Process for (S)-Ketamine and (S)-Norketamine via Resolution Combined with Racemization

Article abstract of DOI:10.1021/acs.joc.0c01090

A concise, recyclable, and efficient process is presented for the preparation of (S)-ketamine (esketamine, (S)-1a) via classic resolution combined with the recycling of the undesired isomer. With commercially available ketone 2 as the starting material, this procedure features three steps including (1) an unique hydroxylation-ring expansion rearrangement, (2) mild amination via methanesulfonate, and (3) chiral separation using L-(+)-tartaric acid. The three simple steps are all performed in mild conditions and (S)-1a tartrate is obtained in 99.5percent ee without recrystallization. Subsequently, racemization of the unwanted (R)-1a remained in resolution mother liquor was performed in the presence of a Lewis acid in quantitative yield with >99.0percent chemical purity. This original and economical process afforded esketamine in 67.4percent (28.9percent without racemization) overall yield with two times recycling of the mother liquor without column purification. In addition, this procedure can also be applied to the preparation of (S)-norketamine, which is a safer potential antidepressant.

Full text of DOI:10.1021/acs.joc.0c01090

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Article
A Process for (S)-Ketamine and (S)-Norketamine
via Resolution Combined with Racemization
Shenghua Gao, Xuezhi Gao, Zenong Wu, Houyong Li, Zhezhou Yang, and Fu-Li Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01090 • Publication Date (Web): 08 Jun 2020
Downloaded from pubs.acs.org on June 8, 2020
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A Process for (S)-Ketamine and (S)-
Norketamine via Resolution Combined with
Racemization
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‡
§
Shenghua Gao,†,‖ Xuezhi Gao,†,‖ Zenong Wu, Houyong Li, Zhezhou Yang*†,
and Fuli Zhang*,†,§
†Shanghai Institute of Pharmaceutical Industry, China State Institute of
Pharmaceutical Industry, 285 Gebaini Road, Pudong District, Shanghai
201203, China
‡School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong District,
Shanghai 201203, China
§
College of Chemistry and Chemical Engineering , Shanghai University of
Engineering Science, 333 Longteng Road, Shanghai 201620, China
‖Shenghua Gao and Xuezhi Gao contributed equally to this work
For Table of Contents Only
Keywords
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(S)-Ketamine; (S)-Norketamine; Depression; Novel Process; Racemization
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Abstract
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A concise, recyclable and efficient process is presented for the preparation of (S)-
ketamine (esketamine, (S)-1a) via classic resolution combined with the recycling of
undesired isomer. A commercially available ketone 2 as starting material, this
procedure features three steps including (1) an unique hydroxylation-ring expansion
rearrangement, (2) a mild amination via methanesulfonate and (3) a chiral separation
using L-(+)-tartaric acid. The three simple steps are all performed in mild conditions
and (S)-1a tartrate is obtained in 99.5% ee without recrystallization. Subsequently, the
racemization of the unwanted (R)-1a remained in resolution mother liquor was
performed in the presence of a Lewis acid in quantitative yield with >99.0%
chemical purity. This original and economical process afforded esketamine in 67.4%
(28.9% without racemization) overall yield with two times recycling of the mother
liquor without column purification. In addition, this procedure can also be applied to
the preparation of (S)-norketamine, which is a safer potential antidepressants.
Introduction
Ketamine, (±)-2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone (1a), was first
developed as an anesthetic in 1962 and started to be applied clinically in 19651.
However, ketamine was designated as a scheduled drug due to the strong dissociative
side effects of psychotic symptoms (e.g., hallucination and delusion) and potential drug
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addiction.
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In recent times, ketamine has elicited tremendous excitement, since it has presented
rapid and sustained antidepressant efficacy for treating major depressive disorders2-5.
Depression is a common neurological disorder and has become a major public health
problem, affecting about 320 million people worldwide at some point in their lives6-7.
Unfortunately, several weeks even months are required for current antidepressants to
exert their drug efficacy, and there are about 30% treatment-resistant patients for whom
the antidepressants are ineffective6. Ketamine, on the contrary, is effective within hours
(in as little as half an hour) after a single administration, and sustains the antidepressant
effects for 7-10 days1, 8. The racemic ketamine, as the N-methyl-D-aspartate (NMDA)
receptor antagonist, contains equal amounts of (R)-ketamine and (S)-ketamine ((S)-1a,
Scheme 1). Compared with (R)-ketamine, (S)-ketamine displays 3-4 times greater
affinity for NMDA receptor, thus potentially allowing for lower dosages9. Recently,
esketamine (SPRAVATO™) has been approved by FDA to treat the major depression
in adults, which represents a significant milestone for the depression treatment in
decades10.
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Scheme 1. Structures of (S)-Ketamine and (S)-Norketamine
O
RHN
(S)
Cl
1a
R=CH3, (S)-Ketamine (
)
1b
R=H, (S)-Norketamine (
)
At present, the preclinical data11 indicate that the (S)-norketamine ((S)-1b, Scheme
1), a major metabolite of (S)-ketamine by cytochrome P450 enzymes, exhibits a rapid
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and robust antidepressant effect which is equal to (S)-ketamine. Interestingly, (S)-
norketamine, due to the lower affinity for the NMDA receptor12, shows significantly
less side effects in rodents than that of (S)-ketamine. Thus, (S)-norketamine will be a
safer alternative antidepressant, and notably, (S)-norketamine is not designated as a
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scheduled compound12, 13
.
