A novel and facile route for the synthesis of medetomidine as the α2-adrenoceptor agonist

Article abstract of DOI:10.1007/s13738-017-1114-0

Abstract: We report here a novel and facile method for the synthesis of (±)-4(5)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (medetomidine) in a good yield in five steps. The method involves Wittig olefination of the phenylimidazolylketones, followed by a hydrogenation. We demonstrate that the Wittig alkenylation reaction provides a convenient step for the synthesis of medetomidine without requiring methylation and dehydration steps, which are problematic processes in the previous methods. Graphical Abstract: Novel route for the synthesis of medetomidine.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s13738-017-1114-0

J IRAN CHEM SOC
DOI 10.1007/s13738-017-1114-0
ORIGINAL PAPER
A novel and facile route for the synthesis of medetomidine as the
α2‑adrenoceptor agonist
Babak Kaboudin1 · Hamideh Haghighat1 · Samira Aieni1 · Leila Behrouzi1 ·
Foad Kazemi1 · Jun‑ya Kato2 · Hiroshi Aoyama2 · Tsutomu Yokomatsu2
Received: 10 August 2016 / Accepted: 31 March 2017
© Iranian Chemical Society 2017
Abstract We report here a novel and facile method for
the synthesis of ( )-4(5)-[1-(2,3-dimethylphenyl)ethyl]-
1H-imidazole (medetomidine) in a good yield in fve
steps. The method involves Wittig olefnation of the phe-
nylimidazolylketones, followed by a hydrogenation. We
demonstrate that the Wittig alkenylation reaction provides
a convenient step for the synthesis of medetomidine with-
out requiring methylation and dehydration steps, which are
problematic processes in the previous methods.
Graphical Abstract Novel route for the synthesis of
medetomidine.
H
Me
O
Me
O
Me
MgBr
1) THF, 0 oC
N
Me
Tr
N
+
N
2) MnO2, dioxane
reflux, 51% yield
N
Tr
H
CH2 Me
H
CH2 Me
N
Me
N
Me
1) TFA (60%), r.t, 12 h
H2C PPh3
THF, 0 oC, 24 h
2) H2, Pd/C, r.t, 8h,
quant. yield
N
N
52% yield
H
Tr
Keywords Imidazole · Medetomidine · Wittig reaction ·
α2-adrenoceptor agonist · Methanone
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-017-1114-0) contains supplementary
material, which is available to authorized users.
Introduction
* Babak Kaboudin
Imidazole derivartives are an important class of compounds
that exhibit a variety of interesting and useful properties in
biological activities [1–7]. Among the biologically active
imidazole compounds, medetomidine is known as the pro-
totype of a class of α2-adrenoceptor agonist that shows a
high degree of the sedative-analgetic effect [8]. The (S)-
enantiomer of medetomidine is named dexmedetomidine
kaboudin@iasbs.ac.ir
1
Department of Chemistry, Institute for Advanced Studies
in Basic Sciences(IASBS), Gavazang, Zanjan 45137-66731,
Iran
2
School of Pharmacy, Tokyo University of Pharmacy and Life
Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392,
Japan
1 3

J IRAN CHEM SOC
[9, 10] that is commercially available under trade name
Precedex. This drug is used currently in clinic as anesthetic
and offers suffcient sedation with sporadic side effect that
allows surgeries without artifcial ventilation of the patient
(Fig. 1). The chiral form was obtained by enantiomeric sep-
aration of medetomidine using (+)-tartaric acid [11].
Several methods have been reported for the synthesis of
medetomidine [12–20]. The frst synthesis of medetomi-
dine is reported in the patent literature and requires 7 steps
to give low yield (<11%) starting from 2,3-dimethylbro-
mobenzene via stepwise addition of two kinds of Grignard
reagents [12].
