Synthesis of 4-Methylimidazole-2-Carboxylic Acid

Article abstract of DOI:10.1002/jhet.3321

4-Methylimidazole-2-carboxylic acid was synthesized from 4-methylimidazole with a total yield of 65% over four steps including an N-benzyl protection, acylation, debenzylation, and ester hydrolysis. The solvent, base, temperature, and reaction time are op

Full text of DOI:10.1002/jhet.3321

Month 2018
Synthesis of 4-Methylimidazole-2-Carboxylic Acid
*
Xianheng Wang, Changkuo Zhao,
Lei Gao, Yiqi Zhou, and Lang Xu
Department of Medicinal Chemistry, Zunyi Medical University, No. 6, Xue Fu West Road, Xinpu New District, Zunyi
563003, China
*E-mail: zck7103@hotmail.com
Received February 16, 2018
DOI 10.1002/jhet.3321
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
4-Methylimidazole-2-carboxylic acid was synthesized from 4-methylimidazole with a total yield of 65%
over four steps including an N-benzyl protection, acylation, debenzylation, and ester hydrolysis. The solvent,
base, temperature, and reaction time are optimized for this method. This efficient, convenient, and low-cost
protocol uses inexpensive reagents in each step to obtain 4-methylimidazole-2-carboxylic acid in high yield.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
We initially attempted to synthesize various 4-substituted
imidazole-2-carboxylic acid derivatives using the two
methods described earlier. However, neither of these
methods gave satisfactory results. Scheme 1 has several
issues. The substituted aminoacetal material is not
commercially available and requires several steps to
synthesize. Additionally, the substituted amino acetal
cannot provide the desired cyclic product under different
acid-catalyzed conditions. Scheme 2 is limited to the
preparation of 4-aryl-substitutedimidazole-2-carboxylic
acids and cannot be used for the synthesis of 4-alkyl-
substituted imidazole-2-carboxylic acids. Therefore, a new
general protocol for the synthesis of these building blocks
(I) is necessary.
Imidazole-2-carboxylic acid derivatives are important
building blocks in the pharmaceutical industry
and have recently been important targets for drug
discovery. For example,
4-arylimidazole-2-amide
derivatives have shown important inhibition activity
toward phosphodiesterase (PDE) when used to treat
neurodegenerative disorders, psychiatric disorders, or
drug addictions [1–4]. In a recent screen of PDE10A
inhibitors, 4-substituted imidazole-2-carboxylic acid (I)
was chosen as synthone for the syntheses of different
imidazole analogues [5–7]. However, after searching the
literature, we found few studies on the synthesis of
imidazole-2-carboxylic acids derivatives (Fig. 1).
Therefore, a new feasible synthetic method for this
framework was developed.
The first synthesis of an unsubstituted imidazole-2-
carboxylic acid (Ia, R = H) was developed by Galeazzi
et al. [6]. They reacted trichloroacetonitrile with
dimethylaminoacetal to form amidines. Imidazole-2-
carboxylic acid was then efficiently synthesized via an
acid-induced cyclization of the amidines, which was
followed by hydrolysis (Scheme 1).
In short, considering resource availability and procedure
simplicity, we envisioned an improved process (Scheme 3)
for the synthesis of this building block (I). Herein, we
describe our effort to synthesize this moiety.
RESULTS AND DISCUSSION
Choosing benzyl as N-protecting group. We first chose
the commercially available 4-methylimidazole (II) as the
starting material. The 4-methylimidazole was treated with
NaH, followed by benzyl bromide, to give a mixture of
regional isomers (IIIa and IIIb) in a ratio of 2:1 with a
total yield of 85%. The obtained mixture can be used
directly in the next step without further purification.
Ritzen et al. [4,5] reported a new method to prepare 4-
aryl-substituted imidazole-2-carboxylic acids. They
treated acetophenone with an aqueous HBr solution to
form the corresponding aldehyde monohydrate, followed
by a cyclization with ethyl 2-hydroxy-2-methoxyacetate.
