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(11) EP 2 346 850 B1
(12) EUROPEAN PATENT SPECIFICATION
(45) Date of publication and mention
of the grant of the patent:
05.09.2012 Bulletin 2012/36
(21) Application number: 09752269.2
(22) Date of filing: 26.10.2009
(51) Int Cl.:
C07D 401/12
(2006.01)
(86) International application number:
PCT/CZ2009/000127
(87) International publication number:
WO 2010/045900 (29.04.2010 Gazette 2010/17)
(54) METHOD FOR THE PREPARATION OF DABIGATRAN AND ITS INTERMEDIATES
VERFAHREN ZUR HERSTELLUNG VON DABIGATRAN UND DESSEN ZWISCHENPRODUKTEN
PROCD POUR PRPARER LE DABIGATRAN ET SES INTERMDIAIRES
(84) Designated Contracting States:
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR
HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL
PT RO SE SI SK SM TR
(30) Priority: 24.10.2008 CZ 20080669
(43) Date of publication of application:
27.07.2011 Bulletin 2011/30
(73) Proprietor: Zentiva, K.S.
102 37 Praha 10 (CZ)
(72) Inventors:
LUSTIG, Petr
530 03 Pardubice (CZ)
JIRMAN, Josef
100 00 Praha 10 (CZ)
(74) Representative: Jirotkova, Ivana et al
Rott, Ruzicka & Guttmann
Patent, Trademark and Law Offices
Vinohradsk 37
120 00 Praha 2 (CZ)
(56) References cited:
EP-A- 1 609 784 WO-A-98/37075
WO-A-2009/111997 DE-A-102005 061 623
US-A- 6 087 380
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Description
Technical Field
[0001] The invention deals with a new method for the manufacture of 3-([2-[[(4-(N-n-hexyloxycarbonylcarbamimi-
doyl)-phenylamino]-methyl]]-1-methyl-1H-benzimidazole-5-carbonyl]-pyridin-2-yl-amino)ethyl propionate of formula VIII
known under the non-proprietary name dabigatran. Dabigatran is an anticoagulant agent and is used for treatment of
thromboses, cardiovascular diseases, and the like.
Background Art
[0002] Preparation of dabigatran was first described in the document no. WO 9837075; however, this method brings
many technological problems, e.g. very complicated purifying operations, problems with low purity of intermediate prod-
ucts and the resulting low yield and low purity of the final product.
[0003] One of the advanced intermediates during the production of dabigatran is the substance of formula VI.
[0004] The compound of formula VI is prepared by a reaction of substance IV with reagent V as shown in Scheme 1.
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[0005] The procedure described in WO 9837075 produces compound VI in the form of its base or acetate. Both these
products require chromatographic purification, which is very difficult to apply in the industrial scale. This purification
method burdens the process economy very much and has a negative impact on the yield.
[0006] In the next stage acidic hydrolysis of the nitrile function of compound VI and a reaction with ammonium carbonate
is performed to produce the substance of formula VII. The reaction is shown in Scheme 2.
[0007] The procedure in accordance with WO 9837075 produces substance VII in the monohydrochloride form.
[0008] When reproducing the procedure of WO 9837075 we found out, in line with WO 9837075, that compound VII
prepared by this method required subsequent chromatographic purification as it was an oily substance with a relatively
high content of impurities. We did not manage to find a solvent that would enable purification of this substance by
crystallization.
[0009] The last stage is a reaction of intermediate VII with hexyl chloroformate producing dabigatran and its transfor-
mation to a pharmaceutically acceptable salt; in the case of the above mentioned patent application it is the methanesul-
fonate.
[0010] However, the method in accordance with WO 9837075 does not make it possible to prepare dabigatran with
high purity, which is required in the case of a pharmaceutical substance, and in a yield acceptable in the industrial scale.
[0011] The reason is mainly low purity of the intermediate products, which are moreover produced in forms requiring
complicated purification with the use of chromatographic methods.
Disclosure of Invention
[0012] The present invention provides preparation and use of new, not yet described advanced intermediates of
dabigatran:
the monohydrochloride of compound VII in the form of a solvate with ethanol of formula VII-HCl
and the dihydrochloride of compound VII of formula VII-2HCl
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and a new method of preparation of dabigatran based on these intermediates.
