WO2014020555A2 - An improved process for the preparation of dabigatran etexilate mesylate - Google Patents

An improved process for the preparation of dabigatran etexilate mesylate Download PDF

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Publication number
WO2014020555A2
WO2014020555A2 PCT/IB2013/056288 IB2013056288W WO2014020555A2 WO 2014020555 A2 WO2014020555 A2 WO 2014020555A2 IB 2013056288 W IB2013056288 W IB 2013056288W WO 2014020555 A2 WO2014020555 A2 WO 2014020555A2
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formula
methyl
compound
pyridyl
benzimidazol
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PCT/IB2013/056288
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French (fr)
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WO2014020555A3 (en
Inventor
Venkat Raman JAYARAMAN
Samir Patel
Samir Mistry
Mukesh Timbadiya
Bhupendra Parmar
Jignesh Patel
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Alembic Pharmaceuticals Limited
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Publication of WO2014020555A3 publication Critical patent/WO2014020555A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to an improved process for the preparation of l-methyl-2- [N-[4-( -n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide methanesulfonate salt (Dabigatran etexilate mesylate ).
  • the present invention provides a process for purification of Dabigatran etexilate mesylate.
  • the present invention provides a process for the preparation of 1 -methyl -2-[N- (4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2- ethoxy carbonyl eth l)-amide of formula (VI) an intermediate of Dabigatran.
  • the compound of formula (VI) is prepared by a reaction of compound of formula (IV) compound of formula (V) with reagent as shown in Scheme 1.
  • the last stage is a reaction of intermediate (VII) with hexyl chloroformate producing Dabigatran Etexilate and its transformation to a pharmaceutically acceptable salt (methanesulfonate) .
  • Dabigatran Etexilate mesylate can contain process impurities, unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. It is also known in the art that impurities present in an active pharmaceutical ingredient (“API”) may arise from degradation of the API, for example, during storage or during the manufacturing process, including the chemical synthesis.
  • API active pharmaceutical ingredient
  • the present invention is to provide an improved process for the preparation of dabigatran etexilate mesylate in pure form, which ameliorates the problems of the prior art.
  • the process of the present invention is simple, operates in moderate reaction conditions, yields highly pure dabigatran etexilate mesylate compound of formula- la.
  • Yet another object of the present invention is to provide a process for the preparation of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VII) an intermediate of Dabigatran.
  • Yet another object of the present invention is to provide a process for the preparation of 1 -methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2- pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) an intermediate of Dabigatran.
  • Yet another object of the present invention is to provide a process for the preparation of
  • Yet another object of the present invention is to provide a purification process 1 -methyl -
  • Yet another object of the present invention is to provide a process for the preparation of 1- methyl-2-[N-[4-( -n-hexyloxycarbonyl amidino)phenyl]aminomethyl]benzimidazol-5- yl-carboxylicacid-N-(2-pyridyl)-N- (2-ethoxy carbonylethyl)amide compound of formula (VIII) (dabigatran etexilate) comprising: reacting 1 -methyl-2-[N-[4- amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)amide compound of formula (VII) with hexyl chloroformate in presence of a base in a suitable solvent to provide l-methyl-2-[N-[4-( -n- hexyloxycarbonyl amidino)phenyl]a
  • Yet another object present invention is to provide a purification process for dabigatran etexilate mesylate.
  • present invention to provide a process for preparing Dabigatran etexilate mesylate.
  • the present invention provides a process for preparing Dabigatran etexilate mesylate, comprising the steps of:
  • In another aspect of the present invention is to provide a process for the preparation of 1- methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2- pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) an intermediate of dabigatran etexilate mesylate comprising : condensation of Ethyl-3-[ ⁇ [3-amino-4- (methylamino)phenyl]carbonyl ⁇ (pyridin-2-yl)amino] propanoate compound of formula (IV) with the [(4-cyanophenyl)amino] acetic acid compound of formula (V) in presence of inert diluent and Pivaloyl chloride.
  • Yet another aspect of the present invention is to provide a process for the preparation of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VII) an intermediate of Dabigatran comprising the steps of:
  • Yet another aspect of the present invention is to provide a process for the preparation of 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2- pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula (VII) comprising the steps of: a) hydrolysis of l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5- yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide compound of formula (VI) in presence of hydrochloride, isopropyl ether and ethanol; b) treatment of compound of formula (Vila) with ammonia to obtain 1 -Methyl-2- [N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-
  • Yet another aspect of the present invention is to provide a purification process 1 -methyl- 2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)- N-(2-ethoxycarbonylethyl)amide compound of formula (VII) can be further purified with acetone or water or mixture thereoff.
  • Yet another aspect of the present invention is to provide a process for the preparation of 1- methyl-2-[N-[4-( -n-hexyloxycarbonyl amidino)phenyl]aminomethyl]benzimidazol-5- yl-carboxylicacid-N-(2-pyridyl)-N- (2-ethoxy carbonylethyl)amide compound of formula (VIII) (dabigatran etexilate) comprising: reacting 1 -methyl-2-[N-[4- amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)amide compound of formula (VII) with hexyl chloroformate in presence of a base and acetonitrile to provide l-methyl-2-[N-[4-( -n-hexyloxycarbonyl amidino)phenyl]
  • Yet another aspect of the present invention is to provide a purification process 1-methyl- 2-[N-[4-( -n-hexyloxycarbonyl amidino)phenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N- (2-ethoxy carbonylethyl)amide compound of formula (VIII) (dabigatran etexilate) can be further purified with acetone or water or mixture thereoff.
  • present invention is to provide a purification process for dabigatran etexilate mesylate which comprises of the following steps:
  • present invention is to provide process for preparing crystalline form-I of dabigatran etexilate mesylate comprises the steps of:
  • Fig. 1 shows the X-ray powder diffraction pattern of polymorph Form I l-methyl-2-[N- [4-( -n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide methanesulfonate salt (Dabigatran etexilate mesylate ).
  • FIG. 2 shows the DSC pattern of new polymorph Form I of l-methyl-2-[N-[4-( -n- hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2- pyridyl)-N-(2-ethoxycarbonylethyl)amide methanesulfonate salt (Dabigatran etexilate mesylate).
  • crystallizing means crystallizing compounds using methods known in the art. For example either reducing the volume of the solvent with respect to solute or decreasing the temperature of the solution or using both so as to crystallize the compound.
  • treating refers to suspending, dissolving or mixing and contacting or reacting of product with solvent or reagents followed by isolating product by removal of reagents and solvents.
  • trimturating refers to suspending product in solvent and stirring for period of time sufficient for surface contact of solid with solvent and then filtering the compound from the mixture.
  • In another embodiment of the present invention is to provide a process for the preparation of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid - N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VII) an intermediate of Dabigatran comprising the steps of:
  • In another embodiment of the present invention is to provide a process for the preparation of 1 -methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N- (2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) an intermediate of dabigatran etexilate mesylate comprising : condensation of ethyl-3-[ ⁇ [3-amino-4- (methylamino)phenyl]carbonyl ⁇ (pyridin-2-yl)amino] propanoate compound of formula (IV) with the [(4-cyanophenyl)amino] acetic acid compound of formula (V) in presence of inert diluent and pivaloyl chloride.
  • the present invention provides a method for preparing dabigatran Etexilate salt, comprising the steps of: a) treating chloride of compound of formula (I) reacts with compound of formula (II) in tetrahydrofuran in the presence of a base to obtain compound of formula (HI);
  • the condensation in step is carried out in the presence of an inert diluent and a pivaloyl chloride.
  • the correspondingly substituted diaminobenzenes of formula (IV) are known, for example, from International Patent Application WO 98/37075 or may be prepared analogously to those described therein. It is particularly preferable to use 3-amino-4- methylaminobenzoic acid amides, especially 3-amino-4-methylaminobenzoic acid-N-(2- pyridyl)-N-(2-ethoxycarbonylethyl) amides.
  • the inert diluents used may be both aprotic apolar solvents such as, e.g., aliphatic or aromatic, optionally halogenated hydrocarbons, or aprotic polar solvents such as, e.g., ethers and/or amides or lactams and/or mixtures thereof.
