Reinvestigation of Atipamezole Synthesis and Preparation of New Analogs

Full text of DOI:10.1080/00304948.2019.1621085

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Reinvestigation of Atipamezole Synthesis and
Preparation of New Analogs
Behzad Karrabi, Hossein Fakhraian & Abolghasem Moghimi
To cite this article: Behzad Karrabi, Hossein Fakhraian & Abolghasem Moghimi (2019)
Reinvestigation of Atipamezole Synthesis and Preparation of New Analogs, Organic Preparations
and Procedures International, 51:4, 403-408, DOI: 10.1080/00304948.2019.1621085
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Organic Preparations and Procedures International, 51:403–408, 2019
# 2019 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2019.1621085
OPPI BRIEF
Reinvestigation of Atipamezole Synthesis and
Preparation of New Analogs
Behzad Karrabi, Hossein Fakhraian, and Abolghasem Moghimi
Department of Chemistry, Imam Hossein University, Tehran, Iran
Atipamezole (or Antisedan, Scheme 1, 1) is a synthetic a2-adrenergic receptor antagon-
ist1 having high affinity with the two alpha-2 adrenoceptor subtypes (a2A and a2B).2,3
Although it is a drug of choice in veterinary medicine for countering the anesthesia and
sedation produced by such a2 adrenergic agonists as Medetomidine and Xylazine, it
may ultimately also have a role in human medicine. Focus on the a2 agonists and their
antagonists have spurred on their synthesis.4–15 A number of methods for the synthesis
of Atipamezole have been reported.5–15 Significant among these methods has been the
one shown in Scheme 1.13–15 In the present report, we describe a re-investigation of this
method for the synthesis of Atipamezole, including the characterization of some crucial
intermediates and several new analogs of 1. Our work followed the order shown in
Schemes 2A (Atipamezole) and 2B (Analogs).
In the event, the reaction of phthalide and 1-trityl-1H-imidazole-4-carboxaldehyde in
ethyl acetate led without complication to the corresponding indanedione (Scheme 2a, 2,
76%). Treatment of the dione with potassium carbonate and a five-fold excess of ethyl
iodide in acetone produced the alkylated product 3 (77%), as a readily-isolated crystalline
product. Subsequently, an acidic solution of 3 was treated with Pd/C catalyst in a hydro-
gen autoclave system at 3.5-4.0 bar hydrogen pressure at 80 ꢀC for several hours to yield
the target of synthesis 1 (56%) as its hydrochloride. This procedure offers the advantages
of simplicity and convenience. The deprotection step (trityl cleavage) and reduction step
have been combined in our work. Moreover, the precursor carboxaldehyde of our method
is commercially available and is less expensive than the tritylated iodide of Scheme 1.
In extending our work to analogs of Atipamezole, we prepared compounds 4-6 and
fully characterized them, as well as their respective synthetic intermediates.
In sum, we have re-investigated a significant procedure for the synthesis of the a2-
adrenergic receptor antagonist Atipamezole, leading to a simplification and shortening
of the process. We have used our method for the preparation of several analogs of
Atipamezole and have characterized the synthetic intermediates in their production. It is
our hope that the data presented here and the convenience of our method will facilitate
further investigation of this important class of compounds.
Received July 30, 2018; in final form March 14, 2019.
Address correspondence to Hossein Fakhraian, Department of Chemistry, Imam Hossein
University, Tehran, Iran. E-mail: fakhraian@yahoo.com
403

404
Fakhraian et al.
H
Ph3C
MgI
N
O
O
N
O
OMgI
N
H
NH4Cl
MgCl
EtI
Phthalide
NaOMe
DMF
N
N
N
N
N
N
N
I
Ph3C
Ph3C
Ph3C
N
CPh3
2
O
O
O
O
HCl
H2
Pd/C
N
N
N
N
K2CO3
3
1
N
N
H
H
CPh3
Scheme 1
O
N
O
O
O
O
EtI / K2CO3
Acetone
HCl
N
NaOMe in MeOH
Ethyl acetate
80oC
N
+
N
H
N
NH
(A)
O
N
H2, Pd-C
CPh3
O
N
CPh3
1
2
3
CPh3
OH
O
O
CPh3
N
N
N
N
CPh3
OH
O
O
O
O
O
X
HCl
EtI / K2CO3
Acetone
H
+
NaOMe in MeOH
Ethyl acetate
80oC
(B)
O
H2, Pd-C
or
AlH3
X
X
X
O
4-6
X 4: H, 5: p-OMe, 6: O-OMe
Scheme 2
Experimental Section
All solvents and chemical materials were of analytical grade and were supplied by
Aldrich and Merck, except 1-trityl-1H-imdazole-4-carboxaldehyde, supplied by Acros
1
Organics and used as received without any further purification. H-NMR, 13C-NMR
analysis were performed on a 250 MHz Bruker DPX-250 spectrometer (250 MHz for
1H and 62.5 MHz for 13C) and a 300 MHz Bruker Avance spectrometer (300 MHz for
1H and 75 MHz for 13C). CDCl3 and DMSO-d6 were used as NMR solvents, the proton
1
and carbon chemical shifts were recorded in d (ppm) from TMS for H and 13C spectra.
