EP2872500A2 - Procédé perfectionné pour la préparation d'etexilate mésylate de dabigatran et de ses intermédiaires - Google Patents

Procédé perfectionné pour la préparation d'etexilate mésylate de dabigatran et de ses intermédiaires

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Publication number
EP2872500A2
EP2872500A2 EP13816563.4A EP13816563A EP2872500A2 EP 2872500 A2 EP2872500 A2 EP 2872500A2 EP 13816563 A EP13816563 A EP 13816563A EP 2872500 A2 EP2872500 A2 EP 2872500A2
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EP
European Patent Office
Prior art keywords
methyl
acid
formula
compound
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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EP13816563.4A
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German (de)
English (en)
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EP2872500A4 (fr
Inventor
Ravi Ponnaiah
Praveen Kumar Neela
Guruswamy Batthini
Narayana B VEERA
Venkata Narasimha RAO TELEGAREDDY
Ravana K BABU
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Rao Davuluri Ramamohan
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Rao Davuluri Ramamohan
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Publication of EP2872500A2 publication Critical patent/EP2872500A2/fr
Publication of EP2872500A4 publication Critical patent/EP2872500A4/fr
Ceased legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to an improved process for the preparation of DabigatranEtexilateMesylate and the processes for the preparation of Dabigatran single prodrug and DabigatranEtexilate thereof.
  • DabigatranEtexilateMesylate chemically know as N-[[2-[[[4-[[[(hexyloxy) carbonyl] amino]-iminomethyl] phenyl] amino] . methyl]-l -methyl-lH- benzimidazol-5-yl] carbonyI]-N-2- pyridinyl-beta-Alanine ethyl ester methanesulfonate having the formula I as provided below,
  • DabigatranEtexilate is first time reported in the US patent 6087380 (hereinafter referred as US'380) in which the process fo the preparation of DabigatranEtexilate is disclosed in the Example 49, 58a and Example 59, said process for the preparation of DabigatranEtexilate is depicted below:
  • the patent US81 19810 discloses the process for the preparation Dabigatran from 3- ([2-[(4-cyanophenylamino)-methyl]-l-methyl-lH- benzimidazole-5-carbonyl]-pyridin-2-yl-amino) ethyl propionate hydro bromide as one of the intermediate in order to overcome the problem of the process depicted in the product patent.
  • DabigatranEtexilate are exemplified in the examples of the patent US'380.
  • the patent US'380 has no information about the solid state properties of the single prodrug of Dabigatran and DabigatranEtexilate.
  • the PCT publication WO2006131491 discloses the anhydrous form [ of DabigatranEtexilate having the melting point 135°C, anhydrous form II of DabigatranEtexilate having the melting point 150°C, and hydrate form of DabigatranEtexilate having the melting point 90°C.
  • the PCT publication WO2008059029 discloses anhydrous form III of DabigatranEtexilate having melting point 128°C, anhydrous form IV of DabigatranEtexilate having the melting point 133°C, and mono hydrate form I of DabigatranEtexilate having melting point 128°C and mono hydrate form II of DabigatranEtexilate having melting point 123°C.
  • Figure 1 depicts X-Ray Powder Diffraction (XRPD) pattern of crystalline form A of single prodrug of Dabigatran.
  • Figure 2 depicts X-Ray Powder Diffraction (XRPD) pattern of crystalline form IC of DabigatranEtexilate.
  • Figure 3 depicts Differential Scanning Calorimetry (DSC) pattern of crystalline form IC of DabigatranEtexilate.
  • the main objective of the present invention is to provide an improved process for the preparation of DabigatranEtexi lateMesylate.
