 7
##STR00020##
[0194] To the mother liquor of Example 7 (which contains
(S)-ketamine and (-)-camphor-10-sulfonic acid dissolved in a
methyl-THF/water mixture (10.9:1)) was added HCl gas (0.9 g) at
ambient temperatures over 2 min. Spontaneous crystallization of a
solid was observed (pH of the solution 0-1). After stirring for 30
min the solids were filtered off, and the wet cake was rinsed twice
with methyl-THF (5.0 g each time). The resulting solids (5.8 g wet)
were dried in vacuum at 50.degree. C. The mother liquor (107.45 g)
contains 82% (S)-ketamine and 18% (R)-ketamine.
[0195] Yield 3.91 g; Assay Corrected Yield (with respect to the
used rac-ketamine in experiment 7: 34% (68% with respect to
(S)-ketamine)
[0196] Enantiomeric Purity: 99.78%
[0197] Water Content: 0.23%, purity 99.98%, assay 97.56%
Example 9
Classical Resolution Screening Experiments
[0198] Unless otherwise noted, all resolution experiments were
performed on a 1 mmol scale of (.+-.)-ketamine free base and with
addition of 0.5 mol-equivalent of the selected acidic resolving
agent in 3.5 mL of solvent. The acidic resolving agents tested were
as follows:
TABLE-US-00006 ID No. Structure/Name 1 ##STR00021## (1S)-(+)-10-
camphorsulphonic acid 2 ##STR00022## (S)-(-)-phencyphos (P1(+)) 3
##STR00023## L(+)-tartaric acid 4 ##STR00024## L(-)-O,O'-DBTA 5
##STR00025## L(-)-O,O'-DTTA ##STR00026## D(+)-O,O'-DATA 7
##STR00027## L(-)-2-pyrrolidone-5- carboxylic acid 8 ##STR00028##
N-Bz-L-Asp-OH 9 ##STR00029## N-Bz-L-Glu-OH 10 ##STR00030##
(S)-(+)-mandelic acid 11 ##STR00031## (S)-(+)-2-(4-chlorophenyl)-3-
methylbutanoic acid 12 ##STR00032## (S)-(+)-naproxen 13
##STR00033## (S)-N-tosyl-valine 14 ##STR00034##
(R)-N-Tosyl-phenylglycine 15 ##STR00035##
(R)-N-Benzoyl-phenylglycine 16 ##STR00036##
(R)-(-)-1,1'-bisnaphthyl-2,2'-diyl- hydrogenphosphate
Preparation of (.+-.)-Ketamine Free Base
[0199] Racemic ketamine.HCl (15.0 g, 54.7 mmol) was dissolved in
100 mL of water under stirring. To the solution was added 100 mL
CHCl.sub.3 and under vigorous stirring basified by drop-wise
addition of a solution of 2.40 g NaOH (60 mmol) in 30 mL of water.
The white precipitate that was formed was directly extracted into
the CHCl.sub.3 layer (clear solution). The mixture was transferred
into a separation funnel and separated. The aqueous phase was
extracted again with 100 mL chloroform and then with 50 mL of
chloroform. The combined chloroform layers were washed with 50 mL
of water, dried over Na.sub.2SO.sub.4 and concentrated on a Rotavap
to yield a white crystalline solid (solidified oil). Yield: 12.88 g
of white solid (54.2 mmol, 99%); NMR confirmed ketamine free
base.
[0200] The procedure was repeated with 10.15 g (36.9 mmol) of
racemic ketamine and yielded 8.73 g (36.7 mmol, 99.5%) of free
ketamine as a white solid.
RS1: Resolution Screening Experiments in Methanol:
[0201] Ketamine free base (3.93 g, 16.5 mmol) was dissolved in 15
mL methanol (slightly warmed for dissolution), transferred to a 25
mL volumetric flask and the flask filled to 25 mL with methanol (1
mmol=1.52 mL). The weight of this solution was 21.0 g (1 mmol=1.27
g). The resolving agent was dissolved/suspended in 1.60 g (2.0 mL)
of methanol.
