PROCESS FOR THE PREPARATION OF DABIGATRAN ETEXILATE OR
PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
Field of the Invention
The.present invention provides hydrobromide salt of dabigatran etexilate and its process
for the preparation. 'I'he present invention further provides crystalline Form 1 and crystalline
Form I1 of hydrobromide salt of dabigatran etexilate and processes for their preparation. The
present invention further relates to a process for the preparation of pharmaceutically acceptable
salts, including methanesiilfoiiate salt, of dabigatran etexilate using hydrobromide salt of
dabigatran etexilate of the present invention.
Background of the Invention
The drug substance used in the commercial drug product formulation of pradaxaB is the
methanesulfonate salt of dabigatran .etexilate, which is chemically described as P-Alanine, N-
[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]- 1 -methyl- 1 Hbenzimidazo1-
5-y1]carbony1]-N-2-pyridiny1-ethe1s ter, methanesulfonate salt of Formula I.
FORMULA I
Dabigatran etexilate of Formula I1
FORMULA I1
is a prodrug of dabigatran of Formula I11
FORMULA I11 0
which is adirect thrombin inhibitor. Dabigatran etexilate 'is indicated to reduce the risk of stroke
and systemic embolism in patients with non-valvular atrial fibrillation. It may be used alone or
in combination with other therapeutic agents.
Processes for the preparation of dabigatran etexilate or its different salts are described in
U.S. Patent No. 6,087,380; European Patent Publication No. EP 1870100 (equivalent to CA
2,476,054); and PCT Publication Nos, WO 200611 14415 (equivalent to US 2006/0247278), WO
20081043759, WO 20121044595, WO 20121027543, WO 20081059029, WO 201 111 10876, WO
201 111 10478, and WO 20061131491 (equivalent to US 20061276513).
Summary of the Invention
The present invention provides the hydrobromide salt of dabigatran etexilate and its
process for the preparation. The present invention' further provides crystalline Form I and
crystalline Form I1 of hydrobromide salt of dabigatran etexilate and processes for their
preparation. The present invention further relates to a process for the .preparation of
pharmaceutically acceptable salts, including the methanesulfonate salt, of dabigatran etexilate
using hydrobromide salt of dabigatran etexilate of the present invention.
I P Q D E L H I 30-03-261 5 17 149
3
Brief Description of the Drawings
Figure 1 depicts the X-ray powder diffraction (XRPD) pattern of the crystalline Form I
of hydrobromide salt of dabigatran etexilate obtained according to Example 1.
Figure 1A provides the XRPD pattern of the crystalline Form I of hydrobromide salt of
dabigatran etexilate depicted in Figure 1.
Figure 2 depicts the XRPD pattern of the crystalline Form I1 of hydrobromide salt of
dabigatran etexilate obtained according to Example 2.
Figure 2A provides the XRPD pattern of the crystalline Form I1 of hydrobromide salt'of
dabigatran etexilate depicted'in Figure 2.
Detailed Description of the Invention
A first aspect of the present invention provides the hydrobromide salt of dabigatran
etexilate salt of Formula IV.
r0 . HBr
FORMULA IV
A second aspect of the present invention provides a process for the preparation of-the
hydrobromide salt of dabigatran etexilate, wherein the process comprises:
a) contacting. ethyl N-[(2- { [(4-carbamimidoylphenyl)arnino]methyl) - 1 -methyl-3a,7adihydro-
dihydro- 1H -benzimidazol-5-yl)carbonyl]-N-pyridin-2-yl--alaninaotfe F ormula V
or its salt with n-hexyl chloroformate;
b) treating the reaction mixture obtained in step a) with hydrobromic acid; and
c) isolating hydrobromide salt of dabigatran etexilate of compound of Formula IV
from the mixture thereof. '
The ethyl N-[(2-{[(4-carbami~idoylphenyl)amino]methyl) - 1 -methyl-3a,7a-dihydro- 1 Hbenzimidazol-
5-yl)carbonyl]-N-pyridin-2-yl-~-alaninatoef Formula V, or its salt may be
prepared according to methods provided in literature, for example, U.S. Patent No. 6,087,380.