Stimulated by the stronger potency of (S)-ketamine for the NMDA receptor, many
asymmetric synthetic routes have been reported over the years14. For example, the first
asymmetric synthetic process of (S)-ketamine was reported by Kiyooka and
colleagues15. The innovative procedure was conducted in ten steps and (S)-ketamine
was obtained in the yield of 21% (97% ee). Unfortunately, neither the atom economy
nor energy consumption is suit for large-scale production, and the utilization of
excessive chiral BINAL-H catalytic agent (3.4 equiv), and ozone may be inconvenient
for industrialization. Another route with similar idea (the cyanate-to-isocyanate
rearrangement) was put forward by Chen and colleagues in 201916. The highlight of
this method was the construction of the desired quaternary stereocenter of (S)-ketamine
using Overman rearrangement. This optimized procedure was indeed more concise and
efficient than Kiyooka's and (S)-ketamine was obtained with high chiral purity (>99%)
in 49% overall yield. Moreover, hydrolysis of the isocyanate functional group led to
(S)-norketamine. Toste17a reported a three steps process, which afforded the (S)-
ketamine and (S)-norketamine in 30% overall yield (99% ee) using di-tert-butyl
azodicarboxylate to construct the stereocenter. A complex chiral organophosphorus
ligands, the preparation of which required several steps were needed for the key step of
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this route. Additionally, the staring material, o-chlorophenyl cyclohexanone, is not
commercial and prepared in column chromatography with only 59% yield17. Lately,
using (S)-tert-butanesulfinamide as the chiral auxiliary, the desired chiral center of (S)-
ketamine was installed with the unsatisfactory 75% ee18. (S)-Norketamine synthesized
by using asymmetric synthesis strategy was first reported by Biermann and co-
workers19 via Sharpless epoxidation, Ritter reaction and Jones oxidation. Unfortunately,
the key step of SAD gave the unsatisfactory 87% ee, and the Ritter amination was
performed with a low yield (47%) due to the poor selectivity of two hydroxyl groups.
Even though the above asymmetric synthesis of (S)-ketamine have acquired a certain
success, an efficient and scalable synthesis to enantiopure (S)-ketamine and (S)-
norketamine was desired. In view of rac-1a and rac-1b are common pharmaceutical
formulations, classical resolution 20 of the inexpensive racemate (±)-1 remains a better
choice to prepare (S)-1a and (S)-1b from the industrial standpoint.
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Three synthetic routes of racemic ketamine and norketamine were reported in the
literature. The original synthetic route was reported by Stevens21 using
commercially available ketone 2 as the starting material (Scheme 2). This
concise procedure including three steps of bromination, imination and thermal
rearrangement. However, there are some disadvantages in this route, such as
low atomic economy (copper bromide and excessive liquid methylamine) and
o
harsh reaction conditions (-40 °C and 180 C) Recently, Zhang and
colleagues23 reported a new strategy to synthesize (±)-1 using the uncommercial
o-chlorophenyl cyclohexanone as the starting material, which was next
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subjected to direct nitration utilizing excessive ceric ammonium nitrate
((NH4)2Ce(NO3)6). Unfortunately, the nitration step was conducted in
dichloroethane with a low isolated yield (51%) and consequently resulted in an
unsatisfactory total yield (25%). More recently, another environment-friendly
procedure which relies on the continuous flow reactor for the preparation of (±)-
1 was reported by Monbaliu24 (Scheme 2). All the three steps were carried out
in ethanol, however, it is noteworthy that the thermal rearrangement reaction
was performed on montmorillonite K10 at a harsh reaction condition: (35 bar,
180 °C), and the yield was only 65% which was far lower than 95% yield in
kettle reactor.
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Scheme 2 Synthetic Routes to (±)‑1 and (S)-1
O
NR
Br
OH
1) RNH2
2) HCl
Stevens' route
PhCO2Et
HCl
Br2
℃
170
Cl
Cl
16
17
HCl
O
O
O
O
NR
OH
RHN
RHN
OH
RNH2
O2, P(OEt)3
1) Resolving agent
2) HCl
HCl
HCl
B(OiPr)3
5 bar,1 min
35 bar, K10
KOH
,PE
G-4
in
00
Cl
4
Cl
Cl
Cl
(RS)-1
Cl
℃
180
,5 mi n
11
bar
,5 m
(S)-1
2
HCl
16
NaOH
Monbaliu' route
1a, R=CH3
1b, R=H
O
O
HO
MeHN
O2/P(OEt)3/KOH
RNH2
This work
Cl
3
Cl
(R)-1
unwanted isomer
The routes above have some disadvantages in terms of harsh conditions,
uncommercial raw materials and unsatisfactory yield. In addition, the undesired (R)-1
discarded in the resolution mother liquors would lead to a low yield, and release a
substantial amount of waste residue. In order to overcome the defects in the process of
racemic (±)-1 and chiral resolution, we wish to develop a newly efficient synthetic
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process of (S)-1a and (S)-1b via the synthesis of racemic (±)-1 and chiral resolution
combined with racemization (Scheme 2).