  • Aprotic apolar solvents used are preferably branched or unbranched C5-C8 aliphatic alkanes, C4-C 10 cycloalkanes, Ci-C 6 aliphatic haloalkanes, C 6 -Cio aromatic alkanes or mixtures thereof.
  • alkanes such as pentane, hexane, or heptane
  • cycloalkanes such as cyclohexane or methylcyclohexane
  • haloalkanes such as dichloromethane
  • aromatic alkanes such as benzene, toluene, or xylene, or mixtures thereof.
  • Suitable aprotic solvents are polar ethers such as, for example, tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, tert-butylmethylether, or dimethoxyethylether, or amides such as, for example, dimethylformamide, or lactams such as, for example, N-methylpyrrolidone.
  • polar ethers such as, for example, tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, tert-butylmethylether, or dimethoxyethylether
  • amides such as, for example, dimethylformamide
  • lactams such as, for example, N-methylpyrrolidone.
  • [(4-cyanophenyl)amino] acetic acid compound of formula (V) is charged in inert diluents most preferably THF or toluene or N-Methyl-2- pyrrolidinone or mixture thereoff at 25-30°C.
  • inert diluents most preferably THF or toluene or N-Methyl-2- pyrrolidinone or mixture thereoff at 25-30°C.
  • Pivaloyl chloride is added through dropping funnel at 0-5°C to the reaction mixture.
  • Pivaloyl chloride are added in the presence of an organic base, preferably a tertiary amine, DIPEA, to a solution of [(4-cyanophenyl)amino] acetic acid compound of formula (V) and correspondingly substituted diaminobenzene in THF or toluene.
  • the reaction mixture is stirred, preferably at temperatures between -10° C. and 50° C, and then, after the addition of acetic acid, it is evaporated down. It is combined with ethanol and filtered while hot. Then the substance precipitated from the cooled solution is filtered off, washed, and dried.
  • 1 -methyl -2-[N-(4-cyanophenyl)- aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) can be further purified.
  • the present invention provides a process purification of 1 -methyl -2-[N-(4-cyanophenyl)- aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI).
  • the process comprises purification of 1 -methyl -2-[N-(4- cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) by treatment with solvent system.
  • the slurry or solution or suspension of 1 -methyl -2-[N-(4-cyanophenyl)- aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) may be obtained by treating compound of formula (VI) in one or more suitable organic solvent system comprises of water; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like; alcohols such as methanol, isopropanol, 1-propanol, 1 -butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, other than ethanol, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t
  • the solvent system used in the process for process purification of 1 -methyl -2-[N-(4- cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) may be selected from a group of organic, aqueous, solvents either alone or in combinations thereof.
  • solvent system comprieses 1 :9 acetone/water, 1 :9 ethyl acetate/water, 1 :9 ethanol/water, 1 : 1 ethyl acetate/ethanol, 9: 1 toluene/water, 9: 1 tetrahydrofuran/water, or 1 : 1 acetone/methanol mixtures are employed in a process according to the present invention.
  • the embodiments of the process may include heating the slurry or solution or suspension of reaction mass followed by cooling to obtain pure compound of formula (VI).
  • the reaction mass may be heated upto temperature of 40 to 80°C and the cooling at about - 15°C to 10°C.
  • the reaction mass may be stirred for 30 minutes to 10 hours.
  • the substantially pure 1 -methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) may be isolated by filtration, or removal of solvent under vacuum, drying under vacuum or any other techniques known in the art.
  • Suitable solvent is selected for the group of water; ketones such as acetone, butanone, 2- pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like; alcohols such as methanol, isopropanol, 1-propanol, 1 -butanol, t-butyl alcohol, 1 - pentanol, 2-pentanol, other than ethanol, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, hydrocarbons like toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, and the like, nitriles like acetonitrile.
  • ketones such as acetone, butanone, 2- pentanone, 3-pentanone, methyl but
  • hydrolysis of the nitrile function of compound of formula (VI) and treatment with ammonia of compound of formula (Vila) the reaction preferably takes place by addition of second solvent ethyl acetate as an additional solvent into the reaction mixture. Addition of the ethyl acetate solvent during the reaction minimizes the process impurity which is being formed during this stage of preparation of dabigatran.
  • ethyl acetate as an additional solvent into the reaction mixture disclosed herein is that by utilizing a disclosed solvent and controlling the reaction, and the solvent to reactant ratio, a process can be achieved wherein a product- rich phase will separate from the solvent-rich phase at reaction temperatures.
  • a product-rich phase will separate from the solvent-rich phase at reaction temperatures.
  • the product-rich phase contains a greatly solvent to product ratio which can be separated by phase separation at near ambient temperatures.
  • the present invention provides a process purification of 1 -methyl -2- [N-(4- amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) -amide hydrochloride of formula (VII).
  • the process comprises purification of 1 -methyl -2- [N-(4-amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) -amide hydrochloride of formula (VII) by treatment with solvent system.
  • the slurry or solution or suspension of 1 -methyl -2- [N-(4-amidinophenyl) - aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) -amide hydrochloride of formula (VII) may be obtained by treating compound of formula (VII) in one or more suitable organic solvent system comprises of water; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like; alcohols such as methanol, isopropanol, 1-propanol, 1 - butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, other than ethanol, and the like; esters such as ethyl formate, methyl acetate, ethyl
  • the solvent system used in the process for purification of 1 -methyl -2- [N-(4- amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) -amide hydrochloride of formula (VII) may be selected from a group of organic, aqueous, solvents either alone or in combinations thereof.
  • solvent system comprises 1 :9 acetone/water, 1 :9 ethyl acetate/water, 1 :9 ethanol/water, 1 : 1 ethyl acetate/ethanol, 9: 1 toluene/water, 9: 1 tetrahydrofuran/water, or 1 : 1 acetone/methanol mixtures are employed in a process according to the present invention.
  • the embodiments of the process may include heating the slurry or solution or suspension of reaction mass followed by cooling to obtain pure compound of formula (VII).
  • the reaction mass may be heated up to temperature of 40 to 80°C and the cooling at about - 15°C to 10°C.
  • the reaction mass may be stirred for 30 minutes to 10 hours.
  • the substantially pure 1 -methyl -2- [N-(4-amidinophenyl) -amino methyl] benzimidazol - 5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) -amide hydrochloride of formula (VII) may be isolated by filtration, or removal of solvent under vaccum, drying under vaccum or any other techniques known in the art.
  • the reaction is carried out in an inert solvent selected from water, alcohols, nitriles, aromatic hydrocarbons, ethers, chlorinated hydrocarbons, and ketones in the presence of a suitable base, either organic or inorganic (tertiary amines, cyclic tertiary amines, DIPEA, hydroxides, carbonates are cyclohexylamine, dicyclohexylamine NaOH, KOH, LiOH, NaHC0 3 , KHC03, LiHC0 3 , Na 2 C0 3 , K 2 C0 3 , Li 2 C0 3 , Mg(OH) 2 , Ca(OH) 2 , CaC0 3 , MgC0 3 , Ba(OH) 2 , Be(OH) 2 , BaC0 3 , SrC0 3 , (CH3) 3 COK).
  • a suitable base either organic or inorganic (tertiary amines, cyclic tertiary amines, DIPEA, hydrox
  • the procedure in accordance with the present invention enables production of a high-quality product with a low content of impurities and a relatively high yield.
  • the production of pure intermediate compound of formula (VII) significantly simplifies the purifying operations during the manufacture of dabigatran etexilate.
  • 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. 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.
  • inert solvent comprises of water; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like; alcohols such as methanol, isopropanol, 1-propanol, 1 -butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, other than ethanol, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, hydrocarbons like toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, and the like, nitriles like acetonitrile. Most preferable inert solvent is acetonitrile.
  • ketones such as acetone, butanone, 2-pent
  • Dabigatran Etexilate of formula (VIII) can be further purified.
  • the present invention provides a process purification of Dabigatran Etexilate of formula (VIII).
  • the process comprises purification of Dabigatran Etexilate of formula (VIII) by treatment with solvent system.
