FIELD OF THE INVENTION
The present invention relates to an industrially advantageous and improved
process for preparation of dabigatran etexilate of formula I and its
pharmaceutically acceptable salts.
N
N
HN
N
O
N
O
OEt
N
O
O
NH2
Formula I
The present invention also provides a novel and efficient process for preparation
of cyano compound of formula II, a key intermediate in the synthesis of
dabigatran etexilate.
N
N
HN CN
N
O
N
O
OEt
Formula II
BACKGROUND OF THE INVENTION
Dabigatran etexilate, represented by formula I is an anticoagulant drug from the
class of the direct thrombin inhibitors, chemically known as ethyl 3-{[(2-{[(4-{N'-
[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1-methyl-1-H-benzimidazol-
5-yl)carbonyl] (2-pyridinyl)amino}propanoate.
N
N
HN
N
O
N
O
OEt
N
O
O
NH2
Formula I
3
Dabigatran etexilate and its pharmaceutically acceptable salts were first disclosed
in US patent 6,087,380. The patent discloses methodology for preparation of
dabigatran etexilate using 3-({2-[(4-cyano-phenylamino)-methyl]-1-methyl-1Hbenzoimidazole
-5-carbonyl}-pyridin-2-yl-amino)-propionic acid ethyl ester of
formula II as a key intermediate. The process involves preparation of cyano
intermediate of formula II by condensation of 3-[(3-amino-4-methylaminobenzoyl)-
pyridin-2-yl-amino]-propionic acid ethyl ester with (4-cyanophenylamino)-
acetic acid as shown below in scheme 1:
N
N
HN CN
N
O
N
O
OEt
1.CDI/THF
2. CH3COOH
1. HCl/ EtOH
2. (NH4)2CO3 / EtOH
N
N
HN
N
O
N
O
OEt
NH
NH2
.HCl
N
N
HN
N
O
N
O
OEt
NH2
N
O
O
N N OEt
O
O
NH2
NHMe
NC
NH
COOH
+
Scheme 1
The cyano intermediate of formula II as obtained is purified using column
chromatography and converted to amidino intermediate, in particular in the form
of hydrochloride salt which is again purified by column chromatography before
converting to dabigatran etexilate. The patent is silent about the yield and purity of
the intermediates. We have found the process described in the above patent to be
unsatisfactory, wherein using specified reaction condition, condensation reaction
does not go to completion and resulting cyano compound is found to be contaminated
with several impurities which required extensive purification. Major drawback of the
4
said process is that column chromatography is required in each step for isolating
desired intermediates. It imposes burden at industrial scale and is not viable at
commercial scale.
A similar approach has been described in US patent 8,119,810 for the preparation
of dabigatran wherein the cyano intermediate of formula II, is purified by
preparation of hydrobromide salt of compound of formula II as shown below in
scheme 2:
NC
NH
COOH
1.Coupling reagent
2. HBr
+
N
N
HN CN
N
O
N
O
OEt
. HBr
NH
NH2
CH3
N
O
N
O
OEt
Scheme 2
US patent publication 2011/0082299 discloses a process of preparation of
dabigatran etexilate through cyano intermediate of formula II wherein cyano
intermediate is purified by preparing oxalate salt of compound of formula II as
shown below in scheme 3:
NC
NH
COOH
1. CDI/THF
CH3COOH
2. (COOH)2
+
N
N
HN CN
N
O
N
O
OEt
. (COOH)2
NH
NH2
CH3
N
O
N
O
OEt
Scheme 3
Exemplified processes disclose that cyano compound of formula II have purity of
82%, which is purified by preparing oxalate salt. Purity of 82% is very less.
US patent publication 2011/0224441 discloses a process for preparation of
dabigatran etexilate through cyano intermediate of formula II wherein cyano
intermediate is purified by preparation of oxalate salt. The resulting oxalate salt is
then converted to corresponding amidino intermediate, which is isolated as
monohydrochloride and dihydrochloride salts.
5
PCT publication WO 2012/004396 discloses a process for preparation of
dabigatran etexilate through cyano intermediate of formula II wherein cyano
intermediate is purified by preparation of hydrochloride salt as shown below in
scheme 4:
NC
NH
COOH
1. CDI/THF
2. Glacial
acetic acid
+
N
N
HN CN
N
O
N
O
OEt
. HCl
NH
NH2
CH3
N
O
N
O
OEt
3. IPA, HCl
Scheme 4
The process of this application provide crude cyano compound of formula II
having purity of 75% a/a according to HPLC/MS.
PCT publication WO 2012/077136 discloses a preparation of dabigatran etexilate
via purifying amidino intermediate, 1-methyl-2-[N-[4-amidinophenyl]amino
methyl]benzimidazol-5-yl-carboxylic acid–(2-pyridyl)–N-(2-ethoxycarbonyl
ethyl) amide by preparing acid addition salts. But patent is silent about purity of
cyano intermediate.
