WO2014020555A2 - Procédé amélioré de préparation d'étexilate-mésylate de dabigatran - Google Patents

Procédé amélioré de préparation d'étexilate-mésylate de dabigatran Download PDF

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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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WO2014020555A3 (fr
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Venkat Raman JAYARAMAN
Samir Patel
Samir Mistry
Mukesh Timbadiya
Bhupendra Parmar
Jignesh Patel
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Alembic Pharmaceuticals Limited
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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.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne un procédé amélioré de préparation de sel méthanesulfonate de N-(2-pyridyl)-N-(2-éthoxycarbonyléthyl)amide d'acide [N-[4-(N-n-hexyloxycarbonylamidino)phényl]aminométhyl]benzimidazol-5-yl- carboxylique (étexilate-mésylate de dabigatran). Cette invention concerne en outre un procédé de purification dudit étexilate-mésylate de dabigatran. Un procédé de préparation de N-(2-pyridyl)-N-(2-éthoxy-carbonyl-éthyl)- amide d'acide 1-méthyl-2-[N-(4-cyanophényl)-aminométhyl]benzimidazol- 5-yl-carboxylique de formule (VI), un intermédiaire du dabigatran, est également décrit.
PCT/IB2013/056288 2012-08-01 2013-07-31 Procédé amélioré de préparation d'étexilate-mésylate de dabigatran WO2014020555A2 (fr)

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CN104892576A (zh) * 2015-05-27 2015-09-09 上海应用技术学院 一种达比加群酯类似物中间体的纯化方法
CN105037253A (zh) * 2015-05-27 2015-11-11 上海应用技术学院 一种超声逼晶法提纯化合物的方法
CN105294651A (zh) * 2015-09-23 2016-02-03 烟台东诚药业集团股份有限公司 一种用于合成制备达比加群酯脒化中间体的方法
CN105461686A (zh) * 2014-08-25 2016-04-06 江苏豪森药业股份有限公司 制备高纯度甲磺酸达比加群酯晶型的方法
CN105859686A (zh) * 2016-05-24 2016-08-17 浙江华海药业股份有限公司 一种高纯度达比加群酯的制备工艺
CN107686476A (zh) * 2017-09-04 2018-02-13 扬子江药业集团广州海瑞药业有限公司 一种甲磺酸达比加群酯的制备工艺
CN110878083A (zh) * 2018-09-05 2020-03-13 连云港恒运药业有限公司 一种达比加群酯中间体的纯化方法
WO2022198361A1 (fr) * 2021-03-22 2022-09-29 天津睿创康泰生物技术有限公司 Nouvelle forme cristalline d'hydrochlorure d'ester éthylique de dabigatran étexilate, son procédé de préparation et son utilisation

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WO2012027543A1 (fr) * 2010-08-25 2012-03-01 Teva Pharmaceuticals Usa, Inc. Formes solides de dabigatran étexilate et de dabigatran étexilate mésylate et leurs méthodes de préparation
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CN105461686A (zh) * 2014-08-25 2016-04-06 江苏豪森药业股份有限公司 制备高纯度甲磺酸达比加群酯晶型的方法
CN104725360A (zh) * 2015-04-09 2015-06-24 重庆东得医药科技有限公司 一种甲磺酸达比加群酯ⅰ晶型的制备方法
CN104892576A (zh) * 2015-05-27 2015-09-09 上海应用技术学院 一种达比加群酯类似物中间体的纯化方法
CN105037253A (zh) * 2015-05-27 2015-11-11 上海应用技术学院 一种超声逼晶法提纯化合物的方法
CN105294651A (zh) * 2015-09-23 2016-02-03 烟台东诚药业集团股份有限公司 一种用于合成制备达比加群酯脒化中间体的方法
US10538507B2 (en) 2016-05-24 2020-01-21 Zhejiang Huahai Pharmaceutical Co., Ltd Preparation process for high-purity dabigatran etexilate
EP3444244A4 (fr) * 2016-05-24 2019-03-27 Zhejiang Huahai Pharmaceutical Co., Ltd Procédé de préparation d'un étexilate de dabigatran de pureté élevée
US20190152945A1 (en) * 2016-05-24 2019-05-23 Zhejiang Huahai Pharmaceutical Co., Ltd Preparation process for high-purity dabigatran etexilate
CN105859686A (zh) * 2016-05-24 2016-08-17 浙江华海药业股份有限公司 一种高纯度达比加群酯的制备工艺
CN105859686B (zh) * 2016-05-24 2021-10-08 浙江华海药业股份有限公司 一种达比加群酯游离碱的精制方法
CN107686476A (zh) * 2017-09-04 2018-02-13 扬子江药业集团广州海瑞药业有限公司 一种甲磺酸达比加群酯的制备工艺
CN110878083A (zh) * 2018-09-05 2020-03-13 连云港恒运药业有限公司 一种达比加群酯中间体的纯化方法
WO2022198361A1 (fr) * 2021-03-22 2022-09-29 天津睿创康泰生物技术有限公司 Nouvelle forme cristalline d'hydrochlorure d'ester éthylique de dabigatran étexilate, son procédé de préparation et son utilisation

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