  • the slurry or solution or suspension of Dabigatran Etexilate of formula (VIII) may be obtained by treating compound of formula (VIII) in one or more suitable organic solvent system comprises of water; ketones such as acetone, butanone, 2-pentanone, 3- pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like; alcohols such as methanol, isopropanol, 1-propanol, 1 -butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, other than ethanol, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, hydrocarbons like toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, and the like, nitrile
  • the solvent system used in the process for purification of Dabigatran Etexilate of formula (VIII) may be selected from a group of organic, aqueous, solvents either alone or in combinations thereof.
  • solvent system comprises 1 :9 acetone/water, 1 :9 ethyl acetate/water, 1 :9 ethanol/water, 1 : 1 ethyl acetate/ethanol, 9: 1 toluene/water, 9: 1 tetrahydrofuran/water, or 1 : 1 acetone/methanol mixtures are employed in a process according to the present invention.
  • the embodiments of the process may include heating the slurry or solution or suspension of reaction mass followed by cooling to obtain pure compound of formula (VIII).
  • the reaction mass may be heated upto temperature of 40 to 80°C and the cooling at about - 15°C to 10°C.
  • the reaction mass may be stirred for 30 minutes to 10 hours.
  • the substantially pure Dabigatran Etexilate of formula (VIII) may be isolated by filtration, or removal of solvent under vacuum, drying under vacuum or any other techniques known in the art.
  • the base used is selected from amines are triethylamine, DIPEA, cyclohexylamine, dicyclohexylamine; alcoholates, hydroxides, phosphates and carbonates are NaOH, KOH, LiOH, NaHC0 3 , KHC03, LiHC0 3 , Na 2 C0 3 , K 2 C0 3 , Li 2 C0 3 , Mg(OH) 2 , Ca(OH) 2 , CaC0 3 , MgC0 3 , Ba(OH) 2 , Be(OH) 2 , BaC0 3 , SrC0 3 , (CH3) 3 COK.
  • Triethylamine appears to be the most suitable base to obtain compound of formula (III).
  • the next production stage is reduction of the nitro group to the amino group compound of formula (III) as depicted by scheme 6 below.
  • reducing agent such as metal catalyst selected from Platinum, Ruthenium, Osmium, Iridium, and especially Palladium, Raney-nickel, and sodium dithionite along with a suitable solvent chosen from water, alcohol having C1-C4 alkyl group, tetrahydrofuran, toluene, xylene, ethyl acetate, hexane, heptane, isopropylether, dioxane, the like and mixtures thereof.
  • reducing agent such as metal catalyst selected from Platinum, Ruthenium, Osmium, Iridium, and especially Palladium, Raney-nickel, and sodium dithionite
  • a suitable solvent chosen from water, alcohol having C1-C4 alkyl group, tetrahydrofuran, toluene, xylene, ethyl acetate, hexane, heptane, isopropylether, dioxane, the like and mixtures thereof.
  • the procedure according to the present invention is also performed in a solvent mixture of ethanol and water and sodium dithionite as reagent this process is less costly and more advantageous.
  • the compound of formula (III) reacts in its salt form other than its hydrochloride salt form, which has a positive influence on the course of the reaction and purity of the product. Using the combination of changing the quality and composition of the starting compound and of the method of reduction of the nitro group it is possible to obtain compound of formula (IV) with a minimum content of impurities.
  • Any solvent which can dissolve both starting materials may be employed so far as it does not disturb the reaction, and more preferably one is exemplified by alcohols such as methanol, ethanol, propanol, the like, ketones such as acetone, methyl ethyl ketone, the like, ethers such as ether, tetrahydrofuran, dioxane, ethyl acetate the like, or mixture thereof.
  • alcohols such as methanol, ethanol, propanol, the like
  • ketones such as acetone, methyl ethyl ketone, the like
  • ethers such as ether, tetrahydrofuran, dioxane, ethyl acetate the like, or mixture thereof.
  • the crystalline polymorphic Form I of dabigatran etexilate mesylate characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at 2 ⁇ at about 4.5, 9.0, 9.3, 9.6, 11.0, 12.7, 14.4, 15.9, 16.5, 18.1, 18.7, 20.1, 20.7, 21.2, 23.0, 25.1, 26.8, 28.1, 29.4, 36.2.
  • XRD X-ray powder diffraction
  • the preferred embodiments of the process include heating the slurry or solution or suspension of reaction mass followed by cooling of dabigatran etexilate mesylate with ethyl acetate solvent.
  • the reaction mass may be heated upto temperature of 40 to 80°C and most preferably at about 60°C temperature and the cooling at about -15°C to 10°C.
  • the reaction mass may be stirred for 30 minutes to 10 hours.
  • Example 1 The present invention is described by the following Examples, which are for illustrative purpose only and should not be construed so as to limit the scope of the invention in any manner.
  • Example 1 The present invention is described by the following Examples, which are for illustrative purpose only and should not be construed so as to limit the scope of the invention in any manner.
  • Isopropyl ether 1000ml was added to the above reaction mass, stirred it for 5-10min. Ethanol was added to the residue to give clear solution.
  • the reaction mixture was allowed to stir at r. t. for about 20-24hr.
  • the reaction mass was filtered and washed with ethanol.
  • To this filtered was added equal amount of ethyl acetate and allowed to stir it for 3-4hr. Filtered the product and washed with ethyl acetate followed by Hexane. Collected solid was dried at 50°C.
  • Dabigatran etexilate l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride (100.0 gm) was dissolved in acetonitrile (500 ml) and water (500 ml). Hexyl chloroformate (47.28 ml) and triethylamine (103.8 ml) was added to it at a temperature of at 20-30°C.
  • the precipitated product is filtered off and washed with acetone (500 ml) /water (500 ml) at 25-30°C. Dissolved the obtained solid in acetonitrile under heating and then filtered. The isolated substance is dried under reduced pressure at 45° C.

Abstract

The present invention relates to an improved process for the preparation of 1-methyl-2- [N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide methanesulfonate salt (Dabigatran etexilate mesylate ). Further, the present invention provides a process for purification of Dabigatran etexilate mesylate. Further, the present invention provides provide a process for the preparation of 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N- (2-ethoxy carbonyl ethyl)-amide of formula (VI) an intermediate of Dabigatran.

Description

TITLE : - AN IMPROVED PROCESS FOR THE PREPARATIONOF
DABIGATRAN ETEXILATE MESYLATE.
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of l-methyl-2- [N-[4-( -n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide methanesulfonate salt (Dabigatran etexilate mesylate ).
Further, the present invention provides a process for purification of Dabigatran etexilate mesylate.
Further, the present invention provides a process for the preparation of 1 -methyl -2-[N- (4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2- ethoxy carbonyl eth l)-amide of formula (VI) an intermediate of Dabigatran.
Figure imgf000002_0001
BACKGROUND OF THE INVENTION
Preparation of Dabigatran Etexilate was first described in the PCT application WO9837075 however this method brings many technological problems, e.g. very complicated purifying operations, problems with low purity of intermediate products and the resulting low yield and low purity of the final product. One of the advanced intermediates during the production of Dabigatran Etexilate compound of formula (VI)
Figure imgf000003_0001
The compound of formula (VI) is prepared by a reaction of compound of formula (IV) compound of formula (V) with reagent as shown in Scheme 1.
Figure imgf000003_0002
(IV) (V) (VI)
Scheme 1
The procedure described in PCT application WO 9837075 produces compound of formula (VII) 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.
In the next stage acidic hydrolysis of the nitrile function of compound of formula (VI) and a reaction with ammonium carbonate is performed to produce the compound of formula (VII). The reaction is shown in Scheme 2.
Figure imgf000003_0003
Scheme 2
The procedure in accordance with WO9837075 produces compound of formula (II) in the mono-hydrochloride form.
When reproducing the procedure of WO9837075 we found out, in line with WO9837075, that compound of formula (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. The compound of formula (VII) in its hydrochloride salts was obtained in its amorphous form with a relatively high content of impurities, this compound subsequent required chromatographic purification
The last stage is a reaction of intermediate (VII) with hexyl chloroformate producing Dabigatran Etexilate and its transformation to a pharmaceutically acceptable salt (methanesulfonate) .
However, the method in accordance with WO9837075 does not make it possible to prepare Dabigatran Etexilate with high purity, which is required in the case of a pharmaceutical substance, and in a yield acceptable in the industrial scale. 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.