Infrared spectra (FT-IR) were made on a Perkin Elmer spectrometer using KBr pellets.
1
In the case of known compounds, the FT-IR, H-NMR and 13C-NMR spectra were
compatible with the proposed structures and were submitted for review. Copies are
available from the corresponding author upon request.
2-(1-Trityl-1H-imidazole-4-yl)-1,3-indanedione (2)
In a 2-neck round bottom flask, phthalide (3.75 g, 0.028 mol) and 1-trityl-1H-imidazole-
4-carboxaldehyde (9.47 g, 0.028 mol) were added to ethyl acetate (25 mL). A cooled
solution of sodium methoxide (10%, 50 mL) was added dropwise to the reaction

Atipamezole
405
mixture, and the mixture was stirred for 5 h at 80 ꢀC. After vacuum removal the solvent,
the residue was poured into water and acidified by 1N hydrochloric acid to pH ¼ 4.5.
The precipitate was filtered and washed with water and recrystallized from ethanol to
afford 9.75 g (76%) of crystalline product 2, mp 212-214 ꢀC (lit.13 213-215 ꢀC).
2-Ethyl-2-(1-trityl-1H-imidazole-4-yl)-1,3-indanedione (3)
The product of the previous step, 2-(1-trityl-1H-imidazole-4-yl)1,3-indanedione (4 g,
0.009 mol), was added to a mixture of potassium carbonate (18.5 g, 0.135 mol), iodo-
ethane (7.01 g, 0.045 mol) and acetone (75 mL). The reaction mixture was refluxed for
10 hours, then cooled and filtered and the solid was washed twice with cold acetone.
The filtrate was concentrated and poured into water and stirred for 1 hour. The precipi-
tate was filtered and recrystallized from ethanol, yielding 3.3 g (77%) of crystalline
product 3, mp 197-199 ꢀC (lit.13 196-197 ꢀC).
5-(2-Ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole, Atipamezole hydrochloride (1)
A hydrochloric acid solution of 2-ethyl-2-(1-trityl-1H-imidazole-4-yl)-1,3-indanedione,
prepared by the addition of 3 (2.5 g, 0.005 mol) to 5N hydrochloric acid solution
(20 mL), and 0.25 g of 10% Pd/C were mixed in a hydrogen autoclave system.
Hydrogen gas (3.5-4.0 bar) was applied in to the autoclave and the reaction mixture was
stirred for 7 hours at 80 ꢀC. Then, the reaction mixture was cooled to ambient tempera-
ture and filtered to remove catalyst and triphenylmethanol. The filtrate was cooled to
-5 ꢀC and the formed precipitate was separated by filtration and dried under vacuum to
afford 0.7 g (56%) of product 1, mp (HCl salt) 210-214 ꢀC (lit.13 211-215 ꢀC).
2-Phenyl-1,3-indanedione
It was prepared using phthalide (3.75 g, 0.028 mol) and benzaldehyde (2.97 g,
0.028 mol), in a similar manner as mentioned for the synthesis of 2 affording 5.5 g
(88%) of crystalline solid, mp 146-149 ꢀC (lit.26 148-151 ꢀC and lit.27 147.9-150.3 ꢀC).
2-Ethyl-2-phenyl-1,3-indanedione
It was prepared in a similar manner to 3, using 2-phenyl-1,3-indanedione (2 g,
0.009 mol), potassium carbonate (3.75 g, 0.027 mol) and iodoethane (4.21 g, 0.027 mol)
1
yielding 2.1 g (93%) crystalline solid, mp 92-95 ꢀC. H-NMR (250 MHz, CDCl3): d
0.82 (t, 3H, J ¼ 7.5 Hz), 2.32 (q, 2H, J ¼ 7.5 Hz), 7.23-7.42 (m, 5H), 7.88-8.04 (m, 4H).