Kudzma et al. [15] reported another approach for the
synthesis of medetomidine (Scheme 1). In this method,
the arylketone, prepared from 2,3-dimetheylbenzoyl
chloride and the doubly protected imidazole via the regi-
oselective lithiation, was treated with MeLi to give the
tertiary alcohol, which was reduced with Li/NH3 to give
medetomidine. The method requires at least 8 synthetic
steps, low temperatures, and high protection of moisture
during the reaction.
and followed by subsequent addition of methylmagne-
sium bromide to give the tertiary alcohol. The authors
emphasized that the tertiary alcohol was converted to
the corresponding alkene in the presence of Et3SiH and
TFA in CH2Cl2 at a low temperature, and subsequent
hydrogenation of the alkene over Pd/C gave medetomi-
dine. However, no evidence is disclosed about the for-
mation of the alkene. Moreover, in our hand, we cannot
reproduce last three steps in the Cordi method to give
medetomidine from tertiary carbinol as reported in the
literature.
Purpose of this paper is to report an alternative
method for the synthesis of medetomidine, in which the
Cordi ketone was unambiguously transformed to the alk-
enyl compound by a Wittig olefnation and subsequent
hydrogenation gave medetomidine in good yield. We
also disclose experimental details and the physical data
for newly synthesized alkenyl compound 5, which are
not reported previously (Scheme 3).
Cordi et al. [16] reported a novel route starting from
the protected imidazole carbaldehyde and 2,3-dimethe-
ylphenylmagnesium bromide as shown in Scheme 2. In
this route, the Grignard adduct was oxidized by MnO2,
Materials and methods
All chemicals were commercial products and distilled or
recrystallized before use. NMR spectra were taken with
a 400 MHz Bruker Avance instrument with the chemi-
cal shifts being reported as δ ppm and coupling constants
expressed in Hertz. Silica gel column chromatography
was carried out with Silica gel 100 (Merck No. 10184).
Merck Silica gel 60 F254 plates (No. 5744) were used for
the preparative TLC. Melting points are uncorrected.
X-ray crystal data of alkene 5 were collected by a
Bruker SMART APEX II diffractometer. The structure
was solved by a direct method using SHLEXS-97 (Schel-
drik 1997) and refned with a full matrix laser-squares
Me Me
Me Me
N
Me
N
Me
N
N
H
H
Dexmedetomidine
Medetomidine
(Precedex or Dextor)
Fig. 1 Structures of medetomidine and dexmedetomidine
Scheme 1 Kudzma et al.
method
1) BuLi/THF, -78 oC
2) TBDMSCl, r.t
N
1) BuLi/THF, -78 oC
2) 2,3-dimethylbenzoyl
chloride, r.t.
N
TBDMS
N
N
SO2NMe2
SO2NMe2
N
N
HCl, reflux
TBDMS
SO2NMe2
N
Me
N
H
O
Me
O
1) MeLi, THF, DME, 0 oC
2) Li/NH3, NH4Cl, -78 oC
N
3) iPrOH/Et2O/HCl
Me
N
H
Me Me
1 3

J IRAN CHEM SOC
Scheme 2 Cordi et al. method
H
O
Me
Me
O
N
Me
1) THF, 0 oC
Me
MgBr
Tr
N
+
N
2) MnO2, dioxane
reflux
N
Tr
Me Me
OH Me
H3C
N
1) Et SiH, TFA, DCM, -10 oC
N
Me
Me
3
MeMgBr
THF, 0 oC, 3 h
2) H2, Pd/C, r.t
N
H
N
Tr
Scheme 3 Our method
H
Me
O
Me
O
Me
MgBr
1) THF, 0 oC
N
Me
Me
Tr
