An improved Process for the preparation of Dabigatran Etexilate
or its salts thereof
Field of the Invention
The present invention relates to the process for the preparation of N-[[2-[[[4-
[[[~exyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]- 1 -methyl- 1 Hbenzimidazol-
5-yl]carbonyl]-N-2-pyridinyl ethyl ester known as dabigatran etexilate or its
methanesulfonate salt commonly known as dabigatran etexilate mesylate.
Background of the Invention
N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomeyl]phenyl]amino]methyl]- 1 -methyl- 1 Hbenzimidazol-
5-yl]carbonyl]-N-2-pyridinyle thyl ester methanesulfonate is commonly known
as dabigatran etexilate mesylate: Dabigatran etexilate mesylate is an anticoagulant drug
selected from the class of the direct thrombin inhibitors developed by Boehringer Ingelheim
and is used for the treatment of thrombosis, cardiovascular diseases and the like. Dabigatran
etexilate mesylate was approved both in US and Europe and commercially available under
the brand name of Pradaxa. Dabigatran etexilate (1) and its methanesulfonate salt (la) is
represented by the following structural formulas:
Dabigatran etexilate (1)
Dabigatran etexilate mesylate (la)
Dabigatran etexilate and process for its preparation was first disclosed in WO 98137075.
According to the process disclosed in WO 98/37075,4-methylamino-3-nitro-benzocyhll oride
(2) was reacted with 3-(pyridin-2-y1amino)propionic acid ethyl ester in the presence of a base
and a solvent to give 3-[(4-methylamino-3-nitrophenyl)carbonyl-pyridin-2-ylaminolpropionic
acid ethylester (3). Comp~und(3 ) was hydrogenated to yield 3-[{[3-amino-
4-(methylamino)phenyl]carbonyl)(pyridin-2-yl)amino]propionic acid ethyl ester (4) which
on further cyclization in presence of a cyclising agent and 4-cyanophenyl glycine (5) yield 3-
((2-[(4-cyanophenylamino)methyl]- 1 -methyl- 1 H-benzoimidazole-5-carbony1)pyridin-2-ylarnino)
propionic acid ethyl ester (6). The compound of formula (6) was treated with saturated
ethanolic hydrochloric acid and ammonium carbonate to give a 1-methyl-2-[N-(4-
amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridy1)-N-(2-ethoxy
carbonylethy1)amide hydrochloride (7) which on further hydrolysis with a base in the
presence of ethanol provides compound of formula (8). Compound of formula '(7) can be
coupled with n-hexyl chloroformate and a base to yield dabigatran etexilate (I), (Scheme 1).
I
HN Q lo%PdlC - -0 SOCI,ITEAA'HF -O. N+
0 0 0 .
0 0
CI
. (2) (3) (4) 1 CDllTHFlAcetic acid I 4-Cyanophenyl glycine (5)
I .
,N
Sat.ethanol.HC1
N- qoadmmonium 4 carbonate - 0 0
I /n-hexyl
W02006/000353 provides the process for the preparation of dabigatran etexilate mesylate
starting from 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid (9). Compound of
formula (9) was condensed with 3-[{[3-amino-4-(methylamino)phenyl]carbonyl)(pyridin-2-
yl)amino]propionic acid ethyl ester (4) in presence of CDI 1 PPA / pivaloyl chloride
followed by treatment with acetic acid to give a compound of formula (10) which was
reduced with palladiwn/charcoal in presence of hydrogen to give 1-methyl-2-[N-[4-
'amidinophenyl]aminomethyl]benzimidazol-5-ylcarboxylic acid-N-(2-pyridy1)-N-(2-
ethoxycarbonylethyl)amide, and further treated with PTSA to give salt of formula (1 1).
Compound of formula (1 1) was treated with n-hexyl chloroformate in the presence of a base
to yield dabigatran etexilate (I) which on further treatment with methanesulphonic acid yields
dabigatran etexilate mesylate (1 a), (Scheme 2).
1 1. PPAlTHF or CDI/THF or pivaloyl
chloride
2. AcOH. EtOH or AcOH
CH3
1 1. H2, PdIC, EtOH, AcOH
2. PTSA, EtOH
CH3
The process for the preparation of mesylate salt of dabigatran etexilate and its polymorphic
forms was disclosed in US 20051234104. The disclosed process involves the reaction of
dabigatran etexilate with methanesulphonic acid in acetone to provide dabigatran etexilate
mesylate (1 a).
US20060183779Al discloses process for the preparation of mesylate salt of dabigatran
etexilate and its oral administration application. The disclosed process involves the reaction
of dabigatran etexilate with methanesulphonic acid in ethylacetate to provide dabigatran
etexilate mesylate (1 a).