Purity of an API as well as intermediates is of great importance in the field of
pharmaceutical chemistry. It is well documented in the art that direct product of a
chemical reaction is rarely a single compound with sufficient purity to comply
with pharmaceutical standards. The impurities that can be present in
pharmaceutical compounds are starting materials, by-products of the reaction,
products of side reactions, or degradation products. Similarly, the synthetic
strategy employed for the preparation of dabigatran etexilate is complex, which
may results in the formation of several undesired by products due to competing
side reactions. Impurities in dabigatran etexilate or any other active
pharmaceutical ingredient are undesirable and in extreme cases, might even be
harmful to a patient being treated with a dosage form containing the API.
According to ICH guidelines, process impurities should be maintained below set
limits by specifying the quality of raw materials, their stoichiometric ratios,
6
controlling process parameters, such as temperature, pressure, time and including
purification steps, such as crystallization, distillation and liquid-liquid extraction
etc., in the manufacturing process. Typically, these limits are less than about 0.15
% by weight of each identified impurity. Limits for unidentified and/or
uncharacterized impurities are obviously lower, typically less than 0.10 % by
weight. The limits for genotoxic impurties could be much lower depending upon
the daily dose of the drug and duration of the treatment. Therefore, in the
manufacture of a drug substance, the purity of the products, such as dabigatran
etexilate is required before commercialization. Therefore, pharmaceutical active
compounds must be either free from these impurities or contain impurities in
acceptable limits. In addition to this, regulatory authorities worldwide require that
drug manufacturers should isolate, identify and characterize the impurities in their
products.
In view of the above, most of the prior art processes yield intermediates of low
purity as well as in low yield, which in turn need purification either by column
chromatography or by salt formation. Use of column chromatography for
purification in each step is cumbersome and makes the process commercially
unviable. The low purity of the intermediates results in low yield and purity of the
final API.
Thus, there is an urgent need for the development of a synthetic process which
produces final API i.e. dabigatran etexilate and its pharmaceutically acceptable
salts of high purity and having impurities in either acceptable amounts or free
from the impurities. The present invention fulfills the need in the art and provides
an improved, industrially advantageous process for the synthesis of dabigatran
etexilate and its pharmaceutically acceptable salts thereof, which avoids
cumbersome purification process of column chromatography at intermediate
stages. The replacement of chromatographic purification with crystallization leads
to a considerable improvement of economy of the whole production process.
7
OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved and
industrially advantageous process for the preparation of dabigatran etexilate and
pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide a process for the synthesis of
cyano intermediate of formula II in pure form.
Yet another object of the present invention is to provide a process for the
synthesis of cyano intermediate of formula II in pure form from isolated solid
intermediate of formula III.
N
O
N
O
OEt
N
H3C
O
NH
NH2
CN
Formula III
Yet another object of the invention is to provide an intermediate of formula III in
solid form.
Yet another object of the invention is to provide an intermediate of formula III in
crystalline, amorphous or mixtures thereof.
Yet another object of the invention is to provide a process for the synthesis of
dabigatran etexilate or pharmaceutically acceptable salt thereof from isolated
solid intermediate of formula III.
SUMMARY OF THE INVENTION
The present invention provides an improved and industrial advantageous process
for preparation of dabigatran etexilate of formula I and pharmaceutically
acceptable salts thereof
N
N
HN
N
O
N
O
OEt
N
O
O
NH2
Formula I
8
from isolated solid intermediate of formula III.
N
O
N
O
OEt
N
H3C
O
NH
NH2
CN
Formula III
According to one other embodiment, present invention provides a process for
preparation of a key intermediate of formula II,
N
N
HN CN
N
O
N
O
OEt
Formula II
in high purity and high yield from isolated solid intermediate of formula III.
According to one another embodiment, present invention provides an intermediate
of formula III in solid form.
According to one another embodiment, present invention provides an intermediate
of formula III in crystalline, amorphous or mixtures thereof.
According to one embodiment, present invention provides a process for the
preparation of dabigatran etexilate or pharmaceutically acceptable salt thereof
comprises:
a) condensing (4-cyano-phenylamino)-acetic acid compound of formula IV,
NC
NH
COOH
Formula IV
with 3-[(3-amino-4-methylamino-benzoyl)-pyridin-2-yl-amino]-propionic acid
ethyl ester compound of formula V,
9
NH
NH2
CH3
N
O
N
O
OEt
Formula V
in presence of a suitable condensing agent, optionally a base, in a suitable solvent;
b) isolating the intermediate of formula III as solid;
N
O
N
O
OEt
N
H3C
O
NH
NH2
CN
Formula III
c) optionally purifying the resulting intermediate of formula III from a
suitable solvents;
d) cyclizing the intermediate of formula III in presence of an acid to give cyano
compound of formula II;
N
N
HN CN
N
O
N
O
OEt
Formula II
e) optionally purifying the resulting cyano compound from a suitable solvent; and
f) converting cyano compound of formula II into dabigatran etexilate or
pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Figures 1A to 1D are exemplary XRPD patterns of intermediate compound of
Formula III
Figures 2A to 2D are exemplary DSC of intermediate compound of Formula III
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved and industrially advantageous
process for preparation of dabigatran etexilate and pharmaceutically acceptable
10
salts thereof. According to one aspect, present invention provides a process for the
preparation of dabigatran etexilate or pharmaceutically acceptable salts thereof
starting from (4-cyano-phenylamino)-acetic acid of formula IV. Generally, the
process involves peptide coupling of (4-cyano-phenylamino)-acetic acid
compound of formula IV with 3-[(3-amino-4-methylamino-benzoyl)-pyridin-2-ylamino]-
propionic acid ethyl ester of compound of formula V in presence of
suitable coupling agent to give 3-({2-[(4-cyano-phenylamino)-methyl]-1-methyl-
1H-benzoimidazole-5-carbonyl}-pyridin-2-yl-amino)-propionic acid ethyl ester
[intermediate of formula III]. Intermediate of formula III is converted into cyano
compound of formula II, via cyclization using a suitable cyclizing agent, which is
further converted to amidino intermediate of formula VI and salts thereof,
preferably hydrochloride salt using suitable reagent.