[0202] At room temperature 1.27 g (1.0 mmol) of the prepared
ketamine free base solution in methanol was added to the prepared
resolving agent in methanol mixture. All resulting solutions were
observed to become clear, except Exp. #1.2 and #1.9, which were
heated to effect dissolution. After standing for 22 h at room
temperature, all solutions were still clear. The screw caps were
removed after 2 days, to allow slow evaporation. After 5 days, most
of the solvent was evaporated and in most vials a thick oil
remained, as indicated in Table RS1, below. To the vials with a
solid layer was added 1 mL of MeOH to re-dissolve any solids.
Addition of the methanol resulting in most of the solid
re-dissolving, and then 3 mL of cyclo-pentyl methyl ether (CPME) as
anti-solvent was added. After 4 hours standing, all vials were
again opened again for slow evaporation. After 2 days slow
evaporation of the CPME to -2 mL, a thick turbid oil was observed
to form in some of the vials (see Table RS1). These vials were
closed and heated to reflux for dissolution (if necessary a few
drops of MeOH were added for dissolution). In vials of Exp. #1.4,
#1.5 and #1.9 oils were formed again. In vial of Exp. #1.16 a solid
was formed and the mother liquid (and 0.5 mL CPME washing) was
removed with a pipette, although the solid exhibited an e.e.
<5%. Vials/experiments which did not yield a solid after 7 days
(with addition of CPME as anti-solvent) were held at room
temperature for up to an additional 7 days (total of 14 days) in an
effort to effect crystallization.
[0203] Table 6 below summarized the conditions and results of
screening experiments with the 16 resolving agents identified
above, using methanol as the solvent. Note: in experiments where no
observation is noted in the columns "5-day evaporation" and/or "7
days+CPME, up to 14 days", no solid or oil was obtained.
TABLE-US-00007 TABLE 6 Resolution Screening Results, MeOH solvent
mg* 5 day 7 days + CPME, up to Exp # Resolving Agent (0.5 mmol)
evaporation 14 days 1.1 (1S)-(+)-10- 116 camphorsulfonic acid 1.2
(S)-(+)-phencyphos 121 solid (P1(+)) 1.3 L(+)-tartaric acid 75 8
days: turbid (oil layer) 14 d: solidified 1.4 L(-)-O,O'-DBTA 188 9
days: turbid oil 1.5 L(-)-O,O'-DTTA 193 9 9 days: turbid oil 1.6
D(+)-O,O'-DATA 209 9 days: turbid oil(clear after heating + MeOH)
1.7 L(-)-2-pyrrolidone-5- 65 5 d: solid 8 days: turbid oil (clear
carboxylic acid (needles) + after heating + MeOH) MeOH: re-
dissolved 1.8 N-Bz-L-Asp-OH 119 9 days: turbid oil 1.9
N-Bz-L-Glu-OH 126 solid turbid oil after addition CPME 1.10
(S)-(+)-mandelic acid 76 1.11 (S)-(+)-2-(4- 106 solid 14 days:
solid in oil after chlorophenyl)-3- evaporation methylbutanoic acid
1.12 (S)-(+)-Naproxen 115 solid + MeOH: re- dissolved 1.13
(S)-N-Tosyl-valine 136 solid 1.14 (R)-N-Tosyl- 153 solid
phenylglycine 1.15 (R)-N- 128 solid Benzoylphenylglycine 1.16
(R)-(-)-1,1'- 87** 9 days: turbid oil, bisnaphthyl-2,2'-diyl
crystallized after heating hydrogenphosphate Solid: 78 mg e.e.
<5% ML: e.e. <5% *+/-1 mg; **0.25 mmol resolving agent in 1
mL methanol, added 0.64 g (0.50 mmol) ketamine MeOH solution
[0204] In summary: no crystals were obtained when methanol was used
as the solvent. After evaporation of methanol, the obtained oils
were re-dissolved in a small amount of methanol and CPME (as
anti-solvent). In three experiments, #1.3, #1.11 and #1.16 some
solids were obtained. For Exp. #1.1, the % ee of the mother liquor
and solid were determined to be very low (<5%).