Finally, the resultant ester was easily hydrolyzed to
afford the 4-aryl-imidazole-2-carboxylic acid (Scheme 2).
Optimization of step 2.
In step 2, chloroformate is
added to acylate the N-protected imidazole. As this is a
© 2018 Wiley Periodicals, Inc.

X. Wang, C. Zhao, L. Gao, Y. Zhou, and L. Xu
Vol 000
be carried out using a 10% Pd/C catalyst and 4 atm
pressure. However, when the reaction was scaled-up, these
conditions no longer worked for the hydrogenation. At
larger scales, an alternate catalyst Pd (OH)2/C (10%) was
used, and the desired product was produced in excellent
yield.
To demonstrate the synthetic advantages of this method,
we successfully carried out this reaction with VIa and VIb
on a large scale (100 g) (Scheme 4).
Figure 1. Structure of 4-substituted imidazole 2-carboxylic acid.
Scheme 1. Synthetic route of imidazole-2-carboxylic acid (Ia, R = H).
Hydrolysis of ester V.
Finally, the hydrolysis of
4-methyl-1H-imidazole-2-carboxylate (V) is conducted
under aqueous alkaline conditions (NaOH) to give the
desired product (I) in a 96% yield (Scheme 5).
Summary.
In conclusion, we have developed a
convenient process to synthesize 4-methylimidazole
2-carboxylic acid, which can be used as a building block
for the synthesis of various PDE10A-inhibiting imidazole
derivatives. This method is being extended to other alkyl-
substituted imidazoles and is readily scalable for
industrial production.
Scheme 2. Synthetic route of 4-benzylimidazole-2-carboxylic acid.
EXPERIMENTAL SECTION
Melting points were determined by a Mettler Toledo
FP62 melting point apparatus and are uncorrected. 1H
NMR spectra were recorded at 400 MHz on a Varian
Unity INOVA 400 MHz NMR spectrometer using
tetramethylsilane as an internal standard, and 13C NMR
spectra were recorded at 100 MHz. Mass spectra were
run on a Waters UPLC–MS instrument. UV spectra
were determined by a Lambda 25 spectrometer. HPLC
spectra were run through a Waters Sunfire™ C18, 5 μm,
4.6 mm × 250 mm column on a Waters apparatus
(pump: e2695; detector: 2998). TLC plates (GF 254)
were bought from Branch Qingdao Haiyang Chemical
Plant.
Scheme 3. Retro-synthesis to the building block (I).
1-Benzyl-4-methyl-1H-imidazole IIIa and 1-benzyl-5-
methyl-1H-imidazole IIIb.
A solution of 4-methyl-1H-
imidazole (100 g, 1.15 mol) in DMF (500 mL) was
added NaH (50.4 g, 70%, 1.5 mol) in portions at 0°C,
and the resulting mixture was stirred at 50°C for 2 h.
Then benzyl bromide (219.0 g, 1.3 mol) was added
dropwise at 0–5°C over 1 h, and the reaction mixture
was stirred at room temperature overnight. Water and
ethyl acetate were added together. The organic layer
was separated, and the aqueous layer was extracted
with ethyl acetate (3 × 500 mL). The combined organic
layers were washed with saturated brine, dried over
Na2SO4, and concentrated under reduced pressure. The
residue was purified by flash column chromatography
through a silica gel column, eluting with petroleum
ether: ethyl acetate = 1:1 to give a mixture of product
IIIa and IIIb (178 g, 84.8%) in a ratio of 2:1. 1H
key step, different bases, molar ratios, and solvents were
tried in order to optimize the reaction conditions
(Table 1). The best result (entry 9) uses triethylamine as
the base, dichloromethane as the solvent, and a cooling
bath at À5°C to give the expected products VIa and VIb
with an optimized total yield of 85%.
Effect of different catalysts on hydrogenation.
