Synthesis, characterization and suppression of impurities during optimization of dabigatran etexilate

Article abstract of DOI:10.3987/COM-13-12746

The synthetic methods for two impurities of dabigatran etexilate are firstly described, and both of two impurities are characterized by NMR and MS spectral data. The suppression of impurities as well as the optimization process of dabigatran etexilate is also disclosed.

Full text of DOI:10.3987/COM-13-12746

HETEROCYCLES, Vol. 87, No. 8, 2013
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HETEROCYCLES, Vol. 87, No. 8, 2013, pp. 1699 - 1710. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 15th May, 2013, Accepted, 19th June, 2013, Published online, 27th June, 2013
DOI: 10.3987/COM-13-12746
SYNTHESIS, CHARACTERIZATION AND SUPPRESSION OF
IMPURITIES DURING OPTIMIZATION OF DABIGATRAN ETEXILATE
Yu Chen,* Jun Liang, Huansheng Chen, and Li Yuan
Shanghai AoBo Bio-pharmaceutical Technology Co., Ltd., No.1011, Halei Road,
Zhangjiang High-Tech Park, Shanghai 201203, P. R. China. E-mail:
chenykk@hotmail.com
Abstract – The synthetic methods for two impurities of dabigatran etexilate are
firstly described, and both of two impurities are characterized by NMR and MS
spectral data. The suppression of impurities as well as the optimization process of
dabigatran etexilate is also disclosed.
INTRODUCTION
Dabigatran etexilate (1, Figure 1) is the oral double pro-drug of dabigatran, developed by Boehringer
Ingelheim with the brand name Pradaxa.1 This substance is a reversible thrombin inhibitor which is
indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial
fibrillation.2 Dabigatran etexilate (1) was first disclosed in WO 9837075,3 afterwards, although several
improved processes for this drug have been developed,4 few concerned the impurities.5
Figure 1
During our exploration on process development of dabigatran etexilate (1), we found that according to the
known processes, the purity of 1 could not reach the desired level formulated by ICH.6 Total impurities in
about 1−1.5% content by HPLC analysis were observed even after the free base or salt such as MeSO3H

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HETEROCYCLES, Vol. 87, No. 8, 2013
salt of 1 was carefully recrystallized for three times.7 Three major impurities in the range of 0.1−0.9%
each were separated and characterized as 2−4 (Figure 2). The first one, ethyl
2-[[4-[(n-hexyloxycarbonyl)aminoiminomethyl]phenylamino]methyl]-1-methyl-1H-benzimidazole-5-
carboxylate (2), has a similar structure with dabigatran etexilate. This impurity was first reported in WO
2012152855.8 But according to that method, compound 2 was obtained as a minor byproduct and had to
be separated from the reaction mixture by column chromatography in low content with the structure
deduced only by HPLC. The second is ethyl 3-[[2-[(4-carbamimidoyl-phenylamino)-methyl]-1-methyl-
1H-benzimidazole-5-carbonyl]-pyridin-2-yl-amino]-propionate (3). It was presumptively from the
hydrolysis of 1 in the reaction course or the purification operation at a higher temperature.9 In addition,
we also found a new impurity, ethyl 3-[(2-methyl-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-
amino]-propionate (4). We know that the discovery and control of the impurities plays an important role
in ensuring the quality and safety of the drug products. Herein, we report the convenient synthesis and
characterization for impurities 2 and 4, which would provide sufficient quantities to satisfy the analytical
need under regulatory requirements. Moreover, this would also help in the mechanistic aspect of the
formation of these impurities to realize the optimization of dabigatran etexilate (1) with high purity as
well as the control of all the impurities no more than 0.05% level.
O
Me
N
O
N
OEt
N
NH
H2N
O
2
O
N
O
Me
N
N
N
N
OEt
HN
Me
N
OEt
N
N
NH
Me
H2N
4
3
O
O
Figure 2
RESULTS AND DISCUSSION
We began with the synthesis of ethyl 3-[[2-[(4-cyanophenylamino)-methyl]-1-methyl-1H-
benzimidazole-5-carbonyl]-pyridin-2-yl-amino]-propionate (7), which was obtained from the reaction of
ethyl 3-[[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino]-propionate (5) with [(4-cyanophenyl)-
amino]acetic acid (6) according to the known method (Scheme 1).3,4a-b