N
N
HN
N
O
N
O
OEt
NH
NH2
Formula VI
Compound of formula VI or its pharmaceutically acceptable salts, is finally
converted into the dabigatran etexilate of formula I and pharmaceutically
acceptable salts thereof.
Generally the intermediate of formula III is prepared by reacting the compound of
formula IV and V via peptide coupling reaction in the presence of a base.
Optionally, the reaction can be performed without using base. The base can be
selected from the class of tertiary amine such as triethyl amine, 4-
methylmorpholine, 4-ethylmorpholine, diisopropylethylamine, 2,6-di-tert-butyl-4-
methylpyridine, 1,1,3,3-tetramethylguanidine. In a more preferred embodiments
diisopropylethylamine is used.
According to one aspect of the invention the coupling agent conventionally used
for peptide synthesis are selected from N,N'-dicyclohexylcarbodiimide, N,N'-
11
diisopropylcarbodiimide, N,N'-carbonyldiimidazole and carbonyl-di-(1,2,4-
triazole). In addition to these, there are several reagents that activate the carboxyl
group in situ in the presence of a nucleophile. Many of these are based on the
chemistry of the carbodiimide group where the neighboring C=N bonds are
susceptible to nucleophilic attack by the carboxyl group such as 1-ethyl-3-(3’-
dimethylaminopropyl)carbodiimide. Generally, along with above agent, a
catalytic auxiliary nucleophiles such as l-hydroxbenzotriazole, 1-hydroxy-7-azabenzotriazole,
ethyl 2-cyano-2-(hydroxyimino)acetate, (benzotriazol-1-yloxytripyrrolidino
phosphonium hexafluorophosphate, benzotriazole-1-yl-oxy-tris-
(dimethylamino)-phosphonium hexafluorophosphate, N-hydroxysuccinimide and
N-hydroxy-5-norbene-endo-2,3-dicarboxamide and a like can also be used.
The compounds of formulae IV and V can be dissolved separately or together in a
suitable solvent selected from the group comprising of halogenated solvents such
as dichloromethane, dichloroethane, chloroform chlorobenzene; esters such as
methyl acetate, ethyl acetate, propyl acetate, isopropylacetate, butyl acetate;
hydrocarbons such as benzene, toluene, xylene; ethers such as tetrahydrofuran, 2-
methyl tetrahydrofuran, dioxane, isopropyl ether, methyl-tert-butyl ether,
diethylether, bis(2-methoxyethyl)ether; nitriles such as acetonitrile, propionitrile,
benzonitrile, 2-methoxybenzonitrile; protic or aprotic solvents such as N,Ndimethylformamide,
N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone,
diethylamine, propylamine, butylamine, sulfolane, dimethyl sulfoxide; alcohols
such as methanol, ethanol, n-propanol, isopropanol or benzylalcohol and mixtures
thereof, of which dichloromethane is preferred. In a more preferred embodiment
compound of formula IV and V are dissolved in the same solvent.
According to one other aspect of the present invention, compound of formula IV
can be reacted with a suitable haloformate in a suitable solvent to generate mixed
anhydride, which can subsequently react with the compound of formula V to
obtain the intermediate of formula III.
12
Suitable haloformate can be selected from methyl chloroformate, ethyl chloro
formate, n-propyl chloroformate, isopropyl chloroformate, isobutyl chloro
formate, benzyl chloroformate, phenyl chloroformate, aryloxy chloroformate,
benzyloxy chloroformate and suitable solvent C5-8 aliphatic or aromatic
hydrocarbons such as n-pentane, n-hexane, n-heptane, cyclopentane, cyclohexane,
cycloheptane, toluene, xylene; C1-4 halogenated hydrocarbons such as
dichloromethane, dichloroethane, chloroform, carbon tetrachloride; C3-6 esters
such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl
acetate, isobutyl acetate and like; C4-8 ethers such as diethyl ether, di-isopropyl
ether, methyl t-butyl ether, 1,2-dimethoxy ethane, 1,2-diethoxy ethane,
tetrahydrofuran, 2-methyl tetrahydrofuran and dioxane; C3-6 ketones such as
acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, and
alkylnitriles such as acetonitrile, propionitrile and amides such as N,Ndimethylformamide,
N,N-dimethylacetamide; sulfoxide such as dimethyl
sulfoxide and mixture thereof. Preferably solvent used is dichloromethane.