RS2: Resolution Screening Experiments in 2-butanone (MEK)
[0205] Ketamine free base (3.93 g, 16.5 mmol) was dissolved in 15
mL 2-butanone (slightly warmed for dissolution), transferred to a
25 mL volumetric flask and the flask filled to 25 mL with
2-butanone (1 mmol=1.52 mL). The weight of this solution was 21.29
g (1 mmol=1.29 g). The resolving agent was dissolved/suspended in
1.60 g (2.0 mL) of 2-butanone.
[0206] At room temperature 1.29-1.32 g (1.0 mmol) of the prepared
ketamine solution in 2-butanone was added to the prepared resolving
agent solution. All solution became clear, except vials in Exp.
#2.3, #2.6, #2.7, #2.8, #2.9, #2.14 and #2.15. These vial were
heated for dissolution. In vials of Exp. #2.3 and #2.9 some solid
remained, whereas vials for Exp. #2.14 and #2.15 became opaque.
After 20 h at room temperature, the vials of Exp. #2.3 (tartaric
acid), #2.7 (pyroGlu) and #2.9 (N-BzGlu) contained some crystals.
The solution in vials of Exp. #2.14 and #2.15 became slightly
turbid. In all other vials the solution remained clear, therefore
after 2 days, the screw caps of these vials were removed for slow
evaporation. After 5 days slow evaporation to half volume no
additional crystallization was observed to occur. After 7 days the
clear solutions in vials of Exp #2.4 and #2.5 were seeded with the
L-(-)-DATA salt of S-ketamine (prepared as described in RS5: #4.2
which follows), however, no crystallization occurred and the seed
crystals dissolved. Vials/experiments which did not yield a solid
after 7 days were held at room temperature for up to an additional
7 days (total of 14 days) in an effort to effect
crystallization.
[0207] Table 7 below summarized the results of screening
experiments with 16 resolving agents and 2-butanol as the solvent.
NOTE: Where no observation is noted in the columns "20 h room
temperature", "5-day slow evapor." and/or "7-14 days", no solid or
oil was obtained.
TABLE-US-00008 TABLE 7 Resolution Screening Results, 2-Butanone
(MEK) mg 20 h 5 day, slow Exp # Resolving agent (0.5 eq.) RT
evapor. 7-14 days 2.1 (1S)-(+)-10- 116 camphorsulfonic acid 2.2
(S)-(+)- 121 phencyphos (P1(+)) 2.3 L(+)-tartaric acid 75 crystals
8 days: Solid: 183 mg e.e. 58% (S) ML: e.e. 31% (R) 2.4
L(-)-O,O'-DBTA 188 2.5 L(-)-O,O'-DTTA 193 2.6 D(+)-O,O'-DATA 209
crystals 8 days: @ 24 h Solid: 245 mg e.e. 61% (S) ML: e.e. 32% (R)
2.7 L(-)-2- 65 few thick oil pyrrolidone-5- crystals carboxylic
acid 2.8 N-Bz-L-Asp-OH 119 8 d: few crystals 2.9 N-Bz-L-Glu-OH 126
crystals 8 days: Solid: 149 mg e.e. <5% ML: e.e. <5% 2.10
(S)-(+)-mandelic 76 acid 2.11 (S)-(+)-2-(4- 106 8 d: few
chlorophenyl)-3- crystals methylbutanoic acid 2.12 (S)-(+)- 115
Naproxen 2.13 (S)- N-Tosyl- 136 valine 2.14 (R)- N-Tosyl- 153
turbid 8 days: turbid phenylglycine 2.15 (R)- N- 128 turbid pink
solution Benzoylphenyl- glycine 2.16 (R)-(-),1,'- 87**
bisnaphthyl-2,2'- diyl hydrogen phosphate *+/-1 mg; **0.25 mmol
resolving agent in 1 mL 2-butanone, added 0.66 g (0.50 mmol)
ketamine solution
[0208] As shown in Table RS2 above, when 2-butanol was used as the
solvent, L-(+)-tartaric acid and D-(+)-O,O'-DATA yielded a solid,
with some resolution of the (S)- and (R)-ketamine stereoisomers.
