Monday, 7 September 2015


MEGAFINE PHARMA (P) LTD. [IN/IN]; Sethna, 4th Floor 55, Maharishi Karve Road, Marine Lines Mumbai 400002 (IN)

The present invention relates to an improved process for the preparation of Dabigatran etexilate and its acid addition salts thereof, wherein the said process substantially eliminates the potential impurities. The present invention also relates to an intermediate of Dabigatran etexilate and process for preparation thereof.

Dabigatran etexilate mesylate is an oral anticoagulant from the class of the direct thrombin inhibitors. Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin. It is used to help prevent strokes or serious blood clots in people who have atrial fibrillation (a condition in which the heart beats irregularly, increasing the chance of clots forming in the body and possibly causing strokes) without heart valve disease. Dabigatran etexilate mesylate is approved in both US and Europe and commercially available under the brand name of Pradaxa.
Dabigatran etexilate mesylate is a double prodrug of the active substance, Dabigatran of formula (II). It is the pharmacologically active molecule formed through hydrolysis c

Dabigatran and process for its preparation was first disclosed in WO9837075 (henceforth Ό75) disclosed process involves the reaction of l-methyl-2-[N-[4amidinophenyl] aminomethyl]benzimidazol-5 -yl-carboxylicacid-N-(2-pyridyl)- N-(2-ethoxycarbonylethyl)amide hydrochloride of formula (VI) with hexylchloroformate in presence of potassium carbonate in tetrahydrofuran/water to provide l-methyl-2-[N -[4-(N -n-hexyloxycarbonylamidino) phenyl Jaminomethyl Jbenzimidazol- 5-yl-carboxylicacid- N-(2-pyridyl)- N-(2-ethoxy carbonylethyl)amide (herein after referred as dabigatran etexilate) of compound of formula (I). But WO'075 does not discuss or exemplify process for preparation of Dabigatran etexilate mesylate salt.
The key step of the disclosed process is the conversion of the nitrile of the Formula (V) into the amidine hydrochloride of formula (VI) by pinner reaction. The low yields of the pinner reaction can be derived from the water sensibility of the reaction on the one hand while the realization of the reaction is rendered more difficult on the other by the fact that the ester as well as amide, function of the molecule is susceptible to hydrolysis. According to Example 58b of said patent in an analogous manner to Example 25d 1.2 g of l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-5-benzimidazole-carboxylic acid-N-(2-pyridyl)-N-[2-(ethoxycarbonylethyl]-amide (V) is reacted with ethanol saturated with hydrochloric acid in large dilution. The evaporated crude product is then converted to hydrochloric acid salt of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5- benzimidazole-carboxylic acid-N-(2-pyridyl)-N-[2-(ethoxycarbonyl)-ethyl]- amide compound of formula(VI) using ethanol and ammonium carbonate. The disclosed process was not suitable for large scale production because of tedious workup procedures, less yield, low purity, separation by column chromatography, which in turn results in excessive production time and costlier process and less eco-friendly. The purification step performed by using large dilutions and column chromatography makes scale up and
commercialization of the process strongly limited. Hence, this process commercially viable.

Formula (VI)
Example 1 13 of WO'075 reveals the total yield of the final compound (I) is 22%.
J.Med.Chem. 2002, 45, 1757-1766 describes a process for preparation of compound of formula (III) as depicted in scheme -II.