  • the first aspect of the present invention is to provide a process for the preparation of DabigatranEtexilateMesylate comprising the steps of:
  • step(a) adding dicarboxylic acid having 3 to 10 carbon atoms to the reaction mixture obtained in step(a) and maintaining the mixture for a sufficient time to obtain a compound 3-( ⁇ 2-[(4-cyano-phenylamino)methyl]-l-methyl-lH-benzoimidazole- 5-carbonyl ⁇ pyridin-2-ylamino)propionicacid ethyl ester, dicarboxylic acid addition salt havin 3 to 10 carbon atoms having the formula-VI;
  • step (c) dissolving the compound of formula IV obtained in step (c) in a mixture of ethanol and esters thereof ;
  • step (e) adding an ammonia source periodically to the reaction mixture prepared in step (e) and maintaining the reaction mixture for a sufficient time to obtain a compound of formula II;
  • the second aspect of the present invention provides a process for the pure 3-( ⁇ 2-[(4-cyano-phenyIamino) methyl]-l-methyl-lH-benzoimidazole-5-carbonyl ⁇ pyridin-2-yiamino) propionic acid ethyl ester of the compound of formula IV
  • step(a) adding dicarboxylic acid having 3 to 10 carbon atoms to the reaction mixture obtained in step(a) and maintaining the mixture for a sufficient time to obtain a compound 3-( ⁇ 2-[(4-cyano-phenylamino)methyl]- l -methyl- IH-benzoimidazole- 5-carbonyl ⁇ pyridin-2-ylamino)propionic acid ethyl ester, dicarboxylic acid having 3 to 10 arbon atoms having the formula- VI acid having 3 to 10 carbon atoms Formula VI
  • the third aspect of the present invention provides a novel compound 3- ( ⁇ 2-[(4-cyano-phenylamino) methyl]- 1 -methyl- l H-benzoimidazole-5-carbonyl ⁇ pyridin-2-ylamino) propionic acid ethyl ester dicarboxylic acid having 3 to 10 carbon atoms of formula VI. acid having 3 to 10 carbon atoms
  • the fourth aspect of the present invention provides a process for the preparation of om
  • step (c) adding an ammonia source periodically to the reaction mixture prepared in step (b) and maintaining the reaction mixture for a sufficient time to obtain a compound of formula II.
  • the fifth aspect of the present invention is to provide a process for the preparation of th compound of formula II as free base in pure form
  • step (b) adding an ammonia source periodically to the reaction mixture obtained in step (b) and maintaining sufficient time to obtain the compound of formula II.
  • the sixth aspect of the present invention is to provide a novel compound of formula VII
  • the seventh aspect of the present invention is to provide a novel process for the purification of Dab igatranEtexi late involving the step of crystallizing Crude Dab igatranEtexi late in isopropanol.
  • The. eighth aspect of the present invention provides a process for the preparation of DabigatranEtexilateMesylate comprising the steps of:
  • step (a) adding a mixture of methane sulphonic acid in ethylacetate to the mixture prepared in step (a);
  • the n inth aspect of the present invention is to provide a crystalline form of ethyl 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ -l- methyl-l H- benzimidazole ⁇ 5-carbonyl)- pyridin-2-yl-amino]-propionate, - designated as the Form IC characterized by X-ray powder diffraction pattern (Fig 2) having characteristic peaks at reflection angle 2 ⁇ ( ⁇ 0.2° 20) 5.84, 6.5, 11.7, 17.47, 19.9, 20.49, 24.77, 26.44, 27.02.
  • the present invention is providing the improved process for the preparation of DabigatranEtexilateMesylate with a novel intermediate comprising the steps of:
  • step(a) adding dicarboxylic acid having 3 to 10 carbon atoms to the reaction mixture obtained in step(a) and maintaining the mixture for a sufficient time to obtain a compound of 3-( ⁇ 2-[(4-cyano-phenylamino)methyl]-l-methyl-lH- benzoimidazole-5-carbonyI ⁇ pyridin-2-ylamino)propionic acid ethyl ester, dicarboxylic acid addition salt having 3 to 10 carbon atoms having the formula- VI,
  • step (e) adding an ammonia source periodically to the reaction mixture obtained in step (e) and maintaining sufficient time to obtain the compound of formula II;
  • step (d) filtering the compound obtained in the step (d); h) purifying the compound obtained in step (e) with a polar organic solvent or mixtures thereof;
  • the coupling reagent employed in the step (a) is selected from "the group comprising of 0-(Benzotriazol-l -yl)-N, N, ⁇ ', N'- tetramethyluroniumhexafluorophosphate (HBTU) and 0-(Benzotriazol-l-yl)-N, N, N', N'-tetramethyluroniumtetrafluoroborate (TBTU) 3- (Diethylphosphoryloxy)-l,2,3-benzotriazin-4(3H)-one, ⁇ , ⁇ '- Carbonyldiimidazole, preferablyN,N'-Carbonyldi imidazole.