According to one another aspect of the present invention, it is advantageous to use
non-ether solvent during peptide condensation reaction, as it results in completion
of reaction and coupled product can be isolated as solid in purer form.
Non-ether solvent includes but not limited to halogenated solvents such as
dichloromethane, dichloroethane, chloroform, chlorobenzene; esters such as
methyl acetate, ethyl acetate, isopropylacetate, butyl acetate; hydrocarbons such
as toluene, n-hexane, n-heptane; protic or aprotic solvents such as N,Ndimethylformamide,
N,N-dimethylacetamide, sulfolane, dimethyl sulfoxide,
acetonitrile and the like and mixtures thereof.
According to one other aspect of the invention, the coupling reaction of
compound of formula IV and V can be carried out at ambient temperature to
reflux temperature of solvent. Generally reaction is carried out at 25-50 ºC,
preferably 30-40 ºC. The reaction mixture can be stirred over a period of 4 to 20
hours; preferably the reaction for 1 to 12 hours, more preferably till completion of
13
the reaction. The completion of reaction can be monitored by any one of
chromatographic techniques such as thin layer chromatography (TLC), High
pressure liquid chromatography (HPLC), Ultra-pressure liquid chromatography
(UPLC) and the like. The intermediate of formula III can be isolated from the
reaction mixture using suitable techniques known in the art.
Specifically, the intermediate of formula III can be isolated from reaction mixture
by generation of biphasic system in reaction mixture. After layer separation, the
organic layer can be subsequently washed with suitable acid, base and water.
Optionally, solvent is distilled off under reduced pressure. It may optionally be
advantageous to entrain any residual amounts of the solvent originally used which
are present in the distillation residue by adding another solvent. Traces of reaction
solvent used at this point are distilled off together with another solvent.
Another solvent can selected from halogenated solvent or hydrocarbons or
mixtures thereof. The resulting solid material, can optionally be purified using
solvent selected from the group comprising alcohols such as methanol, ethanol, npropanol,
n-butanol, isopropanol, benzylalcohol; esters such as methyl acetate,
ethyl acetate, propyl acetate; ketones such as methyl isobutyl ketone, methyl ethyl
ketone, acetone; ethers such as tetrahydrofuran, dioxane, methyl-tert-butyl ether,
isopropylether; halogenated solvents such as dichloromethane, dichloroethane,
chloroform, chlorobenzene hydrocarbons such as benzene, toluene, n-hexane, nheptane;
protic or aprotic solvents such as N,N-dimethylformamide, N,Ndimethylacetamide,
sulfolane, dimethyl sulfoxide, acetonitrile and mixtures
thereof. Purification can be carried out by any method known in the art, such as
crystallization, acid base treatment; dissolution and distillation of solvent,
dissolution and precipitation by adding anti solvent etc.
The intermediate of formula III thus prepared by the present invention is found to
be highly pure having purity more than 95% by HPLC, preferably more than 98
%, more preferably more than 99.5%.
14
According to another aspect of the invention, the isolation of intermediate of
formula III as a solid is novel and form inventive part of the invention. Isolated
solid can be in any form crystalline, amorphous or having the characteristics of
both crystalline and amorphous. In one other aspect of invention, the intermediate
of formula III, obtained by distillation of solvent such as halogenated solvents,
hydrocarbons shows the characteristics of amorphous material and have melting
range of 155-160°C. DSC thermogram shows endotherm in the range of 158-161
ºC. In another aspect, the intermediate of formula III is isolated as crystalline
solid, isolated from solvents selected from the class of esters, alcohols, ketones, either
by crystallization or distillation. Crystalline compound isolated from different solvents
shows endothermic peak in DSC thermogram in the range of 163-172ºC. Solid isolated
intermediate of formula III as described by the present invention can be further
characterized by suitable techniques known in the art. Preferably, it can be
characterized by various spectroscopic techniques like 1H and 13C Nuclear
magnetic resonance (NMR), Mass spectrometry (MS), Infrared spectroscopy (IR),
and X-ray diffraction chromatogram (XRD) etc. Specifically intermediate of
formula III is characterized as below:
Infra-red spectrum (IR): shows the peak at 1728.64, 2214.53, 2823.37, 2904.01,
30.54.40, 3427.29 cm-1
.
1H-NMR(CDCl3): 1.21 (t, 3H), 2.58 (s, 3H), 2.73 (t, 2H), 3.87 (s, 2H), 4.07 (q,
2H), 4.36 (t, 2H), 5.82 (bs), 6.20 (d, 1H), 6.66 (d, 2H), 6.75 (d, 1H), 6.79 (dd,
1H), 7.06 (dd, 1H), 7.18 (d, 1H), 7.45 (m, 3H), 8.18 (S, 1H), 8.43 (m, 1H).