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Results and Discussion
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Oxidation-Rearrangement Reaction of Ketone 2
When the methylamine step in the Stevens’ route was repeated with 40% methylamine
aqueous solution, we found that the compound 4 would convert to compound 3 via ring
25
expansion rearrangement under mild condition in our early works . Furthermore, a
brief literature 21e, 24, 26 survey revealed that the cyclic α-hydroxyketone could easily be
rearranged through expanding or shrinking rings in the presence of alkali. Inspired by
the above results, our initial thought was that the starting material 2 was oxidized to 4
and then 4 was rearranged to 3 under the alkalinity or high temperature. In view of both
hydroxylation and rearrangement were carried out under the same alkaline condition,
we envisaged that the compound 3 could be synthesized in one step starting from ketone
2 (Scheme 3).
Scheme 3 the Synthetic Routes to 3 Starting from 2
O
Br
OH-
Br2
Cl
17
Stevens' route in
methylamine aqueous
O
O
O
OH
HO
O2 / P(OEt)3
OH-
Cs2CO3 or KOH
℃
25
Cl
Cl
Cl
3
Jiao and Monbaliu'
2
4
4
process for
This work
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We started the work from ketone 2 which is commercially available 24 (Scheme 3).
In various methods of preparing tertiary α-hydroxyl ketones directly from ketones, the
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best industrialized prospect and low toxicity procedure was disclosed by Jiao and co-
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worker
using molecular oxygen as a primary oxidizer with 20 mol% cesium
carbonate (Cs2CO3) and an inexpensive and readily available reductant triethyl
phosphite (P(OEt)3) in DMSO.
The potassium carbonate (K2CO3), cheaper and more suitable for industrial
production, but didn’t work in the Jiao’s report, was selected to substitute for Cs2CO3
(in DMSO) after analyzing literatures data. To our delight, the main product (90%) was
compound 4 while 9.2% for the rearrangement product 3 (Table 1, entry 1). To increase
the content of target product 3, KOH with higher alkalinity was used. As we expected,
the content of 3 was up to 72.7% in 1h (Table 1, entry 2). However, an over oxidized
impurity 5 accounts for 6.4% was detected due to the newly generated product 3 still
contains a carbonyl α-H, which would continue to be hydroxylated in the reaction
mixture. When KOH was added into the reaction solution, the mixture was turned black
brown soon. We believe the good solubility of KOH in DMSO should be responsible
for this phenomenon. The short reaction time lead to the poor reaction selectivity.
Subsequently, ethanol, with smaller solubility of KOH, was considered to replace
DMSO. To our delight, the main product (98%) was the target ring-expanding product
3, while the intermediate state 4 was only 1.1% in 48 h (Table 1, entry 3). The reaction
rate was decreased and the selectivity of hydroxylation-rearrangement was improved
significantly, which greatly reduced the over oxidized impurity 5. In order to shorten
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the reaction time, the temperature was raised to 50 °C by heating in oil bath, but it was
found that the over oxidized impurity 5 increased to 9.6% (Table 1, entry 4). Moreover,
other reductants such as sodium sulfite (Na2SO3) and sodium phosphite (Na2PO3) were
attempted. What disappointed us was that the over oxidized impurity 5 or the residue of
2 was increased due to the poor conversion and selectivity (Table 1, entries 5-7). The
existing experimental data demonstrated that the KOH/P(OEt)3/O2 was an appropriate
system for the hydroxylation combined with rearrangement of compound 2.
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Table 1. The Oxidation-Rearrangement Reaction under a Variety of Conditions a
O
O
O
O
OH
HO
OH
HO
O2
Cl
Cl
Cl
5
Cl
3
2
4
HPLC b (%)
Entry
Reductants
Alkali
Solvent T (°C)
t (h)
2
4
3
5
1
2
3
4
5
6
7
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
Na2SO3
Na2SO3
Na2PO3
K2CO3
KOH
KOH
KOH
KOH
K2CO3
KOH
DMSO
DMSO
EtOH
EtOH
EtOH
EtOH
EtOH
25
25
30
50
30
30
30
35
1
0.1
0
90.7
20.9
1.1
9.2
-
72.7
98.0
88.8
34.2
14.7
25.4
6.4
0.7
9.6
64.8
12.5
42.5
48
20
20
60
20
0.2
0.2
0.2
1.4
0.8
66.8
30.5
5.9
1.4
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a Reaction conditions: 2 (1.0g), reductants (1.5eq), base (1.0eq), solvent (10mL);
the mixture was stirred under the atmosphere of O2 (standard atmospheric
condition); b only peaks of 2, 3, 4 and 5 were integrated; Heating in oil bath.
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The optimal result was obtained when 2 was performed with molecular oxygen in
the presence of 1.0 equiv KOH and 1.5 equiv P(OEt)3 in EtOH under 30 °C for 48 h.
The faint yellow solid with 99.0% purity was obtained in 83% yield after the workup
procedure. The Single crystal X-ray diffraction (SCXRD) of 3 can be found in
Supporting Information.
Based on the above results and related literatures 24, 27, the probable mechanism is
proposed in Scheme 4. At first, the deprotonation of ketone 2 by KOH obtains the
corresponding carbanion 6 with keto-enol tautomerism. And then, carbanion 6 reacts
with O2 to produce a peroxide anion 7, which could acquire a proton from ketone 2 to
form a peroxide 8 and reproduce another 6. Compound 8 would subsequently be
reducted by P(OEt)3 and underwent ring expansion rearrangement simultaneously to
give the oxygen anion 9. Then, the desired product 3 is obtained from 9.
Scheme 4 the Probable Mechanism of Oxidation-Rearrangement Reaction
O
O
O
O
O
O
H
O2
OH
Cl
7
Cl
Cl
Cl
2
6
6
H
O
P(OEt)3
O
O
O
HO
O
O
O
H
(EtO)3P
6
2
PO(OEt)3
Cl
8
Cl
Cl
9
3
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The preparation of ketamine and norketamine
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In view of the similarity of the structure of 3 with ketamine and norketamine, our
initial idea was that norketamine could be obtained by direct amination via Ritter
reaction under acidic conditions. The Ritter amination of intermediate 3 was conducted
in the general condition of H2SO4/ACN 28 followed by acid hydrolysis at 90 °C for 24
h to the norketamine. However, what puzzled us was that the obtained compound was
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not norketamine but its isomer 10 which was confirmed by NMR spectra (in supporting
21d
information). The literature
revealed that the aryl migration and rearrangement
would occur on the compounds with similar structure of 3 under acid condition. The
specific rearrangement and the corresponding Ritter reaction is shown in Scheme 5.
Scheme 5 the Specific Rearrangement of 3 and Corresponding Ritter Reaction
OH
O
OH
HO
OH
HO
HO
HO
H3O
allylic
=
rearragement
Heat
Cl
Cl
3
Cl
Cl
12
12
11
O
O
O
O
HO
H2N
HN
H3O
ACN/H2SO4
Cl
Cl
10
Cl
14
13
In order to synthesize norketamine and ketamine more efficiently, we explored
another methods to convert hydroxyl group into amino group. Activating the hydroxyl
group with sulfonate to increase its leaving ability is considered to be an efficient and
simple approach to prepare amino from hydroxyl 29. Hence, p-toluene sulfonyl chloride
was the primary choice considering its solid properties and low toxicity. Unfortunately,
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no product was obtained when the p-toluene sulfonyl chloride react with 3, probably
due to its large steric hindrance. To our delight, 3 can be activated via methanesulfonate
strategy. Treatment of 3 with mesyl chloride (MsCl) afforded methanesulfonate 15
followed by adding excessive methylamine ethanol solution and ketamine was obtained
in good yield. During the experiment, we found that the methanesulphonate 15 was
very unstable and easy to eliminate, especially at high temperature. Considering the
instability of 15, there was no NMR data of the methanesulphonate, and we prepared
ketamine and norketamine in one pot process as illustrated in Scheme 6: sulfonation
and amination to afford ketamine with 85% unoptimized yield in 99.5% purity. When
methylamine was replaced by ammonia, the norketamine was produced in the yield of
83%.
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Scheme 6. Synthesis of Ketamine and norketamine via Methanesulfonate
O
O
O
MsO
HO
RHN
MsCl,Et3N
RNH2
THF
0 °C
15- 20 °C
Cl
15
Cl
(rac)-1
Cl
3
1a
, R=CH3 85%
1b
, R=H 83%
Resolution of Ketamine and Norketamine.
20
Basing on the literature and the previous work of our group 25, 30, the
chiral resolution of racemic ketamine was carried out in acetone/water at the
ratio of 15:1 with the frequently-used L-(+)-tartaric acid as resolution agent. The
resulting tartrate of ketamine was obtained in the yield of 41% with the 99.5%
chiral purity. Subsequently, the white solid esketamine base gradually
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precipitated out when the tartrate alkalized by 1N NaOH aqueous solution. The
products could be easily separated by simple filtration. The structure of (S)-
ketamine was identified by HRMS, 1D NMR 2D NMR and SCXRD, and all the
spectra were shown in the Supporting Information. Similarly, the resolution of
norketamine was performed in EtOH/H2O by using L- pyroglutamic acid and the best
proportion of EtOH/H2O was screened to 12:1. The (S)-norketamine was obtained
in 42% yield with >99.5% chiral purity.
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Racemization of the Undesired (R)-1 isomer
The route overall yield would be improved and the discharge of waste would
be reduced supposing that the discarded (R)-1 could be racemized and
recycled. Hence, the racemization of the undesired (R)-1 isomer was studied.
However, since the chiral center is a quaternary carbon without hydrogen, it is
a challenge for us to achieve its racemization. At present, there is no relevant
literature about the racemization of (R)-1.
Although (R)-1 isomer does not seem easy to achieve racemization, we have
successfully converted the undesired (R)-1 back to the racemic ketamine
through the reversible reaction under the catalysis of a Lewis acid in our
previous study 25, 30. According to our early research, the order of catalytic
capability of some commonly-used Lewis acids were as follow:
AlCl3≈MgCl2>FeCl3>ZnCl2>BF3>CaCl2. Finally, we deemed AlCl3 was the most
appropriate catalyst in view of its good catalytic capacity and removability.
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Further optimization of the amount of AlCl3 on the racemization of (R)-
ketamine and (R)-norketamine was tried (Table 2). In our early studies, we had
found that the racemization of (R)-ketamine demanded 0.2 equiv AlCl3 (entry
1), and only partial (R)-ketamine achieved the racemization (65.2/34.8) with 0.1
equiv AlCl3 in 10 h (entry 2). Surprisingly, the racemization of (R)-ketamine was
nearly completed (53.6:46.3) as the reaction time prolonged to 24h (entry 3).
Moreover, we tried to lower the reaction temperature, and the racemization rate
at 130 °C with 0.2 equiv AlCl3 was much slower than that at 150 °C (entry 4).
Similarly, (R)-norketamine could also be racemized completely (R-1b/S-1b
(50.4/49.6)) under 150 °C with 0.2 equiv AlCl3 for 15h (entry 5). The optimized
procedure of the racemization was that the hydrochloride of (R)-ketamine or
(R)-norketamine was heated in ethyl benzoate with 0.1-0.2 equiv AlCl3 at 150°C
for 10-15h.
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Table 2. Further Optimization for the (R)-1 Racemization a
Entry
AlCl3 (eq)
0.2
T (°C)
150
t (h)
10
(R)-1/(S)-1 (%)b
49.8/50.2
1
2
3
4
0.1
150
10
65.2/34.8
0.1
150
24
53.6/46.4
0.2
130
10
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5c
0.2
150
15
50.4/49.6
6
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9
a
Reaction conditions: 0.1 g/mL hydrochloride of (R)-1a with 98.5%ee;
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b
c
Solvent: ethyl benzoate. performed on a column of Chiralpak OD-3. (R)-1b
hydrochloride (98.0%ee) was the substrate; Measured on a column of
Chiralpak IA; Heating in oil bath.
Scheme 7 the Recycling Procedure of (R)-1
O
O
RHN
RHN
1) resolution agent
2) NaOH
Cl
Cl
41-42%
(S)-1
(RS)-1
1)NaOH
R=H, 1b;
R=CH3, 1a
L
e
w
2)HCl
i
s
1
a
5
c
0
i
d
9
9
°
C
%
O
RHN
HCl
Cl
(R)-1
HCl
When the reaction completed, the racemized ketamine or norketamine
hydrochloride could obtained after a simple filtration from ethyl benzoate. The
chemical purities of the racemized ketamine and norketamine were above 99.0%.
Subsequently, the obtained hydrochloride was treated with 2 N NaOH aqueous
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solution and the precipitated free base of ketamine or norketamine was
subjected to a new resolution to get (S)-1 in 41%-42% yield with >99.0% ee
(Scheme 7). The yield of the resolution step was up to 80%, and the overall yield of
this route could reach to 67.4% (28.9% without racemization) after two times
recovery of the (R)-ketamine. This racemization process was concise and economical
and could be applied to the industry to recycle the unwanted (R)-1, and (S)-1 was
obtained in high chiral purity via the resolution procedure.
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Scheme 8. Our Concise Process of (S)-1
O
O
O
O
HO
RHN
RHN
O2, KOH
1) resolving agent
41-42%
1) MsCl , 0°C
2) NaOH
P(OEt)3
30°C
Cl
2) RNH2
15-20 °C
83%-85%
Cl
(S)-1
Cl
Cl
2
(rac)-1
3
83%
NaOH
O
1
)
H
C
1a
(R=CH3)
l
2
)
A
l
C
1b (
R=H )
9
9
l
3
%
RHN
Cl
(R)-1
CONCLUSION
In conclusion, a concise and novel procedure was developed for the preparation of
(S)-ketamine and (S)-norketamine via classic resolution followed by the racemization
of the undesired isomer (Scheme 8). Starting from the commercially available substrate
2, racemic ketamine was obtained through hydroxylation-rearrangement-amination in
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two simple steps with >99.0% chemical purity. This procedure for the preparation of
racemic ketamine and norketamine has obvious advantages including less production
steps, mild reaction conditions, excellent quality and low production cost. The racemic
ketamine and norketamine was separated by L-tartaric acid or L- pyroglutamic acid to
give (S)-1 isomer in the yield 41%-42% with 99.5% ee. This practicable process to
racemize the undesired (R)-1 hydrochloride was conducted in the ethyl benzoate under
150°C in the presence of 0.2 equiv AlCl3, and the racemized ketamine and norketamine
were obtained in quantitative yield with the chemical purity of 99.0%. The overall
yield of this new route was increased to 67.4% from 28.9% with two times
recycling of undesired isomer. This concise, efficient and economical procedure to (S)-
ketamine and (S)-norketamine has distinct value in the industrial production.
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EXPERIMENTAL SECTION
General. (2-chlorophenyl) (cyclopentyl) methanone 2 was prepared from our
laboratory with the purity of 98.5%. Other chemicals were purchased from
market and used as received. For the reactions that require heating, the heat
source was oil bath. The 1D NMR and 2D NMR spectra were obtained on the
Avance III 600 MHz and 400 MHz spectrometers (Bruker, Karlsruhe, Germany).
The samples were dissolved with CDCl3, DMSO-d6 and MeOD. HRMS spectral
data were recorded using a Bruker maxis 4G-TOF mass spectrometer. The
DSC spectra were performed on the TA Instruments DSC Q2000 apparatus.
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The optical rotations values were determined by an Anton Paar MCP 500
polarimeter at 20°C, 589nm (sodium ray). The TGA spectra were obtained from
a TA TGA Q500 analyzer. The data of SCXRD were acquired on a Bruker D8
VENTURE. Chemical purity was determined with a Dionex UItiMate 3000
chromatograph system using a DAD detector. The mobile phase was ACN (A)
and 10 mM KH2PO4 aqueous solution (B); Column: Waters X-Bridge (C18, 4.6
mm × 150 mm, 3.5 μm); Column temperature: 35°C, Wavelength: 210nm.
LCMS spectra was obtained on an Agilent LC/MS system including an Agilent
1260-LC system, a single quadruple mass detector (Agilent Technologies,
Santa Clara, CA, USA). The optical purity was recorded on a Dionex UItiMate
3000 chromatograph system with a Chiralpak OD-3 column (4.6 mm × 250 mm,
3.0 μm) for (S)-ketamine at a flow rate of 0.8 mL/min; the mobile phase was n-
hexane / 2-propanol (95:5); Wavelength: 210 nm. For (S)-norketamine:
Chiralpak IA column (4.6 mm × 250 mm, 5.0 μm); the eluent and wavelength
were same as (S)-ketamine.
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Synthesis of 2-(2-chlorophenyl)-2-hydroxycyclohexanone (3). The (2-
chlorophenyl) (cyclopentyl) methanone 2 (50.0 g, 0.24 mol), P(OEt)3 (59.8 g,
0.36 mol), ethanol (500 mL), and KOH (13.5g, 0.24mol) were added to a 1.0 L
three-necked flask under an atmosphere of oxygen in a balloon. The mixture
was stirred under 30°C for 48h. When the HPLC showed that 2 was less than
0.5%, the reaction was regarded as completed. In workup procedure, the
mixture was decompressed to remove most ethanol (about 330 mL).
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Subsequently, the obtained suspension was diluted slowly with 1500 mL
deionized water, meanwhile, stirred vigorously for 2h at 5-10 °C. The diluted
suspension was filtered to isolate the precipitates which was then washed three
times with deionized water (500 ml) followed by vacuum drying at 50°C to obtain
the faint yellow solid 3 (44.8 g, yield 83.4%, HPLC purity 99.1%). 1H NMR (600
MHz, CDCl3) δ 7.68 (dd, J = 7.8, 1.0 Hz, 1H), 7.42 – 7.33 (m, 2H), 7.32 – 7.25
(m, 1H), 4.51 (s, 1H), 3.04 – 2.88 (m, 1H), 2.68 – 2.54 (m, 1H), 2.46 (td, J =
11.9, 5.8 Hz, 1H), 2.07 (dd, J = 12.7, 4.0 Hz, 1H), 1.85 – 1.71 (m, 4H). 13C{1H}
NMR (151 MHz, CDCl3) δ 212.6, 137.5, 133.9, 131.3, 129.7, 128.6, 127.1, 80.6,
41.8, 38.8, 29.5, 22.8. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C12H13O2NaCl:
247.0502; Found 247.0509. The assignment is supported by an X-ray
crystallographic structure determination.
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Synthesis of 2-(2-chlorophenyl)-2-(methylamino) cyclohexanone (ketamine,
1a). A 250 mL reactor was charged with 3 (20.0 g, 0.089 mol), triethylamine
(31.6 g, 0.312 mol), and tetrahydrofuran 130 mL in nitrogen atmosphere. Mesyl
chloride (30.6 g, 0.267 mol) combined with 30 mL tetrahydrofuran was added
to the mixing system drop by drop. The temperature was maintained at -5-0 °C
through regulating the dropping speed. After finishing the dropping, the mixture
was stirred for another 1h. It was regarded proceed to the next operation when
the HPLC showed that 3 was below to 1.0%. 30% methylamine ethanol solution
(120 mL) were put in the reactor, subsequently, the temperature was gradually
rised to 15-20 °C and continued stirring 3-4h. In workup procedure, most of the
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EtOH and THF were evaporated at negative pressure followed by 150 mL water and
dichloromethane were added. After the extraction, aqueous phase was
discarded, and organic phase was acidated with 1N dilute hydrochloric acid to
the pH at 3-4. Then, the collected upper aqueous phase was alkalized to the
pH = 9-10 by using 1N sodium hydroxide. Subsequently, the alkalized water
phase was extracted by dichloromethane (150 mL) three times and then
dichloromethane was dried with anhydrous Na2SO4 followed by desolventizing
to yield the ketamine. The obtained solid underwent vacuum drying process at
50 °C to get the crude ketamine (18.0 g, yield: 85.3%, HPLC purity 99.5%). 1H
NMR (400 MHz, MeOD) δ 7.99 (dd, J = 6.1, 2.4 Hz, 1H), 7.70 – 7.62 (m, 3H),
4.87 (s, 2H), 3.52 – 3.38 (m, 1H), 2.63 – 2.52 (m, 2H), 2.43 (s, 3H), 2.21 – 2.13
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(m, 1H), 2.02 – 1.91 (m, 2H), 1.80 (qdd, J = 12.9, 9.2, 4.2 Hz, 2H). C{1H}
NMR (101 MHz, MeOD) δ 206.5, 134.0, 132.1, 131.5, 131.5, 128.0, 127.4, 71.9,
+
39.0, 35.8, 29.2, 26.3, 21.0. HRMS (ESI-TOF) m/z: [M+H]
C13H17ClNO: 238.0999; Found 238.0996.
Calcd for
Synthesis of 2-amino-2-(2-chlorophenyl) cyclohexanone hydrochloride (1b). A 250
mL reactor was charged with 3 (20.0g, 0.089mol), triethylamine (31.6g, 0.312mol), and
tetrahydrofuran 130 mL in nitrogen atmosphere. Mesyl chloride (30.6 g, 0.267 mol)
combined with 30 mL tetrahydrofuran was dropped to the mixing system. The
temperature was kept at -5-0 °C through controlling the dropping rate. After finishing
the dropping, the mixture was stirred for another 1h. It was regarded proceed to the next
operation when the HPLC showed that 3 was below to 1.0%. Added 7.0 mol/L ammonia
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methanol solution (130 mL) to the reaction mixture, subsequently, the temperature was
gradually rised to 15-20°C. The workup procedure was the same as ketamine. The
obtained solid was underwent vacuum drying process at 50 °C to get the crude
norketamine (16.5 g, yield: 83.0%, HPLC purity 97.2%). 1H NMR (600 MHz, DMSO)
δ 8.82 (s, 3H), 7.90 (dd, J = 7.7, 1.7 Hz, 1H), 7.61 – 7.52 (m, 3H), 3.18 (dd, J = 14.3,
2.7 Hz, 1H), 2.48 (dd, J = 9.1, 6.2 Hz, 1H), 2.40 (td, J = 12.5, 5.9 Hz, 1H), 2.03 (dd, J
= 7.6, 4.5 Hz, 1H), 1.96 (td, J = 14.2, 3.5 Hz, 1H), 1.79 (d, J = 13.9 Hz, 1H), 1.70 –
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1.51 (m, 2H). C{1H} NMR (151 MHz, DMSO) δ 207.5, 133.7, 132.3, 132.0, 131.8,
+
131.6, 128.6, 67.2, 39.3, 38.1, 29.6, 21.5. HRMS (ESI-TOF) m/z: [M+H] Calcd for
C12H15ClNO: 224.0842; Found 224.0848.
Synthesis of (S)-2-(2-chlorophenyl)-2-(methylamino) cyclohexanone tartrate
(Esketamine tartrate). A 250 mL reactor was charged with ketamine base (18.0
g, 0.058mol), L-tartaric acid (4.8g, 0.032mol) and the solvent of acetone
(168mL) and water (12mL). The reaction mixture was heated to reflux for 30
min until it was clarified and then cooled naturally to 55-58°C. Add a few crystal
seeds to the clear solution, and keep stirring at 55°C for 2h, after that, cool the
suspension to 10-15°C at the rate of about 5 °C/h. After stirring overnight, the
precipitates were obtained through simple filtration and washed two times with
acetone (300mL). The (R)-1a was collected from mother liquor through
decompression concentration for the next resolution. The crude product
underwent vacuum drying process overnight and yield the esketamine tartrate
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13.3g (>99.5% ee, chemical purity >99.5%, yield: 41.5%), [ɑ]20 D +65.8 (c 1.0,
H2O). (lit., 20a [ɑ]20 D +68.8 (c 2.0, H2O)).
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Synthesis of (S)-2-(2-chlorophenyl)-2-(methylamino) cyclohexanone hydro
chloride, (S)-1a. The obtained tartrate (13.0g, 0.03mol) was alkalized with 1N
NaOH aqueous solution (50mL). Subsequently, the suspension was filtered to
isolate the precipitates which were then washed two times with 50 ml H2O
followed by the vacuum drying process to obtain the esketamine base (7.2 g).
After salting with 2.0 N HCl-EA, the esketamine hydrochloride was obtained
and went through the vacuum dry to constant weight at 40°C (8.2 g). A 250mL
three necked flask was charged with crude esketamine hydrochloride,
deionized water (9mL) and acetone (75mL) which was heated at 65°C for 1h.
When the clear solution cooling to 50 °C, a small amount of crystal seeds were
added and then kept stirring at 50 °C for 2h. Subsequently, cool the suspension
to room temperature at the rate of about 5 °C/h. Subsequently, the suspension
was filtered to isolate the precipitates and then washed with 50 mL acetone two
times followed by vacuum drying to give esketamine hydrochloride. (6.56g,
yield: 80.2%, 99.9% ee, and chemical purity >99.8%). [ɑ]20 D +91.522 (c 1.0,
H2O). 1H NMR (400 MHz, MeOD) δ 8.05 – 7.91 (m, 1H), 7.67 (qd, J = 5.6, 3.4
Hz, 3H), 4.87 (s, 2H), 3.53 – 3.38 (m, 1H), 2.64 – 2.52 (m, 2H), 2.43 (s, 3H),
13
2.21 – 2.12 (m, 1H), 2.02 – 1.91 (m, 2H), 1.89 – 1.71 (m, 2H). C{1H} NMR
(101 MHz, MeOD) δ 206.5, 134.0, 132.1, 131.5, 131.5, 128.0, 127.4, 71.9, 39.0,
35.8, 29.2, 26.3, 21.0. HRMS (ESI-TOF) m/z: [M+H] + Calcd for C13H17ClNO:
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238.0999; Found 238.1002. Anal. Calcd for C13H17Cl2NO: C, 56.95; H, 6.25; N,
5.11. Found: C, 56.83; H, 6.25; N, 5.09. The assignment is supported by an X-
ray crystallographic structure determination.