N
+
N
2) MnO2, dioxane
reflux
N
1
Tr
H
2
3
Me Me
CH2 Me
N
N
Me
1) TFA (60%), r.t, 12 h
2) H2, Pd/C, r.t, 8h
H2C PPh3(4)
THF, 0 oC, 24 h
N
N
Tr
5
6
method. Molecular formula = C32H28N2, MW = 440.56,
triclinic, space group= P−1, 9.6788(9) Å,
Procedure for the preparation 4‑(1‑(2,3‑dimethylphe‑
nyl)vinyl)‑1‑trityl‑1H‑imidazole (5) A solution of meth-
yltriphenyl phosphonium bromide (2.5 g, 7.1 mmol) in dry
THF (80 mL) under Ar atmosphere was treated with butyl-
lithium (2.5 M hexane solution, 5 mL) dropwise at 0 °C,
and the reaction mixture was stirred for 1 h at 0 °C. A solu-
tion of (2,3-dimethylphenyl)(1-trityl-1H-imidazol-4-yl)
methanone 3 (1 g, 2.26 mmol) in dry THF (10 mL) was
added dropwise to the reaction mixture, and the result-
ing mixture was stirred for 24 h at 0 °C. Then, the reac-
tion mixture was quenched with water (30 mL), and the
solvent was removed under reduced pressure. The residue
was dissolved in CHCl3 (100 mL) and washed with water
(2 × 50 mL) and saturated NaCl. Separated organic layer
was dried over Na2SO4, fltered and concentrated under
reduced pressure. The crude product was subjected to
fash column chromatography on silica gel. Elution with
EtOAc/n-hexane (1:9 to 9:1) gave pure product 5 (0.52 g)
in 52% yield. Analytical samples of compound 5 for X-ray
analysis were obtained by recrystallizing several times
from a mixture of EtOAc/n-hexane. The product 5 gave
satisfactory spectral data in accord with the assigned struc-
a
=
b = 9.8481(9) Å, c = 14.8413(14) Å, V=1205.37(19) Å3,
T=90 K, Z=2, Dx=1.214 Mg/m3, (Mo-Kα) = 0.71073
Å, R=0.0210 over independent refections. Crystallo-
graphic data (excluding structure factors) for the X-ray
crystal structure analysis reported in this paper have
been deposited with the Cambridge Crystallographic
Data Center (CCDC) as supplementary publication No.
CCDC 1465213; copies of these data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax:+44(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
Preparation of (2,3‑Dimethylphenyl)(1‑trityl‑1H‑imi‑
dazol‑4‑yl)methanone (3) This compound was obtained
according to the method reported by Cordi et al. [16].
The product gave satisfactory spectral data in accord-
ance with the assigned structure and literature report. A
1
white solid; mp: 171–172 °C {Lit [16]. 171 °C}; H NMR
(CDCl3, 400 MHz): 2.28 (s, 3H, CH3), 2.31 (s, 3H), 7.12–
7.39 (m, 18H, Ar), 7.52 (d, 1H, J = 1.2 Hz), 7.60 (d, 1H,
J = 1.2 Hz), 13C NMR (CDCl3, 100.6 MHz): 16.7, 20.3,
76.2, 124.8, 126.1, 128.3, 128.4, 128.5, 129.7, 131.6,
134.7, 137.7, 139.5, 140.1, 141.1, 141.7, 192.8.
1
ture. A white solid; mp: 200–204 °C. H NMR (CDCl3,
400 MHz): 2.00 (s, 3H, CH3), 2.21 (s, 3H, CH3), 5.04 (d,
1H, J = 1.6 Hz, =CH2), 6.14 (d, 1H, J = 1.6 Hz, =CH2)
1 3

J IRAN CHEM SOC
6.28–7.50 (m, 20H, Ar), 13C NMR (CDCl3, 100.6 MHz):
16.7, 20.4, 75.4, 120.3, 125.2, 127.4, 128.0, 128.1, 128.1,
128.7, 128.8, 129.7, 129.8, 134.5, 136.7, 139.1, 140.8,
142.2. HRMS for C32H29N2 calculated [MH] 441.2330;
found m/z= 441.2332.