The salts of compound of ethyl N-[(2- {[(4-carbamimidoylphenyl)a'mino]methyl) - 1 -
methyl-3a,7a-dihydro- 1H -benzimidazol-5-yl)carbonyl]-N-pyridin-2-yl--alaninaotef Formula V
may be selected from hydrochloride, hydrobromide, or acetate salt. Preferably, the salt of
compound of Formula V is an acetate salt.
The compound of Formula V or its salt is contacted with n-hexyl chloroformate in the
presence of a solvent selected from the group consisting of water, ethers, halogenated
hydrocarbons, esters, or mixtures thereof. The ether solvent may be selected from the group
cdmprising tetrahydrofuran, diisopropyl ether, or methyl t-butyl ether. The halogenated
hydrocarbon solvent may be dichloromethane. The ester solvent may be ethyl acetate.,
Preferably, the solvent is tetrahydrofuran, either alone or in combination with water. The nhexyl
chloroformate may be used either as a solid or in solution form with tetrahydrofuran.
The compound of Formula V or its salt is contacted with the n-hexyl chloroformate in
the presence of an organic or inorganic base. The organic base may be selected from the group
comprising ethylamine or diisopropyl ethyl amine. The inorganic base may be selected from the
group comprising sodium carbonate or potassium carbonate. Preferably, the base is potassium
carbonate.
The compound of Formula V or its salt is contacted with the n-hexyl chloroformate at a
temperature of about 1 0 0 t~o about 40°C, for example, about 15OC to about 25OC. The
compound of Formula V or its salt may be contacted with'n-hexyl chloroformate for about 3
hours to about 6 hours, for example, about 4 hours to about 6 hours.
The reaction mixture may be subjected to carbon treatment. The reaction mixture may
optionally be treated with butylated hydroxytoluene. The solvent may be recovered from the
reaction mixture and the reaction mixture used as such for the next step.
The reaction mixture obtained in step a) is treated with hydrobromic acid in the presence
of a solvent selected from the group consisting of ketones, esters, alcohols, or mixtures thereof.
The ketone solvent may be selected from the group comprising acetone, methyl butyl ketone, or
methyl' isopropyl ketone. 'l'he ester solvent may be selected from the group comprising ethyl
acetate, isopropyl acetate, or butyl acetate. The alcohol solvent may be selected from the group
comprising ethanol, methanol, n-propanol, or butanol. Preferably, the solvent is acetone. The
hy'drobromic acid may be used as a solid or in solution form with acetone.
The reaction mixture obtained in step a) is treated with hydrobromic acid at a
temperature of about 10°C to about 40°C, for example, about 15°C to about 25°C. The reaction
mixture obtained in s'tep a) is treated with hydrobromic acid for about 3 hours to about 6 hours,
for example, about 4 hours to about 6 hours.
The hydrobromide salt of dabigatran etexilate may be isolated by filtration, decantation,
evaporation, distillation or a combination thereof. The hydrobromide salt of dabigatran etexilate
has substantially the same X-ray powder diffraction (XRPD) pattern as depicted in Figure 1, and
is referred to herein as crystalline Form I of the hydrobromide salt of dabigatran etexilate.
A third aspect of the present invention provides crystalline Form I of the hydrobromide
salt of dabigatran etexilate.
The crystalline Form I of the hydrobromide salt of dabigatran etexilate has substantially
the same XRPD pattern as depicted in Figure 1. The crystalhe Form I of the hydrobromide salt
of dabigatran etexilate salt of Formula IV is characterized by an XRPD pattern having
interplanar spacing (d) values substantially at 18.55, 4.89, 4.54, 4.03, and 3.80 A. The
crystalline Form I of the hydrobromide salt of dabigatran etexilate salt of Formula IV is further
characterized by an XRPD pattern having interplanar spacing (d) values substantially at 18.55,
12.32, 10.30, 8.94, 7.46, 6.66, 5.55,4.89,4.54,4.03, 3.80, 3.64, and 3.17 A.
A fourth aspect of the present invention provides a process for the purification of the
hydrobromide salt of dabigatran etexilate, wherein the process comljrises:
a) treating .the hydrobromide salt of dabigatran etexilate of Formula IV with an
alcohol solvent; and
b) isolating the purified hydrobromide salt of dabigatran etexilate of Formula IV from
the mixture thereof.