Interestingly, we found that when the reaction was at a
small scale (less than 1 g), the hydrogenation reaction can
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of 4-Methylimidazole-2-Carboxylic Acid
Table 1
Impact of different reaction conditions on the yield of step 2.
Entry
Molar ratioa
Base
Solvent
Temp. (°C)/time
Yieldb (%)
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
2.0
3.0
2.0
2.0
2.0
2.0
2.0
Pyridine
Hunig base
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH3CN
THF
CH2Cl2
CH3CN
CH3CN
CH2Cl2
0/overnight
0/overnight
0/overnight
0/overnight
0/overnight
0/overnight
0/overnight
0/overnight
À5/overnight
À15/overnight
25/overnight
40
37
45
48
76
77
60
64
85
80
57
9
10
11
Et3N
Et3N
aMethylchloroformate to imidazole mixture IIIa + IIIb.
bCalculated by both of two region-isomers IVa + IVb.
Ethyl 1-benzyl-4-methyl-1H-imidazole 2-carboxylate VIa
and ethyl 1-benzyl-5-methyl-1H-imidazole-2-carboxylate
Scheme 4. Synthesis of 4-methyl-1H-imidazole-2-carboxylate V.
VIb.
1-Benzyl-4-methyl-1H-imidazole (IIIa) and 1-
benzyl-5-methyl-1H-imidazole (IIIb) (103.2 g, 0.6 mol)
were dissolved in acetonitrile (600 mL), followed by the
addition of triethylamine (170 mL, 1.2 mol) in one
portion. The reaction mixture was then cooled to À5°C.
Neat ethyl chloroformate (120 mL, 1.2 mol) was added
slowly over 30 min. The turbid mixture was then warmed
to room temperature and maintained overnight. The solid
of triethylamine hydrochloride was filtered off. The
filtrate was concentrated in vacuum. Dichloromethane
(500 mL) was added to dilute the mixture, and the
resulting solution was extracted with water (300 mL).
The organic phase was separated and dried over
magnesium sulfate. After removal of the solvent, the
residue was purified by flash column chromatography
(PE/EA = 8/1) to provide a mixture of product VIa
Scheme 5. Hydrolysis of 4-methyl-1H-imidazole-2-carboxylate V.
1
(41.93 g, 35%) and VIb (83.87 g, 51%). VIa: H NMR
(CDCl3) δ = 7.23–7.31 (m, 3H), 7.14 (d, J = 8 Hz, 2H),
6.77 (s, 1H), 5.54 (s, 2H), 4.35 (q, J = 8 Hz, 2H), 2.22
(s, 3H), 1.36 (t, J = 8 Hz, 3H). 13C NMR (CDCl3)
δ = 159.07, 139.00, 136.55, 128.82, 128.78, 127.95,
127.32, 122.48, 61.37, 51.33, 14.31, 13.75. VIb: 1H
NMR (CDCl3) δ = 7.18–7.27 (m, 3H), 6.93–6.97 (m,
3H), 5.60 (s, 2H), 4.30 (q, J = 8 Hz, 2H), 2.12 (s, 3H),
1.33 (t, J = 8 Hz, 3H). 13C NMR (CDCl3) δ = 159.15,
136.31, 133.76, 128.75, 128.47, 127.49, 126.00, 61.22,
48.26, 14.22, 9.86.
NMR (CDCl3) δ = 7.11–7.31 (m, 3H), 6.84–6.96 (m,
2H), 6.41–6.65 (s, 1H), 4.79–4.82 (s, 2H), 1.87–2.04
(s, 3H). 13C NMR (CDCl3) δ = 138.42, 137.19,
136.45, 136.38, 136.30, 128.76, 128.73, 127.93,
127.12, 127.05, 126.44, 115.64, 50.41, 48.11, 13.64,
9.07. HRMS (TOF ES+): m/z calcd for C11H13N2
[(M + H)+], 173.2264; found: 173.1091.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

X. Wang, C. Zhao, L. Gao, Y. Zhou, and L. Xu
Vol 000
Ethyl 4-methyl-1H-imidazole-2-carboxylate V.