  • HBTU 0-(Benzotriazol-l -yl)-N, N, ⁇ ', N'- tetramethyluroniumhexafluorophosphate
  • TBTU tetramethyluroniumtetrafluoroborate
  • the organic solvent employed in the step (a) is selected from the group comprising of dimethylacetamide, N-methyl-2-pyrrolidone, MDC, dimethylformamide, HMPA , esters containing CI to C6 carbon atoms such as Butyl acetate Sec-Butyl acetate , Tert-Butyl acetate, Ethyl acetoacetate, Ethyl butyrate, Ethyl lactate, Isopropyl acetate, Methyl acetate and mixtures thereof preferably mixture of dimethylformamide and Methylene chloride.
  • the dicarboxylic acid having C3 to C I O carbon atoms employed in the ' step (b) is selected from the group comprising of acetonedicarboxylic acid, camphoric acid, diaminopimelic acid, dimercapto succinic acid, folic acid, glutaconic acid, adipic acid, maleic acid, phthalic acid, tartaric acid, fumaric acid, succinic acid, malonic acid, glutamic acid, preferably succinic acid.
  • the esters employed in the step (d) is selected from the group comprising of Butyl acetate Sec-Butyl acetate, Tert-butyl acetate, Ethyl acetoacetate, Ethyl butyrate, Ethyl acetate, Isopropyl acetate, Methyl acetate and mixtures thereof .
  • the ammonium source employed in step (f) is selected from the group comprising of ammonium hydroxide, ammonium carbonate and ammonium chloride.
  • the ammonium source is ammonium carbonate.
  • the polar solvent employed in the step (h) is selected from the group of alcohol solvents containing C3 to CIO carbons such as propanols water or substituted propanols, butanols or substituted butanols preferably isopropyl alcohol and or ketone such as butanone, pentanone, water and mixture thereof preferably a mixture of acetone and water.
  • alcohol solvents containing C3 to CIO carbons such as propanols water or substituted propanols, butanols or substituted butanols preferably isopropyl alcohol and or ketone such as butanone, pentanone, water and mixture thereof preferably a mixture of acetone and water.
  • the base employed in step (i) is selected from the group of alkali metal bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and others such as ammonium hydroxide and ammonium carbonate.
  • the present invention provides a process for the preparation of compound 3-( ⁇ 2-[(4-cyano-phenylamino) methyl]- 1 -methyl- 1H- benzoimidazole-5-carbonyl ⁇ pyridin-2-ylamino) propionic acid .
  • ethyl ester of the compound of formula IV
  • step(a) adding dicarboxylic acid having 3 to 10 carbon atoms to the reaction mixture obtained in step(a) and maintaining the mixture for a sufficient time to obtain a compound 3-( ⁇ 2-[(4-cyano-phenylamino)methyl]-l-methyl-lH-benzoimidazole- 5-carbonyl ⁇ pyridin-2-ylamino)propionic acid ethyl ester, dicarboxylic acid addition salt having 3 to 10 carbon atoms salt of the compound having the formula-VI; c) basifying the compound of formula VI prepared in the step (b) to obtain the 3- ( ⁇ 2-[(4-cyano-phenylamino)methyl]-l -methyl- lH-benzoimidazole-5- carbonyl ⁇ pyridin-2-ylamino)propionic acid ethyl ester free base of formula IV.
  • step (b) The employment of the dicarboxylic acid having 3 to 10 carbon atoms to the reaction mixture in step (b) in the process for the preparation of compound 3- ( ⁇ 2-[(4-cyano-phenylamino) methyl]- ! -methyl- l H-benzoimidazole-5-carbonyl ⁇ pyridin-2-ylamino) propionic acid ethyl ester of the compound of formula IV enhances the recovery of the final product from the reaction mixture.
  • the coupling reagent employed in the step (a) is selected from the group comprising of 0-(Benzotriazol- l -yl)-N, N, ⁇ ', N'- tetramethyluroniumhexafluorophosphate (HBTU) and 0-(Benzotriazol-l -yl)-N, N, N', N'-tetramethyluroniumtetrafluoroborate (TBTU) 3- (Diethylphosphoryloxy)-l ,2,3-benzotriazin-4(3H)-one, preferably N, N'- Carbonyldiimidazole.