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Synthesis of (S)-2-amino-2-(2-chlorophenyl)cyclohexanone hydrochloride, (S)-1b.
Similarly, The resolution of norketamine by using L- pyroglutamic acid in EtOH / H2O
at the ratio of 12:1. Racemic norketamine base (16.0g, 0.0717 mol) and 100 mL ethanol
were added to 250 mL reactor. The mixture was heated in the oil bath at 65°C for 30
min until the solution was clarified. L-pyroglutamic acid (5.1 g, 0.0394 mol) was
dissolved in the mixture of 48mL ethanol and 12mL deionized water to be a clarified
solution, and then dropped to the mixture. The clear solution was kept stirring at 75°C
for 1h. Subsequently, cool the suspension to 15°C at the rate of about 5 °C/h.
Subsequently, the precipitates were isolated via vacuum filtration and then washed with
100 mL ethanol three times followed by vacuum drying to give crude product 10.6 g
(99.4% ee, yield: 42%). Anal. Calcd for C12H14ClNO: C, 64.43; H, 6.31; N, 6.26. Found:
C, 64.36; H, 6.29; N, 6.27. [ɑ]20 D -72.038 (c 1.0, MeOH).
According to the operation procedure of (S)-ketamine hydrochloride, the
(S)-norketamine hydrochloride was obtained. (7.9g, yield: 79.6%, 99.6% ee,
chemical purity >99.8%).1H NMR (400 MHz, DMSO) δ 8.84 (s, 3H), 7.89 (dd,
J = 7.4, 1.8 Hz, 1H), 7.62 – 7.49 (m, 3H), 3.18 (dd, J = 14.3, 2.5 Hz, 1H), 2.48
– 2.34 (m, 2H), 2.05 – 1.88 (m, 2H), 1.85 – 1.73 (m, 1H), 1.70 – 1.50 (m, 2H).
13C{1H} NMR (101 MHz, DMSO) δ 206.9, 133.2, 131.8, 131.5, 131.3, 131.1,
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+
128.1, 66.7, 37.6, 29.1, 21.1. HRMS (ESI-TOF) m/z: [M+H]
Calcd for
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C12H15ClNO: 224.0842; Found 224.0846.
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The Racemization of (R)-1 isomer. The (R)-1 was collected from mother liquors
through decompression concentration and then the obtained solid was
alkalized with 1 N NaOH. Subsequently, the (R)-1 base was underwent vacuum
drying process at 50 °C to constant weight and then salted with EA-HCl to yield
the (R)-1 hydrochloride. The (R)-1a hydrochloride (9.0g, 0.038mol) was
dissolved in 90 mL ethyl benzoate and stirred in the presence of AlCl3 (1.0 g,
0.0076 mol) at the temperature of 150 °C by heating in oil bath. After the (R)-
1a was racemized completely, the suspension was cooled naturally to 10-15°C.
In order to precipitate the product fully, 50mL cyclohexane was added to the
mixture. The precipitates were filtered, washed, and dried to give the racemized
1 ((R)-1a/(S)-1a) (50.3%/49.7%) 9.3 g. The yield of this racemization was
quantitative and the chemical purity of the product was 99.5%. The
racemization process of (R)-1b hydrochloride is the same as that of (R)-1a.
ASSOCIATED CONTENT
Supporting Information
Analytical spectrograms of 3, Ketamine, Norketamine, (S)-norketamine and (S)-
ketamine; SCXRD of (S)-ketamine hydrochloride and compound 3; The Analytical
spectra of the racemized Ketamine and Norketamine;
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AUTHOR INFORMATION
Corresponding Author
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Zhezhou Yang − Shanghai Institute of Pharmaceutical Industry, China State
Institute of Pharmaceutical Industry, Shanghai, China; ORCID: 0000-0001-
6703-3673; Email: yangzz2046@163.com
Fuli Zhang − Shanghai Institute of Pharmaceutical Industry, China State
Institute of Pharmaceutical Industry, Shanghai, China; ORCID: 0000-0002-
4175-4795; Email: zhangfuli1@sinopharm.com
Other Authors
Shenghua Gao − Shanghai Institute of Pharmaceutical Industry, China State Institute
of Pharmaceutical Industry, Shanghai, China
Xuezhi Gao − Shanghai Institute of Pharmaceutical Industry, China State Institute of
Pharmaceutical Industry, Shanghai, China
Zenong Wu − School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong
District, Shanghai 201203, China
Houyong Li − Shanghai University of Engineering Science, Shanghai, China
Notes: The authors declare no competing financial interest.
ACKNOWLEDGMENTS:
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We are appreciate for the financial support from the China State Institute of
Pharmaceutical Industry (CSIPI).
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