US20 1 10082299A 1 provides a process for the preparation of dabigatran etexilate (1). 4-
Methylamino-3-nitrobenzoic acid compound of formula (12) was reacted with ethyl-3-
(pyridin-2-ylamino)propanoate, and was converted to the hydrochloride using a hydrogen
chloride solution to give ethyl 3-[(4-methylamino)-3-nitrobenzoy1)pyridine-2-
ylaminolpropionate compound of formula (1 3), in which the nitro group is reduced by means
of reaction with sodium dithionite. The resulting compound ethyl 3-[(4-methylamino)-3-
aminobenzoy1)pyridine-2-ylamino]propionate of formula (4) is reacted with [(4-
cyanophenyl)amino]acetic acid (5) in presence of carbonyldiimidazole/THF/acetic
acid/oxalic acid to give a compound of formula (14). The compound of formula (14) is
treated with an acid, which on further reaction with ammonium carbonate provides the
intermediate of formula (7). The intermediate compound of formula (7) was further converted
to dabigatran etexilate (1) by reacting with n-hexyl chloroformate, (Scheme 3).
Scheme3
a N/H M e +
Q J 1. s0cI2,c at,, DMF w N oN ~ ~ doEt .HcI
HOOC NO2 NH OE~ 23.. THECN~TIEH~FO H
(1 2)
NHMe
(1 3)
acid 1. CDI N N
THF O%hoc, \ 2. Acetic acid NH C O O H + OkNH' 3. Oxalic acid NHf
(14) (5) (4)
HCI
O%ibNai: \ TEN n-hexyl chloroformate/chloroform
(7) US201 11022444 1A1, US20 1 1102950 18A1, US78800 16B2 etc also discloses the possible
methods of preparing dabigatran etexilate, its salts and- intermediates thereof.
It is known that synthetic compounds can contain extraneous compounds or impurities
resulting from their synthesis or degradation. The impurities can be unreacted starting
I materials, by-products of the reaction, products of side reactions, or degradation products.
1 Generally, impurities in a compound may arise from degradation of the compound itself, or
during the preparation of the API. Impu~ities in dabigatran etexilate or any active
pharmaceutical ingredient (API) are undesirable and might be harmful, as they would be
carried over to pharmaceutical compositions, used for human consumption.
Regulatory authorities worldwide require drug manufactures to isolate, identify and
characterize the impurities in their products. Furthermore, it is required to control the levels
of these impurities in the final drug substance obtained by the manufacturing process and to
ensure that the impurity is present in the lowest possible levels and' within the limits, even if
structural determination is not possible.
The processes disclosed above for the preparation of dabigatran, its esters and salts thereof
have one or other drawbacks, ranging from low yields, low purity, complicated purifying
operations and extremely onerous process with respect to manufacturing as it generates large
amount of solid waste to be disposed etc.
Thus, there remains a need to develop an industrial friendly, substantially free of impurities
process for the preparation of dabigatran, its esters and 'salts thereof on commercially
economical scale and yielding high purity with higher yields.
Description of the Drawings
FIG. 1 represents a powder X-ray diffractogram of ethyl 3-(2-(((4-cyanopheny1)amino)
methyl)- 1 -methyl-N-(pyridin-2-y1)- 1 H-benzo[dJimidazole-5-carboxamido)propanoate.
FIG. 2 represents a powder X-ray diffractogram of ethyl 3-(2-(((4-carbamimidoyl
pheny1)amino)methyl)- 1 -methyl-N-(pyridin-2-y1)- 1 H-benzo[~imidazole-5-carboxamid0)-
propanoate hydrochloride
FIG. 3 represents a powder X-ray diffractogram of dabigatran etexilate.
FIG. 4 represents a powder X-ray diffractogram of dabigatran etexilate mesylate.
FIG. 5 represents a differential scanning calorimetry (DSC) of dabigatran etexilate mesylate.
Summary of the Invention
The present invention relates to the process for the preparation of N-[[2-[[[4-
benzimidazol-5-yl]carbonyl]-N-2-pyridinyl ethyl ester known as dabigatran etexilate
compound of formula (1) or its salt; preferably methanesulfonate salt (1 a).
It is an another object of the present invention to provide a simple, convenient, commercially
viable, industrial friendly proce'ss for synthesizing dabigatran etexilate or its salt thereof.
In an another object of present invention, it provides a process for preparation of dabigatran
etexilate (1) or its methanesulfonate salt (la) which comprises the steps of: (a) reacting 3-
[{[3-amino-4-(methylamino)phenyl]carbonyl) (pyridin-2-yl)amino]propionic acid ethyl ester
compound of formula (4) with N-(4-cyanophenyl) glycine compound of formula (5) to obtain
3 -({2-[(4-cyanophenylamino)methyl]- 1 -methyl- 1 H-benzoimidazole-5-carbony1)pyridin-2-ylarnino)
propionic acid ethyl ester compound of formula (6); (b) reacting compound of formula
(6) with saturated ethanolic hydrochloric acid and ammonium carbonate to give l-methyl-2-
[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridy1)-N-(2-
ethoxy carbonylethy1)amide hydrochloride compound of formula (7); (c) reacting compound
of formula (7) with n-hexyl chloroformate and a base to obtain dabigatran etexilate (1) (d)
reacting dabigatran etexilate compound of formula (1) with an acid to obtain dabigatran
etexilate acid addition salt preferably mesylate salt (la).
A yet another object of the present invention provides a process for producing dabigatran
etexilate (1) or its methanesulfonate salt (la) which comprises use of single solvent in all the
steps of the above mentioned process.
A yet another object of the present invention provides a process for producing dabigatran
etexilate (1) or its methanesulfonate salt (la) which comprises use of single solvent in the
above mentioned process till the formation of 1 -methyl-2-[N-(4-
amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridy1)-N-(2-ethoxy
carbonylethy1)amide hydrochloride compound of formula (7), starting from 3-[{[3-amino-4-
(methylmino)phenyl)carbonyl)(pyridin-2-yl)amino]propionic acid ethyl ester compound of
formula (4).
A yet another object of the present invention. provides a process for producing dabigatran
etexilate (1) or its methanesulfonate salt (la) which comprises use of single solvent in all the
1 .
I ' *
I '
! steps of the above mentioned process, wherein the solvent is preferably selected from ester
solvents such as ethyl acetate and the like.
In an another object of present invention, it provides a process for preparation of dabigatran
etexilate methanesulfonate salt (1 a) which comprises the steps of reacting dabigatran etexilate
with methanesuphonic acid at a temperature of about 55OC to about refluxing temperature of
the solvent.
In an another object of present invention, it provides a process for preparation of dabigatran
etexilate (I) or its methanesulfonate salt (la) which comprises the step of purifying
dabigatran etexilate using any purification technique; such as acid base treatment or
purification of dabigatran etexilate using a suitable solvent or mixture thereof.
In an another object of present invention, it provides powder X-ray diffractogram of ethyl 3-
(2-(((4-cyanopheny1)amino) methyl)- 1 -methyl-N-(pyridin-2-y1)-1 H-benzo[~imidazole-5-
carboxamido)propanoate as depicted in fig 1
In an another object of present invention, it provides powder X-ray diffractogram of ethyl 3-
(2-(((4-carbamimidoyl pheny1)amino)methyl)- 1 -methyl-N-(pyridin-2-y1)- 1 Hbenzo[~
imidazole-5-carboxamid0)-propanoathey drochloride as depicted in fig 2.
In an another object of present invention, it provides powder X-ray diffractogram of
dabigatran etexilate as depicted in fig 3.
In an another object of present invention, it provides powder X-ray diffiactogram of
dabigatran etexilate mesylate, as depicted in fig 4.
In an another object of present invention, it provides differential scanning calorimetry (DSC)
of dabigatran etexilate mesylate, as depicted in fig 5.
The above and other objects are further attained and supported by the following embodiments
described herein. However the scope of the invention is not restricted to described
embodiments herein after.
Detailed Description of the Invention
In an object the present invention provides a process for preparation of dabigatran etexilate
(1) or its salts preferably methanesulfonate salt (1 a) (Scheme 4) comprising the steps of:
a) reacting 3-[{[3 -amino-4-(methylamino)phenyl]carbonyl} (pyridin-2-yl)amino]
propionic acid ethyl ester compound of formula (4) with N-(4-cyanophenyl) glycine
compound of formula (5) to obtain 3-((2-[(4-cyanophenylamino)methyl]- 1 -methyl-
1H-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)propionic acid ethyl ester
compound of formula (6);
b) reacting compound of formula (6) with saturated ethanolic hydrochloric acid and
ammonium carbonate to give 1 -methyl-2-[N-(4-
amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridy1)-N-(2-
ethoxy carbonylethy1)amide hydrochloride compound of formula (7);
c) reacting compound of formula (7) with n-hexyl chloroformate and'a base to obtain
dabigatran etexilate (1) ;
d)' optionally, purifying dabigatran etexilate (1) ;
e) optionally, converting dabigatran etexilate into to its salt (1 a) and
f) optionally purifying dabigatran etexilate mesylate (la) using a suitable solvent or
mixture thereof.
In an object the present invention provides a process for preparation of dabigatran etexilate
(1) or its salts preferably methanesulfonate salt (la) (Scheme 4) comprising the steps of:
a) reacting 3 -[{[3-amino-4-(methylamino)phenyl)carbonyl} (pyridin-2-yl)amino]
propionic acid ethyl ester compound of formula (4) with 4-cyanophenyl glycine
compound of formula (5) in presence of suitable solvent and a coupling agent orland
additive to obtain compound of formula (6a) which is further cyclized, with or
without isolation, to 3-((2-[(4-cyanophenylamino)methyl]- 1 -methyl- 1 Hb
e n z o i m i d a z o l e - 5 - c a r b o n y l } P y r i d i n - 2 - y l - ~ cac id ethyl ester compound .
of formula (6);
b) reacting compound of formula (6) with saturated ethanolic hydrochloric acid to obtain
compound of formula (7a) followed by treatment with ammonium carbonate to obtain
compound of formula (7) which is further converted, with or without isolation, to 1-
(2-pyridy1)-N-(2-ethoxy carbonylethy1)amide hydrochloride compound of formula
(7);
c) reacting compound of formula (4) with n-hexyl chloroformate and a base to obtain
I dabigatran etexilate (1) ;
I d) optionally, purifiying dabigatran etexilate (1) using any purification technique, such
I as acid base treatment or purification of dabigatran etexilate using a suitable solvent
I or mixture thereof;
I e) optionally, converting dabigatran etexilate into to its salt (la) and
I f) optionally purifying dabigatran etexilate mesylate (la) using a suitable solvent or
I mixture thereof.
I Scheme 4
NH 1 AcOH
CH3 CH3
HCI
CH3
0
NH' 0
Et3N
DCM I Water
CH3
A yet another object of the present invention provides a process for producing dabigatran
etexilate (1) or its methanesulfonate salt (la) which comprises use of single solvent in all the
steps of the above mentioned process.
A yet another object of the present invention provides a process for producing dabigatran
-/ etexilate (1) or its methanesulfonate salt (la) which comprises use of single solvent in the
above mentioned process till the formation of 1 -methyl-2-[N-(4-
amidinophenyl)aminomethyl]bemimidazol-5-yl-carboxylic acid-N-(2-pyridy1)-N-(2-ethoxy
carbonylethy1)amide hydrochloride compound of formula (7), starting from 3-[{[3-amino-4-
(methylamino)phenyl)carbonyl)~yridin-2-yl)amino]propionic acid ethyl ester compound of
formula (4).
A yet another object of the present invention provides a process for producing dabigatran
etexilate (1) or its methanesulfonate salt (la) which comprises use of single solvent in all the
steps of 'the above mentioned process, wherein the solvent is preferably selected from ester
solvents such as ethyl acetate and the like.
In an another object of present invention, it provides a process for preparation of dabigatran
etexilate methanesulfonate salt (1 a) which comprises the steps of reacting dabigatran etexilate
with methanesuphonic acid at a temperature of about 55OC to about refluxing temperature of
the solvent.
In an another object of present invention, it provides a process for preparation of dabigatran
etexilate (1) or its methanesulfonate salt (la) which comprises the step of purifying
dabigatran etexilate using any purification technique; such as acid base treatment or
purification of dabigatran etexilate using a suitable solvent or mixture thereof.
In an another object of present invention, it provides powder X-ray diffractogram of ethyl 3-
(2-(((4-cyanophenyl)amino) methyl)- 1- methyl-N-byridin-2-y1)1-H -benzo[dJimidazole-5-
carboxamido)propanoate as depicted in fig 1.
In an another object of present invention, it provides powder X-ray diffractogram of ethyl 3-
(2-(((4-carbamimidoyl pheny1)amino)methyl)- 1 -methyl-N-byridin-2-y1)- 1 Hbenzo[
d]imidazo'le-5-carboxamido)-propanoate hydrochloride as'depicted in fig 2.
In an another object of present invention, it provides powder X-ray diffractogram of
dabigatran etexilate as depicted in fig 3.
-. In an another object of present invention, it provides powder X-ray diffractogram of
dabigatran etexilate mesylate, as depicted in fig 4.
In an another object of present invention, it provides differential scanning calorimetry (DSC)
of dabigatran etexilate mesylate, as depicted in fig 5.
The solvent used in any of the above mentioned processes can be selected from the group
comprising of nitriles, alcohols, ketones, esters, halogenated hydrocarbons, ethers, amides,
dialkylsulfoxides, hydrocarbons, water or the mixtures thereof. Nitriles are selected from the
group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like,
preferably acetonitrile. Alcohols are selected from the group comprising of methanol,
ethanol, n-propanol, isopropanol, n-butanol and the like. Ketones are selected from the group
comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like.
! Esters as defined above are selected from the group comprising of ethyl acetate, propyl
acetate, isopropyl acetate, butyl acetate and the like. Halogenated hydrocarbons are selected
from the group comprising of dichloromethane (DCM), chloroform, dichloroethane,
chlorobenzene and the like. Ethers are selected from the group comprising of diethyl ether,
methyl tert-butyl ether (MTBE), .diisopropyl ether, tetrahydrofuran (THF), dioxane and the
like. Amides are selected from the group comprising of N, N-dimethylformamide (DMF), N,
N-dimethylacetamide (DMA), N-methylformamide, N-methylpyrrolidone and the like.
Dialkyl sulfoxides can be selected from the group comprising of dimethylsulfoxide,
diethylsulfoxide, dibutylsulfoxide and the like. Aliphatic hydrocarbons are selected from the
group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, octane,
cyclohexane, cyclopentane and the like. Aromatic hydrocarbons are selected from the group
comprising of toluene, xylene and the like. The solvent is preferably selected from ester
solvents more preferably ethyl acetate.
A suitable base as defined above can be selected from a group comprising of an organic or
inorganic bases. The inorganic base is selected from group comprising of carbonates,
bicarbonates, hydroxides of alkali and alkaline earth metals and the like. Organic base is
selected from the group comprising of triethylamine (TEA), N,N-diisopropylethylamine,
tributylamine, triisopropylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 13-
diazabicyclo[4.3 .O]non-Sene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-
dimethylarninopyridine (4-DMAP), 1,8-bis-(dimethylamino)naphthalene, 1 -ethylpiperidine,
1-methylmorpholine, lutidine and mixtures thereof. Carbonates are selected from the group
comprising of K2CO3, Cs2C03 and Na2C03 etc. Bicarbonates are selected from the group
comprising of NaHC03, MC03 etc. Hydroxides are selected from the group comprising of
NaOH, KOH, LiOH, CsOH etc.
Coupling agents used for the coupling of 3-[{[3-amino-4-
(methylamino)phenyl]carbonyl) (pyridin-2-yl)amino] propionic acid ethyl ester compound of
formula (4) with N-(4-cyanophenyl) glycine compound of formula (5) to obtain dabigatran
etexilate (1) with or without additives can be selected from diisopropylcarbodiimide (DIC),
N,N'-carbonyldiimidazole (CDI), (benzotriazol- 1 -yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate (BOP), benzotriazol- 1 -yl-oxytripyrrolidinophosphonium
1
I hexafluorophosphate (PyBOP), (7-azabenzotriazol- 1 -yloxy)tripyrrolid~nophosphonium
hexafluorophosphate (PyAOP), 0-(benzotriazol- 1 -yl)-N,N,N1,N'-tetramethyluronium
tetrafluoroborate (TBTU), 1 H-benzotriazolium 1 -[bis(dimethylamino)methylene]
-5chloro-,hexafluorophosphate (1-),3-oxide (HCTU), O-(benzotriazol-l-yl)-N,N,N',Nytetramethyluronium
hexafluorophosphate (HBTU), N,NY-dicyclohexylcarbodimide( DCC),
N-(3-dimethylaminopropy1)-NY-ethylcarbonate(E DC) and the like.
The additives used for the coupling of 3-[{[3-amino-4-
(methylamino)phenyl]carbonyl)(pyridin-2-yl)amino] propionic acid ethyl ester compound of
formula (4) with N-(4-cyanophenyl) glycine compound of formula (5) can be selected fiom a
group comprising of 4-dimethylaminopyridine (4-DMAP), diisopropylethylamine (DIPEA),
2-methylpyridine, 2,6-dimethylpyridine (lutidine), 2,4,6-trimethylpyridine (collidine), 4-
(tetrahydropyrr01idinyl)pyridine~ imidazole, N-methylimidazole, diazabicycloundecane
(DABCO), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboximide
(HONB), 1 -hydroxybenzotriazole (HOBt), 6-chloro- 1 -hydroxybenzotriazole (Cl-HOBt), 1 -
hydroxy-7-azabenzotriazole (HOAt) and 3 -hydroxy-4-0x0-3,4-dihydrol-,2 ,3-benzotriazine
(HODhbt), its aza derivative (HODhat) and the like, preferably 4-dimethylaminopyridine (4-
DMAP).
A suitable salt as defined above can be selected fiom an acid salt formed. fiom group
comprising of an organic or inorganic acids. Organic acid is selected from the group
comprising of methane sulphonic acid, benzene sulphonic acid, acetic acid, tartaric acid,
malic acid, maleic acid etc. The inorganic acid is selected from group comprising of
hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid and the like.
A process for preparation of dabigatran etexilate (1) or its methanesulfonate salt (la) which
comprises the steps of reacting dabigatran etexilate with methanesuphonic acid is at a
temperature of about 5S°C to about refluxing temperature of the solvent. Further, the process
comprises of the step of purifying dabigatran etexilate using any purification technique;
including acid base treatment or purification of dabigatran etexilate using a suitable solvent
or mixture thereof.
In another aspect there is provided a pharmaceutical composition that includes a
therapeutically effective amount of dabigatran etexilate (I) prepared according to the process
of the present invention and one or more pharmaceutically acceptable carriers, excipients or
diluents.
In another aspect there is provided a pharmaceutical composition that iricludes a
therapeutically effective amount of dabigatran etexilate mesylate (la) prepared according to
the process of the present invention and one or more pharmaceutically acceptable carriers,
excipients or diluents.
The details of the process of the invention are provided in the Examples given below, which
are provided by way of illustration only and therefore are not intended to limit the scope of
the invention.
Examples
Example-1
Preparation of ethyl 3-(2-(((4-cyanopheny1)amino) methyl)-1-methyl-N-(pyridin-2-y1)-1HCDI
(59 g) was added to a mixture of (4-cyanopheny1)glycine (64.38) in' ethyl acetate
(600mL) and maintained at room temperature for 3 hrs. Ethyl 3-(3-amino-4-(methylamino)-
N-(pyridin-2-y1)benzamido) propanoate (100g) was added and maintained for 3 hrs at 40-45'
1
C. After the completion of reaction, glacial acetic acid (100mL) was added and stirred at 75- 8 0 ' ~fo r 3 hrs. Water was then added and layers were separated. The organic layer was
concentrated and ethyl acetate and 5% aq. sodium bicarbonate was added to the reaction
mixture and stirred for 2 hrs at room temperature. Slurry obtained was filtered and dried
under vacuum (Yield: 120g).
Example-2
Preparation of ethyl 3-(2-(((4-carbamimidoyl pheny1)amino)methyl)-1-methyl-N-
(pyridin-2-yl)-1H-benzo[~imidazole-5-carboxamido)propanoathe ydrochloride
Ethyl-3-(2-(((4-cyanopheny1)amino)methyl)- 1 -methyl-N-(pyridin-2-y1)- 1 H-benzo[dJimidazole-
5-carboxamido)propanoate (1 00g) in ethanol (5OOinL) was saturated with dry HC1
gas for 6-7 hrs and maintained at room temperature for 6-7 hrs. Reaction mixture was
concentrated under vacuum. Ethanol (1000mL) was added to the concentrated mass and the
temperature was maintained for 10-15 min at 40-45°C. Ammonium carbonate (200g) was
added and stirred for 2-3 hrs at 40-45°C. Reaction mass was filtered and washed with
ethanol. Concentrated the filtrate mother liquor to approximately 50% under vacuum and
stirred at room temperature for 12- 15 hrs. Filtered the reaction mass, washed and dried under
vacuum (Yield: 80g).
Example3
Preparation of Ethyl 3-(2-(((4-(N-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)-
methyl)-1-methyl-N-(pyridin-2-y1)-1H-benzo[ dli midazole-5-carboxamido)propanoate
(Dabigatran etexilate) .
Triethylamine (26 g) was added to ethyl 3-(2-(((4-carbamimidoyl pheny1)amino)methyl)-1-
methyl-N-(pyridin-2-y1)- 1 H-benzo[dJimidazole-5-carboxmido)-propanoate hydrochloride
(50g) in a 1:l mixture of dichloromethane and water. N-hexyl chloroformate (18 g) was
added to the reaction mixture at room temperature and maintained for 1 hr. pH of the reaction
mixture was adjusted to 1-1.5 and layers were partitioned. pH was adjusted again to 7.5-8.5
after adding water (100ml) to the organic layer. Layers were partitioned and concentrated the
organic layer under vacuum. Ethyl acetate (500mL) was added and heated up to 7540°C for
30 min. Reaction mixture was cooled to room temperature and stirred for 15 hrs. Filtered the
reaction mass, washed with ethyl acetate and dried under vacuum (Yield: 37.58).
Example-4
Preparation of dabigatran etexilate mesylate
Ethyl 3-(2-(((4-(N-((hexyloxy)carbonyl)carbamimidoyl)phenyl)mino)methyl)- 1 -methyl-N-
(pyridin-2-yl)-1H-benzo[~imidazole-5-carboxamido)propanoate (20g) in ethyl acetate
(400mL) was heated up to 60-65OC and maintained for 30 min. Methanesulfonic acid (3.1 g)
was added and maintained for another 30 min. Reaction mixture was cooled to 20-30°C and
maintained for 2-3 hrs. Filtered the reaction mass, washed and dried under vacuum (Yield:
22g).
I
I
Claims:
1. A process for the preparation of dabigatran etexilate (1) or its salt thereof from
comprising the steps of:
a) reacting 3 -[{[3 -amino-4-(methylamino)phenyl)carbonyl} (pyridin-2-yl)amino]
propionic acid ethyl ester compound of formula (4) with N-(4-cyanophenyl)
glycine compound of formula (5) to obtain 3-((2-[(4-cyanophenylamino)methyl]-
1 -methyl- 1H -benzoimidazole-5-carbonyl}pyridin-2-yl-amino)propioniacc id ethyl
ester compound of formula (6);
b) reacting compound of formula (6) with saturated ethanolic hydrochloric acid and
ammonium carbonate to give 1 -methyl-2-[N-(4-
amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridy1)-N-
(2-ethoxy carbonylethy1)amide hydrochloride compound of formula (7);
c) reacting compound of formula (7) with n-hexyl chloroformate and a base to obtain
dabigatran etexilate (1) ;
d) optionally, purifying dabigatran etexilate (1) ;
e) optionally, converting dabigatran etexilate into to its salt (la) and
f) optionally purifying of dabigatran etexilate mesylate (la) using a suitable solvent
or mixture thereof.
2. A process for the preparation of dabigatran etexilate (1) or its salt thereof from
comprising the steps of:
a) reacting 3-[{[3-amino-4-(methylamino)phenyl)carbonyl} (pyridin-2-yl)arnino]
propionic acid ethyl ester compound of formula (4) with N-(4-cyanophenyl)
glycine compound of formula (5) in presence of suitable solvent and a coupling
agent orland additive to obtain compound of formula (6a) which is further
cyclized, with or without isolation, to 3-((2-[(4-cyanophenylamino)methyl]-1-
methyl-lH-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)propionic acid ethyl
ester compound of formula (6);
b) reacting compound of formula (6) with saturated ethanolic hydrochloric acid and
ammonium carbonate to obtain compound of formula (7a) which is further
converted, with or without isolation, to 1-methyl-2-IN-(4-
I amidinophenyl)aminomethyl] benzimidazol-5-yl-carboxylic acid-N-(2-pyridy1)-
N-(2-ethoxy carbonylethy1)amide hydrochloride compound of formula (7);
c) reacting compound of formula (7) with n-hexyl chloroformate and a base to obtain
dabigatran etexilate (1) ;
d) optionally, purifiying dabigatran etexilate (1) using any purification technique,
such as acid base treatment or purification of dabigatran etexilate using a suitable
solvent or mixture thereof;
e) optionally, converting dabigatran etexilate into to its salt (1 a) and ~ f) optionally purifying dabigatran etexilate mesylate (la) using a suitable solvent or ~ mixture thereof.
3. A process for the preparation of dabigatran etexilate (1) or its salt thereof according
to any of the proceeding claims which comprises use of single solvent in all the steps.
4. A process for the preparation of dabigatran etexilate (1) or its salt thereof according to
any of the proceeding claims which comprises use of single solvent in the above
mentioned processes till the formation of 1 -methyl-2-[N-(4-
amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridy1)-N-(2-
ethoxy carbonylethy1)amide hydrochloride compound of formula (7), starting from 3-
[{[3-amino-4-(methylarnino)phenyl)carbonyl) (pyridin-2-yl)amino]propionic ' acid
ethyl ester compound of formula (4).
5. A process for the preparation of dabigatran etexilate (1) or its salt thereof according to
any of the proceeding claims which comprises use of single solvent in all the steps of
the above mentioned process, wherein the solvent is preferably selected from ester
solvents more preferably ethyl acetate. ' '
6. A process fo'r the preparation of dabigatran etexilate methanesulfonate salt (1 a) which
comprises the step of reacting dabigatran etexilate with methanesuphonic acid at a
temperature of about 55°C to about refluxing temperature of the 'solvent.
7. A process for the preparation of dabigatran etexilate (1) or its salts thereof according
to any of the proceeding claims which comprises the step of purifying dabigatran
etexilate using any purification. technique; including acid base treatment or
purification of dabigatran etexilate using a suitable solvent or mixture thereof.
8. A process according to any of the preceding claims, wherein
a) solvent used is selected from the group con~prising of nitriles selected fi-om
acetonitrile, propionitrile, butyronitrile, valeronitrile; alcohols selected from
methanol, ethanol, n-propanol, isopropanol, n-butanol; ketones selected from acetone,
methyl ethyl ketone, methyl isobutyl ketone; esters selected from ethyl acetate, propyl
acetate, isopropyl acetate, butyl acetate; halogenated hydrocarbons selected from
dichloromethane (BCM), chloroform, dichloroethane, chlorobenzene; ethers selected
from diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran
dioxane; amides selected from N,N-dimethylformamide (DMF), N,Ndimethylacetamide
(DMA), N-methylformamide; dialkylsulfoxides selected from
dimethylsulfoxide, diethylsulfoxide, dibutylsulfoxide, water and mixtures thereof;
b) base used is selected from the organic or inorganic bases selected from the group
comprising of mines, carbonate, bicarbonate and hydroxides of alkali or alkaline
earth metals selected from triethylamine (TEA), N,N-diisopropylethylamine (DIPEA),
tributylamine, triisopropylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), 1,5-diazabicyclo[4.3 .O]non-Sene (DBN), 1,4-diazabicyclo[2.2.2]octanc
(DABCO), 4-dimethylaminopyridine (4-DMAP), 1,8-bis-
(dimethylamino)naphthalene), 1 -ethylpiperidine, 1 -methylmorpholine, lutidine,
K2CO3, Cs2C03 and Na2C03, NaHC03, KHC03, NaOH, KOH, LiOH and CsOH;
c) coupling agent used can be with or without additives wherein coupling agent is
selected from the group comprising of diisopropylcarbodiimide (DIC), N,NYcarbonyldiimidazole
(CDI), (benzotriazol- 1 -yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate (BOP), benzotriazol- 1 -yl-oxytripyrrolidinophosphonium
hexafluorophosphate (PyBOP), (7-azabenzotriazol- 1 -
yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), 0-(benzotriazol- 1 -
y1)-N,N,N',N1-tetramethyluroniumte trafluoroborate (TBTU), 1H -benzotriazolium 1-
[bis(dimethylamino)methylene]-5chloro-,hexafluorophosphate (I-),3-oxide (HCTU),
0-(benzotriazol- 1 -yl)-N,N,N ';N'-tetramethyluronium hexafluorophosphate (HBTU),
N,N'-dicyclohexylcarbodimide (DCC), N-(3-dimethylaminopropy1)-N'-
ethylcarbonate (EDC); and additives can be selected from the group comprising of 4-
dimethylaminopyridine (4-DMAP), diisopropylethylamine (DIPEA), 2-
methylpyridine, 2,6-dimethylpyridine (lutidine), 2,4,6-trimethylpyridine (collidine),
4-(tetrahydropyrrolidinyl)pyridine, imidazole, N-methylimidazole,
diazabicycloundecane (DABCO), N-hydroxysuccinimide (HOSu), N-hydroxy-5-
norbornene-2,3-dicarboximide (HONB), 1 -hydroxybenzotriazole (HOBt), 6-chloro- 1 -
hydroxybenzotriazole (6-C1-HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) and 3-
hydroxy-4-0x0-3,4-dihydrol-, 2,3-benzotriazine (HODhbt), its aza derivative
(HODhat).
9. A process for the preparation of dabigatran etexilate (1) or its salt thereof according to
any of the proceeding claims wherein
a) powder X-ray diffractogram of ethyl 3-(2-(((4-cyanopheny1)amino) methyl)- 1 -
methyl-N-(pyridin-2-y1)-1 H -benzo[dlimidazole-5-carboxamido)propanoate is as
depicted in fig 1
b) powder X-ray diffractogram of ethyl 3-(2-(((4-carbamimidoyl pheny1)amino)methyl)-
I 1 -methyl-N-(pyridin-2-y1)- 1 H-benzo[dJimidazole-5-carboxamid0)-propanoate
hydrochloride is as depicted in fig 2.
c) powder X-ray diffiactograrn of dabigatran etexilate is as depicted in fig 3.
d) powder X-ray diffractogram of dabigatran etexilate mesylate is as depicted in fig 4. or
e) differential scanning calorimetry (DSC) of dabigatran etexilate mesylate is as depicted
in fig 5.
10. There process according to any of the proceeding claims wherein dabigatran etexilate
or its salt thereof is used in the preparation of pharmaceutical composition that
includes a therapeutically effective amount of dabigatran etexilate or its salt and one
or more pharmaceutically acceptable carriers, excipients or diluents.