A
47.62%, H 4.80%, N 22.21%; found: C 47.43%, H
4.54%, N 22.44%.
solution of ethyl 1-benzyl-4-methyl-1H-imidazole-2-
carboxylate (VIa, 120 g) in methanol (1500 mL) was
hydrogenated in the catalyze of palladium hydroxide on
charcoal (12.0 g, 20%) under 4 atm pressure. After the
starting material disappeared completely, the reaction
mixture was filtered, and the catalyst was washed
thoroughly with methanol. Concentration of the filtrate to
afford the title compound (V, 70.0 g, 93%) as a white
solid. 1H NMR (CDCl3) δ = 6.96 (s, 1H), 4.37 (q,
J = 8 Hz, 2H), 2.29 (s, 3H), 1.32 (t, J = 8 Hz, 3H). 13C
NMR (CDCl3) δ = 159.34, 136.75, 61.61, 14.18.
Elemental analysis: Cal: C 54.54%, H 6.54%, N 18.17%;
found: C 44.32%, H 6.38%, N 18.01%.
Acknowledgments. I would like to thank the financial support
from the program of Joint fund project of Guizhou Provincial
Department of Science and Technology (QianKeHe LH Zi
[2014]7545), meanwhile for the support from the project of
Science and Technology Department of Guizhou Province
(QKHSY[2015]3030), I am also appreciated very much. I
would also like to thank Dr. Jianyong Zhang’s useful
explanation on HPLC and LC/MS spectra data.
REFERENCES AND NOTES
In the same condition, ethyl 1-benzyl-5-methyl-1H-
imidazole-2-carboxylate VIb can also afford the same
compound V in >90% yield.
[1] A. Lemus, R. Lindstrom, A. Vickers, T. Wilson, M. Zapf,
J. Weinhouse, M. I. International patent 158998, 2014.
[2] Albrecht, B. K.; Bellon, S. F.; Gehling, V. S. International
Patent 035062, 2015.
4-Methyl-1H-imidazole-2-carboxylic acid I. A solution
of ethyl 4-methyl-1H-imidazole-2-carboxylate (V, 77 g,
0.5 mol) in absolute methanol (600 mL) was added
250 mL aqueous solution of sodium hydroxide (40%) at
room temperature. The solution was heated to 50°C and
maintained at that temperature for 1 h and then cooled to
room temperature, and the solution was acidified to
pH = 6 with concentrated HCl solution (37%). The
solvent was removed under reduced pressure, and the
residue was purified by chromatography using
dichloromethane/methanol = 10/1 as eluent to give
product (I, 60.2 g, 96%) as a white solid. 1H NMR
(D2O) δ = 6.98 (s, 1H), 2.27 (s, 3H). 13C NMR (D2O):
162.61, 140.88, 132.67, 119.42, 10.02. LC–MS: 127
(M + 1). HPLC purity: >98%. Elemental analysis: Cal: C
[3] Flohr, A. International Patent 078836, 2015.
[4] Ritzen, A.; Kehler, J.; Langgard, M.; Nielsen, J.; Kilburn, J. P.;
Farah, M. M. International Patent 152825, 2009.
[5] Ritzen, A.; Kehler, J.; Langgard, M.; Nielsen, J.; Kilburn, J. P.;
Farah, M. M. US Patent 0016303, 2010.
[6] Galeazzi, E.; Guzman, A.; Nava, J. L.; Liu, Y. Z.; Maddox,
M. L.; Muchowski, J. M. J Org Chem 1995, 60, 1090.
[7] Yoon, U. C.; Chae, E. A.; Cho, D. W.; Park, H. J.; Choi, J. H.
Iridium complex and organic light-emitting diodes. International patent
093176, 2010.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet