PROCESS FOR THE PREPARATION OF DABIGATRAN ETEXILATE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
Field of the Invention
The present invention relates to a process for the preparation of dabigatran
etexilate. The present invention also relates to trifluoroacetate salt of dabigatran etexilate
and a process for its preparation. The present invention further relates to crystalline Form
I and crystalline Form II of trifluoroacetate 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.
Background of the Invention
The drug substance used in the commercial drug product formulation of Pradaxa®
is the methanesulfonate salt of dabigatran etexilate, which is chemically designated as b-
Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-lmethyl-
lH-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate salt
of Formula I .
FORMULA I
Dabigatran etexilate of Formula II
FORMULA II
is an etexilate prodrug of dabigatran ethyl ester of Formula III
FORMULA III
which is a prodrug of dabigatran of Formula IV
FORMULA IV
which is a direct 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 1 870 100
(equivalent to CA 2,476,054); and PCT Publication Nos. WO 2006/1 14415 (equivalent to
US 2006/0247278), WO 2008/043759, WO 2012/044595, WO 2012/027543, WO
2008/059029, WO 201 1/1 10876, WO 201 1/1 10478, and WO 2006/13 1491 (equivalent to
US 2006/276513).
Summary of the Invention
The present invention relates to a process for the preparation of dabigatran
etexilate. The present invention also relates to trifluoroacetate salt of dabigatran etexilate
and a process for its preparation. The present invention further relates to crystalline Form
I and crystalline Form II of trifluoroacetate 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 methanesulfonate salt, of dabigatran etexilate.
Brief Description of the Drawings
Figure 1 depicts the X-ray powder diffraction (XRPD) pattern of the crystalline
Form I of trifluoroacetate salt of dabigatran etexilate obtained according to Example 3.
Figure 1A provides the XRPD pattern of the crystalline Form I of trifluoroacetate
salt of dabigatran etexilate depicted in Figure 1.
Figure 2 depicts the XRPD pattern of the crystalline Form II of trifluoroacetate salt
of dabigatran etexilate obtained according to Example 4.
Figure 2A provides the XRPD pattern of the crystalline Form II of trifluoroacetate
salt of dabigatran etexilate depicted in Figure 2.
Figure 3 depicts the XRPD pattern of the crystalline Form of methanesulfonate salt
of dabigatran etexilate obtained according to Example 6.
Figure 3A provides the XRPD pattern of the crystalline Form of methanesulfonate
salt of dabigatran etexilate depicted in Figure 3.
Detailed Description of the Invention
A first aspect of the present invention provides a process for the preparation of
acetic acid salt of dabigatran ethyl ester of Formula V
.CH3COOH
FORMULA V
wherein the process comprises:
a) reacting the compound of Formula VI
FORMULA VI
with the compound of Formula VII
FORMULA VII
to prepare the compound of Formula VIII;
FORMULA VIII
optionally isolating the compound of Formula VIII from the reaction mixture;
converting the compound of Formula VIII to the compound of Formula IX;
FORMULA IX
d) converting the compound of Formula IX to the acetic acid salt of dabigatran
ethyl ester of Formula V; and
e) isolating the acetic acid salt of dabigatran ethyl ester of Formula V from the
reaction mixture.
The compound of Formula VI and compound of Formula VII may be reacted in the
presence of a condensing agent and a solvent. The condensing agent may be selected from
the group comprising carbonyl diimidazole, phosgene, triphosgene, or mixtures thereof.
Preferably, the condensing agent is carbonyl diimidazole. The solvent may be selected
from the group consisting of ethers, ketones, esters, or mixtures thereof. The ether solvent
may be selected from the group comprising tetrahydrofuran and diisopropyl ether. The
ketone solvent may be selected from the group comprising acetone, ethyl methyl ketone
and ethyl butyl ketone. The ester solvent may be selected from the group comprising ethyl
acetate and propyl acetate. Preferably, the solvent is tetrahydrofuran. The compound of
Formula VI and compound of Formula VII may be reacted in the presence of butylated
hydroxyl toluene. The compound of Formula VI and the compound of Formula VII are
reacted at about 10°C to about 80°C, for example, about 20°C to about 60°C. The
compound of Formula VI and the compound of Formula VII are reacted for about 30
minutes to about 4 hours, for example, about 1 hour to about 3 hours. The compound of
Formula VIII obtained by the reaction of the compound of Formula VI and the compound
of Formula VII may optionally be isolated.
The compound of Formula VIII may be converted to the compound of Formula IX
in the presence of a cyclizing agent and a solvent. The cyclizing agent may be, for
example, acetic acid. The acetic acid may also act as a solvent. The solvent may be
selected from the group consisting of water, esters, alcohols, ketones, or mixtures thereof.
The alcohol solvent may be selected from the group comprising ethanol and 2-propanol.
The ketone solvent may be selected from the group comprising acetone, ethyl methyl
ketone, and ethyl butyl ketone. The ester solvent may be selected from the group
comprising ethyl acetate and propyl acetate. Preferably, the solvent is ethyl acetate, 2-
propanol, or mixtures thereof. The conversion of the compound of Formula VIII to the
compound of Formula IX is carried out at about 10°C to about 100°C, for example, about
20°C to about 90°C. The conversion of the compound of Formula VIII to the compound
of Formula IX is carried out for about 6 hours to about 25 hours, for example, about 10
hours to about 20 hours. The compound of Formula IX may optionally be isolated by
filtration, decantation, evaporation, distillation, or combinations thereof.
The compound of Formula IX may optionally be converted to the compound of
Formula X.
FORMULA X
The conversion of the compound of Formula IX to the compound of Formula X is
carried out in the presence of hydrochloric acid and a solvent. The solvent may be
selected from the group consisting of alcohols, amides, esters, or mixtures thereof. The
alcohol solvent may be selected from the group comprising ethanol and 2-propanol. The
amide solvent may be dimethyl formamide. The ester solvent may be selected from the
group comprising ethyl acetate and propyl acetate. Preferably, the solvent is
dimethylformamide, ethanol, or mixtures thereof. The conversion of the compound of
Formula IX to the compound of Formula X is carried out at about -20°C to about 60°C, for
example, about -10°C to about 50°C. The conversion of the compound of Formula IX to
the compound of Formula X is carried out in about 6 hours to about 25 hours, for example,
about 10 hours to about 20 hours.
The compound of Formula IX or compound of Formula X is converted to the
acetic acid salt of dabigatran ethyl ester of Formula V in the presence of ammonium
acetate, and a solvent. The solvent may be selected from the group consisting of water,
alcohols, ketones, esters, or mixtures thereof. The alcohol solvent may be selected from
the group comprising ethanol and 2-propanol. The ketone solvent may be selected from
the group comprising acetone and ethyl methyl ketone. The ester solvent may be selected
from the group comprising ethyl acetate and propyl acetate. Preferably, the solvent is
water, ethanol, acetone, or mixtures thereof. The conversion of the compound of Formula
IX or the compound of Formula X to the acetic acid salt of dabigatran ethyl ester of
Formula V is carried out at about 0°C to about 60°C, for example, about 5°C to about
50°C. The conversion of the compound of Formula IX or the compound of Formula X to
acetic acid salt of dabigatran ethyl ester of Formula V is carried out in about 1 hour to
about 25 hours, for example, about 10 hours to 20 hours.
The acetic acid salt of dabigatran ethyl ester of Formula V may exist in the form of
the mono-acetate or di-acetate. The acetic acid salt of dabigatran ethyl ester of Formula V
may be isolated by filtration, decantation, evaporation, distillation, or combinations
thereof.
A second aspect of the present invention provides a process for the preparation of
dabigatran etexilate of Formula II
FORMULA II
or a salt thereof wherein the process comprises:
a) reacting the compound of Formula VI
FORMULA VI
with the compound of Formula VII
FORMULA VII
to prepare the compound of Formula VIII;
FORMULA VIII
optionally isolating the compound of Formula VIII from the reaction mixture;
converting the compound of Formula VIII to the compound of Formula IX;
FORMULA IX
d) converting the compound of Formula IX to the acetic acid salt of dabigatran
ethyl ester of Formula V;
e) optionally isolating the acetic acid salt of dabigatran ethyl ester of Formula V
from the reaction mixture;
reacting the acetic acid salt of dabigatran ethyl ester of Formula V with a
reagent capable of providing an etexilate group; and
g) isolating the dabigatran etexilate of Formula II or a salt thereof from the
reaction mixture.
The compound of Formula VI and the compound of Formula VII may be reacted
as described in the first aspect. The compound of Formula VIII obtained by the reaction
of the compound of Formula VI and the compound of Formula VII may optionally be
isolated. The compound of Formula VIII may be converted to a compound of Formula IX
as described in the first aspect. The compound of Formula IX may optionally be isolated
by filtration, decantation, evaporation, distillation, or combinations thereof.
The compound of Formula IX may optionally be converted to the compound of
Formula X as described in the first aspect. The compound of Formula IX or the
compound of Formula X may be converted to the acetic acid salt of dabigatran ethyl ester
of Formula V as described in the first aspect.
The acetic acid salt of dabigatran ethyl ester of Formula V may exist in the form of
mono-acetate or di-acetate. The acetic acid salt of dabigatran ethyl ester of Formula V
may be isolated by filtration, decantation, evaporation, distillation, or combinations
thereof.
The acetic acid salt of dabigatran ethyl ester of Formula V is converted to
dabigatran etexilate of Formula II or its salt by contacting with a reagent capable of
providing an etexilate group and a solvent. Preferably, the salt of dabigatran etexilate is
trifluoroacetate salt. The reagent capable of providing the etexilate group may be n-hexyl
chloroformate. The solvent may be selected from the group consisting of water, ethers,
halogenated hydrocarbons, esters, ketones, or mixtures thereof. The ether solvent may be
selected from the group comprising tetrahydroiuran, diisopropyl ether, and methyl t-butyl
ether. The halogenated hydrocarbon solvent may be dichloromethane. The ester solvent
may be ethyl acetate. The ketone solvent may be selected from the group comprising
acetone and ethyl methyl ketone. Preferably, the solvent is tetrahydroiuran either alone, or
in combination with water. The n-hexyl chloroformate may be used either as a solid or in
solution form with tetrahydroiuran.
The acetic acid salt of dabigatran ethyl ester of Formula V is contacted with nhexyl
chloroformate is the presence of an organic base or an inorganic base. The organic
base may be selected from the group comprising ethylamine and diisopropyl ethyl amine.
The inorganic base may be selected from the group comprising sodium carbonate and
potassium carbonate. Preferably, the base is potassium carbonate.
The acetic acid salt of dabigatran ethyl ester of Formula V is contacted with the nhexyl
chloroformate at a temperature of about 10°C to about 40°C, for example, about
15°C to about 25°C. The acetic acid salt of dabigatran ethyl ester of Formula V is
contacted with the n-hexyl chloroformate for about 3 hours to about 6 hours, for example,
about 4 hour to about 6 hours.
The reaction mixture of the acetic acid salt of dabigatran ethyl ester of Formula V
and the n-hexyl chloroformate may be subjected to carbon treatment. The reaction
mixture of the acetic acid salt of dabigatran ethyl ester of Formula V and the n-hexyl
chloroformate 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 the previous step may be treated with a suitable
reagent to prepare the salt of dabigatran etexilate. Preferably, the salt of dabigatran
etexilate is trifluoroacetate salt of dabigatran etexilate salt of Formula XL
FORMULA XI
The salt of dabigatran etexilate, for example, trifluoroacetic acid salt, may be
prepared 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, and methyl isopropyl ketone. The ester solvent
may be selected from the group comprising acetate, isopropyl acetate, and butyl acetate.
The alcohol solvent may be selected from the group comprising ethanol, methanol, npropanol,
and butanol. Preferably, the solvent is acetone. The trifluoroacetic acid may be
used as a solid or in solution form with acetone.
The salt of dabigatran etexilate is prepared at a temperature of about 10°C to about
40°C, for example, about 15°C to about 25°C. The salt of dabigatran etexilate is prepared
in about 3 hours to about 6 hours, for example, about 4 hours to about 6 hours.
The dabigatran etexilate of Formula II or its salt, for example, trifluoroacetic acid
salt, may be isolated by filtration, decantation, evaporation, distillation, or combinations
thereof.
A third aspect of the present invention provides a process for the preparation of the
methanesulfonate salt of dabigatran etexilate of Formula I
FORMULA I
salt thereof wherein the process comprises:
a) reacting the compound of Formula VI
FORMULA VI
with the compound of Formula VII
FORMULA VII
to prepare the compound of Formula VIII;
FORMULA VIII
optionally isolating the compound of Formula VIII from the reaction mixture;
converting the compound of Formula VIII to the compound of Formula IX;
FORMULA IX
d) converting the compound of Formula IX to the acetic acid salt of dabigatran
ethyl ester of Formula V;
e) optionally isolating the acetic acid salt of dabigatran ethyl ester of Formula V
from the reaction mixture;
f) reacting the acetic acid salt of dabigatran ethyl ester of Formula V with a
reagent capable of providing etexilate group;
g) optionally isolating the dabigatran etexilate of Formula II or salt thereof from
the reaction mixture;
h) converting dabigatran etexilate of Formula II or salt thereof to
methanesulfonate salt of dabigatran etexilate of Formula I; and
i) isolating the methanesulfonate salt of dabigatran etexilate of Formula I from
the reaction mixture.
The compound of Formula VI and the compound of Formula VII may be reacted
as described in the first aspect. The compound of Formula VIII obtained by the reaction
of the compound of Formula VI and the compound of Formula VII may optionally be
isolated. The compound of Formula VIII may be converted to the compound of Formula
IX as described in the first aspect. The compound of Formula IX may optionally be
isolated by filtration, decantation, evaporation, distillation, or combinations thereof.
The compound of Formula IX may optionally be converted to the compound of
Formula X as described in the first aspect. The compound of Formula IX or the
compound of Formula X may be converted to the acetic acid salt of dabigatran ethyl ester
of Formula V as described in the first aspect. The acetic acid salt of dabigatran ethyl ester
of Formula V may exist in the form of the mono-acetate or di-acetate. The acetic acid salt
of dabigatran ethyl ester of Formula V may be isolated by filtration, decantation,
evaporation, distillation, or combinations thereof.
The acetic acid salt of dabigatran ethyl ester of Formula V may be converted to
dabigatran etexilate of Formula II or its salt, for example, trifluoroacetic acid salt, as
described in the second aspect.
The dabigatran etexilate of Formula II or its salt, for example, trifluoroacetic acid
salt, may be isolated by filtration, decantation, evaporation, distillation, or combinations
thereof.
The dabigatran etexilate of Formula II or its salt, for example, trifluoroacetic acid
salt, is converted to the methanesulfonate salt of dabigatran etexilate. The dabigatran
etexilate of Formula II or its salt, for example, trifluoroacetic acid salt, is treated with a
solvent and a base before treating with methanesulfonic acid. The solvent may be selected
from the group consisting of 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, and
butyl acetate. The ketone solvent may be selected from the group comprising acetone,
methyl butyl ketone, and methyl isopropyl ketone. The alcohol may be selected from the
group comprising ethanol, methanol, n-propanol, and butanol. Preferably, the solvent is
dichloromethane, ethyl acetate, or mixtures thereof.
The base may be an inorganic base or an organic base. The inorganic base may be
selected from the group comprising sodium carbonate and potassium carbonate. The
organic base may be selected from the group comprising ethyl amine, isopropyl amine,
and diisopropylethyl amine. Preferably, the base is sodium carbonate or potassium
carbonate. The dabigatran etexilate of Formula II or its salt, preferably trifluoroacetate
salt, 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. The dabigatran etexilate of Formula II or its salt,
preferably trifluoroacetate salt, 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 dabigatran etexilate of Formula II or its salt, for example, trifluoroacetic acid
salt is treated with methanesulfonic 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, and methyl isopropyl
ketone. The ester solvent may be selected from the group comprising ethyl acetate,
isopropyl acetate, and butyl acetate. The alcohol solvent may be selected from the group
comprising ethanol, methanol, n-propanol, and butanol. Preferably, the solvent is ethyl
acetate. The methanesulfonic acid may be used as a solid or in solution form with ethyl
acetate.
The dabigatran etexilate of Formula II or its salt, for example, the trifluoroacetic
acid salt, 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 reaction mixture obtained in step a) 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 a combination thereof. The methanesulfonate salt
of dabigatran etexilate may be characterized by XRPD pattern.
A fourth aspect of the present invention provides a process for the preparation of
the acetic acid salt of dabigatran ethyl ester of Formula V
.CH3COOH
FORMULA V
wherein the process comprises:
a) converting the compound of Formula IX
FORMULA IX
to the compound of Formula X;
FORMULA X
b) converting the compound of Formula X to the acetic acid salt of dabigatran
ethyl ester of Formula V; and
c) isolating the acetic acid salt of dabigatran ethyl ester of Formula V from the
reaction mixture.
The compound of Formula IX may be prepared as described in the first aspect.
The compound of Formula IX may optionally be converted to the compound of Formula X
as described in the first aspect.
The compound of Formula X may be converted to the acetic acid salt of dabigatran
ethyl ester of Formula V as described in the first aspect. The acetic acid salt of dabigatran
ethyl ester of Formula V may exist in the form of mono-acetate or di-acetate. The acetic
acid salt of dabigatran ethyl ester of Formula V may be isolated by filtration, decantation,
evaporation, distillation, or combinations thereof.
A fifth aspect of present invention provides the use of the acetic acid salt of
dabigatran ethyl ester of Formula V for the preparation of dabigatran etexilate or salt
thereof.
A sixth aspect of present invention provides the use of the trifluoroacetic acid salt
of dabigatran etexilate of Formula XI for the preparation of methanesulfonate salt of
dabigatran etexilate.
A seventh aspect of the present invention provides the trifluoroacetate salt of
dabigatran etexilate of Formula XL
FORMULA XI
An eighth aspect of the present invention provides a process for the preparation of
the trifluoroacetate salt of dabigatran etexilate of Formula XI, wherein the process
comprises:
a) contacting ethyl N- [(2- {[(4-carbamimidoylphenyl)amino]methyl} - 1-methyl-
3a,7a-dihydro-lH-benzimidazol-5-yl)carbonyl]-N-pyridin-2-yl -P-alaninate of
Formula III
FORMULA III
or its salt with n-hexyl chloroformate;
treating the reaction mixture obtained in step a) with trifluoroacetic acid; and
c) isolating the trifluoroacetate salt of dabigatran etexilate of Formula XI from
the mixture thereof.
The ethyl N-[(2- {[(4-carbamimidoylphenyl)amino]methyl} - 1-methyl-3a,7adihydro-
lH-benzimidazol-5-yl)carbonyl]-N-pyridin-2-yl -P-alaninate of Formula III or its
salt may be prepared according to the method provided in literature, for example, U.S.
Patent No. 6,087,380.
The salts of the compound of ethylN-[(2-{[(4-carbamimidoylphenyl)amino]
methyl} - 1-methyl-3a,7a-dihydro-lH-benzimidazol-5-yl)carbonyl]-N-pyridin-2-yl - -
alaninate of Formula III may be selected from the hydrochloride, hydrobromide, or acetate
salts. Preferably, the salt of compound of Formula III is an acetate salt.
The compound of Formula III or its salt is contacted with the 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 comprising tetrahydrofuran, diisopropyl ether, and 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 n-hexyl chloroformate may be used either as a solid or in
solution form with tetrahydrofuran.
The compound of Formula III or its salt is contacted with n-hexyl chloroformate in
the presence of an organic base or an inorganic base. The organic base may be selected
from the group comprising ethylamine and diisopropyl ethyl amine. The inorganic base
may be selected from the group comprising sodium carbonate and potassium carbonate.
Preferably, the base is potassium carbonate.
The compound of Formula III or its salt is contacted with n-hexyl chloroformate at
a temperature of about 10°C to about 40°C, for example, about 15°C to about 25°C. The
compound of Formula V is 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 trifluoroacetic 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, and methyl isopropyl ketone. The ester solvent may be selected from
the group comprising ethyl acetate, isopropyl acetate, and butyl acetate. The alcohol
solvent may be selected from the group comprising ethanol, methanol, n-propanol, and
butanol. Preferably, the solvent is acetone. The trifluoroacetic acid may be used as a solid
or in solution form with acetone.
The reaction mixture obtained in step a) is treated with trifluoroacetic 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 step a) is treated with the trifluoroacetic acid for about 3
hours to about 6 hours, for example, about 4 hours to about 6 hours.
The trifluoroacetate salt of dabigatran etexilate may be isolated by filtration,
decantation, evaporation, distillation, or combinations thereof. The trifluoroacetate salt of
dabigatran etexilate has substantially the same XRPD pattern as depicted in Figure 1, and
is referred to herein as crystalline Form I of trifluoroacetate salt of dabigatran etexilate.
A ninth aspect of the present invention provides crystalline Form I of
trifluoroacetate salt of dabigatran etexilate.
The crystalline Form I of trifluoroacetate salt of dabigatran etexilate has
substantially the same XRPD (X-ray powder diffraction) pattern as depicted in Figure 1.
The crystalline Form I of trifluoroacetate salt of dabigatran etexilate salt of Formula XI is
characterized by an XRPD pattern having interplanar spacing (d) values substantially at
19.09, 17.56, 4.99, 4.66, 4.08, and 3.61 A. The crystalline Form I of the trifluoroacetate
salt of dabigatran etexilate salt of Formula XI is further characterized by an XRPD pattern
having interplanar spacing (d) values substantially at 22.48, 19.09, 17.56, 12.69, 11.18,
9.53, 8.51, 7.57, 7.03, 6.66, 6.33, 5.83, 5.63, 5.39, 4.99, 4.66, 4.36, 4.08, 3.92, 3.61, 3.43,
3.29, 2.96, 2.81, and 2.49 A.
A tenth aspect of the present invention provides a process for the purification of
the trifluoroacetate salt of dabigatran etexilate, wherein the process comprises:
a) treating the trifluoroacetate salt of dabigatran etexilate of Formula XI with an
alcohol solvent; and
b) isolating purified trifluoroacetate salt of dabigatran etexilate of Formula XI
from the mixture thereof.
The alcohol solvent used for the purification may be selected from the group
comprising methanol, ethanol, isopropanol, n-propanol, or mixtures thereof. Preferably,
the alcohol solvent is ethanol. The trifluoroacetate salt of dabigatran etexilate may be
treated with alcohol solvent at a temperature of about 10°C to about 70°C, for example,
about 20°C to about 60°C. The trifluoroacetate salt of dabigatran etexilate may be treated
with an alcohol solvent for about 2 hours to about 6 hours, for example, about 3 hours to
about 4 hours.
The purified trifluoroacetate salt of dabigatran etexilate may be isolated by
filtration, decantation, evaporation, distillation, or combinations thereof. The purified
trifluoroacetate salt of dabigatran etexilate has substantially the same XRPD pattern as
depicted in Figure 2 and is referred to herein as crystalline Form II of the trifluoroacetate
salt of dabigatran etexilate salt of Formula XI.
An eleventh aspect of the present invention provides crystalline Form II of the
trifluoroacetate salt of dabigatran etexilate salt of Formula XL
The crystalline Form II of the trifluoroacetate salt of dabigatran etexilate salt of
Formula XI has substantially the same XRPD (X-ray powder diffraction) pattern as
depicted in Figure 2. The crystalline Form II of trifluoroacetate salt of dabigatran etexilate
salt of Formula XI is characterized by an XRPD pattern having interplanar spacing (d)
values substantially at 17.65, 15.72, 5.70, 5.07, and 4.54 A. The crystalline Form II of the
trifluoroacetate salt of dabigatran etexilate salt of Formula XI is further characterized by
an XRPD pattern having interplanar spacing (d) values substantially at 22.52, 17.65,
15.72, 12.92, 11.25, 8.84, 8.34, 7.70, 7.27, 6.69, 6.43, 5.89, 5.70, 5.56, 5.07, 4.91, 4.64,
4.54, 4.44, 4.31, 4.17, 3.92, 3.67, 3.53, 3.43, 3.36, 3.15, 2.94, 2.78, and 2.49 A.
A twelfth 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 trifluoroacetate salt of dabigatran etexilate of Formula XI with
methanesulfonic acid; and
b) isolating methanesulfonate salt of dabigatran etexilate from the mixture
thereof.
The trifluoroacetate salt of dabigatran etexilate of Formula XI may be treated with
a suitable acid to prepare the pharmaceutically acceptable salts of dabigatran etexilate.
Pharmaceutically acceptable salts of dabigatran etexilate may be, for example,
methanesulfonate salt of dabigatran etexilate. The trifluoroacetate salt of dabigatran
etexilate of Formula XI is treated with a solvent and a base before treating with the
methanesulfonic acid. The solvent is selected from the group consisting of halogenated
hydrocarbons, esters, ketones, alcohols, or mixtures thereof. The halogenated
hydrocarbon may be, for example, dichloromethane. The ester solvent may be selected
from the group comprising ethyl acetate, isopropyl acetate, and butyl acetate. The ketone
solvent may be selected from the group comprising acetone, methyl butyl ketone, and
methyl isopropyl ketone. The alcohol solvent may be selected from the group comprising
ethanol, methanol, n-propanol, and 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
selected from the group comprising sodium carbonate and potassium carbonate. The
organic base may be selected from the group comprising ethyl amine, isopropyl amine,
and diisopropylethyl amine. Preferably, the base is sodium carbonate or potassium
carbonate. The trifluoroacetate salt of dabigatran etexilate of Formula XI 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. The trifluoroacetate salt of dabigatran etexilate of Formula XI 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 trifluoroacetate salt of dabigatran etexilate of Formula XI is treated with
methanesulfonic 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, and methyl isopropyl ketone. The
ester solvent may be selected from the group comprising ethyl acetate, isopropyl acetate,
and butyl acetate. The alcohol solvent may be selected from the group comprising
ethanol, methanol, n-propanol, and butanol. Preferably, the solvent is ethyl acetate. The
methanesulfonic acid may be used as a solid or in solution form with ethyl acetate.
The trifluoroacetate 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 trifluoroacetate 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
has substantially the same XRPD (X-ray powder diffraction) pattern as depicted in Figure
3. The methanesulfonate salt of dabigatran etexilate is characterized by an XRPD pattern
having interplanar spacing (d) values substantially at 19.54, 4.97, 4.89, 4.03, and 4.00 A.
The methanesulfonate salt of dabigatran etexilate is further characterized by an XRPD
pattern having interplanar spacing (d) values substantially at 19.54, 9.78, 9.45, 9.16, 7.99,
6.92, 6.51, 6.27, 5.59, 5.36, 4.97, 4.89, 4.73, 4.46, 4.19, 4.03, 4.00, 3.86, 3.67, 3.54, 3.32,
3.18, 3.04, 2.79, 2.61, 2.48, and 2.35 A.
The XRPD of the samples were determined by using a PANalytical X'Pert PRO XRay
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 X'Celerator 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 ethyl w- 2-{ 4-cvanophenyl amino1methyl}- l -methyl-3a 7adihydro-
lH-benzimidazol-5-yl)carbonyl1 -N-pyridin-2-yl -P-alaninate (compound of
Formula IX)
N,N-Carbonyl diimidazole (5.82 g) and 2-[(4-Cyanophenyl)amino]acetic acid
(compound of Formula VII) (6.28 g) were added to tetrahydrofuran (120 mL) at 20°C to
25°C. Ethyl N- {[3-amino-4-(methylamino)cyclohexa- 1,5-dien- 1-yljcarbonyl} -N-pyridin-
2-yl -P-alaninate (compound of Formula VI) (10 g) was added to the reaction mixture and
the temperature of the reaction mixture was increased to 50°C to 55°C. Butylated
hydroxyl toluene ( 1 g) was added to the reaction mixture and tetrahydrofuran was
recovered under vacuum at 55°C.
Acetic acid (40 mL) was added to the reaction mixture and stirred at 90°C to 95°C
until the reaction was complete. Acetic acid was completely recovered under vacuum at
65°C to 70°C. The reaction mixture was cooled to 20°C to 25°C. De-ionized water (50
mL) was added and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The
organic layer was washed with 5% aqueous sodium bicarbonate solution (70 mL). Ethyl
acetate was recovered under vacuum at 55°C to 60°C. 2-Propanol (60 mL) was added to
the reaction mixture and stirred at 55°C to 60°C. The reaction mixture was cooled to 20°C
to 25°C and stirred for 16 hours at 20°C to 25°C. The reaction mixture was filtered and
washed with 2-propanol (10 mL). The wet material was dried under vacuum to obtain the
title compound.
Yield: 8.35 g
Example 2 : Preparation of the acetate salt of dabigatran ethyl ester (compound of Formula
Y
Ethyl N- [(2- {[(4-cyanophenyl)amino]methyl} - 1-methyl-3 a,7a-dihydro- 1Hbenzimidazol-
5-yl)carbonyl ]-N-pyridin-2-yl -P-alaninate (compound of Formula IX) (100
g) was added to dimethylformamide (250 mL). Hydrochloric acid gas dissolved in ethanol
(250 mL) was added to the reaction mixture for 10 hours at 0°C to -10°C. The reaction
mixture was stirred until the reaction was complete. Aqueous potassium carbonate
solution was added to the reaction mixture and extracted using dichloromethane (1500
mL) and washed with 25% sodium chloride solution (500 mL).
Dichloromethane was recovered completely under vacuum. Ethanol (700 mL) was
added to the reaction mixture followed by the addition of ammonium acetate (104 g) and
the mixture was stirred until the reaction was complete. Ethanol was recovered under
vacuum. Acetone (300 mL) was added to the reaction mixture and recovered completely
under vacuum. Deionized water (1000 mL) was added to the reaction mixture and stirred
for 2 hours at 25°C. The reaction mixture was cooled to 5°C to 10°C stirred, filtered and
dried under vacuum at 45°C to 50°C to obtain the title compound.
Yield: 85 g
Example 3: Preparation of dabigatran etexilate trifluoroacetate salt
Acetate salt of dabigatran ethyl ester (50 g) was added to tetrahydrofuran (750 mL)
and deionized water (250 mL). Potassium carbonate (37.08 g) was added to the reaction
mixture and stirred 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
and stirred for 2 hours at 20°C to 22°C. The layers were separated and butylated
hydroxytoluene (BHT) (0.5 g) was added to the tetrahydrofuran layer. Tetrahydrofuran
was 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 trifluoroacetic acid (9.66 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 at 55°C to obtain the title compound having XRPD data as
depicted in Figure 1.
Yield: 53 g
Example 4 : Purification of dabigatran etexilate trifluoroacetate salt
Dabigatran etexilate trifluoroacetate salt (50 g) obtained in Example 3 was
dissolved in ethanol (350 mL) at 55°C for 15 minutes to 20 minutes. The reaction mixture
was cooled to 10°C to 15°C for 20 minutes to 25 minutes. The reaction mixture was
stirred for 2 hours at 20°C, filtered, and dried under vacuum. 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: 39 g
(M+H) : m/z= 628.5
¾NMR (400 MHz, CDC1 ) : d 0.86-0.89 (t,3H), 1.10-1.13 (t,3H), 1.28-1.30 (m,6H), 1.67
(m,2H), 2.66-2.69 (t,2H), 3.77 (s,3H), 3.94-3.98 (t,2H), 4.22-4.25 (m,4H), 4.68-4.69
(d,2H), 6.85-6.89 (m,3H), 6.90-7.17 (m,2H), 7.40-7.42 (m,2H), 7.47 (t,lH), 7.64-7.67
(dt,3H), 8.37 (dd,lH), 10.0 (s,lH), 10.65 (bs,lH), 11.90 (bs,lH).
Example 5 : Preparation of dabigatran etexilate methanesulfonate salt
Dabigatran etexilate trifluoroacetate salt (100 g) was dissolved in dichloromethane
(2000 mL) at 25°C. The reaction mixture was washed with aqueous potassium carbonate
solution (200 g in 200 mL de-ionized water). Dichloromethane was recovered from the
reaction mixture under vacuum. Ethyl acetate (1700 mL) was added to the reaction
mixture and stirred for 10 minutes. The reaction mixture was heated to 65°C to 70°C and
further cooled to 40°C. Methanesulphonic acid solution ( 11.01 g methanesulphonic acid
dissolved in 200 mL ethyl acetate) was added to the reaction mixture drop-wise at 38°C to
40°C. The reaction mixture was stirred at 20°C to 25°C for 2 hours, filtered, and dried
under vacuum at 45°C to 50°C to obtain the title compound.
Yield: 80 g
Example 6 : Preparation of dabigatran etexilate methanesulfonate salt
Dabigatran etexilate trifluoroacetate 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
dichloromethane was recovered under vacuum. Ethyl acetate (550 mL) was added to the
reaction mixture and stirred for 10 minutes. Methanesulphonic acid solution (3.99 g
methanesulphonic 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 having XRPD data as depicted in Figure 3.
Yield: 29.75 g.

We claim
1. A process for the preparation of acetic acid salt of dabigatran ethyl ester of
Formula V
.CH3COOH
FORMULA V
wherein the process comprises:
a) reacting the compound of Formula VI
FORMULA VI
with the compound of Formula VII
FORMULA VII
to prepare the compound of Formula VIII;
FORMULA VIII
b) optionally isolating the compound of Formula VIII from the reaction mixture;
c) converting the compound of Formula VIII to the compound of Formula IX;
FORMULA IX
d) converting the compound of Formula IX to the acetic acid salt of dabigatran
ethyl ester of Formula V; and
e) isolating the acetic acid salt of dabigatran ethyl ester of Formula V from the
reaction mixture.
2. A process for the preparation of dabigatran etexilate of Formula II
FORMULA II
or a salt thereof wherein the process comprises:
a) reacting the compound of Formula VI
FORMULA VI
with the compound of Formula VII
FORMULA VII
to prepare the compound of Formula VIII;
FORMULA VIII
b) optionally isolating the compound of Formula VIII from the reaction mixture;
c) converting the compound of Formula VIII to the compound of Formula IX;
FORMULA IX
d) converting the compound of Formula IX to the acetic acid salt of dabigatran
ethyl ester of Formula V;
e) optionally isolating the acetic acid salt of dabigatran ethyl ester of Formula V
from the reaction mixture;
f) reacting the acetic acid salt of dabigatran ethyl ester of Formula V with a
reagent capable of providing etexilate group; and
g) isolating the dabigatran etexilate of Formula II or a salt thereof from the
reaction mixture.
3. A process for the preparation of methanesulfonate salt of dabigatran etexilate of
Formula I
FORMULA I
or a salt thereof wherein the process comprises:
a) reacting the compound of Formula VI
FORMULA VI
with the compound of Formula VII
FORMULA VII
to prepare the compound of Formula VIII;
FORMULA VIII
b) optionally isolating the compound of Formula VIII from the reaction mixture;
c) converting the compound of Formula VIII to compound of Formula IX;
FORMULA IX
d) converting the compound of Formula IX to the acetic acid salt of dabigatran
ethyl ester of Formula V;
e) optionally isolating the acetic acid salt of dabigatran ethyl ester of Formula V
from the reaction mixture;
) reacting the acetic acid salt of dabigatran ethyl ester of Formula V with a
reagent capable of providing etexilate group;
g) optionally isolating the dabigatran etexilate of Formula II or a salt thereof
from the reaction mixture;
h) converting the dabigatran etexilate of Formula II or a salt thereof to
methanesulfonate salt of dabigatran etexilate of Formula I; and
i) isolating the methanesulfonate salt of dabigatran etexilate of Formula I from
the reaction mixture.
4. A process for the preparation of the acetic acid salt of dabigatran ethyl ester of
Formula V
.CH3COOH
FORMULA V
which comprises:
a) converting the compound of Formula IX
FORMULA IX
to the compound of Formula X;
FORMULA X
b) converting the compound of Formula X to the acetic acid salt of dabigatran
ethyl ester of Formula V; and
c) isolating the acetic acid salt of dabigatran ethyl ester of Formula V from the
reaction mixture.
5. The process according to claims 1, 2, and 3, wherein the compound of Formula VI
and the compound of Formula VII are reacted in the presence of a condensing agent and a
solvent.
6. The process according to claim 5, wherein the condensing agent is carbonyl
diimidazole, phosgene, triphosgene, or mixtures thereof.
7. The process according to claim 6, wherein the condensing agent is carbonyl
diimidazole.
8. The process according to claim 5, wherein the solvent is selected from the group
consisting of ethers, ketones, esters, or mixtures thereof.
9. The process according to claim 5, wherein the solvent is tetrahydrofuran.
10. The process according to claims 1, 2, and 3, wherein the compound of Formula
VIII is converted to the compound of Formula IX in the presence of a cyclizing agent, and
a solvent.
11. The process according to claim 10, wherein the cyclizing agent is acetic acid.
1 . The process according to claim 10, wherein the solvent is selected from the group
consisting of water, esters, alcohols, ketones, or mixtures thereof.
13. The process according to claim 12, wherein the solvent is ethyl acetate, 2-propanol,
or mixtures thereof.
14. The process according to claims 1, 2, and 3, wherein the compound of Formula IX
is optionally converted to the compound of Formula X.
15. The process according to claims 4 and 14, wherein the conversion of the
compound of Formula IX to the compound of Formula X is carried out in the presence of
hydrochloric acid and a solvent.
16. The process according to claim 15, wherein the solvent is dimethylformamide,
ethanol, or mixtures thereof.
17. The process according to claims 1, 2, 3, and 4, wherein the compound of Formula
IX or the compound of Formula X is converted to acetic acid salt of dabigatran ethyl ester
of Formula V in the presence of ammonium acetate and a solvent.
18. The process according to claim 17, wherein the solvent is water, ethanol, acetone,
or mixtures thereof.
19. The process according to claims 1, 2, 3, and 4, wherein the acetic acid salt of
dabigatran ethyl ester of Formula V exists in the form of mono-acetate or di-acetate.
20. The process according to claims 2 and 3, wherein the acetic acid salt of dabigatran
ethyl ester of Formula V is converted to dabigatran etexilate of Formula II or its salt by
contacting with a reagent capable of providing an etexilate group, and a solvent.
21. The process according to claims 2 and 3, wherein the salt of dabigatran etexilate is
the trifluoroacetate salt.
22. The process according to claim 20, wherein the reagent capable of providing the
etexilate group is n-hexyl chloroformate.
23. The process according to claim 20, wherein the solvent is tetrahydrofuran, either
alone or in combination with water.
24. The process according to claim 3, wherein the dabigatran etexilate of Formula II or
its salt is treated with a solvent and a base before treating with the methanesulfonic acid.
25. Use of the acetic acid salt of dabigatran ethyl ester of Formula V for the
preparation of dabigatran etexilate or a salt thereof.
26. Use of the trifluoroacetic acid salt of dabigatran etexilate of Formula XI for the
preparation of methanesulfonate salt of dabigatran etexilate.
27. A trifluoroacetate salt of dabigatran etexilate salt of Formula XL
FORMULA XI
28. A process for the preparation of trifluoroacetate salt of dabigatran etexilate of
Formula XI, wherein the process comprises:
a) contacting ethyl N-[(2- {[(4-carbamimidoylphenyl)amino]methyl}-l-methyl-
3a,7a-dihydro-lH-benzimidazol-5-yl)carbonyl]-N-pyridin-2-yl -P-alaninate of
Formula III
FORMULA III
or its salt with n-hexyl chloroformate;
b) treating the reaction mixture obtained in step a) with trifluoroacetic acid; and
c) isolating the trifluoroacetate salt of dabigatran etexilate of Formula XI from
the mixture thereof.
crystalline Form I of trifluoroacetate salt of dabigatran etexilate.
30. A crystalline Form I of trifluoroacetate salt of dabigatran etexilate with
substantially the same XRPD (X-ray powder diffraction) pattern as depicted in Figure 1.
31. A crystalline Form I of trifluoroacetate salt of dabigatran etexilate salt of Formula
XI characterized by an XRPD pattern having interplanar spacing (d) values substantially at
19.09, 17.56, 4.99, 4.66, 4.08, and 3.61 A.
32. The crystalline Form I of trifluoroacetate salt of dabigatran etexilate salt of
Formula XI according to claim 31, further characterized by an XRPD pattern having
interplanar spacing (d) values substantially at 22.48, 19.09, 17.56, 12.69, 11.18, 9.53, 8.51,
7.57, 7.03, 6.66, 6.33, 5.83, 5.63, 5.39, 4.99, 4.66, 4.36, 4.08, 3.92, 3.61, 3.43, 3.29, 2.96,
2.81, and 2.49 A.
33. A process for the purification of the trifluoroacetate salt of dabigatran etexilate,
wherein the process comprises:
a) treating the trifluoroacetate salt of dabigatran etexilate of Formula XI with an
alcohol solvent; and
b) isolating purified trifluoroacetate salt of dabigatran etexilate of Formula XI
from the mixture thereof.
34. A crystalline Form II of trifluoroacetate salt of dabigatran etexilate salt of Formula
XL
35. A crystalline Form II of trifluoroacetate salt of dabigatran etexilate salt of Formula
XI with substantially the same XRPD (X-ray powder diffraction) pattern as depicted in
Figure 2.
36. A crystalline Form II of trifluoroacetate salt of dabigatran etexilate salt of Formula
XI characterized by an XRPD pattern having interplanar spacing (d) values substantially at
17.65, 15.72, 5.70, 5.07, and 4.54 A.
37. The crystalline Form II of trifluoroacetate salt of dabigatran etexilate salt of
Formula XI according to claim 36, further characterized by an XRPD pattern having
interplanar spacing (d) values substantially at 22.52, 17.65, 15.72, 12.92, 11.25, 8.84, 8.34,
7.70, 7.27, 6.69, 6.43, 5.89, 5.70, 5.56, 5.07, 4.91, 4.64, 4.54, 4.44, 4.31, 4.17, 3.92, 3.67,
3.53, 3.43, 3.36, 3.15, 2.94, 2.78, and 2.49 A.
38. A process for the preparation of methanesulfonate salt of dabigatran etexilate,
wherein the process comprises:
a) treating trifluoroacetate salt of dabigatran etexilate of Formula XI with
methanesulfonic acid; and
b) isolating methanesulfonate salt of dabigatran etexilate from the mixture
thereof.