XRD having characteristics peaks at 5.9, 8.7, 10.1, 13, 13.7, 14.8, 15.9, 16.4, 17.4,
18.2, 19.3, 20.2, 21.2, 21.7, 22.1, 23.9, 25.1, 25.8, 26.8, 27.8, 28.9, 29.6, 30.1,
32.1, 33.3 and 37.0 + 0.2 °θ.
In one other aspect of invention the compound of formula III obtained above as
solid, can be used as a crude solid product or purified solid for preparation of
cyano compound of formula II.
15
The conversion of condensation product, intermediate of formula III [obtained by
the reaction of (4-cyano-phenylamino)-acetic acid and 3-[(3-amino-4-
methylamino-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester] into cyano
compound of formula II through cyclization with acetic acid is already described
in the state of art. Though it is not isolated at any moment in solid form, but is
directly converted into cyano intermediate. The intermediate of formula III in
solid form has advantage that it is particularly easy to separate by filtration. This
characteristic has a direct effect on the overall yield of the process and, therefore,
is especially important when the process is carried out at an industrial scale, since
a product showing improved separation characteristics can be isolated faster,
better washed and quickly dried.
In one other aspect of invention, compound of formula III can be converted to
cyano compound of formula II by employing cyclization reaction in presence of a
suitable cyclizing agent. Cyclizing agent used for the reaction can be selected
from acid such as formic acid, hydrochloric acid, phosphoric acid, tri-chloro
acetic acid, tri-fluoro acetic acid, acetic acid or mixture thereof. In particular,
acetic acid may be proved beneficial; Presence of solvent is not critical for
cyclization. Reaction can be carried out in both situations, in the presence or
absence of solvent depending upon reaction conditions employed.
Generally compound of formula III is treated with a suitable acid as described
above. The reaction is advantageously carried out 90-140°C and it takes about 3-4
hours for completion of reaction. Thereafter, solvent is removed and resulting
product is isolated in a suitable solvent. The suitable solvent includes but not
limited to halogenated solvents such as dichloromethane, dichloroethane,
chloroform, carbon tetrachloride, chlorobenzene; hydrocarbons such as benzene,
toluene, o-xylene, n-hexane, n-heptane, cyclohexane; esters such as methyl
acetate, ethyl acetate, isopropylacetate, butyl acetate; ethers such as methyl tertbutyl
ether, tetrahydrofuran, dioxane, isopropylether, dimethyl ether, diethyl
16
ether, methyl propyl ether, 2-methyltetrahydrofuran or mixtures thereof.
Thereafter, solvent is distilled off to isolate desired compound.
The purity of the key intermediate is a very important criterion in the field of
pharmaceutical chemistry, as the purity and yield of the final API depend upon
the purity of the key intermediate. Therefore, the compound of formula II may be
optionally purified to enhance the purity as well to remove impurities, if present
in the intermediate. The compound of formula II, may be purified by various
methods such as crystallization, slurry wash or re-crystallization, solventantisolvent
system or combination of one or more procedure. The solvent used for
the purification of compound of formula II includes, but not limited to alcohols
such as methanol, ethanol, n-propanol, isopropanol, butanol, benzylalcohol; esters
such as methyl acetate, ethyl acetate, isopropylacetate, butyl acetate; ketones such
as methyl isobutyl ketone, methyl ethyl ketone, acetone; halogenated solvents
such as dichloromethane, chlorobenzene, dichloroethane, chloroform; nitriles
such as acetonitrile, propionitrile; protic or aprotic solvents such as N,Ndimethylformamide,
N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, dimethyl
sulfoxide; hydrocarbons such as benzene, toluene, xylene, cyclohexane, n-hexane,
n-heptane; ethers such as tetrahydrofuran, dioxane, methyl tert-butyl ether,
isopropyl ether, 2-methyltetrahydrofuran; or mixtures thereof
In another aspect, present invention describes the purified compound of formula II
which is advantageous as compared to prior art wherein purity of compound of
formula II is greatly affected by the purity of isolated compound of formula III.
The purity of compound of formula II using the process of present invention can
be raised manifold without using column chromatography or salt preparation. The
compound of formula II possess purity of more than 95% by HPLC as a crude
product isolated from reaction and more than 98.5% by HPLC after simple
crystallization. Substantially pure compound of formula II, prepared optionally by
simple crystallization, which will in turn gives the highly pure compound of
formula I or pharmaceutically acceptable salts thereof. The compound of formula
17
I prepared by using process of present invention is highly pure and have purity of
greater than 99.5% by HPLC.
Further in another aspect of present invention cyano compound of formula II can
be converted to amidino intermediate of formula VI or pharmaceutically
acceptable salts thereof using suitable reagents known in the art. Specifically
amidino intermediate of formula VI or pharmaceutically acceptable salts thereof
can be prepared by acidic hydrolysis of nitrile group of cyano compound of
formula II with a suitable acid in a suitable solvent and subsequent addition of
ammonia and ammonium salt. Suitable acid includes inorganic acid such as
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like;
or organic acid such as alkyl or aryl carboxylic acid, alkyl or aryl sulfonic acid
and the like and suitable solvent includes but not limited to alcohols such as
methanol, ethanol, n-propanol, isopropanol, butanol, benzylalcohol; ethers such as
tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether,
isopropyl ether or mixtures thereof. Ammonium salt can be selected from any
ammonium salt and preferred salts are ammonium carbonate, ammonium
bicarbonate, ammonium acetate, ammonium formate. The reaction is
advantageously carried out at suitable temperature for few minutes to several
hours, preferably till the completion of reaction to prepare amidino compound.
Further, in another embodiments of present invention amidino intermediate of
formula VI or pharmaceutically acceptable salts thereof can be converted to
compound of formula I and pharmaceutically acceptable salts thereof using the
methods known in the art or the methods with variation as can be employed and
suitable as per present invention. In a preferred embodiment, compound of
formula VI or pharmaceutically acceptable salts thereof produces compound of
formula I by reaction with hexyl chloroformate in presence of an inert solvent
selected from aromatic hydrocarbons, ethers, chlorinated hydrocarbons, nitriles
and ketones in presence of a suitable base, either organic or inorganic for example
tertiary amine, cyclic tertiary amines, hydroxides, carbonates etc. The compound
18
of formula I can be converted to pharmaceutically acceptable salt preferably
mesylate salt is prepared using methanesulfonic acid by methods known in art for
salt formation. The compound of formula I or mesylate salt or amidino
intermediate of formula VI or pharmaceutically acceptable salts thereof may
optionally be purified, if desired, by various methods such as crystallization,
slurry wash or re-crystallization, solvent-antisolvent system, carbon treatment or
combination of one or more procedure.
Main advantage of the present invention is to provide an industrially
advantageous and efficient process for preparation of dabigatran etexilate or
pharmaceutically acceptable salts thereof in high yield and high purity through
isolation of solid intermediates of formula III and by avoiding column
chromatography and salt preparation of cyano intermediate of formula II for
purification. The process of present invention is efficient, reproducible as well as
industrially advantageous.
While the present invention has been described in terms of its specific
embodiments and examples, 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 3-[(3-amino-4-{[2-(4-cyano-phenylamino)-acetyl]-
methyl-amino}-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester
Method A: To a mixture of 2-[(4-cyanophenyl)amino]acetic acid (19.25g), in
dichloromethane (150ml), diisopropylethylamine (23.75g) and lhydroxbenzotriazole
(14.75g), ethyl 3-[{[3-amino-4-(methylamino)phenyl]
carbonyl}-(pyridin-2-yl)amino]propanoate (25.0g) and 1-ethyl-3-(3’-dimethyl
aminopropyl)carbodiimide (23.75g) was added at room temperature. The reaction
mixture was stirred for 6 hours. The reaction mixture was cooled to 0-5ºC
followed by addition of hydrochloric acid (1N, 250ml). Solid precipitate was
19
filtered out and organic layer was separated from filtrate followed by washing of
organic layer with hydrochloric acid (1N), aqueous sodium bicarbonate and water.
The organic layer was dried over sodium sulfate and the solvent was distilled off.
Dichloromethane (50ml) is added again and distilled off under vacuum at 30-
35°C to obtain title compound as solid having purity 92% by HPLC.
Method B:A mixture of 2-[(4-cyanophenyl)amino]acetic acid (3.85g) in
dichloromethane (30ml) and dimethylformamide (0.1ml) was cooled to 20 ºC.
The temperature of reaction mixture was raised to 35-40 ºC for 1 hour and then
followed by cooling the resulting reaction mixture at 15-20 ºC. Adding ethyl 3-
[{[3-amino-4-(methylamino)phenyl]carbonyl}-(pyridin-2-yl)amino]propanoate
(5.0g) and N,N-carbonyldiimidazole (4.75g) to the reaction mixture. The reaction
mixture was stirred for 6 to 8 hours at 35-40 ºC and solvent was distilled off.
Dichloromethane (10ml) was added again and distilled off under vacuum at 30-
35°C to obtain title compound as solid having purity 93.2 % by HPLC.
Method C: To a mixture of 2-[(4-cyanophenyl)amino]acetic acid (2.3g), in ethyl
acetate (30ml), diisopropylethylamine (2.85g) and l-hydroxbenzotriazole (1.77g),
ethyl3-[{[3-amino-4-(methylamino)phenyl]carbonyl}-(pyridin-2-yl)amino]
propanoate (3.0g) and 1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide (2.85g)
was added at room temperature. The reaction mixture was stirred for 6 hours. The
reaction mixture was cooled to 0-5ºC followed by addition of hydrochloric acid (1
N, 30 ml). Solid precipitate was filtered out and organic layer was separated from
filtrate followed by washing of organic layer successively with HCl (1N), aqueous
sodium bicarbonate and water. The organic layer was dried over sodium sulfate
and solvent was distilled off under vacuum at 30-35ºC to obtain title compound as
solid having purity 92.75% by HPLC [yield-95%].
Example 2: Purification of 3-[(3-amino-4-{[2-(4-cyano-phenylamino)-acetyl]-
methyl-amino}-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester
Method A:3-[(3-Amino-4-{[2-(4-cyano-phenylamino)-acetyl]-methyl-amino}-
benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester (3.0g) was heated with
20
ethanol (150ml) at 80-84ºC to get a clear solution. Thereafter, reaction mixture
was cooled to ambient temperature and stirred for 3 hours. The resulting
crystalline solid was filtered, washed with ethanol (3ml) and dried to obtain title
compound having purity 99.12% by HPLC.
Method B: 3-[(3-Amino-4-{[2-(4-cyano-phenylamino)-acetyl]-methyl-amino}-
benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester (3.0 g) was treated with
ethyl acetate (150 ml) at room temperature. The temperature of the reaction
mixture was raised to 78-82 ºC to get a clear solution. The reaction mixture was
cooled to 25-30 ºC and stirred for 3 hours. The resulting 3-[(3-Amino-4-{[2-(4-
cyano-phenylamino)-acetyl]-methyl-amino}-benzoyl)-pyridin-2-yl-amino]-
propionic acid ethyl ester (3.0g) was dissolved in methyl isobutyl ketone (150ml)
at 90-100ºC. The reaction mixture was cooled and stirred for 3.0 hours. The
resulting compound was filtered washed with methyl isobutyl ketone (3ml) and
dried under vacuum at 45-50ºC to obtain title compound in crystalline form
having purity 99.79%.
Method C: 3-[(3-Amino-4-{[2-(4-cyano-phenylamino)-acetyl]-methyl-amino}-
benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester (3.0g) was dissolved in
acetone (30ml) at 60-70ºC. The reaction mixture was cooled to 30-35ºC and
methyl tert-butyl ether (90 ml) was added and stirred for 3 hours. The resulting
compound was filtered, washed with methyl tert-butyl ether (3ml), dried under
vacuum at 40-45ºC to give title compound (90%) in crystalline form having purity
99.56%.
Method D: 3-[(3-Amino-4-{[2-(4-cyano-phenylamino)-acetyl]-methyl-amino}-
benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester (3.0g) was dissolved in a
mixture of toluene (18ml) and ethanol (6.0ml) at 50-55ºC. The reaction mixture
was cooled to 30-35ºC and stirred for 6 hours, filtered, washed with toluene (3ml)
and dried under vacuum at 50-55ºC for 12 hours to give title compound in
crystalline form having purity 99.56 %.
21
Example 3: Preparation of 3-({2-[(4-cyano-phenylamino)-methyl]-1-methyl-
1H-benzoimidazole-5-carbonyl}-pyridin-2-yl-amino)-propionic acid ethyl
ester
Method A: 3-[(3-Amino-4-{[2-(4-cyano-phenylamino)-acetyl]-methyl-amino}-
benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester (20g) was heated in
glacial acetic acid (200ml) at 115-122ºC for 1 hour. After completion of reaction,
acetic acid was distilled off under vacuum at 55-60ºC and dichloromethane
(400ml) was added. The resulting solution was washed with water and organic
layer was dried over sodium sulfate. Dichloromethane was distilled off to give a
title compound having purity 95%. A portion of above crude compound was
recrystallized with isopropyl alcohol to obtain title compound having purity
98.65% by HPLC.
Method B: A mixture of 3-[(3-amino-4-{[2-(4-cyano-phenylamino)-acetyl]-
methyl-amino}-benzoyl)-pyridin -2-yl-amino]-propionic acid ethyl ester (4 g) in
ethyl acetate was heated with acetic acid (40 ml) at 75-80 ºC for 1 hour. After
completion of reaction, the reaction mixture was cooled and pH of the reaction
mixture was adjusted to 7.0-8.0 by using ammonia. The ethyl acetate was distilled
off under vacuum and dichloromethane (80 ml) was added. The resulting solution
was washed with water and organic layer was dried over sodium sulfate.
Dichloromethane was distilled off to give a title compound having purity 95.2 %.
A portion of above crude compound was recrystallized with a mixture of acetone
and ethyl acetate. The resulting compound was filtered, washed with acetone and
recrystallized using mixture of methanol and ethyl acetate, followed by washing
with ethyl acetate to obtain title compound having purity 98.7% by HPLC.
Example 4: Preparation of 3-({2-[(4-carbamimidoyl-phenylamino)-methyl]-
1-methyl-1H-benzoimidazole-5-carbonyl}-pyridin-2-yl-amino)-propionic acid
ethyl ester hydrochloride
3-({2-[(4-Cyano-phenylamino)-methyl]-1-methyl-1H-benzoimidazole-5-
carbonyl}-pyridin-2-yl-amino)-propionic acid ethyl ester (5g) was treated with
22
saturated ethanolic hydrochloric acid at room temperature for 6 hours. After
completion of reaction, solvent was distilled off. The resulting residue was
dissolved in ethanol (200ml) and treated with ammonium carbonate (9.3g) at
room temperature for 12.0 hours. Solvent was distilled off under vacuum and
ethanol (16ml) was added. The resulting solution was filtered to remove salts and
filtrate was distilled under vacuum to give crude compound, which was purified
using isopropyl alcohol to obtain title compound having purity 97.7% by HPLC.
Example 5: Preparation of Dabigatran Etexilate
To a mixture of 3-({2-[(4-carbamimidoyl-phenylamino)-methyl]-1-methyl-1Hbenzoimidazole-
5-carbonyl}-pyridin-2-yl-amino)-propionic acid ethyl ester
hydrochloride (2.5g) in tetrahydrofuran and demineralized water; n-hexyl
chloroformate (1.65g) and potassium carbonate (2.59g) were added and reaction
mixture was stirred for 2.0 hours at room temperature. After completion of
reaction, the reaction mixture was concentrated under vacuum at 40-45ºC. The
resulting product was taken in dichloromethane (46ml) washed with brine
solution. The organic layer was dried over sodium sulphate and solvent was
distilled off under vacuum. Methyl t-butyl ether (20ml) was added and stirred at
30-35ºC for 5 hours. The resulting compound was filtered, washed with methyl tbutyl
ether (5ml) and dried to give the title compound. The compound is found to
have purity 99.5% by HPLC.
Example 6: Preparation of Dabigatran Etexilate Mesylate:
Dabigatran etexilate (2.5g) was dissolved in acetone (17.5ml) and a solution of
methanesulfonic acid (0.04g) in acetone (1.6ml) was added at 25-30ºC and stirred
for 1 hour. Thereafter reaction mass was cooled to 17-23ºC, filtered and washed
with acetone (12.5ml).The resulting product was treated with ethyl acetate (25ml),
stirred for 1.0 hour at 25-30ºC, filtered, washed with ethylacetate (2.5ml) and
dried to obtain title compound having purity 99.8% by HPLC.
23
WE CLAIM
1. A process for the preparation of dabigatran etexilate of formula I and
pharmaceutically acceptable salts thereof
N
N
HN
N
O
N
O
OEt
N
O
O
NH2
Formula I
comprises:
a). condensing (4-cyano-phenylamino)-acetic acid compound of formula
IV;
NC
NH
COOH
Formula IV
with 3-[(3-amino-4-methylamino-benzoyl)-pyridin-2-yl-amino]-propionic
acid ethyl ester compound of formula V;
NH
NH2
CH3
N
O
N
O
OEt
Formula V
in presence of a suitable coupling agent, optionally a base, in a suitable solvent;
b). isolating the intermediate of formula III as solid;
N
O
N
O
OEt
N
H3C
O
NH
NH2
CN
Formula III
24
c). optionally purifying the resulting intermediate of formula III from a
suitable solvent;
d). cyclizing the intermediate of formula III in presence of an acid to give
cyano compound of formula II;
N
N
HN CN
N
O
N
O
OEt
Formula II
e). optionally purifying the resulting cyano compound of formula II from
a suitable solvent; and
f). converting cyano compound of formula II into dabigatran etexilate or
pharmaceutically acceptable salt thereof.
2. The process as claimed in claim 1, wherein in step a) coupling agent is
selected from N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide,
N,N'-carbonyldiimidazole, carbonyl-di-(1,2,4-triazole), 1-ethyl-3-(3’-dimethyl
aminopropyl)carbodiimide preferably selected from 1-ethyl-3-(3’-
dimethylamino propyl) carbodiimide: base is selected from triethyl amine, 4-
methylmorpholine, 4-ethylmorpholine, diisopropylethylamine, 2,6-di-tertbutyl-
4-methylpyridine, 1,1,3,3-tetramethylguanidine
3. The process as claimed in claim 1, wherein in step a) solvent is selected from
halogenated solvents, esters, hydrocarbons, protic or aprotic solvents,
preferably dichloromethane and ethyl acetate.
4. The process as claimed in claim 1, wherein in step c) solvent used for
purifying isolated compound of formula III is selected from alcohol, ester,
ketone, hydrocarbon or mixtures thereof.
5. The process as claimed in claim 1, wherein in step d) acid is selected from
formic acid, hydrochloric acid, phosphoric acid, tri-chloro acetic acid, trifluoro
acetic acid and acetic acid.
25
6. The process as claimed in claim 1, wherein in step e) cyano compound of
formula II is purified using solvent selected from alcohols, esters, ketones,
halogenated solvents, nitriles, protic/aprotic solvents, ethers, hydrocarbons
preferably selected from isopropanol, ethyl acetate, acetone.
7. An isolated compound of formula III in solid form.
N
O
N
O
OEt
N
H3C
O
NH
NH2
CN
Formula III
8. The solid intermediate of formula III as claimed in claim 7 is crystalline,
amorphous or mixtures thereof.
9. A process for the preparation of dabigatran etexilate of formula I and
pharmaceutically acceptable salts thereof, using isolated solid intermediate of
formula III as claimed in claim 7.
10. A process for the preparation of cyano compound of formula II, comprises:
a). condensing (4-cyano-phenylamino)-acetic acid compound of formula
IV with 3-[(3-amino-4-methylamino-benzoyl)-pyridin-2-yl-amino]-
propionic acid ethyl ester compound of formula V in the presence of a
suitable coupling agent, optionally a base in a suitable solvent;
b). isolating the intermediate of formula III as solid;
c). cyclizing the intermediate of formula III in presence of an acid to give
cyano compound of formula II.