Synthesis of 2-(2-fluorophenyl)-2-methylamino-cyclohexanone as a new ketamine derivative

Article abstract of DOI:10.1080/00397911.2014.885053

The main goal of this article is to the present research on the development of ketamine derivatives. The target molecule was a fluoroderivative of ketamine, for which a multistep synthesis has been reported. This novel ketamine derivative, 2-(2-fluorophenyl)-2-methylamino-cyclohexanone, has been called fluoroketamine by our research group. The starting fluorobenzonitrile was reacted with the appropriate Grignard reagent followed by the bromination reaction to obtain α-bromocyclopentyl-(2-fluorophenyl)-ketone. The reaction of the obtained ketone with methylamine at -40 °C then resulted in the formation of α-hydroxycyclopentyl-(2-flourophenyl)-N-methylamine. Finally, the five-memberd ring cyclopentanol was expanded to the cyclohexylketone by a thermal rearrangement reaction. The HCl salt of the target molecule, which is soluble in water, was obtained by the acidification of the free fluoroketamine with HCl. Preliminary animal tests on mice have shown that the resulting fluoroketamine has some advantages over ketamine in terms of the effective dose and the recovery time. Copyright

Full text of DOI:10.1080/00397911.2014.885053

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Synthesis of 2-(2-Fluorophenyl)-2-Methylamino-
Cyclohexanone as a New Ketamine Derivative
Abolghasem Moghimi a , Siyavash Rahmani a b , Reza Zare a & Morteza Sadeghzadeh a
a Department of Chemistry , Imam Hossein University , Tehran , Iran
b Department of Nuclear Medicine , The Educational, Research and Clinical Center, Dr. Masih
Daneshvari Hospital , Tehran , Iran
Accepted author version posted online: 18 Apr 2014.Published online: 18 Apr 2014.
To cite this article: Abolghasem Moghimi , Siyavash Rahmani , Reza Zare & Morteza Sadeghzadeh (2014): Synthesis of 2-(2-
Fluorophenyl)-2-Methylamino-Cyclohexanone as a New Ketamine Derivative, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.885053
To link to this article: http://dx.doi.org/10.1080/00397911.2014.885053
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Synthesis of 2-(2-fluorophenyl)-2-methylamino-cyclohexanone as a new
ketamine derivative
Abolghasem Moghimi1, Siyavash Rahmani1,2, Reza Zare1, Morteza Sadeghzadeh1
1Department of Chemistry, Imam Hossein University, Tehran, Iran, 2Department of
Nuclear Medicine, The Educational, Research and Clinical Center, Dr. Masih Daneshvari
Hospital, Tehran, Iran
Corresponding Author. , E-mail: Siyavash.Rahmani@yahoo.com
Abstract
The main goal of this paper was to the present research on the development of ketamine
derivatives. The target molecule was a fluoro derivative of ketamine; for which a
multistep synthesis has been reported. This novel ketamine derivative, 2-(2-
fluorophenyl)-2-methylamino-cyclohexanone, has been called fluoroketamine by our
research group. The starting fluorobenzonitrile was reacted with the appropriate Grignard
reagent followed by the bromination reaction to obtain α-bromocyclopentyl-(2-
fluorophenyl)-ketone. The reaction of the obtained ketone with methylamine at -40 oC
then resulted in the formation of α-hydroxycyclopentyl-(2-flourophenyl)-N-methylamine.
Finally, the five-memberd ring cyclopentanol was expanded to the cyclohexylketone by a
thermal rearrangement reaction. The HCl salt of the target molecule which is soluble in
water, was obtained by the acidification of the free fluoroketamine with HCl. Preliminary
animal tests on mice have shown that the resulting fluoroketamine has some advantages
over ketamine in terms of the effective dose and the recovery time.
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KEYWORDS: Ketamine, Anesthesia, Bromination, Ring expansion,
Grignard reaction.
1. INTRODUCTION
Ketamine, 2-(2-chlorophenyl)-2-(methylamino)cyclohexanon, is a general, effective and
short acting phencyclidine anesthetic drug that was first introduced as an anesthetic in
1964 and approved for clinical use in 1970. It is among the most important and applicable
general anesthetics that has been in clinical use worldwide for many years. It is used in
infants and toddlers for induction and maintenance of general anesthesia [1] and in the
treatment of neuropathic pain conditions [2] and has long been considered contraindicated
in patients with brain injury.[3] It is also an effective adjunct for postoperative analgesia.
Particular benefit was observed in painful procedures, including upper abdominal,
thoracic, and major orthopedic surgeries.[4] Ketamine has been used for different
purposes, including dentistry, dermatology, prolonged epileptic Seizures, the emergency
department, plastic procedures, heroin and alcohol addiction, interventional radiology in
children and producing a state of dissociative sedation.[1] It can also be safely combined
with other drugs, e.g. propofol and morphine for various procedures.[1-3] From the side
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effect point of views, it has some disadvantageous such as physical harms,
psychotomimetic effects, addiction and recreational use, and rendering new anesthetic
drugs. Therefore, it seems that structural modification is needed to reduce the mentioned
side effects. Such modifications may also introduce new properties and may even change
its well known anesthetic property. Different research groups have tried to introduce new
ketamine derivatives and evaluate their medicinal activities; among which
Methoxetamine (MXE), Tiletamine and Norketamine are some examples.
The present study is in continuation of our studies on the synthesis and evaluation of new
anesthetic drugs especially fluorinated derivatives[5] of ketamine and its analogues.[6a]
Herein we report the synthesis of a new derivative of ketamine as target molecule 5 under
efficient and operationally simple reaction conditions. The target molecule 5 was
prepared in a four-step synthetic method shown in Scheme 1 in higher yield than that
reported for ketamine in the literature.[6] The synthetic route that was originally used for
the synthesis of ketamine[6] was followed with some modifications. The synthetic method
for ketamine reported by Stevens et al. has several drawbacks including low yield, long
reaction times, side products, requirement of purification in its first step and the use of
molecular bromine in chlorinated solvent for bromination in step 2.
2. RESULTS AND DISCUSSION
According to the presented procedure (Scheme 1), the first step for the preparative of 2-
(2-fluorophenyl)-2-methylamino-cyclohexanone 5 was the synthesis of ketone 2. Thus,
our initial experiments focused on the synthesis of this ketone by the reaction of
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cyclopentyl magnesium bromide with 2-Fluorobenzonitrile 1. Although the addition of
Grignard reagents to nitriles has been known for a long time, the preparation of ketones
using bulky reactants usually require harsh conditions, especially in the current case that
cyclopentyl magnesium bromide was used. On the other hand, the yield of reaction using
the previous reaction conditions[7] was very low (20-25%). Therefore, it was essential to
experience new conditions. It is known that the reaction of Grignard reagent with nitriles
is effectively catalyzed by copper (I). Therefore, based on the results reported by S. Hall
et al in Cu-Catalyzed addition of Grignard to nitriles,[8] we examined the effect of copper
(I) catalyst in our case. During the course of our studies on Cu-catalyzed reaction of
Grignard reagent with aromatic nitriles for the preparation of aryl cycloalkyl ketones, we
realized that the reaction product and the yield depend on the nature and the percentage
of the Cu (Ι) catalyst.[6a] Under optimized reaction conditions, from the solvent, amount
of catalyst and reaction temperature point of view, ketone 2 was prepared in 90 %
isolated yield by the addition of 1 mol% of CuBr. Me2S to a stirred solution of
cyclopentyl magnesium bromide and nitriles 1 in THF and refluxing the reaction mixture
for 4h. It should be noted when other Cu (Ι) catalysts such as CuBr or CuCl were used, 2
mol% of copper catalyst was required to afford ketone 2 in lower yield (Table 1). It is
worthy to note that when 2 mol% of other Cu (Ι) catalysts such as CuBr or CuCl were
used, ketone 2 was obtained in 45-73% yield (Table 1).
For the preparation of bromoketone 3, we examined various brominating agents under
different reaction conditions to achieve the best reaction condition and realized that the
use of H2O2-HBr and LiCl under a solvent and organic waste-free reaction condition
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gives the best yield over a shorter reaction time.[9] Bromoketone 3 was obtained in 96%
isolated yield using 2 equiv H2O2 and 1.1 equiv HBr in the presence of 0.5 equiv LiCl at
70 ºC for 1.5h. However the effect of LiCl in this protocol was not clear to us, while in
the bromination of acetophenone, LiCl plays a dual role in increasing selective α-
monobromination versus dibromination and attaining a higher yield in a shorter reaction
time.[9b]
Then, under the controlled low temperature reaction conditions, the α-bromoketone 3
reacted with liquid methylamine and α-hydroxy imine 4 was prepared in high yield
(81%). It is important to note that depending on the reaction temperature α-
hydroxyketone 6 was formed as well. Upon the change of the reaction temperature from -
40 °C to -20 °C, the percentage of expected imine as well as product 4 in the reaction
mixture was decreased. At -13 °C α-hydroxyketone 6 was the only product of the
reaction.
The last step was the rearrangement of α-hydroxyimine 4 to reach fluoro ketamine 5.
First, we examined the reaction condition reported by Stevens et al for the synthesis of
ketamine[6] (refluxing corresponding α-hydroxyimine in decalin for 3h), but found that it
was not applicable to the current case and in a number of experiments carried out, low
yield was obtained (12-19%) (Table 2).We also performed this reaction in diphenyl ether
as the solvent instead of decalin to achieve higher reaction temperature, but
fluoroketamine product 5 could not be detected after 6h under refluxing conditions (Table
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2, entry 3). Then, we experienced new conditions for this ring-expansion reaction
including the use of various catalysts.
In the case of protic and Lewis acid catalysts the best result was obtained when 10 mol%
of ZnCl2/SiO2 (silzic)[10] was used (Table 1, entry 4). (Table 2, entry 4). This result led us
to conclude that acidic catalysts are not efficient and new conditions or catalyst on the
ring-expansion reaction were required to obtain the desired result. Then, based on the
result of Trost, B. M[11] and Nagao, Y[12] in transition metal-catalyzed ring expansion (Pd
and Rh) and our studies in metal-catalyzed cross-coupling reactions,[13] we examined the
effect of Cu and Pd catalysts in the reaction. The use of copper catalyst including CuBr,
CuCl and CuCl2 even in the presence of DABCO and PPh3 as additive was not
successful. When PdCl2 (3 mol %) was used, interestingly 53% isolated yield of the
desired product 5 was obtained (Table 1, entry 5) (Table 2, entry 5) while ligands or
additives that were reported in the literature were not required (Table 1, entry 6). (Table
2, entry 6). A plausible reaction mechanism for Pd-Catalyzed ring expansion of α-
hydroxyimine 4 to fluoro ketamine 5 is proposed as shown in Scheme 3.
In order to prepare fluoro ketamine hydrochloride salt the free base 5 was protonated with
37% aqueous solution of HCl and the final solid product was obtained in 90% yield.
3. EXPERIMENTAL
3.1 Synthesis Of Cyclopentyl-(2-Fluorophenyl)-Ketone (2).
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In a dry and nitrogen-flushed 250 mL three neck flask equipped with a 200mL dropping
funnel with pressure balance, reflux condenser with CaCl2 drying tube and gas inlet tube,
2.48 gr of magnesium turnings was charged. Then, 0.05gr iodine crystals were added and
the flask was heated while stirring until violet fumes were formed. The flask was cooled
to room temperature and 0.09 mol (9.67 mL) of bromocyclopentane in dry THF (70 mL)
was added to the mixture without stirring. When the mixture started to boiling, the
remaining bromocyclopentane was added via a dropping funnel during 1h while stirring.
To this solution 0.075 mol (8 mL) of 2-Fluorobenzonitrile in 140 mL THF was added
followed by the addition of 0.154 gr CuBr.Me2S (1mol %). The mixture was refluxed
under nitrogen for 4h. After cooling to 25 °C, 30 mL of H20 was cautiously added,
followed by 150 mL of 15% H2SO4. After stirring for 4 h, 50 mL of hexane was added,
the organic layer was separated, and the aqueous layer was extracted twice with 30 mL
portions of hexane. The combined organic phase was dried on MgSO4 and was washed
with 25 mL of cooled hexane and concentrated by solvent removal under reduced
pressure to afford 13 gr (90%) of light yellow oil.
IR (KBr): 2955, 2869, 1679, 1608, 1479, 1451, 1271, 1211, 756 cm-1; 1H NMR
(250MHz, CDCl3) δ: 1.6 – 1.72(4H, m), 1.86 – 1.93(4H, m), 3.59 – 3.66(1H, m), 7.06 –
7.23(2H, m), 7.42 - 7.51(1H, m), 7.74 – 7.81(1H, m); 13C NMR (62.90MHz, CDCl3) δ:
26.09(2CH2, s), 29.27(2CH2, d, J = 0.64 Hz), 50.98(CH, d, J = 5.77 Hz), 116.42(CH, d, J
= 23.9 Hz), 124.39(CH, d, J = 3.45 Hz), 126.21(quat-C, d, J = 13.02 Hz), 130.83(CH, d,
J = 2.89 Hz), 133.92(CH, d, J = 8.99 Hz), 159.40(quat-C, d, JC-F = 253.74 Hz),
201.51(quat-C, C=O) ppm.
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3.2 Synthesis Of Α-Bromocyclopentyl-(2-Fluorophenyl)-Ketone (3)
Ketone 2 (0.064 mol (12.48 gr)) was placed in a flask covered with aluminum foil. A
47% aqueous solution of HBr (10.18 mL, 1.1 mol equiv.) was added to ketone. After
stirring the reaction mixture for 5 min at room temperature, 0.03 mol (1.26 gr) of LiCl
was added to the mixture and the mixture was stirred for 1 min. Then, 30% aqueous
solution of H2O2 (12.30 mL, 2 mol equiv.) was added slowly. The reaction mixture was
heated at 70 oC for 1.5h and 35 mL of H2O was cautiously added, followed by 45 mL of
hexane. The organic layer was separated and dried on MgSO4. The insoluble material
was filtered off and then the solvent was evaporated under reduced pressure to afford the
crude reaction mixture (17.1 gr). This oily product was purified by column
chromatography (SiO2, n-hexane: EtOAc 8 : 2) the bromoketone 3 (15.7 gr, 96%) was
obtained as a pure brown oily product.
3.3 Synthesis Of Α-Hydroxycyclopentyl-(2-Flourophenyl)-N-Methylamine (4).
In a sealed vitreous glass reactor containing 35 mL methylamine cooled by Liq. N2 vapor
was added to α-bromocyclopentyl-(2-fluorophenyl)-ketone (15.7 g, 0.06 mmol). After
stirring for 6 h, the excess liquid methylamine was allowed to evaporate and 100 mL of
hexane was added. The organic layer was separated and was concentrated by solvent
removal under reduced pressure and the crude reaction mixture was cooled to afford
brown crystals. The crystals were washed twice with 30mL of methanol and
recrystallized from hexane to obtain 10.4 gr 4 (81%) as shiny crystals.
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3.4 Synthesis Of 2-(2-Fluorophenyl)-2-Methylamino-Cyclohexanone (5).
0.05 mol(10.4 gr) of α-hydroxycyclophenthyl-(2-flourophenyl)-N-methylamine 4 was
dissolved in 85 mL of decalin followed by the addition of 0.25 gr PdCl2 (3 mol%) and
was refluxed for 4h. The solvent was evaporated under reduced pressure and the residue
was extracted with 160 ml of hydrochloric acid (10 %). To this acidic solution 80 mL
NaOH (50 %) was added, followed by the addition of 120 ml of chloroform. The organic
layer was separated, and the aqueous layer was extracted twice with 25 mL of
chloroform. The combined organic phase was dried on MgSO4. The insoluble material
was filtered off and the organic solvent evaporated under reduced pressure to afford 5.5
gr (53%) pure brown oily fluoro ketamine 5.
3.5 Synthesis Of 1-(2-Fluorophenyl)-N-Methyl-2-Oxocyclohexanaminium Chloride
(7)
0.024 mol(5.5 gr) of 2-(2-fluorophenyl)-2-methylamino-cyclohexanone 5 was dissolved
in a 100 mL mixture of H2O/CH2Cl2 (50:50). Then, 2.9 mL of 37% aqueous solution of
HCl was added slowly. The aqueous layer was separated and water was evaporated under
reduced pressure. The pure powder 1-(2-fluorophenyl)-N-methyl-2-
oxocyclohexanaminium chloride 7 (5.6 gr) was obtained in 90% yield.
4. CONCLUSION
In summary, we have developed the synthesis of a new derivative of ketamine. This has
been performed by keeping the main structure of ketamine and replacing Cl with an F
atom. We chose a 4 step synthetic method similar to that previously reported in the
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literature for ketamine. In the first step, we focused on the new reaction conditions
especially using the Cu (Ι) catalyst. We also examined the effect of Pd catalyst on the
rearrangement step 4 to facilitate the ring expansion and increase the reaction yield.
Finally, fluoro ketamine 5 was obtained in high overall yield (40%). Primary biological
tests have shown promising results over ketamine in terms of the effective dose and the
recovery time.
ACKNOWLEDGMENTS
Support of this work by the Department of Chemistry, Imam Hossein University and
Department of Nuclear Medicine, The Educational, Research and Clinical Center, Dr.
Masih Daneshvari Hospital, Tehran, Iran.
SUPPORTING INFORMATION
Full spectral data, 1H and 13C NMR spectra are available. Supplemental data for this
article can be accessed on the publisher’s website
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Table 1. The effect of nature and percentage of Cu (Ι) catalyst on the yield of ketone (2)
from 2-Fluorobenzonitrile.
Entry
Cu catalyst (mol Solvent Time
Yielda
%)
(h)
5
1
2
3
4
5
CuBr (2)
CuBr (2)
CuCl (2)
CuBr (1)
CuBr.SMe2 (1)
THF
63%
73%
67%
45%
90%
Toluene
Toluene
Toluene
THF
5
5
5
4
a isolated yield
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Table 2. Reaction conditions for the preparation of 2-(2-fluorophenyl)-2-methylamino-
cyclohexanone (5).
Entr Solvent
y
Temp
Catalyst (mol %)
Time
(h)
4
Yielda
1
2
3
Decaline
Decaline
reflux
reflux
-
-
-
12%
19%
-
15
7
Diphenyl reflux
Ether
4
5
6
7
Decaline
Decaline
Decaline
reflux
reflux
reflux
ZnCl2-SiO2 (10)
PdCl2(3)
9
4
4
4
27%
53%
50%
34%
PdCl2(3)/PPh3
Diphenyl 200 ºC PdCl2(3)
Ether
a isolated yield.
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Scheme 1. The four-step synthetic method of 2-(2-fluorophenyl)-2-methylamino-
cyclohexanone.
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Scheme 2. Reaction of α-bromoketone with liquid methylamine.
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Scheme 3. The plausible mechanism for Pd-Catalyzed ring expansion of α-hydroxyimine
4 to fluoro ketamine.
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