  • HBTU ⁇ ', N'- tetramethyluroniumhexafluorophosphate
  • TBTU tetramethyluroniumtetrafluoroborate
  • the organic solvent employed in the step (a) is selected from the group comprising , of dimethylacetamide, N-methyl-2-pyrrolidone, MDC, Dimethylformamide and HMPA , esters containing C I to C6 carbon atoms such as Butyl acetate Sec-Butyl acetate , Tert-Butyl acetate, Ethyl acetoacetate, Ethyl butyrate, Ethyl lactate, Isopropyl acetate, Methyl acetate and mixtures thereof preferably mixture of dimethylformamide and methylene chloride.
  • esters containing C I to C6 carbon atoms such as Butyl acetate Sec-Butyl acetate , Tert-Butyl acetate, Ethyl acetoacetate, Ethyl butyrate, Ethyl lactate, Isopropyl acetate, Methyl acetate and mixtures thereof preferably mixture of dimethylformamide and methylene chlor
  • the dicarboxylic acid having C3 to CI O carbon atoms employed in step (b) is selected from the group comprising of acetonedicarboxylic acid, adipic acid, camphoric acid, diaminopimelic acid, dimercapto succinic acid, folic acid, glutaconic acid, maleic acid, phthalic acid, tartaric acid, fumaric acid, succinic acid, malonic acid, glutamic acid, preferably succin ic acid.
  • step (a) for the preparation of compound 3-( ⁇ 2-[(4-cyano- phenylamino) methyl]- 1 -methyl- l H-benzoimidazole-5-carbonyl ⁇ pyridin-2- ylamino) propionic acid ethyl ester of the compound of formula IV may be carried out in the time ranging from 30 minutes to 5 hours, preferably 4 hours.
  • step (a) for the preparation of compound 3-( ⁇ 2-[(4-cyano- phenylamino) methyl]- l-methyl- l H-benzoimidazole-5-carbonyl ⁇ pyridin-2- ylamino) propionic acid ethyl ester of the compound of formula IV may be carried out in temperature ranging between 25°C to 100°C, preferably 35°C to 50°C.
  • step (b) for the preparation of compound 3-( ⁇ 2-[(4-cyano-phenylamino) methyl]- l-methyl-lH-benzoimidazole- 5-carbonyl ⁇ pyridin-2-ylamino) propionic acid ethyl ester of the compound of formula IV may be carried out in time ranging from 2 to 10 hour ' s, preferably 5 to 6 hours.
  • step (b) for the preparation of compound 3-( ⁇ 2-[(4-cyano-phenylamino)methyl]- l -methyl- l H-benzoim idazole- 5-carbonyl ⁇ pyridin-2-ylamino)propionicacid ethyl ester of the compound of formula IV may be carried out in temperatures ranging between 25°C to 100°C, preferably 15°C to 35°C.
  • step (c) for the preparation of compound 3-( ⁇ 2-[(4- cyano-phenylamino)methyl]- l -methyl- I H-benzoim idazole-5-carbonyl ⁇ pyridin-2- lamino)propionicacid ethyl ester of the compound of formula IV carried out in the presence of a base with an Organic solvent for a sufficient time to obtain compound of formula IV.
  • the base employed in step (c) is selected from inorganic and organic bases;
  • the organic bases according to the present invention are selected from the group comprising of isopropyl amine, diisopropyl amine, diisopropyl ethyl-am ine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, N-methyl pyridine, DB U, DABCO and triethylamine; and the inorganic bases according to the present invention are selected from the group comprising of alkali metals such as sodium, potassium, lithium; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate; alkali metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide; metal alkoxides such as alkoxides of sodium, lithium or potassium, sodium tert- butoxide; al
  • the solvent employed in step (c) is selected from the group comprising of hydrocarbons such as pentane, hexane, heptanes, octane, petroleum ether; aromatic hydrocarbons such as toluene, xylenes; chlorinated hydrocarbons such as chlorobenzene, o-dichlorobenzene, 1,2- dichloroethane; esters such as ethyl acetate; ethers such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, dimethoxyethane; N,N-dimethyl formamide, dimethyl sulfoxide, ⁇ , ⁇ -dimethyl acetamide; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol; or mixtures thereof.
  • hydrocarbons such as pentane, hexane
  • step (a) of reacting ethyl 3- ⁇ l-[3-amino-4-(methylamino) benzoyl]-N- (pyridin-2-yl) amino ⁇ propanoate with 2-[(4-cyanophenyl)amino] acetic acid in presence of a coupling reagent in an organic solvent of the present invention may be carried out in single or two step process.
