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Note: Within nine months of the publication of the mention of the grant of the European patent in the European PatentBulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with theImplementing Regulations. Notice of opposition shall not be deemed to have been fi led until the opposition fee has beenpaid. (Art. 99(1) European Patent Convention).

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(19)

EP

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6850B1

&(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 alRott, 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 ofthromboses, cardiovascular diseases, and the like.

Background Art

[0002] Preparation of dabigatran was first described in the document no. WO 9837075; however, this method bringsmany 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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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 incomparison to crystallization of the hitherto described hydrochloride.[0014] The procedure in accordance with WO 9837075 provides product VII in the quality of 85-90%. Transformationof 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, whichis 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 ammoniumcarbonate (see Scheme 2).[0017] Use of the starting substance VI in the oxalate form in accordance with the presented procedure produces themonohydrochloride 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 formulaVII-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 formulaVII-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 mostsuitable 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 itis necessary to purify compound VII with the use of chromatographic methods. Consequently, this means very significantsimplification 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 dabigatranand 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 tertiaryamines, hydroxides, carbonates).[0026] A preferable embodiment of the entire procedure in accordance with the presented invention is shown inScheme 3.


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[0027] The invention also includes a convenient process of obtaining new intermediates. The purifying abilities of thedescribed solvate or dihydrochloride can be advantageously combined with those of the salts of their precursors. Thismethod 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 withsubstance 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 theseproducts 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 withoxalic acid. This salt is simply re-purified by further crystallization and this way the advanced intermediate VI is obtainedwith 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 C1 to C5 alcohols,e.g. from ethyl alcohol.[0033] The procedure in accordance with the presented invention enables production of a high-quality product with alow 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 willsignificantly 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 productionprocess.[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 thelaboratory temperature for 14 hours. Then, ethanol with hydrogen chloride is evaporated and the evaporation residueis dissolved in 1000 ml of ethanol. 110 g of ammonium carbonate are added to this solution and the whole mixture isstirred at the laboratory temperature for 26 hours. After expiration of this time period the undissolved fraction is removedby aspiration and the filtrate is concentrated. The resulting product is dissolved in 560 ml of a 2:1 mixture of ethyl acetateand ethanol at the laboratory temperature. After 30 minutes a white precipitate results, which is cooled in a refrigeratorand 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 ethanolin the proportion of 3:1 (VII-HCl). 1H 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) 13C NMR: (DMSO-d6, 30C, 62.90 MHz) [ppm]: 14.02 (CH3), 30.07 (CH3), 33.11 (CH2), 39.93 (CH2), 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 hydrogenchloride in ethanol containing an equimolar amount of the acid is added to this solution dropwise. After separation ofthe 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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1H NMR: 1H 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) 13C 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 (CH2), 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 areadded. Then, a solution of 3.1 ml (0.018 mol) of hexyl chloroformate in chloroform is added dropwise at the laboratorytemperature. After one hour the reaction mixture is shaken with brine and the organic layer is separated, which is driedwith 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. Theseparated 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 addedto this solution and then a solution of 3.4 ml (0.02 mol) of hexyl chloroformate in chloroform was added dropwise. Afterone hour the reaction mixture is shaken with brine, the organic layer is separated, which is dried with sodium sulfateand 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. Theseparated 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 fromethers, ketones, chlorinated hydrocarbons or acetonitrile and the obtained dabigatran is optionally transformed toa pharmaceutically acceptable salt.

2. The method according to claim 1, characterized in that the reaction is carried out in a chlorinated hydrocarbon inthe 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, characterizedin 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 carbonatewith ethanol, after filtration and evaporation of the solvents an isolate is obtained, which is then re-crystallized fromethanol 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 C1-C6 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 C3 to C6 ethers, ketones, esters or C1 to C5 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 Kohlenwasserstoffin 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 Verbindungder Formel VI-oxal

in zwei Stufen reagiert wird, erst in einer Lsung von Chlorwasserstoff in Ethanol und dann in einem Gemisch vonAmmoniumkarbonat mit Ethanol, nach Filtration und Verdampfen der Lsungsmittel erhlt man ein Isolat, welchesdann 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 Gemischvon Ethanol + ein organisches Lsungsmittel, ausgewhlt aus der Gruppe von Estern der C1-C6 organischen Suren,gerhrt wird.

7. Verfahren gem Ansprchen 5 oder 6, dadurch gekennzeichnet, dass das gewonnene Isolat in einem Gemischvon Ethanol + Ethylacetat gerhrt wird.

8. Verfahren gem Ansprchen 5-7, dadurch gekennzeichnet, dass das Rhren bei Temperatur von 0 bis 60 Cdurchgefhrt 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 C3 bis C6 Ethern,Ketonen, Estern oder C1 bis C5 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 choisiparmi des thers, ctones, hydrocarbures chlors ou lactonitrile, et ventuellement on transforme le dabigatranobtenu 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 formuleVI-oxal

en deux tapes, dabord en solution de chlorure dhydrogne dans lthanol et puis dans un mlange du carbonatedammonium 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 C1-C6.


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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 choisiparmi des thers, ctones, esters C3 C6 ou alcools C1 C5.


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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]

Documents

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