Although D-(+)-O,O'-DATA yielded a solid, the solid was determined
(by .sup.1H NMR) to be a 1:1 salt of the undesired enantiomer,
containing 1 mol of 2-butanone as a solvate molecule. Additionally,
N-Bz-L-Glu-OH yielded a solid, although analysis of this solid
indicated that no significant amount of resolution was
achieved.
RS3: Resolution Screening Experiments in 10:1 v:v IPA/H.sub.2O
[0209] Ketamine free base (3.93 g, 16.5 mmol) was dissolved in a
10:1 v:v mixture of 2-propanol/water to a total volume of 25 mL
(warmed for dissolution and kept hand warm to prevent
crystallization). The weight of this solution was 21.1 g (1
mmol=1.27 g=1.52 mL). The resolving agent was dissolved/suspended
in 1.60 g (2.0 mL) of a 10:1 v:v mixture of 2-propanol/water.
[0210] At room temperature 1.27-1.30 g (1.0 mmol) of the prepared
ketamine solution was added to the prepared resolving agent
solution, except Exp #3.12 where 1.43 g (1.12 mmol) of the prepared
ketamine solution was added to the corresponding prepared resolving
agent solution. The resulting solutions became clear, except Exp
#3.2, #3.3, #3.5, #3.6, #3.9, #3.14 and #3.15 which were heated for
dissolution. In the vial of Exp. #3.9 some solid remained even
after heating. After 18 h at room temperature only the vial of Exp.
#3.9 contained some crystals (possibly the resolving agent) and the
vial of Exp. #3.15 became slightly turbid. In all other vials the
solution remained clear, therefore the screw caps were removed for
slow evaporation to half volume over 5 days. In 4 vials a crystal
ring was formed on the glass wall above the surface (possible
Marangoni-like effect) that was scratched back into the mother
liquid. For Exp #3.8 these crystals were observed to re-dissolve.
Vials/experiments which did not yield a solid were held at room
temperature for up to a total of 14 days, in an effort to effect
crystallization.
[0211] Table 8 below summarized the results of screening
experiments with 16 resolving agents and the 10:1 v:v mixture of
IPA:water as the solvent. Note: Where no observation is noted in
the columns "18 h RT", "5 day, slow evap." and/or "6-14 day", no
solid or oil was obtained.
TABLE-US-00009 TABLE 8 Resolution Screening Results 10:1 v:v
IPA/H.sub.2O mg 18 h 5 day Exp # Resolving agent (0.5 eq) RT slow
evap. 6-14 days 3.1 (1S)-(+)-10- 116 camphorsulfonic acid 3.2
(S)-(+)- 121 phencyphos (P1(+)) 3.3 L(+)-tartaric acid 75 3.4
L(-)-O,O'-DBTA 188 3.5 L(-)-O,O'-DTTA 193 3.6 D(+)-O,O'-DATA 209
3.7 L(-)-2-pyrrolidone- 65 crystal ring 8 days: 5-carboxylic acid
Solid: 71 mg e.e. <5% ML: e.e. <5% 3.8 N-Bz-L-Asp-OH 119
crystal ring, re-dissolved in ML 3.9 N-Bz-L-Glu-OH 126 few crystal
ring 8 days: crystals Solid: 92 mg e.e. <5% ML: e.e. <5% 3.10
(S)-(+)-mandelic 76 acid 3.11 (S)-(+)-2-(4- 106 6 d: slow 8 days:
chlorophenyl)-3- crystallization Solid: 83 mg e.e. <5%
methylbutanoic (needles) ML: e.e. <5% acid 3.12 (S)-(+)-Naproxen
115 6 d: slow 8 days: crystallization Solid:103 mg e.e. <5%
(needles) ML: e.e. <5% 3.13 (S)- N-Tosyl-valine 136 3.14 (R)-
N-Tosyl- 153 Turbid phenylglycine 3.15 (R)- N-Benzoyl- 128 turbid
crystal ring 8 days: phenylglycine Solid: 39 mg e.e. <5% ML:
e.e. <5% 3.16 (R)-(-)-1,1'- 87** bisnaphthyl-2,2'- diyl hydrogen
phosphate * +/-1 mg; **0.25 mmol resolving agent in 1 mL 2-PrOH/H2O
10:1, added 0.65 g (0.50 mmol) ketamine solution
[0212] As shown in Table 8 above, when a 10:1 v:v IPA/water mixture
was used as the solvent, L(-)-2-pyrrolidone-5-carboxylic acid,
N-Bz-L-Glu-OH, (S)-(+)-2-(4-chlorophenyl)-3-methylbutanoic acid,
(S)-(+)-Naproxen and (R)--N-Benzoyl-phenylglycine yielded a solid,
although analysis of said solids indicated that no significant
amount of resolution was achieved for any of these resolving
agents.