  • DabigatranEtexilateMesylate in ppm.
  • the presence of this potential impurity in DabigatranEtexilateMesylate is not pharmaceutically acceptable.
  • the present invention provides a process for the preparation of the compound of formula IT as a pure free base, ormula II
  • step (b) adding an ammonia source periodically to the reaction mixture obtained in step (b) and maintaining sufficient time to obtain the compound of formula II;
  • step (d) purifying the compound obtained in step (d) with a polar organic solvent or mixtures thereof.
  • the esters employed in the step (a) is selected form the group of comprising of Butyl acetate , Sec-Butyl acetate , Tert-Butyl acetate, Ethyl acetoacetate , Ethyl butyrate, Ethyl lactate, Isopropyl acetate, Methyl acetate and mixtures thereof preferably Ethyl acetate.
  • the "polar solvents " employed in the step (e) is selected from the group comprising of water, alcohols containing C3 to CIO carbons such , as propanol or substituted propanol, butanols or substituted butanols, isopropyl alcohol ketone such as butanone, pentanone and mixtures thereof preferably mixture of acetone and water.
  • the ammonium source employed in step (c) is selected from the group comprising of ammonium hydroxide, ammonium carbonate and ammonium chloride.
  • the ammonium source is ammonium carbonate.
  • step (b) for the preparation of the compound of formula II may be carried out in time ranging from 10 to 50 hours, preferably 1 1 to 30 hours.
  • step (b) for the preparation of the compound of formula II may be carried out in temperatures ranging from 0°C to 100°C, preferably 15°C to 35°C.
  • step (b) adding an ammonia source periodically to the reaction mixture obtained in step (b) and maintaining sufficient time to obtain the compound of formula II;
  • step (d) purifying the compound obtained in step (d) with a polar solvent or mixtures thereof.
  • the esters employed in the step (a) is selected from the group comprising of Butyl acetate , Sec-Butyl acetate, Tert-Butyl acetate, Ethyl acetoacetate , Ethyl butyrate, Ethyl acetate, Isopropyl acetate, Methyl acetate and mixtures thereof .
  • the ammonium source employed in step (c) is selected from the group comprising of ammonium hydroxide, ammonium carbonate and ammonium chloride.
  • the ammonium source is ammonium carbonate.
  • the "polar solvent " employed in the step (e) is selected from the group of alcohol solvents containing C3 to CIO carbons such as propanols water or substituted propanols, butanols or . substituted butanols preferably isopropyl alcohol and or ketone such as butanone, pentanone, water and mixture thereof preferably a mixture of acetone and water.
  • step (b) for the preparation of the compound of formula II may be carried out in time ranging from 10 to 50 hours, preferably 1 1 to 30 hours.
  • step (b) for the preparation of the compound of formula II may be carried out in temperatures ranging from 0°C to 100°C, preferably 15°C to 35 °C. ⁇
  • the present invention is to provide a crystalline form of Dabigatran sin le prodrug of formula II
  • Form A characterized by X-ray powder diffraction pattern (Fig 1) having characteristic peaks at reflection angle 2 ⁇ ( ⁇ 0.2° 2 ⁇ ) 6.66, 9.40, 11.37, 14.65, 15.61, 16.2, 17.54, 21.91, 23.45, 27.64, 28.35.
  • the present invention also provides a process for DabigatranEtexilate from Dabigatran single prodrug, comprising the steps of: (a) treating the compound of formula II
  • the "base” is selected from the group of alkali metal bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and others such as ammonium hydroxide and ammonium carbonate.
  • the 'ketones solvent' is selected from the group of ketones containing C3-C 10 carbon atoms, such as propanone, butanone, pentanone preferably acetone.
  • the present inventors found that the prior art of diluting methane sulfonic acid with the acetone develops a black reddish color on standing, which is pharmaceutically not acceptable during the preparation of the DabigatranEtexilateMesylate in commercial scale. Further the present inventors have found that dissolving the DabigatranEtexilate in ethyl acetate requires more amount of ethyl acetate which increases the expenditure of the process for DabigatranEtexilate [0066] Surprisingly the present inventors found a process for the preparation of Dab igatranEtexilateMesy late comprising the steps of:
  • step (a) adding a mixture of methansulphonic acid in ethylacetate to the mixture prepared in step (a);
  • step (b) for the preparation of the compound of DabigatranEtexilateMesylate may be carried out in time ranging from 1 to 15 hours, preferably 2 to 6 hours.