[0013] Isolation of either of the two intermediates will considerably increase the purifying ability of crystallization in
comparison to crystallization of the hitherto described hydrochloride.
[0014] The procedure in accordance with WO 9837075 provides product VII in the quality of 85-90%. Transformation
of this compound to VII-HCl and its crystallization improves its quality to 93-95%. Preparation of compound VII-2HCl
leads to further quality improvement, namely to 96-98%.
[0015] Preparation of the above mentioned salts allows avoiding chromatographic purification of substance VII, which
is described in patent no. WO 9837075, and is necessary for obtaining compound VII with high quality.
[0016] The preparation of the compound of formula VII
is carried out by acidic hydrolysis of the nitrile function of compound VI with subsequent reaction with ammonium
carbonate (see Scheme 2).
[0017] Use of the starting substance VI in the oxalate form in accordance with the presented procedure produces the
monohydrochloride of compound VII in the form of a solvate with ethanol of formula VII-HCl.
[0018] This approach has a considerable purifying effect, which leads to the production of the intermediate of formula
VII-HCl with high purity (88-90%) and a higher yield (85-90%).
[0019] Substance VII-HCl can be re-purified by crystallization as contrasted to VII prepared in accordance with WO
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9837075, which can only be purified with the use of chromatographic methods. This way the purity of compound VII-
HCl can be increased to the content of 90-95%.
[0020] An even higher purifying effect was achieved by preparation of the dihydrochloride of compound VII of formula
VII-2HCl.
[0021] A solution of dry hydrogen chloride in a solvent selected e.g. from the group of ethers, esters, ketones or
alcohols is added dropwise to a solution of substance VII-HCl under stirring. Alcohols appear to represent the most
suitable solvents. This compound can also be purified by crystallization. This way, a product with a very high purity
(96-98%) is obtained.
[0022] The preparation of compound VII in the form of the above mentioned salts enables their purification by crys-
tallization as contrasted to compound VII obtained in accordance with the method of document WO 9837075, where it
is necessary to purify compound VII with the use of chromatographic methods. Consequently, this means very significant
simplification and improvement of efficiency of the whole production process since chromatographic purification repre-
sents a serious technological as well as economical problem in industrial applications.
[0023] In addition, the method in accordance with the present invention produces the intermediates of dabigatran, i.e.
VII-HCl and VII-2HCl, with very high purity necessary for the preparation of a high-quality pharmaceutical substance.
[0024] The last stage is a reaction of the intermediate VII-HCl or VII-2HCl with hexyl chloroformate producing dabigatran
and its transformation to a pharmaceutically acceptable salt.
[0025] The reaction is carried out in an inert solvent selected from aromatic hydrocarbons, ethers, chlorinated hydro-
carbons, nitriles and ketones in the presence of a suitable base, either organic or inorganic (tertiary amines, cyclic tertiary
amines, hydroxides, carbonates).
[0026] A preferable embodiment of the entire procedure in accordance with the presented invention is shown in
Scheme 3.
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[0027] The invention also includes a convenient process of obtaining new intermediates. The purifying abilities of the
described solvate or dihydrochloride can be advantageously combined with those of the salts of their precursors. This
method enables preparation of dabigatran with high purity and in an industrially acceptable yield. The change of purifi-
cation operations allowed by the use of these salts, i.e. replacement of chromatographic purification with crystallization,
leads to a considerable improvement of economy of the whole production process.
[0028] The salt of oxalic acid of formula VI-oxal has proved to be especially convenient for these purposes.
[0029] This starting compound can be prepared by the procedure illustrated in Scheme 4. Compound IV reacts with
substance V with the use of oxalic acid.
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[0030] Compound VI prepared by the method in accordance with WO 9837075 is in the acetate form. Both these
products require chromatographic purification, which is very difficult to realize in the industrial scale.
[0031] In the procedure in accordance with the presented invention compound VI is obtained in the form of a salt with
oxalic acid. This salt is simply re-purified by further crystallization and this way the advanced intermediate VI is obtained
with high purity and in the yield that is acceptable for industrial production, of approximately 60 to 80%.
[0032] This crystallization can be performed from a polar protic organic solvent, preferably from lower C
1
to C
5
alcohols,
e.g. from ethyl alcohol.
[0033] The procedure in accordance with the presented invention enables production of a high-quality product with a
low content of impurities (product content: 98%) and with a high yield (65-70%).
[0034] The production of intermediates VI and VII in the form of the following salts: VI-oxal, VII-HCl and VII-2HCl will
significantly simplify purification operations during the production of dabigatran. The chromatographic purification men-
tioned in WO 9837075 cannot be used in the industrial scale. Replacement of chromatographic purification with crys-
tallization represents a considerable technological simplification and improves the economy of the entire production
process.
[0035] The invention is further demonstrated in the following examples:
Example 1:
Preparation of VII-HCl
[0036] 40 g of compound VI-oxal are put into ethanol containing hydrogen chloride. This mixture is stirred at the
laboratory temperature for 14 hours. Then, ethanol with hydrogen chloride is evaporated and the evaporation residue
is dissolved in 1000 ml of ethanol. 110 g of ammonium carbonate are added to this solution and the whole mixture is
stirred at the laboratory temperature for 26 hours. After expiration of this time period the undissolved fraction is removed
by aspiration and the filtrate is concentrated. The resulting product is dissolved in 560 ml of a 2:1 mixture of ethyl acetate
and ethanol at the laboratory temperature. After 30 minutes a white precipitate results, which is cooled in a refrigerator
and aspirated and dried at 50C.
[0037] Yield: 28.5 g (81%); content according to HPLC: 89%. According to NMR the product is a solvate with ethanol
in the proportion of 3:1 (VII-HCl).

1
H NMR (DMSO-d6, 30C, 250 MHz) [ppm]: 1.16 (t, 3H), 1.10 (t, 1H), 2.78 (t, 2H), 3.83 (s, 3H), 3.49 (q, 0.66H), 4.02
(q, 2H), 4.28 (t, 2H) 4.7 (d, 2H , 6.9 (m,1H), 6.9 (d, 2H), 7.18(m, 1H), 7.19 (dd, 1H), 7.45 (d, 1H), 7.53 (d, 1H), 7.56 (m,
1H), 7.60 (m,1H), 7.76 (d, 2H), 8.43 (dd, 1H), 8.86 (bs, 2H), 9.02, (bs, 2H)

13
C NMR: (DMSO-d6, 30C, 62.90 MHz) [ppm]: 14.02 (CH3), 30.07 (CH3), 33.11 (CH2), 39.93 (CH
2
), 44.42 (CH2),
60.07 (CH2), 109.58 , 111.77 , 119.55 , 121.33 , 122.14 , 122.87, 129.71 , 137.96 , 148.74 (all CH), 113.27, 129.45,
137.29, 140.83, 153.13, 153.48, 156.04, 164.52, 170.39, 171.09 (all C-q).
Example 2:
Preparation of VII-2HCl
[0038] 9.7 g of compound VII-HCl-EtOH are dissolved in a mixture of ethanol with ethyl acetate. A solution of hydrogen
chloride in ethanol containing an equimolar amount of the acid is added to this solution dropwise. After separation of
the precipitate the suspension is cooled and the product is aspirated and dried.
Yield: 9.1 g (87.8%); content according to HPLC: 96.2%.
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1
H NMR:
1
H NMR (DMSO-d6, 30C, 250 MHz) [ppm]:
1.16 (t, 3H), 2.56 (t, 2H), 4.03 (m, 5H), 4.26 (t, 2H), 5.04 (bs. 2H), 6.99 (d, 2H), 7.13(d, 1H), 7.21 (dd, 1H), 7.41 (dd, 1H),
7.68 (m, 1H)
7.71 (d, 1H), 7.82 (d,2H), 7.84 (d, 1H), 8.41 (dd, 1H), 8.99 (bs, 2H), 9.17, (bs, 2H)

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C NMR: (DMSO-d6, 30C, 62.90 MHz) [ppm]: 14.03 (CH3), 31.51 (CH3), 32.91 (CH2), 39.59 (CH2), 44.56 (CH2),
60.11 (CH
2
), 112.12, 112.25, 115.20, 121.94, 122.12, 125.35, 129.80, 138.48, 148.87 (all CH), 114.59, 130.73, 133.43,
134.24, 152.42, 153.69, 155.33, 164.50, 168.96, 171.00 (all C-q).
Example 3:
Preparation of dabigatran mesylate
[0039] To 9.1 g of compound VII-2HCl (0.016 mol) 270 ml of chloroform and 9 ml (0.064 mol) of triethylamine are
added. Then, a solution of 3.1 ml (0.018 mol) of hexyl chloroformate in chloroform is added dropwise at the laboratory
temperature. After one hour the reaction mixture is shaken with brine and the organic layer is separated, which is dried
with sodium sulfate and concentrated. The obtained evaporation residue is crystallized from ethyl acetate.
Yield: 8.6 g (86%)
[0040] This product is dissolved in acetone and an equimolar amount of methanesulfonic acid is added dropwise. The
separated precipitate is aspirated and dried at the laboratory temperature. Yield: 75%; content according to HPLC: 99.5%.
Example 4:
Preparation of dabigatran mesylate
[0041] 9 g of compound VII-HCl (0.017 mol) were dissolved in 300 ml of chloroform. 6 ml of triethylamine were added
to this solution and then a solution of 3.4 ml (0.02 mol) of hexyl chloroformate in chloroform was added dropwise. After
one hour the reaction mixture is shaken with brine, the organic layer is separated, which is dried with sodium sulfate
and concentrated. The obtained evaporation residue is crystallized from ethyl acetate.
Yield: 9.6 g (90%)
[0042] This product is dissolved in acetone and an equimolar amount of methanesulfonic acid is added dropwise. The
separated evaporation residue is aspirated and dried at the laboratory temperature.
Yield: 73%; content according to HPLC: 99.5%.
Claims
1. A method for the manufacture of dabigatran, characterized in that the compound of formula VII-2HCl
or of formula VII-HCl
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is reacted with hexyl chloroformate in the presence of an inorganic or organic base in an inert solvent selected from
ethers, ketones, chlorinated hydrocarbons or acetonitrile and the obtained dabigatran is optionally transformed to
a pharmaceutically acceptable salt.
2. The method according to claim 1, characterized in that the reaction is carried out in a chlorinated hydrocarbon in
the presence of a tertiary amine as the base.
3. The compound of formula VII-2HCl
4. The compound of formula VII-HCl
5. A method for the manufacture of the compound of formula VII-HCl, characterized
in that the compound of formula VI-oxal
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is reacted in two steps first in a solution of hydrogen chloride in ethanol and then in a mixture of ammonium carbonate
with ethanol, after filtration and evaporation of the solvents an isolate is obtained, which is then re-crystallized from
ethanol or its mixture with another organic solvent.
6. The method according to claim 5, characterized in that the obtained isolate is further stirred up in a mixture of
ethanol + an organic solvent selected from the group of esters of C
1
-C
6
organic acids.
7. The method according to claims 5 or 6, characterized in that the obtained isolate is stirred up in a mixture of ethanol
- ethyl acetate.
8. The method according to claims 5-7, characterized in that the stirring-up is carried out at a temperature of 0 to 60 C.
9. A method for the manufacture of the compound of formula VII-2HCl, which serves as an intermediate for the prep-
aration of dabigatran, characterized in that the compound of formula VII-HCl or of formula VII
is transformed to the dihydrochloride of formula VII-2HCl by means of a solution of hydrogen chloride in an inert
solvent selected from C
3
to C
6
ethers, ketones, esters or C
1
to C
5
alcohols.
Patentansprche
1. Verfahren zur Herstellung von Dabigatran, dadurch gekennzeichnet, dass die Verbindung der Formel VII-2HCl
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oder der Formel VII-HCl
mit Hexylchlorformiat in Gegenwart von einer anorganischen oder organischen Base in einem inerten Lsungsmittel,
ausgewhlten aus Ethern, Ketonen, chlorierter Kohlenwasserstoffe oder Acetonitril, reagiert wird, und das gewon-
nene Dabigatran gegebenenfalls in ein pharmazeutisch annehmbares Salz verwandelt wird.
2. Verfahren gem Anspruch 1, dadurch gekennzeichnet, dass die Reaktion in einem chlorierten Kohlenwasserstoff
in Gegenwart von einem tertiren Amin als die Base durchgefhrt wird.
3. Verbindung der Formel VII-2HCl
4. Verbindung der Formel VII-HCl
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5. Verfahren zur Herstellung von Verbindung der Formel VII-HCl, dadurch gekennzeichnet, dass die Verbindung
der Formel VI-oxal
in zwei Stufen reagiert wird, erst in einer Lsung von Chlorwasserstoff in Ethanol und dann in einem Gemisch von
Ammoniumkarbonat mit Ethanol, nach Filtration und Verdampfen der Lsungsmittel erhlt man ein Isolat, welches
dann aus Ethanol oder dessen Gemisch mit einem anderen organischen Lsungsmittel umkristallisiert wird.
6. Verfahren gem Anspruch 5, dadurch gekennzeichnet, dass das gewonnene Isolat ferner in einem Gemisch
von Ethanol + ein organisches Lsungsmittel, ausgewhlt aus der Gruppe von Estern der C
1
-C
6
organischen Suren,
gerhrt wird.
7. Verfahren gem Ansprchen 5 oder 6, dadurch gekennzeichnet, dass das gewonnene Isolat in einem Gemisch
von Ethanol + Ethylacetat gerhrt wird.
8. Verfahren gem Ansprchen 5-7, dadurch gekennzeichnet, dass das Rhren bei Temperatur von 0 bis 60 C
durchgefhrt wird.
9. Verfahren zur Herstellung von Verbindung der Formel VII-2HCl, welche als Intermediat fr Herstellung von Dabi-
gatran dient, dadurch gekennzeichnet, dass die Verbindung der Formel VII-HCl oder der Formel VII
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mittels einem Lsung des Chlorwasserstoffs in einem inerten Lsungsmittel, ausgewhlt aus C
3
bis C
6
Ethern,
Ketonen, Estern oder C
1
bis C
5
Alkoholen, in das Dihydrochlorid der Formel VII-2HCl verwandelt wird.
Revendications
1. Procd pour prparer le dabigatran, caractris en ce que lon fait ragir le compos de formule VII-2HCl
ou de formule VII-HCl
avec le chloroformiate dhexyle en prsence dune base inorganique ou organique dans un solvant inerte choisi
parmi des thers, ctones, hydrocarbures chlors ou lactonitrile, et ventuellement on transforme le dabigatran
obtenu en un sel pharmaceutiquement acceptable.
2. Procd selon la revendication 1, caractris en ce que lon effectue la raction dans un hydrocarbure chlor en
prsence dune amine tertiaire en tant que base.
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3. Le compos de formule VII-2HCl
4. Le compos de formule VII-HCl
5. Procd pour prparer le compos de formule VII-HCl, caractris en ce que lon fait ragir le compos de formule
VI-oxal
en deux tapes, dabord en solution de chlorure dhydrogne dans lthanol et puis dans un mlange du carbonate
dammonium avec lthanol, aprs filtration et vaporation des solvants on obtient un isolat qui est puis recristallis
partir de lthanol ou de son mlange avec un autre solvant organique.
6. Procd selon la revendication 5, caractris en ce que lon agit en outre lisolat obtenu dans un mlange de
lthanol + un solvant organique choisi parmi le groupe desters des acides organiques C
1
-C
6
.
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7. Procd selon les revendications 5 ou 6, caractris en ce que lon agit lisolat obtenu dans un mlange de lthanol
- actate dthyle.
8. Procd selon les revendications 5-7, caractris en ce que lon effectue lagitation sous une temprature de 0
60 C.
9. Procd pour prparer le compos de formule VII-2HCl qui sert comme intermdiaire pour la prparation du dabi-
gatran, caractris en ce que lon transforme le compos de formule VII-HCl ou de formule VII
en dichlorhydrate de formule VII-2HCl laide dune solution de chlorure dhydrogne dans un solvant inerte choisi
parmi des thers, ctones, esters C
3
C
6
ou alcools C
1
C
5
.
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REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the readers convenience only. It does not form part of the European
patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be
excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description
WO 9837075 A [0002] [0005] [0007] [0008] [0010]
[0014] [0015] [0019] [0022] [0030] [0034]