The alcohol solvent used for purification may be selected from the group comprising
methanol, ethanol, isopropanol, n-propanol, or mixtures thereof. Preferably, the alcohol solvent
is ethanol. The hydrobromide salt of dabigatran etexilate is treated with an alcohol solvent at a
temperature of about 10°C to about 70°C, for example, about 20°C to about 60°C. The
hydrobromide salt of dabigatran etexilate is treated with an alcohol solvent for about 2 hours to
about 6 hours, for example, about 3 hours to about 4 hours.
The purified hydrobromide salt of dabigatran 'etexilate may be isolated by filtration,
decantation, evaporation, distillation, or combinations thereof. The purified hydrobromide salt
of dabigatran etexilate has substantially the same XRPD pattern as depicted in Figure 2, and is
referred to herein as crystalline Form I1 of hydrobromide salt of dabigatran etexilate.
A fifth aspect of the present invention provides crystalline Form I1 of hydrobromide salt
of dabigatran etexilate.
The ~ r ~ s t a l l i n e ~ oI1r omf hydrobromide salt of dabigatran etexilate has substantially the '
same XRPD pattern as depicted in Figure 2. The crystalline Form I1 of hydrobromide salt -of
dabigatran etexilate is characterized by an XRPD pattern having interplanar spacing (d) values
substantially at 19.44, 8.03, 4.8 1, 4.69, 4.5 1, 4.37, 4.24, 3.97, 3.77, and 3.52 A. The crystalline
Form I1 of themhydrobromides alt of dabigatran etexilate is further characterized by an XRPD
pattern having interplanar spacing (d) values substantially at 26.45, 19.44, 17.83, 13.56, 10.88,
9.83, 8.97, 8.03, 7.14, 6.54, 6.42, 5.88, 5.61, 5.46,.5.38, 5.25, 5.'10, 4.81, 4.69, 4.51, 4.37, 4.24,
4.09, 4.03, 3.97, 3.88, 3.77, 3.61, 3.52, 3.48, 3.44, 3.40, 3.37, 3.26, 3.17, 3.01, 2.98, 2.90, 2.83,
2.66,2.58,2.55,2.51, 2.42, and 2.37 A.
A sixth aspect of'the present invention provides a process for the preparation of the
methanesulfonate salt of dabigatran etexilate, wherein the process comprises:
a) treating the , hydrobromide salt of dabigatran etexilate of Formula IV with
methanesulfonic acid; and
b) ' isolating the methanesulfonate salt of dabigatran etexilate from the mixture thereof.
The hydrobromide salt of dabigatran etexilate of Formula IV may be treated with a
suitable acid to prepare the pharmaceutically acceptable salts of dabigatran etexilate.
Pharn~aceutically acceptable salts of dabigatran etexilate may be, for example, the
methanesulfonate salt of dabigatran etexilate. The hydrobromide salt ,of dabigatran etexilate of
Formula IV is treated with a solvent and a base before treating with methanesulfonic acid. The
solvent may be selected from the group consisting halogenated hydrocarbons, esters, ketones,
alcohols, or mixtures thereof. The halogenated hydrocarbon may be dichloromethane. The ester
solvent may be selected from the group comprising ethyl acetate, isopropyl acetate, or butyl
acetate. The ketone solvent may be selected from the group comprising acetone, methyl butyl
ketone, or methyl isopropyl ketone. The alcohol solvent may be selected from the group
comprising ethanol, methariol, n-propanol, or butanol. Preferably, the solvent is
dichloromethane, ethyl acetate, or a mixture thereof.
The base may be an inorganic base or an organic base. The inorganic base may be, for
example, sodium carbonate or potassium carbonate. The organic base may be, for example,
ethyl amine, isopropyl amine;or diisopropylethyl amine. Preferably, the base is sodium
carbonate or potassium carbonate. The hydrobromide salt of dabigatran etexilate of Formula IV
is treated with a solvent and a base at a temperature of about 10°C to about 80°C, for example,
about 20°C to .about 60°C. h he hydrobromide salt of dabigatran etexilate of Formula. IV is
treated with a solvent and a base for about 30 minutes to about 3 hours, for example, about 1
hour to about 2 hours.