13C-NMR (62.5 MHz, CDCl3): d 9.7, 29.2, 62.7, 123.4, 126.8, 127.6, 128.7, 135.9,
137.0, 142.1, 201.9. IR: 1701, 1746 cmꢁ1
.
Anal. Calcd for C17H14O2: C, 81.58; H, 5.64. Found: C, 81.70; H, 5.66.
2-Ethyl-2-phenyl-2,3-dihydro-1H-indene (4). (Reducing agent, H2/Pd-C 10%).
2-Ethyl-2-phenyl-1,3-indanedione (2.5 g, 0.01 mol) was dissolved in methanol (25 mL)
and acidified by addition of 5N hydrochloric acid solution (10 mL). Palladium catalyst

406
Fakhraian et al.
(0.35 g of 10% Pd/C) was added, hydrogen gas (3.5-4.0 bar) was applied and the reac-
tion mixture was stirred for 7 hours at 80 ꢀC. The catalyst was filtered off at ambient
temperature and the solvent was removed under reduced pressure. A saturated solution
of sodium bicarbonate was then added and the aqueous layer was extracted with ethyl
acetate which was dried over MgSO4 and concentrated to afford a light orange oil 1.2 g
1
(54%), which solidified slowly on standing. H-NMR (250 MHz, CDCl3): d 0.83 (t, 3H,
J ¼ 7.5 Hz), 2.33 (q, 2H, J ¼ 7.5 Hz), 3.25 (d, 2H, J ¼ 15 Hz), 3.46 (d, 2H, J ¼ 15 Hz),
7.12-7.40 (m, 6H), 7.46 (m, 3H). 13C-NMR (62.5 MHz, CDCl3): d 9.1, 32.5, 47.0, 53.7,
122.9, 126.8, 127.5, 128.8, 131.4, 135.9, 143.0. IR: 2921, 2987, 3166 cmꢁ1
.
Anal. Calcd for C17H18: C, 91.84; H, 8.16. Found: C, 91.89; H, 8.11.
2-Ethyl-2-phenyl-2,3-dihydro-1H-indene (4). (Reducing agent, AlH3).
Addition of suspended aluminum chloride (1.3 g, 0.01 mol) in dry diethyl ether (10 mL)
to a suspension of lithium aluminum hydride (1.9 g, 0.05 mol) in dry diethyl ether
(10 mL) at 0-5 ꢀC afforded AlH3. To this mixture was added 2-ethyl-2-phenyl-1,3-inda-
nedione (0.6 g, 0.002 mol). The mixture was stirred under reflux conditions for 24 h and
the composition was followed by TLC, then H2O (10 mL) and sodium hydroxide 25%
(10 mL) were added very slowly to the mixture at ambient temperature. The mixture
was filtered, the organic layer was dried and vacuum stripped to afford a yellow oil.
The resulting crude product was purified by column chromatography using EtOAc/pet-
roleum ether (1:4) mixture to give a pale yellow oil 0.23 g (44%), which solidified
slowly on standing, identical to the above material.
2-(4-Methoxyphenyl)-1,3-indanedione
It was prepared using phthalide (1 g, 0.007 mol), 4-methoxybenzaldehyde (1.01 g,
0.007 mol) and sodium methoxide 10% (15 mL) affording 1.61 g (91%) of crystals, mp
155-160 ꢀC (lit.26 152-153 ꢀC, lit.28 154-155 ꢀC and lit.29 155-156 ꢀC).
2-Ethyl-2-(4-methoxyphenyl)-1,3-indanedione
It was prepared using 2-(4-methoxyphenyl)-1,3-indanedione (1 g, 0.004 mol), potassium
carbonate (1.75 g, 0.012 mol), iodoethane (1.9 g, 0.012 mol) and acetone (30 mL), yield-
1
ing 0.98 g (87%) of crystals, mp 102-106 ꢀC. H-NMR (300 MHz, CDCl3): d 0.83 (t,
3H, J ¼ 7.5 Hz), 2.30 (q, 2H, J ¼ 7.2 Hz), 3.76 (s, 3H, -OMe), 6.84 (d, 2H, J ¼ 8.7 Hz),
7.34 (d, 2H, J ¼ 8.7 Hz), 7.87 (m, 2H), 8.04 (m, 2H). 13C-NMR (62.5 MHz, CDCl3): d
9.2, 28.7, 54.7 (C in –OMe), 61.6, 113.7, 123.0, 127.6, 128.6, 135.4, 141.6, 158.5,
201.7. IR: 1703, 2928-2961 cmꢁ1
.