The process for the 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 sulphonic acid in acetone to provide dabigatran etexilate mesylate. The purity of the obtained crystalline dabigatran etexilate mesylate was not satisfactory i.e., around 97-98% by HPLC. There is no specific purification process disclosed for the purification of dabigatran etexilate mesylate.
Several methods for the preparation of Dabigatran Etexilate mesylate have been described. Like any synthetic compound, Dabigatran Etexilate, or a pharmaceutically- acceptable salt thereof can contain process impurities, unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. It is also known in the art that impurities present in an active pharmaceutical ingredient ("API") may arise from degradation of the API, for example, during storage or during the manufacturing process, including the chemical synthesis.
While developing a process for the preparation of Dabigatran Etexilate mesylate, present inventors serendipitously found an improved process for the preparation of highly pure Dabigatran Etexilate mesylate which minimizes process impurity.
OBJECT OF THE INVENTION
The present invention is to provide an improved process for the preparation of dabigatran etexilate mesylate in pure form, which ameliorates the problems of the prior art. The process of the present invention is simple, operates in moderate reaction conditions, yields highly pure dabigatran etexilate mesylate compound of formula- la.
Therefore, it is an object present invention to provide a process for preparing Dabigatran etexilate mesylate.
Yet another object of the present invention is to provide a process for the preparation of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VII) an intermediate of Dabigatran.
Figure imgf000005_0001
(VII) Yet another object of the present invention is to provide a process for the preparation of 1 -methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2- pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) an intermediate of Dabigatran.
Figure imgf000006_0001
Yet another object of the present invention is to provide a process for the preparation of
1 - methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2- pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI).
Yet another object of the present invention is to provide a purification process 1 -methyl -
2- [N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N- (2-ethoxy carbonyl ethyl)-amide of formula (VI) can be further purified with acetone or water or mixture thereoff.
Yet another object of the present invention is to provide a process for the preparation of 1- methyl-2-[N-[4-( -n-hexyloxycarbonyl amidino)phenyl]aminomethyl]benzimidazol-5- yl-carboxylicacid-N-(2-pyridyl)-N- (2-ethoxy carbonylethyl)amide compound of formula (VIII) (dabigatran etexilate) comprising: reacting 1 -methyl-2-[N-[4- amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)amide compound of formula (VII) with hexyl chloroformate in presence of a base in a suitable solvent to provide l-methyl-2-[N-[4-( -n- hexyloxycarbonyl amidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2- pyridyl)-N- (2-ethoxy carbonylethyl)amide compound of formula (VIII) (dabigatran etexilate) Yet another object present invention is to provide a novel process for the preparation of crystalline form-I of dabigatran etexilate mesylate.
Yet another object present invention is to provide a purification process for dabigatran etexilate mesylate.
SUMMARY OF THE INVENTION
In one aspect, present invention to provide a process for preparing Dabigatran etexilate mesylate.
In another aspect, the present invention provides a process for preparing Dabigatran etexilate mesylate, comprising the steps of:
a) reacting ethyl-3-[ {[3-amino-4-(methylamino)phenyl]carbonyl} (pyridin-2- yljamino] propanoate compound of formula (IV) with the [(4- cyanophenyljamino] acetic acid compound of formula (V) in presence of inert diluent and Pivaloyl chloride;
b) reacting 1 -methyl-2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl- carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide compound of formula (VI) with hydrochloride in presence of isopropyl ether and ethanol and ammonia to obtain l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]- benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)- amide hydrochloride compound of formula (VII);
c) reacting l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula (VII) with hexyl chloroformate in presence of a base in a suitable solvent to provide l-methyl-2-[N-[4-( -n-hexyloxycarbonyl amidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2- pyridyl)-N- (2-ethoxy carbonylethyl)amide compound of formula (VIII); d) treating the compound of formula (VHI)with methane sulfonic acid in a suitable solvent to provide the dabigatran etexilate mesylate.
In another aspect of the present invention is to provide a process for the preparation of 1- methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2- pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) an intermediate of dabigatran etexilate mesylate comprising : condensation of Ethyl-3-[ {[3-amino-4- (methylamino)phenyl]carbonyl}(pyridin-2-yl)amino] propanoate compound of formula (IV) with the [(4-cyanophenyl)amino] acetic acid compound of formula (V) in presence of inert diluent and Pivaloyl chloride.
Yet another aspect of the present invention is to provide a process for the preparation of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VII) an intermediate of Dabigatran comprising the steps of:
a) reacting ethyl-3-[ {[3-amino-4-(methylamino)phenyl]carbonyl} (pyridin-2- yl)amino] propanoate compound of formula (IV) with the [(4- cyanophenyl)amino] acetic acid compound of formula (V) in presence of inert diluent and pivaloyl chloride;
b) reacting 1 -methyl-2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl- carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide compound of formula (VI) with hydrochloride in presence of isopropyl ether, and ethanol and ammonia to obtain l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]- benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)- amide hydrochloride compound of formula (VII).
Yet another aspect of the present invention is to provide a process for the preparation of 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2- pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula (VII) comprising the steps of: a) hydrolysis of l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5- yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide compound of formula (VI) in presence of hydrochloride, isopropyl ether and ethanol; b) treatment of compound of formula (Vila) with ammonia to obtain 1 -Methyl-2- [N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylicacid-N-(2- pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride compound of formula (VII);
c) addition of second solvent ethyl acetate at the time of reaction in above steps (a) & (b).
Yet another aspect of the present invention is to provide a purification process 1 -methyl- 2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)- N-(2-ethoxycarbonylethyl)amide compound of formula (VII) can be further purified with acetone or water or mixture thereoff.
Yet another aspect of the present invention is to provide a process for the preparation of 1- methyl-2-[N-[4-( -n-hexyloxycarbonyl amidino)phenyl]aminomethyl]benzimidazol-5- yl-carboxylicacid-N-(2-pyridyl)-N- (2-ethoxy carbonylethyl)amide compound of formula (VIII) (dabigatran etexilate) comprising: reacting 1 -methyl-2-[N-[4- amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)amide compound of formula (VII) with hexyl chloroformate in presence of a base and acetonitrile to provide l-methyl-2-[N-[4-( -n-hexyloxycarbonyl amidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N- (2- ethoxy carbonylethyl)amide compound of formula (VIII) (dabigatran etexilate).
Yet another aspect of the present invention is to provide a purification process 1-methyl- 2-[N-[4-( -n-hexyloxycarbonyl amidino)phenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N- (2-ethoxy carbonylethyl)amide compound of formula (VIII) (dabigatran etexilate) can be further purified with acetone or water or mixture thereoff. In another aspect present invention is to provide a purification process for dabigatran etexilate mesylate which comprises of the following steps:
a) treating the dabigatran etexilate mesylate with ethyl acetate solvent at 60°C temperature;
b) isolating the solid obtained in step-a);
c) filtering off the obtained solid and washing with a suitable solvent,
In another aspect present invention is to provide process for preparing crystalline form-I of dabigatran etexilate mesylate comprises the steps of:
a) dissolving dabigatran etexilate mesylate in a solvent that is a mixture of acetone and an ethyl acetate;
b) recovering the solid product.
BRIEF DESCRIPTION OF THE DRAWING
Fig. 1 shows the X-ray powder diffraction pattern of polymorph Form I l-methyl-2-[N- [4-( -n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide methanesulfonate salt (Dabigatran etexilate mesylate ).
FIG. 2 shows the DSC pattern of new polymorph Form I of l-methyl-2-[N-[4-( -n- hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2- pyridyl)-N-(2-ethoxycarbonylethyl)amide methanesulfonate salt (Dabigatran etexilate mesylate).
DETAILS DESCRIPTION OF THE INVENTION
Here the term "crystallizing" means crystallizing compounds using methods known in the art. For example either reducing the volume of the solvent with respect to solute or decreasing the temperature of the solution or using both so as to crystallize the compound.
The term "treating" refers to suspending, dissolving or mixing and contacting or reacting of product with solvent or reagents followed by isolating product by removal of reagents and solvents.
The term "triturating" refers to suspending product in solvent and stirring for period of time sufficient for surface contact of solid with solvent and then filtering the compound from the mixture.