Procedure for the preparation of medetomidine (6)
A
solution of 5 (88 mg, 0.2 mmol) in aqueous TFA solution
(60%, 5 mL) was stirred overnight. The solvents were evapo-
rated, and the residue was diluted with CHCl3 (15 mL) and
treated with HCl solution (10%, 15 mL). The organic layer
was washed again with HCl solution (10%, 3 × 5 mL). The
combined acidic solutions were neutralized to pH~10 and
then extracted with CHCl3 (4 × 20 mL). The organics were
dried over Na2SO4, fltered and concentrated under reduced
pressure to give trityl-deprotected 5. To a solution of trityl-
deprotected 5 in MeOH (4 mL) was hydrogenated over
10% Pd/C (3 mg) at 40 Psi of hydrogen for 8 h. The catalyst
was fltered through celite. The celite pad was washed with
MeOH (2 × 10 mL). The combined fltrate was concentrated
in vacuo to give 36 mg (95%) of medetomidine 6. The prod-
uct gave satisfactory spectral data in accordance with the
assigned structure and literature report [16]. Yellow viscous
Fig. 2 ORTEP drawing of compound 5
Trityl protecting group is readily removed from alkene
5 using a mixture of TFA/H2O (60:40 v/v) at ambient tem-
perature in nearly quantitative yield. Subsequent treatment
of crude deprotected free base with hydrogen gaseous in
the presence of 10% palladium on charcoal for 8 h afforded
medetomidine 6 in quantitatively yield.
In summary, we report herein a novel and simple route
for the synthesis of medetomidine via the reaction of eas-
ily available Wittig reagent CH2PPh3 with methanone 5.
The alkenylation reaction gave compound 5 which readily
converted to medetomidine 6 via deprotection and hydro-
genation processes. Mild reaction condition, relatively
good yield, a simple workup, and clean reactions make this
method an attractive and a useful contribution to current
methodology.
1
oil; H NMR (CDCl3, 400 MHz): 1.57 (d, 3H, J = 7.2 Hz,
CH3), 2.20 (s, 3H, CH3), 2.27 (s, 3H, CH3), 4.38 (q, 1H,
J = 7.2 Hz, CH), 6.17 (s, 1H), 6.90–7.05 (m, 3H), 7.40 (s,
13
1H), 7.50–8.0 (br, 1H);
C NMR (CDCl3, 100.6 MHz):
15.5, 21.5, 21.7, 34.9, 125.4, 126.4, 128.8, 134.9, 135.3,
137.7, 143.8; analytically calculated for C13H16N2, C, 77.96;
H, 8.05; N, 13.99; found: C, 77.65; H, 8.33; N, 13.69.
Results and discussion
Supplementary Material
Treatment of 1-trityl-1-H-imidazole-4-carboxaldehyde 1
[21] with 2,3-dimethylphenylmagnesium bromide 2 (pre-
pared by reaction of 2,3-dimethyl phenylbromide with
magnesium metal in THF) followed by oxidation of result-
ing tertiary alcohol with manganese oxide to form metha-
none 3 as reported in the literature. Wittig reaction is a very
convenient, general, and useful method for the conver-
sion of aldehyde or ketones to alkenes. Phosphorus ylides
are used as a Wittig reagent that easily generated from a
phosphonium salt.8 Addition of [MePPh3]Br to a solution
of butyllithium in THF forms Wittig reagent CH2=PPh3 4,
which is allowed to react in situ with methanone 3 under an
argon atmosphere to give 4-(1-(2,3-dimethylphenyl)vinyl)-
1H-imidazole 5 in 52% yield. The structure of 5 was unam-
biguously determined by X-ray crystallographic analysis.
ORTEP drawing of alkene 5 is shown in Fig. 2 [22–24].
Copies of 1H NMR and 13C NMR for compounds 1, 3, 5, 6
and X-ray data of compound 5. Supplementary data associ-
ated with this article can be found, in the online version.
Acknowledgements The Iran National Science Foundation (INSF)
is thanked for supporting this work. The authors also thank Mr.
Haruhiko Fukaya, Tokyo University of Pharmacy and Life Sciences
for his helps carrying out the X-ray crystallographic analysis.
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