The process for preparation of mesylate salt of dabigatran etexilate and its polymorphic forms was disclosed in US2005/234104. The disclosed process involves the reaction of Dabigatran etexilate with methane sulfonic acid in acetone to provide Dabigatran etexilate mesylate.
According to WO 2012/153158 (henceforth W0' 158) dabigatran etexilate base compound of formula (I) is characterized by mass spectrum, 1H NMR and melting point (128-129°C).WO 2008/059029 reports the melting point of 128 ±3°C for the anhydrous form-Ill. Further W0' 158 discloses that according to WO2006/000353 dabigatran etexilate of formula (I) is prepared as described in Examples 5A and 5B by reacting the tosylate salt of (6) and hexylchloroformate in an acetone-aqueous medium, obtained product is dried at 45°C and is not characterized by analytical data. On the basis of the calculations the product is presumed to be anhydrous. Thus according to WO 2006/000353 dabigatran etexilate is prepared by crystallization from an acetone/water system (Example 5A) and in said process no drying agent or other dehydrating agent is used.
Further W0' 158 reveals that on following the example 5A of WO 2006/000353 authors failed to obtain anhydrous dabigatran etexilate but rather modification thereof containing four moles of water was observed in dabigatran etexilate.
Further W0' 158 discloses that two anhydrous and tetrahydro form of dabigatran etexilate are described in WO 2006/131491. In this international patent application no process is disclosed for preparation of dabigatran etexilate but reference is made rather to basic patent and hence the said new forms are obtained by recrystallization from ethyl acetate (anhydrous form-I and anhydrous II Examples 1 and 2) and a mixture of acetone and water (tetrahydrate form, example 3).
According to disclosure of W0' 158, WO 2007/007142 three further variants are disclosed for the preparation of dabigatran etexilate (1) starting from the tosylate salt of the amidine (6); said procedures differ from each other in the reaction conditions and the work-up method. Thus Example 6A is identical with Example 5A of WO 2006/000353, however in the working up method of new variants 6B and 6C an azeotropic distillation is employed using butyl acetate for dehydration. Accordingly in these cases actually the anhydrate of dabigatran etexilate (1) is formed and consequently the yield is lower (yield of 1 using ditosylate of 6).
As per W0' 158, an article published in 2009 (UP .'Com. Journal 2009, 9, 20) reports a detailed process for the realization of the Pinner-reaction mentioned in the basic patent, wherein the hydrolysis of the nitrile derivative of formula (V) is carried out at room temperature with the aid of an approximately 100 molar amount of hydrochloric acid. The process involves five re-crystallization steps to obtain pure di-hydrochloride (characterized by XRD). The disadvantages of the disclosed process are high dilution ratio, low yield, process is restricted to smaller batch size at commercial scale, process results in formation of impurities and is not cost effective at commercial scale, and involve 5 purification steps thereby making the said process unsuitable at industrial scale.
WO 2010/045900 discloses the preparation of free base of dabigatran etexilate of formula (I), from oxalate salt of nitrile compound of formula (V) via monohydrochloride and dihydrochloride of the amidine of formula (VI). These salts are found to degrade and lead to the formation of impurities and thereby yield dabigatran etexilate with low purity. Thus making the process less favorable at industrial scale.
Like any synthetic compound, Dabigatran etexilate mesylate contain extraneous compounds or impurities that can come from many sources. They may be un-reacted starting materials, by-products of reaction, products ,of side reaction, and/or degradation products. To meet the regulatory quality norms, identification, isolation, synthesis and characterization of the impurities followed by their control to the ICH levels in the final drug compound is a must. Potential impurities of Dabigatran etexilate mesylate are disclosed in EP2522662 and it also addresses the stability issues associated with dabigatran etexilate mesylate. Additionally W0' 158 discloses the additional set of impurities which are formed due to the use of poor quality of hexyl chloroformate. Hence, there is a need of simple, efficient and production friendly process for the preparation of dabigatran etexilate mesylate with high purity, yield and higher throughput.

The present invention relates to an improved process for preparation of l-methyl-2- [N-[4-(N-nhexyloxycarbonylamidino)phenyl]aminomethyl]benz imidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula (I) also known as dabigatran etexilate and its methane sulfonate salt compound of formula (la), represented by the following structural formulae:

Dabigatran Etexilate Dabigatran Etexilate Mesylate
The process of the present invention is an improved, commercially viable and industrially advantageous process for the preparation of Dabigatran etexilate mesylate wherein, the said process substantially eliminates the impurities formed during the preparation of Dabigatran etexilate mesylate.
Further, the present invention also provides novel acid additions salts of ethyl N-[(2- { [(4-cyanophenyl)amino]methyl} - 1 -methyl- 1 -H-benzimidazol-5-yl0carbonyl]-N- pyridin-2-yl-beta-alaninate (DEM-III), preferably p-toluene sulfonic acid salt, represented by structural formula (V), an useful intermediate in the synthesis of highly pure compound (la).

.p-toluene sulfonic acid addition sail
Formula (V)

Formula (la)

Formula (la)

n)Dabigatran etexilate mesylate:
52.6 gm ' of ethyl 3-[(2{[4(hexyloxycarbonylaminoiminomethyl)phenylamino] methyl} - 1 -methyl- 1 H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate dihydrate was added to 293 gm of acetone. The obtained mixture was heated to 40-46° C. with stirring. After a clear solution has formed, the contents of the apparatus was filtered and the filtrate was cooled to 30° C. to 36° C. 42 gm of acetone was precooled to 0° C. to 5° C and to it was added 7.5gm of 99.5% methanesulfonic acid. The obtained methanesulfonic acid solution was added in to the solution of ethyl 3-[(2- { [4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl } - 1 -methyl- 1 H-benzimi-dazole-5-carbonyl)pyridin-2-ylamino]propionate base at 26° C. to 36° C. within 15 to 40 minutes. Then the mixture was stirred for 40 to 60 minutes at 26° C. to 33° C. It was then cooled to 17° C. to 23° C. and stirred for a further 40 to 80 minutes. The crystal suspension was filtered and washed 270 ml of acetone. The product was dried under vacuum at 45-50° C. for at least 4 hours.
Yield: 53g (91.93%); Purity by HPLC: 99.81%.
1. A process for the preparation of dabigatran etexilate of formula (I) or its acid addition salts thereof, comprising;
a. reacting hexyl-4-riitrophenyl carbonate compound of formula (XII) with 1- methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide (VI) or its acid addition salt in presence of a base and in a suitable organic solvent to provide dabigatran etexilate (I);

44. The process as claimed in claim 18, wherein the form-I of dabigatran etexilate mesylate has purity greater than 99%; preferably 99.5%; more preferably 99.81% when determined by HPLC.
45. The process of any of the preceding claims, dabigatran etexilate of formula (I) or its acid addition salt of formula (la) has less than about 0.2% of DBIMP-1 impurity, has less than about 0.2% of DBIMP-2 impurity, has less than about 0.2% of DBIMP-3 impurity, has less than about 0.2% of DBIMP-4 impurity, has less than about 0.2% of DBIMP-5 impurity, has less than about 0.2% of DBIMP-6 impurity, has less than about 0.2% of DBIMP-7 impurity, has less than about 0.2% of DBIMP-8 impurity, has less than about 0.2% of DBIMP-9 impurity, has less than about 0.2% of DBIMP-10 impurity, has less than about 0.2% of DBIMP-11 impurity, has less than about 0.2% of DBIMP-12 impurity.





The company's R&D strengths are in creating intellectual property assets by developing non-infringing, novel, cost effective and environmentally friendly processes for APIs and finding easier solutions to complex chemistry challenges. We are specialized in constructing chiral molecules with strong expertise and experience in the resolution processes. Our R&D team consists of more than 60 qualified scientists with extensive expertise and experience in Process Research and Development activities for APIs and their critical intermediates. Our main philosophy is backward integration of APIs synthesis starting from basic raw material, thereby being self-dependent for critical intermediates to control cost and quality. Solid state studies, particularly polymorphism and particle size are proving to be bottle neck in marketing newer APIs. At Megafine, scientists are skilled in providing solutions to the problems associated with them. We have two research centres, one at Nashik, Maharashtra, India and another at Vapi, Gujarat, India. R&D centre at Vapi is mainly focused to provide critical intermediates with high purity and low cost through intensive research to our main R&D centre at Nashik and as well as to API manufacturers around the globe. A well - equipped R&D centre is supported by kilo lab having reactors from 5 lit to 250 lit, SSR/GLR vessels to solve scale-up issues at production. We are very specific in creating online documentations for various phases of process development including the scale-up, safety, and engineering reports which help production to have a safe and robust process and also to support regulatory filings.
Megafine, established in 1995, is a privately owned and professionally managed enterprise with it's corporate office in Mumbai and two multipurpose manufacturing sites at Vapi & Nashik in India, both successfully inspected by US-FDA & the Nashik facility is also approved by EMEA, PMDA & KFDA. Both the plants are also certified by WHO GMP, ISO 9001:2008, 14001:2004 & OHSAS 18001:2007 and have been audited by several Innovators and leading Generic companies from time to time.
Megafine provides innovative & integrated API solutions with it's decades of experience and skill in the development of novel chemical processes catering to the global drug discovery and generic companies. Our continuous investment in research and development generates a steady flow of APIs enabling timely introduction of new products in the market. Megafine is committed to respecting third party intellectual property rights, manufacture products which are commercially competitive and meet the most stringent quality standards. Besides manufacturing its own Active Pharmaceutical Ingredients (APIs) & Advanced Intermediates, we also contract manufacture for global drug discovery and generic companies.
Our focus is on niche products; with a presence in more than 40 countries. Our partners are essentially drug discovery and generic drug companies across the globe for whom we develop a range of new niche products in select therapeutic categories like Anthelmintic, Cardiology, Urinary Incontinence, CNS (Central Nervous System), & a few others. We supply a wide range of high quality generic and custom manufactured APIs in volumes that range from a few grams to tons.
Megafine has special expertise in Polymorphs and Chiral products.
A perfect blend of Human talent, R&D Labs, Pilot Plant & cGMP manufacturing facilities backed by our Quality Assurance, Regulatory Affairs and Intellectual Property cell gives Megafine an edge.
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