In one of the embodiment of the present invention provides a process for preparing Dabigatran etexilate mesylate, comprising the steps of:
a) reacting ethyl-3-[ {[3-amino-4-(methylamino)phenyl]carbonyl} (pyridin-2- yl)amino] propanoate compound of formula (IV) with the [(4- cyanophenyl)amino] acetic acid compound of formula (V) in presence of inert diluent and pivaloyl chloride;
b) reacting 1 -methyl-2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl- carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide compound of formula (VI) with alcoholic hydrochloride, isopropyl ether in mixture of solvents of alcohol and chlorinated solvent and ammonia to obtain 1-Methyl- 2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylicacid-N- (2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride compound of formula (VII);
c) reacting 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula (VII) with hexyl chloroformate in presence of a base in a suitable solvent to provide l-methyl-2-[N-[4-( -n-hexyloxycarbonyl amidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2- pyridyl)-N- (2-ethoxy carbonylethyl)amide compound of formula (VIII); d) treating the compound of formula (VHI)with methane sulfonic acid in a suitable solvent to provide the dabigatran etexilate mesylate.
In another embodiment of the present invention is to provide a process for the preparation of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid - N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VII) an intermediate of Dabigatran comprising the steps of:
a) reacting ethyl-3-[ {[3-amino-4-(methylamino)phenyl]carbonyl} (pyridin-2- yl)amino] propanoate compound of formula (IV) with the [(4- cyanophenyl)amino] acetic acid compound of formula (V) in presence of inert diluent and Pivaloyl chloride;
b) reacting 1 -methyl-2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl- carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide compound of formula (VI) with alcoholic hydrochloride, isopropyl ether in mixture of solvents of alcohol and chlorinated solvent and ammonia to obtain 1-Methyl- 2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylicacid-N- (2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride compound of formula (VII).
In another embodiment of the present invention is to provide a process for the preparation of 1 -methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N- (2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) an intermediate of dabigatran etexilate mesylate comprising : condensation of ethyl-3-[{[3-amino-4- (methylamino)phenyl]carbonyl}(pyridin-2-yl)amino] propanoate compound of formula (IV) with the [(4-cyanophenyl)amino] acetic acid compound of formula (V) in presence of inert diluent and pivaloyl chloride.
In another embodiment, the present invention provides a method for preparing dabigatran Etexilate salt, comprising the steps of: a) treating chloride of compound of formula (I) reacts with compound of formula (II) in tetrahydrofuran in the presence of a base to obtain compound of formula (HI);
b) reduction of the nitro group to the amino group compound of formula (III);
c) compound of formula (IV) reacts with the compound of formula (V) producing the compound of formula (VI) in presence of inert diluent and pivaloyl chloride; d) treating compound of formula (VI) with alcoholic hydrochloride, isopropyl ether in mixture of solvents of ethanol and dichloromethane and ammonia to obtain compound of formula (VII);
e) treating compound of formula (VII) with isopropyl alcohol , acetonitrile or ethyl acetate or mixture of solvent to obtain compound or formula (VII); and f) treating of compound or formula (VII) to obtain compound of formula (VIII); g) treating the compound of formula (VHI)with methane sulfonic acid in a suitable solvent to provide the dabigatran etexilate mesylate.
The condensation in step is carried out in the presence of an inert diluent and a pivaloyl chloride. The correspondingly substituted diaminobenzenes of formula (IV) are known, for example, from International Patent Application WO 98/37075 or may be prepared analogously to those described therein. It is particularly preferable to use 3-amino-4- methylaminobenzoic acid amides, especially 3-amino-4-methylaminobenzoic acid-N-(2- pyridyl)-N-(2-ethoxycarbonylethyl) amides.
The inert diluents used may be both aprotic apolar solvents such as, e.g., aliphatic or aromatic, optionally halogenated hydrocarbons, or aprotic polar solvents such as, e.g., ethers and/or amides or lactams and/or mixtures thereof. Aprotic apolar solvents used are preferably branched or unbranched C5-C8 aliphatic alkanes, C4-C10 cycloalkanes, Ci-C6 aliphatic haloalkanes, C6-Cio aromatic alkanes or mixtures thereof. It is particularly preferable to use alkanes such as pentane, hexane, or heptane, cycloalkanes such as cyclohexane or methylcyclohexane, haloalkanes such as dichloromethane, aromatic alkanes such as benzene, toluene, or xylene, or mixtures thereof. Suitable aprotic solvents are polar ethers such as, for example, tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, tert-butylmethylether, or dimethoxyethylether, or amides such as, for example, dimethylformamide, or lactams such as, for example, N-methylpyrrolidone.
In a another preferred embodiment [(4-cyanophenyl)amino] acetic acid compound of formula (V) is charged in inert diluents most preferably THF or toluene or N-Methyl-2- pyrrolidinone or mixture thereoff at 25-30°C. Pivaloyl chloride is added through dropping funnel at 0-5°C to the reaction mixture. The correspondingly substituted diaminobenzene (Ethyl-3-[ {[3-amino-4-(methylamino)phenyl]carbonyl} (pyridin-2-yl)amino] propanoate of formula (IV)) in inert diluents most preferably THF or toluene and acetic acid is added to the reaction mixture. The reaction mixture is stirred preferably at temperatures between -10° C. and 50° C. it is evaporated down, combined with water, and the solid substance is filtered off, washed, and dried.
In a the preferred embodiment Pivaloyl chloride are added in the presence of an organic base, preferably a tertiary amine, DIPEA, to a solution of [(4-cyanophenyl)amino] acetic acid compound of formula (V) and correspondingly substituted diaminobenzene in THF or toluene. The reaction mixture is stirred, preferably at temperatures between -10° C. and 50° C, and then, after the addition of acetic acid, it is evaporated down. It is combined with ethanol and filtered while hot. Then the substance precipitated from the cooled solution is filtered off, washed, and dried.
Figure imgf000014_0001
In the preferred embodiment of the present invention 1 -methyl -2-[N-(4-cyanophenyl)- aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) can be further purified. The present invention provides a process purification of 1 -methyl -2-[N-(4-cyanophenyl)- aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI). The process comprises purification of 1 -methyl -2-[N-(4- cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) by treatment with solvent system.
In general, the slurry or solution or suspension of 1 -methyl -2-[N-(4-cyanophenyl)- aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) may be obtained by treating compound of formula (VI) in one or more suitable organic solvent system comprises of water; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like; alcohols such as methanol, isopropanol, 1-propanol, 1 -butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, other than ethanol, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, hydrocarbons like toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, and the like, nitriles like acetonitrile.
The solvent system used in the process for process purification of 1 -methyl -2-[N-(4- cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) may be selected from a group of organic, aqueous, solvents either alone or in combinations thereof. Generally solvent system comprieses 1 :9 acetone/water, 1 :9 ethyl acetate/water, 1 :9 ethanol/water, 1 : 1 ethyl acetate/ethanol, 9: 1 toluene/water, 9: 1 tetrahydrofuran/water, or 1 : 1 acetone/methanol mixtures are employed in a process according to the present invention.
The embodiments of the process may include heating the slurry or solution or suspension of reaction mass followed by cooling to obtain pure compound of formula (VI). The reaction mass may be heated upto temperature of 40 to 80°C and the cooling at about - 15°C to 10°C. The reaction mass may be stirred for 30 minutes to 10 hours. The substantially pure 1 -methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) may be isolated by filtration, or removal of solvent under vacuum, drying under vacuum or any other techniques known in the art.
In a another preferred embodiment acidic hydrolysis of the nitrile function of compound of formula (VI) and a reaction with hydrochloride in solvent mixture and treated with isopropyl ether followed by treatment with ammonia to the residue dissolved in alcoholic solvent to obtain 1 -methyl -2- [N-(4-amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) -amide hydrochloride of formula (VII), the product is than treated with ethanol and ethyl acetate and followed by treatment with isopropanol, acetonitrile or ethyl acetate producing the or compound of formula (VII) as depicted in scheme 4 .
Figure imgf000016_0001
VII
Scheme 4
Suitable solvent is selected for the group of water; ketones such as acetone, butanone, 2- pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like; alcohols such as methanol, isopropanol, 1-propanol, 1 -butanol, t-butyl alcohol, 1 - pentanol, 2-pentanol, other than ethanol, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, hydrocarbons like toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, and the like, nitriles like acetonitrile.
In the preferred embodiment of the present invention is to provide a process for the preparation of 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula (VII) comprising the steps of:
a) hydrolysis of l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5- yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide compound of formula (VI) in presence of hydrochloride, isopropyl ether and solvent; b) treatment of compound of formula (Vila) with ammonia to obtain 1 -Methyl-2- [N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylicacid-N-(2- pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride compound of formula (VII);
c) addition of second solvent ethyl acetate at the time of reaction in above steps (a) & (b).
In the preferred embodiment hydrolysis of the nitrile function of compound of formula (VI) and treatment with ammonia of compound of formula (Vila) the reaction preferably takes place by addition of second solvent ethyl acetate as an additional solvent into the reaction mixture. Addition of the ethyl acetate solvent during the reaction minimizes the process impurity which is being formed during this stage of preparation of dabigatran.
An important advantage addition of ethyl acetate as an additional solvent into the reaction mixture disclosed herein is that by utilizing a disclosed solvent and controlling the reaction, and the solvent to reactant ratio, a process can be achieved wherein a product- rich phase will separate from the solvent-rich phase at reaction temperatures. Thus, as the compound of formula (VII) product is formed, it separates, and can be removed. This is especially advantageous for process since a product-rich phase can be easily and economically removed. The product-rich phase contains a greatly solvent to product ratio which can be separated by phase separation at near ambient temperatures.
In the preferred embodiment of the present invention 1 -methyl -2- [N-(4-amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy- carbonyl ethyl) -amide hydrochloride of formula (VII) can be further purified.
The present invention provides a process purification of 1 -methyl -2- [N-(4- amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) -amide hydrochloride of formula (VII). The process comprises purification of 1 -methyl -2- [N-(4-amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) -amide hydrochloride of formula (VII) by treatment with solvent system.
In general, the slurry or solution or suspension of 1 -methyl -2- [N-(4-amidinophenyl) - aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) -amide hydrochloride of formula (VII) may be obtained by treating compound of formula (VII) in one or more suitable organic solvent system comprises of water; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like; alcohols such as methanol, isopropanol, 1-propanol, 1 - butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, other than ethanol, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, hydrocarbons like toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, and the like, nitriles like acetonitrile.
The solvent system used in the process for purification of 1 -methyl -2- [N-(4- amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) -amide hydrochloride of formula (VII) may be selected from a group of organic, aqueous, solvents either alone or in combinations thereof. Generally solvent system comprises 1 :9 acetone/water, 1 :9 ethyl acetate/water, 1 :9 ethanol/water, 1 : 1 ethyl acetate/ethanol, 9: 1 toluene/water, 9: 1 tetrahydrofuran/water, or 1 : 1 acetone/methanol mixtures are employed in a process according to the present invention.
The embodiments of the process may include heating the slurry or solution or suspension of reaction mass followed by cooling to obtain pure compound of formula (VII). The reaction mass may be heated up to temperature of 40 to 80°C and the cooling at about - 15°C to 10°C. The reaction mass may be stirred for 30 minutes to 10 hours.
The substantially pure 1 -methyl -2- [N-(4-amidinophenyl) -amino methyl] benzimidazol - 5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) -amide hydrochloride of formula (VII) may be isolated by filtration, or removal of solvent under vaccum, drying under vaccum or any other techniques known in the art.
In another embodiment wherein 1 -methyl -2- [N-(4-amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) -amide hydrochloride of formula (VII) is reacted with hexyl chloro formate producing Dabigatran Etexilate of formula (VIII) and its transformation to a pharmaceutically acceptable salt. The reaction is carried out in an inert solvent selected from water, alcohols, nitriles, aromatic hydrocarbons, ethers, chlorinated hydrocarbons, and ketones in the presence of a suitable base, either organic or inorganic (tertiary amines, cyclic tertiary amines, DIPEA, hydroxides, carbonates are cyclohexylamine, dicyclohexylamine NaOH, KOH, LiOH, NaHC03, KHC03, LiHC03, Na2C03, K2C03, Li2C03, Mg(OH)2, Ca(OH)2, CaC03, MgC03, Ba(OH)2, Be(OH)2, BaC03, SrC03, (CH3)3COK). The procedure in accordance with the present invention enables production of a high-quality product with a low content of impurities and a relatively high yield. The production of pure intermediate compound of formula (VII) significantly simplifies the purifying operations during the manufacture of dabigatran etexilate. 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. 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.
In the preferred embodiment of the present invention inert solvent comprises of water; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like; alcohols such as methanol, isopropanol, 1-propanol, 1 -butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, other than ethanol, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, hydrocarbons like toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, and the like, nitriles like acetonitrile. Most preferable inert solvent is acetonitrile.
In the preferred embodiment of the present invention Dabigatran Etexilate of formula (VIII) can be further purified.
The present invention provides a process purification of Dabigatran Etexilate of formula (VIII). The process comprises purification of Dabigatran Etexilate of formula (VIII) by treatment with solvent system.
In general, the slurry or solution or suspension of Dabigatran Etexilate of formula (VIII) may be obtained by treating compound of formula (VIII) in one or more suitable organic solvent system comprises of water; ketones such as acetone, butanone, 2-pentanone, 3- pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like; alcohols such as methanol, isopropanol, 1-propanol, 1 -butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, other than ethanol, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, hydrocarbons like toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, and the like, nitriles like acetonitrile.
The solvent system used in the process for purification of Dabigatran Etexilate of formula (VIII) may be selected from a group of organic, aqueous, solvents either alone or in combinations thereof. Generally solvent system comprises 1 :9 acetone/water, 1 :9 ethyl acetate/water, 1 :9 ethanol/water, 1 : 1 ethyl acetate/ethanol, 9: 1 toluene/water, 9: 1 tetrahydrofuran/water, or 1 : 1 acetone/methanol mixtures are employed in a process according to the present invention.
The embodiments of the process may include heating the slurry or solution or suspension of reaction mass followed by cooling to obtain pure compound of formula (VIII). The reaction mass may be heated upto temperature of 40 to 80°C and the cooling at about - 15°C to 10°C. The reaction mass may be stirred for 30 minutes to 10 hours.
The substantially pure Dabigatran Etexilate of formula (VIII) may be isolated by filtration, or removal of solvent under vacuum, drying under vacuum or any other techniques known in the art.
Procedure as described in the present invitation:
Figure imgf000021_0001
Scheme 5 Procedure for the preparation of Dabigatran Etexilate according to the present invention wherein Ethyl-3-[ {[3-amino-4-(methylamino)phenyl]carbonyl} (pyridin-2-yl)amino] propanoate compound of formula (IV) process comprises, reaction of chloride of compound of formula (I) with compound of formula (II) in tetrahydrofuran in the presence of a base. The base used is selected from amines are triethylamine, DIPEA, cyclohexylamine, dicyclohexylamine; alcoholates, hydroxides, phosphates and carbonates are NaOH, KOH, LiOH, NaHC03, KHC03, LiHC03, Na2C03, K2C03, Li2C03, Mg(OH)2, Ca(OH)2, CaC03, MgC03, Ba(OH)2, Be(OH)2, BaC03, SrC03, (CH3)3COK. Triethylamine appears to be the most suitable base to obtain compound of formula (III). The next production stage is reduction of the nitro group to the amino group compound of formula (III) as depicted by scheme 6 below.
Reduction of compound of formula (III)
Figure imgf000022_0001
was conducted by using reducing agent such as metal catalyst selected from Platinum, Ruthenium, Osmium, Iridium, and especially Palladium, Raney-nickel, and sodium dithionite along with a suitable solvent chosen from water, alcohol having C1-C4 alkyl group, tetrahydrofuran, toluene, xylene, ethyl acetate, hexane, heptane, isopropylether, dioxane, the like and mixtures thereof. Preferably the reaction can favorably be conducted in the presence of palladium, charcoal and ethyl acetate. The procedure according to the present invention is also performed in a solvent mixture of ethanol and water and sodium dithionite as reagent this process is less costly and more advantageous. The compound of formula (III) reacts in its salt form other than its hydrochloride salt form, which has a positive influence on the course of the reaction and purity of the product. Using the combination of changing the quality and composition of the starting compound and of the method of reduction of the nitro group it is possible to obtain compound of formula (IV) with a minimum content of impurities.