The hydrobromide salt of dabigatran etexilate of Formula IV may be treated with
methanesulfbnic acid in the presence of a solvent selected from the group consisting of ketones,
esters, alcohols, or mixtures thereof. The ketone solvent may be selected from the group
comprising acetone, methyl butyl ketone, or methyl isopropyl ketone. The ester solvent may be
selected from the 'group comprising ethyl acetate, isopropyl acetate, or butyl acetate. The
alcohol solvent may be selected from the group comprising ethanol, methanol, n-propanol, or
butanol. Preferably, the solvent is ethyl acetate. The methanesulfonic acid may be used as a
solid or in the solution form with ethyl acetate.
The hydrobromide salt of dabigatran etexilate is treated with methanesulfonic acid at a
temperature of about 10°C to about 60°C, for example, about 20°C to about 50°C. The
hydrobromide salt of dabigatran etexilate is treated with methanesulfonic acid for about 3 hours
to about 6 hours, for example, about 4 hours to about 6 hours.
The methanesulfonate salt of dabigatran etexilate may be isolated by filtration,
decantation, evaporation, distillation, or combinations thereof. The methanesulfonate salt of
dabigatran etexilate prepared by the present invention may be characterized by XRPD pattern.
I P O DELHI 30-83-2015 17 149
8
The XRPD of the samples were determined by using a PANalytical XYPert PRO X-Ray
Powder Diffractometer in the range 3-40 degree 2 theta and under tube voltage and current of 45
Kv and 40 mA respectively. Copper radiation of wavelength 1.54 angstrom and XYCelerator
detector was used.
While the present invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those skilled in the art and are intended
to be included within the scope of the present invention.
EXAMPLES
Example 1 : Preparation of dabigatran etexilate hydrobromide salt
h he acetate salt of ethyl ~-[(2-{[(4-carbamimido~l~hen~l)ami&]meth~l}-l-meth~l-
3a,7a-dihydro-lH-benzimidazol-5-yl)carbonyl]-N-pyridin-2-yl-~-alanin(a5t0e g) was added to
tetrahydrofuran (750 mL) and deionized water (250'mL) and the reaction mixture was stirred for
20 minutes. Potassium carbonate (37.08 g) was added to the reaction mixture and the reaction
mixture was stirre'd for 30 minutes. A solution'of n-hexyl chloroformate (16.19 g) dissolved in
tetrahydrofuran (250, mL) was added to the reaction mixture at 18°C to 20°C. The reaction
mixture was stirred for 2 hours at 20°C to 22°C. The tetrahydrofuran layer was collected.
Potassium carbonate (40 g) was addedto the reaction mixture, and the reaction mixture was
stirred for 30 minutes.
The layers obtained were separated and the tetrahydrofuran layer was used further.
Carbon (5 g) was added to the reaction mixture and stirred for 20 minutes. The reaction mixture
was filtered through celite. The tetrahydrofuran layer was collected and butylated
hydroxytoluene (BHT) (0.5 g) was added to the reaction mixture. The solvents were recovered
under vacuum. Acetone (150 mL) was added to the reaction mixture and stirred for 20 minutes,
The acetone was recovered under vacuum. The solid obtained was dissolved in acetone (392
mL). A solution of 45% hydrobromic acid (15.24 g) in acetone (56 mL) was added to the
reaction mixture at 18°C to 20°C. The reaction mixture was stirred at 20°C to 22°C for 2 hours,
filtered, and dried under suction. The reaction mixture was further dried under vacuum at 55°C
for 15 hours to obtain the title compound having XRPD data as depicted in Figure 1.
Yield: 42 g
EPO DELHI, 250-63-2615 17 '. 49
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Example 2: Purification of dabigatran etexilate hydrobromide salt
Dabigatran etexilate hydrobromide salt (40 g) obtained in Example 1 was dissolved in
ethanol (280 mL) at 55°C for 15 minutes to 20 minutes. Thc rcaction misturc was coolcd to
10°C to 15°C for 20 minutes. The reaction mixture was stirred for 2 hours at 20°C, filtered and
dried under suction. The reaction mixture was washed with ethanol (50 mL), and then dried
under vacuum at 55°C for 15 hours to obtain the title compound having XRPD data as depicted
in Figure 2.
Yield: 42 g
'H NMR (400 MHz, CDC13): 6 0.86-0.89 (t,3H), 1.10-1.13 (t,3H), 1.29-1.30 (m,6H), 1.65-1.67
(m,2H), 2.66-2.69 (t,2H), 3.78 (s,3H), 3.94-3.99 (t,2H), 4.20-4.27 (m,4H), 4.69-4.70 (d,2H),
6.86-6.89 (m,3H), 6.91-7.17 (m,2H), 7.41-7.43 (m,2H), 7.47 (t,lH), 7.55-7.66 (dt,3H), 8.37-8.39
(dd,lH), 10.0 (s,lH), 10.65 (bs,lH), 11.90 (bs,lH)
Example 3 : Preparation of dabigatran etexilate methanesulfonate salt
Dabigatran etexilate hydrobromide salt (35 g) was dissolved in dichloromethane (350
mL) at 25°C. A 5% aqueous sodium carbonate solution (210 mL) was added to the reaction
mixture and stirred for 10 minutes. The dichloromethane layer was separated and the
dichloromethane was recovered under vacuum. Ethyl acetate (550 mL) was added to the
reaction mixture and stirred for 10 minutes. Methane sulphonic acid solution (3.99 g methane
sulphonic acid dissolved in 55 mL ethyl acetate) was added to the reaction mixture drop-wise at
20°C to 25°C. The reaction mixture was stirred at 20°C to 25°C for 2 hours. The reaction
mixture was filtered under vacuum and washed with ethyl acetate (27 mL). The solid obtained
was dried under vacuum at 55°C for 14 hours to 15 hours to obtain the title compound.
Yield: 29.75 g

WE CLAIM:
1. A hydrobromide salt of dabigatran etexilate salt of Formula IV.
2. A process for the preparation of a hydrobromide salt of dabigatran etexilate of Formula
, IVY wherein the process comprises:
a) contacting ethyl N-[(2-([(4-carbamimidoylphenyl)amino]methyl) - 1 -methyl-3a,7adihydro-
dihydro- 1H -benzimidazol-5-yl)carbonyl]-N-pyridin-2-yl--alaninaotef Formula V
'or its salt with n-hexyl chloroformate;
b) treating the reaction mixture obtained in step a) with hydrobromic acid; and
c) isolating hydrobromide salt of dabigatran etexilate of Formula IV from the mixture
thereof.
3. The process according to claim 2, wherein the salt of compound of ethyl N-[(2-{[(4-
carbainimidoylphenyl)amino]methyl)- 1 -methyl-3a,7a-dihydro- 1 H-benzimidazol-5-
yl)carbonyl]-~-pyridin-2-yl-~-alaninoaft eF ormula V is selected from h. y.d rochloride,
hydrobromide, or acetate salts.
4. The process according to claim .2, wherein the compound of or mu la V or its salt is
contacted with n-hexyl chloroformate in the presence of a solvent selected from the
group consisting of water, ether, halogenated hydrocarbon, ester, or mixtures thereof.
5. .The process according to claim 2, wherein the compound of c or mu la V or its salt is
contacted with n-hexyl chloroformate in the presence of a base.
6. The process according to claim 2, wherein the reaction mixture obtained in step a) is
treated with hydrobromic acid in the presence of a solvent selected from the group
consisting of ketones, esters, alcohols, or mixtures thereof.
LBO D E L H I 5 8 - 6 3 - 2 0 1 5 17:49
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7. A process for the purification of a hydrobromide salt of dabigatran etexilate, wherein the
process comprises:
a) treating hydrobromide salt of dabigatran etexilate of Formula IV with an alcohol
solvent; and
b) isolating purified hydrobromide salt of dabigatran etexilate of Formula IV from the
mixture thereof.
8. A process for the preparation of a methane sulfonate salt of dabigatran etexilate, wherein
the process comprises:
a) treating hydrobromide salt of dabigatran etexilate of Formula IV with
methanesulfonic acid; and
b) ' isolating the methanesulfonate salt of dabigatran etexilate from the mixture thereof. . -
9. The process according to claim 8, wherein the hydrobromide salt of dabigatran etexilate
of Formula IV is treated with a solvent and a base before treating with methanesulfonic
acid.
10. The process according to claim 8, wherein the hydrobromide salt of dabigatran etexilate .
of Formula IV is treated with methanesulfonic acid in the presence of a solvent selected
from the group consisting of ketones, esters, alcohols, or mixtures thereof.