HETEROCYCLES, Vol. 87, No. 8, 2013
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Scheme 1
During the development, we found that alcoholysis impurity 9 was easily produced through the Pinner
reaction10-amination of 7 according to the published method for 1. Specially, the higher temperature in
Pinner reaction was used, the more alcoholysis impurity was produced. In the end, the acylated derivative
2 would be brought to dabigatran etexilate (1) which led to a hard purification because of the
structure-similarity. Therefore, in order to synthesize 2 (Scheme 2), we carried out Pinner reaction at a
higher temperature (35 °C) for 2 days on purpose to make 7 be transformed to 8-HCl completely. The
obtained oil compound 8-HCl which was observed to be a little unstable, underwent amination quickly to
give another oil crude ethyl 2-[[4-(aminoiminomethyl)phenylamino]methyl]-1-methyl-1H-
benzimidazole-5-carboxylate (9). However, oil crude 9 must be purified by column chromatography
before acylation, assuring to obtain high-qualified 2. Unfortunately, the high polarity of 9 led to a very
hard separation. Attempt to transform this oil 9 to its HCl salt also gave an oil.
Scheme 2
We found the key point laid in the low purity of 7 prepared from the present method. In terms of the
present method,3,4a-b 7 was formed in excess of HOAc as solvent at a high temperature. After the reaction,
several impurities were formed, one of which, was the main impurity identified as 4 by NMR and MS.
Notably, 7 was obtained as a semisolid which was found not to be easy for purification by
recrystallization. Consequently, low purity of 7 caused more impurities in the following reactions.

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HETEROCYCLES, Vol. 87, No. 8, 2013
Because impurity 4 was brought to the final molecule, either the impurity 2 or dabigatran etexilate (1), we
had to make sure that compound 7 had enough purity first.
To overcome the problem, we employed ethyl acetate as solvent with 1 equiv of HOAc after the
condensation of 5 with 6. The reaction proceeded very well with the greatly reduced amount of impurity
4.11 As soon as the ring-closing reaction finished, succinic acid was added directly into the mixture, and
its salt (10) precipitated easily in 82% yield with 99.7% purity (impurity 4 was not detected12). It meant
that 10 had enough purity not to be recrystallized further. The succinic acid form of 10 was superior to its
oxalic acid one reported in WO 2009111997,13 which needed further recrystallization to acquire higher
purity (97.8%) at the cost of yield (57.2%). Moreover, the great reduction of HOAc helps reducing acidic
corrosion as well as strengthening environmental protection. Subsequently, 10 was dissolved in 7 mol/L
o
(7N) HCl-EtOH solution at 35 C for 2 days. Due to the enough purity of 10, solid precipitated from the
mixture. This solid was treated with 4.5 mol/L (4.5N) NH3-EtOH solution immediately after filtration.
After further treatment with HCl-EtOH solution, compound 9 was obtained in the form of salt to
precipitate as a white solid in 64% yield from 10. Finally, 2 was synthesized by the acylation of 9-HCl
with n-hexyl chloroformate. The whole route for 2 started from 5 or 6 in 31% overall yield without
separation by chromatography column for every step (Scheme 3).
Scheme 3
Evidently, the formation of 4 was from the ring-closing of residual compound 5 with HOAc. Therefore,
after refluxed reaction of 5 in HOAc as solvent, 4 could be obtained in good yield (Scheme 4). Of course,
using our improved method, impurity 4 could be completely eliminated in 10.