Figure imgf000023_0001
The above reactions can be carried out advantageously in the presence of solvent. Any solvent which can dissolve both starting materials may be employed so far as it does not disturb the reaction, and more preferably one is exemplified by alcohols such as methanol, ethanol, propanol, the like, ketones such as acetone, methyl ethyl ketone, the like, ethers such as ether, tetrahydrofuran, dioxane, ethyl acetate the like, or mixture thereof.
According to Example 3 of patent application no.WO2003074056Al the preparation of dabigatran etexilate mesylate the polymorphic form of the compound is crystalline polymorphic Form I characterised as follow:
The crystalline polymorphic Form I of dabigatran etexilate mesylate characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at 2Θ at about 4.5, 9.0, 9.3, 9.6, 11.0, 12.7, 14.4, 15.9, 16.5, 18.1, 18.7, 20.1, 20.7, 21.2, 23.0, 25.1, 26.8, 28.1, 29.4, 36.2. The crystalline polymorphic Form I of dabigatran etexilate mesylate characterized is depicted in Fig. I.
The crystalline polymorphic Form I of dabigatran etexilate mesylate characterized by melting point of Tsm p . = 180 ± 3 ° C (form I) (determined by DSC; evaluation of peak maximum, heating rate: 10 ° C / min) DSC depicted in Fig. II.
In another preferred embodiment of the present invention is to provide a purification process for dabigatran etexilate mesylate which comprises of the following steps:
a) treating the dabigatran etexilate mesylate with ethyl acetate solvent at about 60°C temperature;
b) isolating the solid obtained in step (a);
c) filtering off the obtained solid and washing with a suitable solvent,
The preferred embodiments of the process include heating the slurry or solution or suspension of reaction mass followed by cooling of dabigatran etexilate mesylate with ethyl acetate solvent. The reaction mass may be heated upto temperature of 40 to 80°C and most preferably at about 60°C temperature and the cooling at about -15°C to 10°C. The reaction mass may be stirred for 30 minutes to 10 hours.
In another preferred embodiment of the present invention is to provide process for preparing crystalline form-I of dabigatran etexilate mesylate comprises the steps of:
a) dissolving dabigatran etexilate mesylate in a solvent that is a mixture of acetone and an ethyl acetate;
b) recovering the solid product.
The present invention is described by the following Examples, which are for illustrative purpose only and should not be construed so as to limit the scope of the invention in any manner. Example 1
Preparation of ethyl 3-[[4-(methylamino)-3-iiitrobenzoyl](pyridiii-2-yl)amino] propanoate hydrochloride hemisulfate
In the mixture of thionyl chloride and THF were added to 100 g of 4-(methylamino)-3- nitrobenzoic acid compound of formula (I) under inert atmosphere. The mixture was brought to boil. During that 4-(methylamino)-3-nitrobenzoic acid got dissolved in several minutes and produced a dark brown solution. Then, the solution was refluxed for another 40-45 minutes. After that, excessive thionyl chloride was distilled off. To the brown residue toluene were added under inert atmosphere and the toluene was removed by distillation. This operation was repeated once again. The obtained brown crystalline residue was dissolved in dry THF at an increased temperature.
After cooling of the solution of acid chloride of formula (I) to the temperature of 40° C. dry triethylamine was added. To this solution a solution of ethyl 3-(pyridin-2- ylamino)propanoate in dichloromethane was added dropwise. Then, the reaction mixture was stirred without heating for 2 hours. After sucking off triethylamine hydrochloride dichloromethane was evaporated. The evaporation residue was dissolved in chloroform and shaken with water. The separated organic layer was shaken with 2 M HC1 and then with water. The organic layer was dried with sodium sulphate.
The crude product was dissolved in dichloromethane. Solutions of sulfuric acid were added slowly to the solution dropwise under intensive stirring. During the stirring a yellow precipitate separates. After cooling in a fridge it was filtered off and dried. EXAMPLE 2
Preparation of ethyl 3-[[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino]- propanoate (IV)
The product ethyl 3-[[4-(methylamino)-3-nitrobenzoyl](pyridin-2-yl)amino]propanoate hydrochloride hemisulfate was dissolved in ethanol— water mixture 1 : 1 and heated up to 50° C. To the solution of ethyl 3-[[4-(methylamino)-3-nitrobenzoyl](pyridin-2- yl)amino]propanoate hydrochloride hemisulfate was reduced with palladium, charcoal and passing hydrogen gas in autoclave. After the completion of reaction the reaction mixture was concentrated in a vacuum evaporator. After separation of oil the concentration was completed and the product was extracted with ethyl acetate. After its drying with sodium sulphate the solvent is evaporated. The product is obtained as a brown, very viscous liquid.
EXAMPLE 3
Preparation of 3-([2-[(4-cyanophenyl amino)-methyl]-l-methyl-lH-benzimidazole-5- carbonyl] -pyridin-2-yl-amino)ethyl propionate (VI)
Toluene (400 ml) and [(4-cyanophenyl)amino]acetic acid (54.02 gm) at 25-30°C, Then reaction mass was cooled at -2 to - 10°C and pivaloyl chloride was charged to the reaction mass, slowly N,N-Diisopropylethylamine (58.10 ml) was added through dropping funnel at -10 to -10°C within 1-2 hr. After 1-2 hr ethyl 3-[[3-amino-4-(methylamino) benzoyl] (pyridin-2-yl)amino]-propanoate (lOOgm) and acetic acid (100 ml) at -2 to -10°C is added to the mixture and the mixture is heated up to 90-95°C for 1 hr. After completion of reaction mixture is slightly cooled and than process water and ethyl acetate is added. Product is recovered form the organic layer. Dissolved the obtained solid in ethanol under heating and then filtered. The title product was crystallized by the addition of ethanol and water. The isolated substance was dried.
Wet weight : HOgm to 120gm
Dry weight : 85.0-95.0 gm Yield (w/w) 0.85-0.95
Theoretical Yield (w/w) 1.40
Molar Yield 60.7-67.8%
EXAMPLE 4
Process for the preparation of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) - amide hydrochloride
Purge HC1 gas to the solution of 1 -methyl -2-[N-(4-cyanophenyl)-aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide (lOO.Ogm) in Ethanol (500 ml) at 15-30°C (Purge HC1 gas by passing HC1 gas to above reaction mixture till the HC1 content of the reaction mixture comes to 30-40% at 15- 25°C). After completion of addition, reaction mixture was allowed to stir at 20-45°C for about 5-10hr. After that the reaction was terminated and taken for work up. Isopropyl ether (1000ml) was added to the above reaction mass, stirred it for 5-10min. Ethanol was added to the residue to give clear solution. To this solution, was added previously prepared ammonical ethanol (Ammonia gas passed into ethanol) at 15-30°C. The reaction mixture was allowed to stir at r. t. for about 20-24hr. The reaction mass was filtered and washed with ethanol. To this filtered was added equal amount of ethyl acetate and allowed to stir it for 3-4hr. Filtered the product and washed with ethyl acetate followed by Hexane. Collected solid was dried at 50°C.
Wet weight : 140.0 gm to 180.0 gm
Dry weight : 75.0-85.0 gm
Yield (w/w) : 0.75-0.85
Theoretical Yield (w/w): 1.1 1
Molar Yield : 67.5-76.6% EXAMPLE 5
Preparation of Dabigatran etexilate: l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride (100.0 gm) was dissolved in acetonitrile (500 ml) and water (500 ml). Hexyl chloroformate (47.28 ml) and triethylamine (103.8 ml) was added to it at a temperature of at 20-30°C. After the end of the reaction, the precipitated product is filtered off and washed with acetone (500 ml) /water (500 ml) at 25-30°C. Dissolved the obtained solid in acetonitrile under heating and then filtered. The isolated substance is dried under reduced pressure at 45° C.