RS4: Preparation of L-(-)-DATA Salt of S-Ketamine
[0213] Ketamine (racemic, 238 g, 1 mmol) was dissolved in MEK (3.5
mL) and the resulting solution was added to dry L-(-)-DATA (0.5
mmol). The mixture (in a vial) was warmed to reflux to complete
dissolution and then cooled. Slow crystallization started after 24
hours (scratching with spatula), to yield a solid (167 mg, 23%)
which exhibited 54% e.e.
[0214] The resolution screening experiments described above
confirmed that L-tartaric acid is useful as a resolving agent for
ketamine, and suggested that D-(+)-DATA, and L-(-)-DATA
(derivatives of tartaric acid), may also be effective.
[0215] Although additional optimization experiments with D-(+)-DATA
and L-(-)-DATA were completed, for large scale manufacturing,
material costs for these resolving agents are not cost-effective
and/or prohibitive.
Example 10
Resolution Experiments
(+)-CSA in Organic Solvent/Water Mixture
[0216] Although contrary to the results of the screening
experiments described above and contrary to the teachings in
HUDYMA, T. W., et al. (DE 2062620 A), which disclosed that attempts
at resolution of ketamine with camphorsulfonic acid (CSA) were
unsuccessful, additional experiments were nonetheless undertaken in
an effort to develop a method for the resolution of ketamine using
camphorsulfonic acid in aqueous solvent mixture.
[0217] Table 9 below details three representative experiments
reacting racemic ketamine with (+)-CSA in (a) a mixture of THF and
water, (b) a mixture of acetone and water, and (c) a mixture of
2-methyl-THF and water. Each experiment resulted in formation of
(S)-ketamine.(+)-CSA salt in high enantiomeric excess, as noted in
the Table below. All reaction mixtures were heated, with stirring
as noted. The resulting precipitate was then isolated by
filtration, washed with the corresponding organic solvent (no
water) and dried at under vacuum 50.degree. C.
TABLE-US-00010 TABLE 9 Preparation of (+)-CSA salt of S-Ketamine
E-1 E-2 E-3 (Rac)- 10 g 5 g 10 g Ketamine (+)-CSA 5.3 g 2.65 g 9.8
g Solvent 60 g THF + 40 g Acetone + 60 g 2-Me--THF + 1.2 g H.sub.2O
2.5 g H.sub.2O 3.8 g H.sub.2O Rxn 63.degree. C. for 30 min;
55.degree. C.; 73.degree. C.; mixture not Conditions 50.degree. C.,
1 hr; 10.degree. C., 2 hr cooling; dissolved; 20.degree. C., 2 hr;
10.degree. C., 30 min, stirring; add 10 g 2-Me--THF + stirred
overnight; continued stirring 1.9 g H.sub.2O; overnight; 63.degree.
C., seeded & stirred for 1 hr; 50.degree. C. 1 hr, 20.degree.
C. 1 hr, 2 hr stirring Notes: first crystallization crystallization
observed Seeded at 63.degree. C. observed during at 42.degree. C.
heating to 63.degree. C. Yield.sup.a 8.12 g (39.4%) 3.53 g (34.3%)
9.24 g (44.6%) % ee 97.3% ee 98.0% ee 98.4% ee .sup.aMaximum yield
of desired product (S-enantiomer) from racemate is 50%.
Formulation Example 1
Solid, Oral Dosage Form--Prophetic Example
[0218] As a specific embodiment of an oral composition, 100 mg of a
product prepared as in Example 1, 2 or 3 is formulated with
sufficient finely divided lactose to provide a total amount of 580
to 590 mg to fill a size 0 hard gel capsule.
[0219] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *