1254 Sharif et al.
Asian J. Chem.
1.2 g of l-methyl-2-[N-(4-cyanophenyl)aminomethyl]-5-
benzimidazole-carboxylic acid-N-(2-pyridyl)-N-[2-(ethoxy-
carbonylethyl]amide (V) is reacted with ethanol saturated with
hydrochloric acid in large dilution. The evaporated crude
product is then converted to hydrochloric acid salt of l-methyl-
2-[N-(4-amidinophenyl)-aminomethyl]-5-benzimidazole-
carboxylic acid-N-(2-pyridyl)-N-[2-(ethoxycarbonyl)-ethyl]-
amide compound of formula(VI) using ethanol and ammonium
carbonate. The disclosed process was not suitable for large
scale production because of tedious workup procedures, less
yield, low purity, separation by column chromatography, which
in turn results in excessive production time and costlier process
and less eco-friendly. The substance requires complex puri-
fying operations, such as chromatography for the production
of high-qualityAPI. Further the chromatographic purification
is expensive and difficult to implement in large scale. The impu-
rity in the dabigatran single prodrug and dabigatran etexilate
affects the purity of the final product dabigatran etexilate
mesylate [1,10]. Hence, there is a necessity to maintain the purity
level of every intermediate involved in the preparation of
dabigatran etexilate mesylate.
purification. Nuclear magnetic resonance (NMR) spectra were
recorded on bruker instrument operating at 500 MHz and 1H
NMR spectra are obtained with TMS as internal standard in
CDCl3 solvent. 13C NMR spectra are also obtained in CDCl3
instrument operating at 125 MHz IR and mass spectra were
recorded. The reactions were assayed by thin-layer chromato-
graphy (TLC) and terminated as judged by the consumption
of starting material. When peak multiplicities are reported.
Intermediates are sensitive towards methanol. So don’t wash
equipments with these solvents, use only acetone for cleaning
of equipments.
Step-1: Ethyl 3-[2-((4-cyanophenylamino)methyl)-1-
methyl-N-(pyridin-2-yl)-1H-benzo(d)imidazole-5-
carbaxamido]propanoate: To the solution 4-cyano phenyl
glycine (15.4 g; mol) in absolute THF (25 mL). The CDI (16.1
g was in four lots over a period of 40-45 min and stirred at
room temperature. Slowly charge (20 g) maintain the reaction
mixture for 20-24 h at 30-35 °C, charge acetic acid (120 mL)
to reaction mixture and heated to 60-65 °C and maintained
6-7 h. Cool the reaction mixture 20-30 °C and add water (120
mL) separate the organic layer distill off total solvent under
vacuum and dried with sodium sulphate.Add acetone (20 mL)
and methane sulphonic acid (4.2 g) heated to 50-55 °C for 45-
60 min. Cooled at 2-8 °C filter the solid and wash the solid
with acetone (120 mL) and cyclohexane (40 mL) dry at 55-60
°C the solid is 22-23 g molar yield is 85 %.
1H NMR (500 MHz, in DMSO) δ: 8.39 (dd, 1H), 7.55
(dt, 1H), 7.47 (dd, 3H), 7.41 (d, 1H), 7.25 (t, 1H for NH), 7.17
(dd, 1H), 7.12 (dd, 1H), 6.82 (d, 2H), 6.90 (d, 1H), 4.60 (d,
2H), 4.23 (t, 2H), 3.98 (q, 2H), 3.76 (s, 3H), 2.69 (t, 2H), 1.13
(t, 3H). 13C NMR (500 MHz, in DMSO) δ: 170.9 (ethyl ester),
170.2 (amide), 109.4 (cyano), 155.9, 153.2, 151.7, 148.6, 140.8,
137.8, 137.2, 133.2, 129.3, 122.7, 122.04, 121.2, 120.3, 119.4,
Further, other improved processes were reported for
synthesis of dabigtran etexilae mesylate [10,11] in the lite-
rature. However, all procedures suffer due to use of expensive
and moisture sensitive catalysts, high temperature and longer
reaction times. The impurities are formed due to n-hexyl chloro
formate used in step-3. Furthermore, the procedures’involving
these reagents requires harsh and inert conditions [7]. Herein,
we reported an improved synthetic process for synthesis of
dabigtran etexilate mesylate in Scheme-I, in step-3 replace
the n-hexyl chloro formate by pure n-hexanol in order to avoid
the formation of impurities as reported in step-3. The improved
process has a number of industrial advantages.
112.3, 96.7, 59.9, 44.3, 39.5, 33.04, 29.8, 13.9. IR (neat, λmax
,
cm–1): 3271.27, 2940.47, 2215.24, 1731.11, 1639.49, 1604.77,
1581.62, 1529.55, 1435.03, 1389.31, 1328.95, 1273.01,
1243.32, 1179.35, 827.46, 777.31, 746.45. MS: m/z = 483.2
[M + H] +, m.w.: 482.
EXPERIMENTAL
All starting materials and other reagents were purchased
from commercial suppliers and were used without further
O
O
O
O
CDI/THF
AcOH
N
N
O
N
H N
2
O
N
O
NC
NH
N
HN
N
OH
NC
NH
Formula(V)
Formula(III)
Formula(IV)
HCl/EtOH
(NH ) CO
4 2
3
O
O
O
O
O
N
N
O
N
O
N
N
N
THF/H O
2
O
HN
NH
N
N
N
H N
2
NH
ClCO2(CH2)5CH3/K2CO3
H N
2
Formula(VI)
Formula(I)
Scheme-I