Anal. Calcd for C18H16O3: C, 77.12; H, 5.75. Found: C, 77.20; H, 5.78.
2-Ethyl-2-(4-methoxyphenyl)-2,3-dihydro-1H-indene (5). (Reducing agent, H2/Pd-
C 10%)
It was prepared using a hydrochloric acid solution of 2-ethyl-2-(4-methoxyphenyl)-1,3-
indanedione, prepared by addition of the above compound (2.5 g, 0.009 mol) to 5N

Atipamezole
407
hydrochloric acid solution (10 mL), and 0.35 g of 10% Pd/C, affording 1.15 g (50%) of
product. 1H-NMR (250 MHz, CDCl3): d 0.81 (t, 3H, J ¼ 7.5 Hz), 1.90 (q, 2H,
J ¼ 7.5 Hz), 3.03 (d, 2H, J ¼ 15.25 Hz), 3.25 (d, 2H, J ¼ 15.25 Hz), 3.92 (s, 3H, -OMe),
6.79 (d, 2H, J ¼ 9 Hz), 7.07 (d, 2H, J ¼ 9 Hz), 7.19 (m, 2H), 7.29 (m, 2H). 13C-NMR
(62.5 MHz, CDCl3): d 9.0, 27.8, 44.8, 52.3, 55.1 (C in –OMe), 113.7, 124.0, 127.6,
128.5, 136.7, 142.0, 159.5. IR: 1519, 1586, 1614, 2933, 2958 cmꢁ1. A similar result
was obtained using AlH3 (43%).
Anal. Calcd for C18H20O: C, 85.67; H, 7.99. Found: C, 85.59; H, 8.02.
2-(2-Methoxyphenyl)-1,3-indanedione
1.65 g (88%) of crystalline compound, mp 165-170 ꢀC (lit.28 170.5-172.5 ꢀC).
2-Ethyl-2-(2-methoxyphenyl)-1,3-indanedione
1
0.98 g (88%) of crystalline material, mp 110-115 ꢀC. H-NMR (250 MHz, CDCl3): d
0.79 (t, 3H, J ¼ 7.5 Hz), 2.31 (q, 2H, J ¼ 7.5 Hz), 3.25 (s, 3H, -OMe), 6.7 (d, 1H,
J ¼ 7.5 Hz), 7.05 (m, 1H), 7.26 (m, 1H), 7.49 (m, 1H), 7.84 (m, 2H), 8.00 (m, 2H). 13C-
NMR (62.5 MHz, CDCl3): d 8.9, 25.8, 54.4 (C in –OMe), 59.7, 110.5, 120.5, 121.0,
122.0, 128.3, 128.6, 134.5, 141.2, 155.6, 203.2. IR: 1706, 1744 cmꢁ1
.
Anal. Calcd for C18H16O3: C, 77.12; H, 5.75. Found: C, 77.21; H, 5.78.
2-Ethyl-2-(2-methoxyphenyl)-2,3-dihydro-1H-indene (6)
1
1.15 g (50%) of crystalline 6. H-NMR (250 MHz, CDCl3): d 0.69 (t, 3H, J ¼ 7.5 Hz),
2.00 (q, 2H, J ¼ 7.5 Hz), 2.92 (d, 2H, J ¼ 15 Hz), 3.14 (d, 2H, J ¼ 15 Hz), 3.58 (s, 3H,
-OMe), 6.76-6.84 (m, 2H), 6.96-7.10 (m, 2H), 7.15-7.25 (m, 4H). 13C-NMR
(62.5 MHz, CDCl3): d 9.0, 26.8, 45.0, 52.7, 54.4 (C in –OMe), 112.6, 119.8, 122.0,
122.1, 126.6, 128.3, 134.5, 141.3, 156.6. IR: 1583, 1600, 1620, 2968, 2996 cmꢁ1
.
Anal. Calcd for C18H20O: C, 85.67; H, 7.99. Found: C, 85.61; H, 8.04.
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