Wet weight 150.0-180.0 gm
Dry weight 80.0-90.0 gm
Yield (w/w) 0.80-0.90
Theoretical Yield (w/w): 1.17
Practically Yield : 68.4-76.9%
EXAMPLE 6
Preparation of dabigatran etexilate mesylate: l-methyl-2-[N-[4-( -n-hexyloxycarbonylamidino)phenyl] amino methyl]benzimidazol-5- yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonyl ethyl) amide (100 gm) was dissolved acetone (1000 ml) under heating at 25-35 °C. A solution of methane sulfonic acid (13.77 gm) in acetone (100 ml) was added to the reaction mixture. The solution is filtered and after the addition of acetone cooled to approximately 20° C. The precipitated product was filtered and washed with acetone then dried at 50° C under reduced pressure.
Wet weight : 0.120-0.140 kg
Dry weight : 0.90-1.0 kg
Yield (W/W) : 0.90-1.0
Theoretical Yield (w/w) : 1.15
Percentage Yield : 78.2-86.9%

Claims

We Claim,
1) A process for preparing Dabigatran etexilate mesylate, comprising the steps of: a) Ethyl-3-[{[3-amino-4-(methylamino)phenyl]carbonyl}(pyridin-2-yl)amino] propanoate compound of formula (IV) is condensed with the [(4- cyanophenyl)amino] acetic acid compound of formula (V) in presence of inert diluent, pivaloyl chloride and base, preferably a tertiary amine, DIPEA;
b) the product obtained l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl] benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)- amide compound of formula (VI) is treated with hydrochloride in presence of isopropyl ether, solvent and ammonia to obtain l-Methyl-2- [N-(4- amidinophenyl) -aminomethyl]- benzimidazol-5-yl-carboxylicacid-N- (2- pyridyl) -N-(2-ethoxycarbonylethyl) -amide hydrochloride compound of formula (VII);
c) reacting 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula (VII) with hexyl chloroformate in presence of a base in a suitable solvent to provide l-methyl-2-[N-[4-( -n-hexyloxycarbonyl amidino) phenyl] aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl) -N- (2- ethoxy carbonylethyl) amide compound of formula (VIII);
d) treating the compound of formula (VHI)with methane sulfonic acid in a suitable solvent to provide the dabigatran etexilate mesylate.
2) A process for preparing Dabigatran etexilate mesylate according to claim 1 wherein inert diluent is aprotic apolar solvents or aprotic polar solvents.
3) A process for preparing Dabigatran etexilate mesylate according to claim 2 wherein inert diluent are selected for the group of aprotic apolar solvents and aprotic polar solvents are pentane, hexane, heptane, cyclohexane, methylcyclohexane, dichloromethane, benzene, toluene, tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, tert-butylmethylether, dimethoxyethylether, dimethylformamide, N-methylpyrrolidone .
4) A process for preparing Dabigatran etexilate mesylate according to claim 2 wherein inert diluent most preferably are THF, toluene, N-Methyl-2-pyrrolidinone or mixture thereof.
5) A process for preparing Dabigatran etexilate mesylate according to claim 1 wherein solvent are water, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, methanol, isopropanol, 1-propanol, 1 - butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, acetonitrile
6) A process for preparing Dabigatran etexilate mesylate according to claim 1 wherein base are triethylamine, DIPEA, cyclohexylamine, dicyclohexylamine, NaOH, KOH, LiOH, NaHC03, KHC03, LiHC03, Na2C03, K2C03, Li2C03, Mg(OH)2, Ca(OH)2, CaC03, MgC03, Ba(OH)2, Be(OH)2, BaC03, SrC03, (CH3)3COK.
7) A process for preparing Dabigatran etexilate mesylate according to claim 6 wherein base most preferably is triethylamine, DIPEA.
8) A process for the preparation of 1 -methyl -2-[N-(4-cyanophenyl)- aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula (VI) an intermediate of dabigatran etexilate mesylate comprising: condensation of Ethyl-3-[{[3-amino-4- (methylamino)phenyl] carbonyl} (pyridin-2-yl)amino] propanoate compound of formula (Γν) with the [(4-cyanophenyl) amino] acetic acid compound of formula (V) in presence of inert diluent, pivaloyl chloride and base, preferably a tertiary amine, DIPEA. 9) A process for preparing Dabigatran etexilate mesylate according to claim 8 wherein inert diluent is aprotic apolar solvents or aprotic polar solvents.
10) A process for preparing Dabigatran etexilate mesylate according to claim 9 wherein inert diluent are selected for the group of aprotic apolar solvents and aprotic polar solvents are pentane, hexane, heptane, cyclohexane, methylcyclohexane, dichloromethane, benzene, toluene, solvents tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, tert-butylmethylether, dimethoxyethylether, dimethylformamide, N-methylpyrrolidone.
11) A process for preparing Dabigatran etexilate mesylate according to claim 9 wherein inert diluent most preferably are THF, toluene, N-Methyl-2-pyrrolidinone or mixture thereof.
12) A process for the preparation of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) - amide hydrochloride of formula (VII) an intermediate of Dabigatran comprising the steps of:
a) reacting ethyl-3-[ {[3-amino-4-(methylamino)phenyl]carbonyl} (pyridin-2- yl)amino] propanoate compound of formula (IV) with the [(4- cyanophenyl)amino] acetic acid compound of formula (V) in presence of toluene, pivaloyl chloride and base, preferably a tertiary amine, DIPEA;
b) reacting l-methyl-2-[N-(4-cyanophenyl)-aminomethyl] benzimidazol-5-yl- carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide compound of formula (VI) with hydrochloride in presence of isopropyl ether, ethanol and ammonia to obtain l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]- benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)- amide hydrochloride compound of formula (VII). 13) A process for the preparation of 1 -methyl-2-[N-[4-amidinophenyl] aminomethyl] benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide compound of formula (VII) comprising the steps of:
a) hydrolysis of l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5- yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide compound of formula (VI) in presence of hydrochloride, isopropyl ether and ethanol to obtain compound of formula (Vila);
b) treatment of compound of formula (Vila) with ammonia to obtain 1 -Methyl-2- [N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylicacid-N-(2- pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride compound of formula (VII);
c) addition of second solvent ethyl acetate at the time of reaction in above steps (a) & (b).
14) A process for purification of 1 -methyl-2- [N-[4-amidinophenyl] aminomethyl] benzimidazol-5-yl- carboxylicacid -N-(2-pyridyl)-N -(2-ethoxycarbonylethyl) amide compound of formula (VII) with acetone or water or mixture thereoff.
15) A process for the preparation of l-methyl-2-[N-[4-( -n-hexyloxycarbonyl amidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N- (2-ethoxy carbonylethyl)amide compound of formula (VIII) (dabigatran etexilate) comprising:
reacting 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula (VII) with hexyl chloroformate in presence of a base and acetonitrile to provide l-methyl-2-[N-[4-( -n-hexyloxycarbonyl amidino) phenyl] aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N- (2-ethoxy carbonylethyl) amide compound of formula (VIII) (dabigatran etexilate). 16) A process for the preparation of l-methyl-2-[N-[4-( -n-hexyloxycarbonyl amidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N- (2-ethoxy carbonylethyl)amide compound of formula (VIII) (dabigatran etexilate) according to claim 15 wherein base are selected from the group triethylamine, DIPEA, cyclohexylamine, dicyclohexylamine, NaOH, KOH, LiOH, NaHC03, KHC03, LiHC03, Na2C03, K2C03, Li2C03, Mg(OH)2, Ca(OH)2, CaC03, MgC03, Ba(OH)2, Be(OH)2, BaC03, SrC03, (CH3)3COK.
17) A process for purification of l-methyl-2-[N-[4-( -n-hexyloxycarbonyl amidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N- (2-ethoxy carbonylethyl)amide compound of formula (VIII) (dabigatran etexilate) with acetone or water or mixture thereoff.
18) A process for the preparation of crystalline form-I of dabigatran etexilate mesylate which comprises steps of:
a) treating the dabigatran etexilate mesylate with ethyl acetate solvent at 60°C temperature;
b) isolating the solid obtained in step-a);
c) filtering off the obtained solid and washing with a suitable solvent,
19) A process for preparing crystalline form-I of dabigatran etexilate mesylate comprises the steps of:
a) dissolving dabigatran etexilate mesylate in a solvent that is a mixture of acetone and an ethyl acetate;
b) recovering the solid product.
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