HETEROCYCLES, Vol. 87, No. 8, 2013
1703
O
N
O
O
N
O
H2N
N
N
OEt
N
OEt
Me
HOAc
reflux
75%
N
MeHN
Me
4
5
Scheme 4
Next, we turned our attention to suppress impurity 2. According to the known method,8 impurity 2 existed
in the final product (1) in about 10% content, which led to very careful purification to get a high quality
product. In order to decrease the content of impurity 2 as much as possible in the crude final product, we
explored the Pinner reaction which was responsible for the formation of this impurity (Scheme 5).
Me
N
Me
N
HCl-EtOH
OEt
N
O
N
O
HN
N
N
OEt
NC
N
N
NH
NH
EtO
HCl
11-HCl
CO2H
HO2C
O
O
10
Scheme 5
First we examined the effect of different acidic level with 7N HCl-EtOH solution on the Pinner reaction
at room temperature (20−25 °C). The results were showed in Table 1. When 20 equiv of HCl was used,
the reaction proceeded a little slowly with more 10 left (Table 1, entry 1). The reaction was not improved
when the reaction time was extended but alcoholysis impurity 8 was slightly increased (Table 1, entry 2).
40 equiv of HCl gave a better result, more 10 was converted with moderate amount of 8 produced in 12 h
(Table 1, entry 4). Shortening the time led to less 8, but, the transformation of 10 was also suppressed
(Table 1, entry 3). The reaction was accelerated when more equiv of HCl was used, but more 8 was
quickly formed even in a shorter time (Table 1, entries 5−8).
Table 1. Effect of acidic level on Pinner reaction at 20−25 °Ca
entry
HCl (equiv)b
time (h)
11 (%)c,d
8 (%)c,e
about 15
about 20
about 10
about 20
10 (%)c
30
1
2
3
4
20
20
40
40
12
18
8
48
46
57
61
26
22
12
12

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HETEROCYCLES, Vol. 87, No. 8, 2013
5
6
7
8
60
60
80
80
8
12
4
56
51
45
35
about 20
about 30
about 30
about 45
13
7
10
5
8
aAll the reactions were carried out with 10 in 7 mol/L HCl-EtOH solution at 20−25 °C. After the reaction
finished at given time, saturated aqueous NaHCO3 was added slowly to neutralize the reaction system at
0 °C. The corresponding compounds which were all in the free base form were isolated by column
b
c
d
chromatography. acidic equiv of 7 mol/L HCl-EtOH. Isolated yield. Compound 11 had better stability
compared with 8. eCompound 8 was a little unstable, about 15−20% was decomposed to other unknown
polarity-similar impurity after column separation. The listed yield of 8 was calculated approximately
minus rough content of the mixed decomposed impurity according to HPLC.
Then we compared different reaction time and temperature with 40 equiv of HCl to obtain a best
condition. From Table 2, we could see that lowing temperature reduced 8 with moderate yield of 11,
although more 10 left (Table 2, entries 1−2). Pleasingly, the reaction took place a little slowly but very
well at 5−10 °C. The desired product 11 was produced in good yield with trace of 8 in 30 h (Table 2,
entries 3−5). Further extension of time did not promote the reaction (Table 2, entry 6). The lower
temperature resulted in the slower reaction. For example, it took 48 h to acquire a good result when the
reaction was carried out at 0−5 oC (Table 2, entries 7−8).
Table 2. Comparison of time and temperature on Pinner reaction with 40 equiv of HCla
entry
temp (°C)
10−15
10−15
5−10
time (h)
8
11 (%)b
46
8 (%)b
less than 10
less than 10
trace
10 (%)b
1
2
43
28
48
24
6
16
57
3
12
45
4
5−10
20
68
trace
5c
5−10
30
89
trace
6
5−10
40
85
trace
5
7
0−5
30
78
trace
13
6
8
0−5
48
85
trace
aAll the reactions were carried out with 10 in 7 mol/L HCl-EtOH solution. After the reaction finished at
given time and temperature, saturated aqueous NaHCO3 was added slowly to neutralize the reaction
system at 0 °C. The corresponding compounds which were all in the free base form were isolated by
column chromatography. bIsolated yield. cSee ref 14.

HETEROCYCLES, Vol. 87, No. 8, 2013
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The synthesis and purification of dabigatran etexilate (1) turned out to be much easier after the
optimization of Pinner reaction was finished. The transformation of 10 to 3 could be realized in one pot.
Compound 3 finally reacted with n-hexyl chloroformate in Et3N-DCM system instead of water-containing
system widely used by published processes to produce dabigatran etexilate (1). Because of good
suppression of alcoholysis impurity in Pinner reaction, its derivative 2 was detected in only 0.27% by
HPLC in the reaction mixture. After simple purification, dabigatran etexilate (1) was obtained in 77%
yield with 99.9% purity, and each impurity was detected no more than 0.05% by HPLC (Scheme 6).
Scheme 6
In the final step, the reagents and solvents using either in the reaction or the purification course have to be
dried in advance. Consequently, the hydrolysis of 1 could be avoided (Scheme 7).
Scheme 7
EXPERIMENTAL
General. Melting points were recorded on an RY-1 melting point apparatus and are uncorrected. 1H (400
13
MHz) and C (100 MHz) NMR spectra were recorded on a Bruker Avance 400 spectrometer in CDCl3,
DMSO-d6 or CD3CO2D using tetramethylsilane (TMS) as internal standards. J values are given in hertz.
Mass spectra were recorded on a Finnigan MAT-95/711 spectrometer. Elemental analysis was performed
on an MOD-1106 instrument. HPLC analysis was performed by a standard method on a Agilent
ZORBAX SB-Phenyl, 250 mm × 4.6 mm (5 m),  = 220 nm, with acetonitrile buffer (2.04 g of KH2PO4

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HETEROCYCLES, Vol. 87, No. 8, 2013
in 1.0 L of water and pH 3.0 with ortho phosphoric acid. The HPLC analysis data are reported in area % and
are not adjusted to weight %.
Ethyl 3-[[2-[(4-cyanophenylamino)-methyl]-1-methyl-1H-benzimidazole-5-carbonyl]-pyridin-2-yl-
amino]-propionate succinic acid salt (10).
To a stirred solution of 6 (51.6 g, 0.29 mol) and CDI (47.5 g, 0.29 mol) in THF (1.2 L) was added 5
(100.0 g, 0.29 mol) at 25 °C. The mixture was stirred for 24 h at 25 °C. EtOAc (1.2 L) was added after
THF was evaporated. Then the organic solution was washed successively with saturated aq sodium
hydrogen carbonate (1 L) and brine (1 L), dried with anhydrous Na2SO4. HOAc (17.4 g, 0.29 mol) was
added to above solution after filtration, and the mixture was heated at 70 °C for 12 h. The solution was
washed successively with saturated aq sodium hydrogen carbonate (500 mL) and brine (500 mL), dried
with anhydrous Na2SO4. Succinic acid (34.2 g, 0.29 mol) was added after filtration. The solid was
collected after precipitation completely, washed with EtOAc (100 mL) and dried at 50 °C under vacuum
to give 10 as a pale-green solid (142.9 g, yield: 82%, purity by HPLC 99.7%, retention time: 18.1 min).
Mp 136−138 °C. 1H NMR (DMSO-d6, 400 MHz):  = 1.10 (t, J = 7.2 Hz, 3H), 2.39 (s, 4H), 2.65 (t, J =
7.2 Hz, 2H), 3.73 (s, 3H), 3.95 (q, J = 7.2 Hz, 2H), 4.20 (t, J = 7.2 Hz, 2H), 4.57 (d, J = 5.6 Hz, 2H), 6.79
(d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.23 (t, J =
8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.42−7.47 (m, 3H), 7.52 (dt, J = 7.6 Hz, 1.6 Hz, 1H), 8.36 (d, J =
13
2.8 Hz, 1H), 12.12 (br s, 2H); C NMR (DMSO-d6, 100 MHz):  = 14.3, 29.3, 30.3, 33.5, 44.9, 60.5,
97.3, 109.9, 112.8, 120.0, 120.9, 121.7, 122.6, 123.4, 129.9, 133.8, 137.7, 138.3, 141.2, 149.1, 152.2,
153.7, 156.5, 170.8, 171.5, 174.2 (one carbon-peak at high field was hidden in the peaks of DMSO)15;
ESI-MS (m/z) 483 [M + H]+.
Ethyl
2-[[4-(aminoiminomethyl)phenylamino]methyl]-1-methyl-1H-benzimidazole-5-carboxylate
hydrochloride (9-HCl).
10 (140.0 g, 0.23 mol) was dissolved in 7 mol/L HCl-EtOH solution (2.5 L) in a three-neck flask
equipped with a drying tube. The mixture was stirred at 35 °C for 2 days. The precipitated solid was
suspended in EtOH (1 L) immediately after filtration, and saturated NH3-EtOH solution (1 L) was then
added at 0 °C. The solvent was removed, after the mixture was stirred at 0 °C for 24 h. EtOH (500 mL)
was added to the residue then was evaporated to eliminate NH3 completely. The residue was slurried in
water (100 mL) to form a crude solid. After dried, this soild was treated with saturated HCl-EtOH
solution (1 L), and the mixture was stirred for 12 h. White solid was collected after filtration, washed with
EtOH (100 mL) and dried at 60 °C under vacuum to give 9-HCl as an off-white solid (58.2 g, yield: 64%,
1
purity by HPLC 99.2%, retention time: 5.0 min). Mp 172−174 °C. H NMR (DMSO-d6, 400 MHz):  =
1.34 (t, J = 7.2 Hz, 3H), 3.88 (s, 3H), 4.32 (q, J = 7.2 Hz, 2H), 4.74 (d, J = 5.2 Hz, 2H), 6.90 (d, J = 9.2
Hz, 2H), 7.57 (t, J = 5.2 Hz, 1H), 7.66−7.69 (m, 3H), 7.89 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 8.20 (d, J = 1.6
13
Hz, 1H), 8.70 (s, 2H), 8.91 (s, 2H); C NMR (DMSO-d6, 100 MHz):  = 14.7, 30.7, 60.9, 110.5, 112.2,

HETEROCYCLES, Vol. 87, No. 8, 2013
1707
113.6, 120.8, 123.7, 123.9, 130.2, 139.8, 141.6, 153.6, 154.5, 164.9, 166.7 (one carbon-peak at high field
was hidden in the peaks of DMSO)15; ESI-MS (m/z) 352 [M + H]+.
Ethyl
2-[[4-[(n-hexyloxycarbonyl)aminoiminomethyl]phenylamino]methyl]-1-methyl-1H-
benzimidazole-5-carboxylate (2).
To the mixture of 9-HCl (58.2 g, 0.15 mol) and Et3N (151.6 g, 1.5 mol) in DCM (1.5 L) was added
n-hexyl chloroformate (123.5 g, 0.75 mol). The insoluble solid was removed by filtration after the
mixture was refluxed for 2 h. The filtrate was washed with water (1 L), dried with anhydrous Na2SO4,
filtered and concentrated to afford oil. The oil was distilled under vacuum at 1 mmHg to remove the
excessive n-hexyl chloroformate. The residue was finally crystallized in EtOAc (400 mL) to give 2 as a
white solid after dried at 40 °C under vacuum (42.4 g, yield: 59%, purity by HPLC 99.3%, retention time:
20.2 min). Mp 107−109 °C. 1H NMR (DMSO-d6, 400 MHz):  = 0.86 (t, J = 7.2 Hz, 3H), 1.28−1.36 (m,
9H), 1.58 (t, J = 7.2 Hz, 2H), 3.87 (s, 3H), 3.98 (t, J = 6.8 Hz, 2H), 4.32 (q, J = 7.2 Hz, 2H), 4.68 (d, J =
5.6 Hz, 2H), 6.81 (d, J = 9.2 Hz, 2H), 7.05 (t, J = 5.2 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.4
Hz, 2H), 7.89 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 8.66 (br s, 1H), 9.18 (br s, 1H); 13C NMR (DMSO-d6, 100
MHz):  = 14.3, 14.6, 22.5, 25.7, 29.0, 30.4, 31.5, 60.9, 64.6, 110.3, 111.9, 120.9, 121.7, 123.7, 123.9,
129.7, 139.9, 141.9, 152.0, 154.7, 164.8, 166.7, 167.0 (one carbon-peak at high field was hidden in the
peaks of DMSO)15; ESI-MS (m/z) 480 [M + H]+. Anal. Calcd for C26H33N5O4: C, 65.12; H, 6.94; N,
14.60. Found: C, 65.23; H, 6.89; N, 14.51.
Ethyl 3-[(2-methyl-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate (4).
A solution of 5 (102.7 g, 0.3 mol) in HOAc (1 L) was refluxed for 12 h. Saturated aq sodium hydrogen
carbonate (500 mL), EtOH (2 L) were successively added after HOAc was evaporated, when stirring to
produce a gray solid. This gray solid was collected after filtration, washed with water (500 mL) and EtOH
(500 mL) and dried at 60 °C under vacuum to give 4 (82.5 g, yield: 75%, purity by HPLC 99.6%,
retention time: 4.5 min). Mp 169−171 °C. 1H NMR (DMSO-d6, 400 MHz):  = 1.12 (t, J = 7.2 Hz, 3H),
2.47 (s, 3H), 2.68 (t, J = 7.2 Hz, 2H), 3.67 (s, 3H), 3.97 (q, J = 7.2 Hz, 2H), 4.23 (t, J = 7.2 Hz, 2H), 6.85
(d, J = 8.0 Hz, 1H), 7.10−7.14 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.53 (dt, J = 8.0, 1.6 Hz, 1H), 8.40 (dd, J
= 4.8, 1.2 Hz, 1H); 13C NMR (CD3CO2D,16 100 MHz):  = 11.3, 13.5, 30.7, 32.7, 45.4, 60.9, 111.5, 115.8,
123.0, 123.5, 125.4, 131.4, 132.7, 134.1, 139.7, 148.6, 153.9, 154.8, 170.5, 172.2; ESI-MS (m/z) 367 [M
+ H]+. Anal. Calcd for C20H22N4O3: C, 65.56; H, 6.05; N, 15.29. Found: C, 65.69; H, 5.99; N, 15.10.
Ethyl
3-[[2-[(4-carbamimidoyl-phenylamino)-methyl]-1-methyl-1H-benzimidazole-5-carbonyl]-
pyridin-2-yl-amino]-propionate (3).
10 (2.40 Kg, 4 mol, synthesized from 5 mol of 6 with the same method mentioned above) was dissolved
in 7 mol/L HCl-EtOH solution (22.8 L) at 5−10 °C, and the mixture was stirred at 5−10 °C for 30 h.
Subsequently, 4.5 mol/L NH3-EtOH solution (44 L) was added slowly at 0 °C, and the mixture was
stirred for 24 h at 0 °C. After the solid was removed by filtration, the filtrate was concentrated to afford

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HETEROCYCLES, Vol. 87, No. 8, 2013
oil, which was then dissolved in a mixture of EtOH (10 L) and the solution of K2CO3 (828 g, 6 mol) in
H2O (2 L). The mixture was stirred at 25 °C for 24 h, then concentrated to 20% of the total volume. Solid
was precipitated when H2O (5 L) was added. This white solid was collected and dried at 70 °C under
vacuum to give 3 (1.70 Kg, yield: 85%, purity by HPLC 98.7%, retention time: 5.5 min). Mp 268−270 °C.
1H NMR (DMSO-d6, 400 MHz):  = 1.12 (t, J = 7.2 Hz, 3H), 2.68 (t, J = 7.2 Hz, 2H), 3.78 (s, 3H), 3.97
(q, J = 7.2 Hz, 2H), 4.23 (t, J = 7.2 Hz, 2H), 4.63 (s, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.0 Hz,
1H), 7.11−7.16 (m, 2H), 7.34 (br, s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 0.8 Hz, 1H), 7.55 (dt, J =
8.0 Hz, 2.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 8.39 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 8.72 (br s, 2H); 13C NMR
(DMSO-d6, 100 MHz):  = 14.4, 30.6, 33.5, 44.8, 60.5, 110.0, 112.1, 113.5, 120.0, 121.8, 122.5, 123.3,
129.7, 130.2, 137.7, 138.4, 141.2, 149.1, 153.5, 153.9, 156.4, 164.9, 170.8, 171.5 (one carbon-peak at
high field was hidden in the peaks of DMSO)15; ESI-MS (m/z) 500 [M + H]+.
Dabigatran etexilate (1).
All the solvents as well as regents were dried in advance. To the mixture of 3 (1.70 Kg, 3.4 mol) and Et3N
(687.0 g, 6.8 mol) in DCM (16 L) was added n-hexyl chloroformate (625.0 g, 3.8 mol). The mixture was
refluxed for 3 h, then cooled to 10 °C and washed with water (10 L) and brine (10 L) successively at that
temperature. The separated organic layer was dried with anhydrous Na2SO4, filtered and concentrated to
afford oil. The oil was dissolved in a refluxed EtOAc (10 L) to give a solid when cooled down. This solid
was dried at 50 °C under vacuum to give 1 as a white solid (1.64 Kg, yield: 77%, purity by HPLC 99.9%,
retention time: 19.1 min). Mp 127−128 °C (lit. mp 128−129 °C).4b 1H NMR (DMSO-d6, 400 MHz):  =
0.87 (t, J = 6.4 Hz, 3H), 1.12 (t, J = 7.2 Hz, 3H), 1.25−1.35 (m, 6H), 1.54−1.61 (m, 2H), 2.68 (t, J = 6.8
Hz, 2H), 3.77 (s, 3H), 3.90−4.00 (m, 4H), 4.22 (t, J = 6.8 Hz, 2H), 4.60 (d, J = 4.8 Hz, 2H), 6.76 (d, J =
8.4 Hz, 2H), 6.89 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 4.4 Hz, 1H), 7.10−7.18 (m, 2H), 7.40 (d, J = 8.4 Hz,
1H), 7.47 (s, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 8.37−8.40 (m, 1H), 8.65 (br s, 1H) ,
9.14 (br s, 1H); 13C NMR (CDCl3, 100 MHz):  = 14.0, 14.1, 22.5, 25.6, 28.9, 29.7, 31.5, 33.3, 40.5, 44.7,
60.5, 65.3, 108.8, 111.9, 120.1, 121.1, 122.4, 122.8, 123.5, 129.1, 129.7, 137.2, 137.4, 141.0, 148.9, 150.5,
152.5, 156.0, 165.0, 167.7, 171.0, 171.6; ESI-MS (m/z) 628 [M + H]+. Anal. Calcd for C34H41N7O5: C,
65.05; H, 6.58; N, 15.62. Found: C, 65.13; H, 6.65; N, 15.50.
Ethyl 3-[[2-[[ethoxy(imino)methyl-phenylamino]-methyl]-1-methyl-1H-benzimidazole-5-carbonyl]-
pyridin-2-yl-amino]-propionate (11).
10 (6.0 g, 0.01 mol) was dissolved in 7 mol/L HCl-EtOH solution (57 mL) at 5−10 °C, and the mixture
was stirred at 5−10 °C for 30 h. Saturated aq sodium hydrogen carbonate (300 mL) was slowly added at
0 °C, then EtOAc (300 mL) was added, and the separated water layer was extracted with EtOAc (150 mL)
again. The combined organic layer was washed with brine (150 mL), dried with anhydrous Na2SO4,
filtered and concentrated to afford a crude sample. This crude sample was purified via silica gel column
chromatography using DCM and MeOH (from 1:10 to 1:1) as eluent to give recovered free base of 10

HETEROCYCLES, Vol. 87, No. 8, 2013
1709
first (0.29 g, yield: 6%) and then 11 (4.7 g, yield: 89%) as a yellow foam-solid. Mp 105−108 °C. 1H NMR
(DMSO-d6, 400 MHz):  = 1.12 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 6.8 Hz, 3H), 2.68 (t, J = 7.2 Hz, 2H), 3.77
(s, 3H), 3.97 (q, J = 7.2 Hz, 2H), 4.23 (t, J = 7.2 Hz, 2H), 4.29 (q, J = 7.2 Hz, 2H), 4.60 (d, J = 5.6 Hz,
2H), 6.79 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.4 Hz, 1H), 7.10−7.18 (m, 3H), 7.40 (d, J = 8.8 Hz, 1H), 7.47
(d, J = 1.2 Hz, 1H), 7.54 (dt, J = 8.0 Hz, 1.6 Hz, 1H), 7.69 (d, J = 8.8 Hz, 2H), 8.40 (dd, J = 8.8 Hz, 1.2
13
Hz, 1H), 9.59 (br s, 1H); C NMR (DMSO-d6, 100 MHz):  = 14.4, 14.4, 30.4, 33.5, 44.8, 60.5, 63.8,
109.9, 112.2, 116.9, 120.0, 121.7, 122.6, 123.3, 129.6, 129.8, 137.7, 138.3, 141.3, 149.2, 152.3, 154.1,
156.5, 167.4, 170.8, 171.5 (one carbon-peak at high field was hidden in the peaks of DMSO)15; ESI-MS
(m/z) 529 [M + H]+. Anal. Calcd for C29H32N6O4: C, 65.89; H, 6.10; N, 15.90. Found: C, 65.99; H, 6.21;
N, 15.83.
ACKNOWLEDGEMENTS
We thank Prof. Dr. Dawei Ma for his generous support and constant encouragement. We are also grateful
for the cooperation from the colleagues of analytic department.
REFERENCES AND NOTES
1. European Medicines Agency. CHMP assessment reports for pradaxa [2011-08-23].
http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/hum
an/000829/WC500041060.pdf
2. M. Sanford and G. L. Plosker, Drugs, 2008, 68, 1699.
3. N. Hauel, U. Ries, H. Priepke, W. Wienen, and J. M. Stassen, W. O. patent 9837075, 1998; CAN
129:216617.
4. (a) N. Hauel, H. Priepke, U. Ries, J. M. Stassen, and W. Wienen, U.S. patent 6,087,380, 2000; CAN
129:189325; (b) N. H. Hauel, H. Nar, H. Priepke, U. Ries, and J. M. Stassen, J. Med. Chem., 2002,
45, 1757; (c) P. Lustig and J. Jirman, W. O. patent 2010045900, 2010; CAN 152:501376; (d) G.
Zerban, A. Hausherr, R. Hamm, G. Koch, K. Schlarb, H. P. Schmitt, and B. Weyell, W. O. patent
2007071743, 2007; CAN 147:118241.
5. R. M. Satyanarayana, C. Nagaraju, R. S. Thirumalai, S. Eswaraiah, R. A. Kodanda, and S.
Raghuram, W. O. patent 2012077136, 2012; CAN 157:104681.
6. ICH Q3A Impurities in New Drug Substances, R2; International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH): Geneva,
Switzerland, October 2006;
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3A_R2/Step4/Q
3A_R2__Guideline.pdf.

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7. The crude compound 1 synthesized according to the method listed in references 3 and 4 was tried for
purification. After screening of the solvent, EtOAc was proved to be best. HPLC showed that the
three main impurities: impurity 4 (0.21%), impurity 3 (0.13%) and impurity 2 (0.82%) still existed
after three recrystallization of crude 1 in EtOAc. On the contrary, our process for 1 was shown to be
well impurities-controlled even just detected for the reaction mixture before purification. Finally,
high purity was obtained through only one recrystallization in EtOAc. For detailed HPLC spectrum,
Please see supporting information.
8. M. J. Serra, L. E. Duran, and L. Rao, W. O. patent 2012152855, 2012; CAN 157:708589.
9. For example, when compound 1 with 0.05% of impurity 3 was dissolved in dried DCM, the content
of 3 kept unchanged after 24 h, so did 3 in DCM which was mixed with 50% (v/v) H2O below 10 °C
after 24 h. However, 3 was increased to about 0.5% at 40 °C after 24 h in above-mentioned mixed
solvent. It showed that it was necessary for drying the solvents and reagents in advance to avoid the
hydrolysis of 1 in the reaction or purification course because of heating.
10. R. Goger and D. G. Neilson, Chem. Rev., 1961, 61, 179.
11. Impurity 4 was decreased from 7.83% to 0.71% by HPLC in the reaction mixture after the
ring-closing was finished, when 1 equiv of HOAc was used at 70 °C instead of excessive HOAc as
the solvent at refluxed temperature.
12. If the ring-closing took place in HOAc as solvent according to the known process, at least three
times recrystallization was necessary for 10 to eliminate impurity 4 completely, even if in the form
of succinic acid.
13. J. Jirman, J. Richter, and P. Lustig, W. O. patent 2009111997, 2009; CAN 151:358757.
14. The detailed operation for the represented example was shown in supporting information.
15. Our compounds had little solubility in most solvents but DMSO, so DMSO-d6 was used as
deuterated solvent. However, the “lack” of one carbon-peak at high field was observed for most
compounds. The peak of NHC was supposed to be hidden in the peaks of DMSO. Luckily,
dabigatran etexilate (1) was easily dissolved in CDCl3. Instead of 13CNMR in DMSO-d6, the
“missing” carbon appeared in CDCl3. Please see Supporting Information.
16. Compound 4 was little soluble in almost all the solvents except HOAc, so 13C NMR had to be run in
CD3CO2D to get a good spectra. Compound 4 might exits in the form of salt in CD3CO2D.