  • step (b) for the preparation of the compound of DabigatranEtexilateMesylate may be carried out in temperatures ranging from 0°C to 100°C, preferably 15°C to 35°C.
  • the present inventors have found that the solvents employed in prior arts do not efficiently purify the Crude DabigatranEtexilate.
  • the purification of the Crude DabigatranEtexilate is essential for the purity of the final product, the DabigatranEtexilateMesylate.
  • the present inventors found a novel process for the purification of DabigatranEtexilate involving the step of crystallizing Crude DabigatranEtexilate in isopropanol.
  • the present invention provides a crystalline form of Ethyl 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl- amino]-pro . pionate, designated as the Form IC characterized by X-ray powder diffraction pattern (Fig 2) having characteristic peaks at reflection angle 2 ⁇ ( ⁇ 0.2° 2 ⁇ ) 5.84, 6.5, 11.7, 17.47, 19.9, 20.49, 24.77, 26.44, 27.02. Form IC exhibits a melting point 82-85°C (DSC endothermic peak) (Fig 3)
  • Anotherembodiment of the present invention provides a process for the preparation of virtually anhydrous crystalline form IC of Ethyl-3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ -1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amiiio]-piOpionate comprising the steps of:
  • the pre nt invention also provides a novel compound of formula VII
  • Example-la Preparation of ethyl 3-([2-[(4-cyanophenyl) amino)-methyl]-l- methyl-lH-benzimidazoIe-5-carbonyl]-pyridin-2-yl-amino) propionate succinic acid salt.
  • N, N'-Carbonyldiimidazole (0.1.4 mol) was dissolved in mixture of methylenechloride (200 ml) DMF (40 ml), added 2-[(4-cyanophenyl) amino] acetic acid (0.13 mol) stirred for 1 hr at 20-30°C.
  • the Ethyl 3- ⁇ l -[3-amino-4- (methylamino) benzoyl]-N-(pyridin-2-yl) amino ⁇ propionate (0. 12 mol) in methylene chloride solution was added to the reaction mixture and raised the reaction mass temperature to 35-40°C, monitored the reaction by HPLC.
  • reaction mass was washed with water and separated the organic layer.
  • the solvent was distilled under vacuum and resulted residue was dissolved in isoprdpyl acetate (280 ml) and acetic acid (16 ml), heated the reaction mass up to 80-90°C, monitored the reaction by HPLC.
  • reaction completion the mass was cooled to 65-70°C, washed with water and added succinic acid to the separated organic layer at the same temperature.
  • the reaction mass was cooled to 25-30°C and stirred for 5 hours at the same temperature.
  • the reaction mass was further cooled to 0-5°C and continued stirring for 2 hours. Filtered the isolated solid and washed with isopropyl acetate, dried at 55-60°C.
  • Example-lb Preparation of ethyl 3-([2-[(4-cyanophenyl) amino)-methyl]-l- methyI-lH-benzimidazole-5-carbonyl]-pyridin-2-yl-amino) propionate succinic acid salt.
  • N, N'-Carbonyldiimidazole (0.14 mol) was dissolved in THF (340 ml), added 2-[(4-cyanophenyl) amino] acetic acid at 35-40°C and stirred for 1 hrs at 35-40°C.
  • the solution of Ethyl 3- ⁇ l -[3-amino-4-(methylamino) benzoyl]-N- (pyridin-2-yl) amino ⁇ propanoate in THF was added to the reaction mixture and the reaction temperature was raised to 50°C and monitored the reaction by HPLC. After completion of the reaction the solvent was distilled under vacuum.
  • Example-2 Preparation of 3-([2-[(4-cyanophenyl amino)-methyl]-l- methyl-lH-benziniidazole-5-carbonyI]-pyridin-2-yl-amino) ethyl propionate fumarate was prepared according to the procedure described in example 1 , in the place of succinic acid, fumaric acid was used. Yield: 85% HPLC: 95%.
  • Example-3 Preparation of 3-([2-[(4-cyanophenyl amino)-methyl]-l- methyl-lH-benzimidazoIe-5-carbonyl]-pyridin-2-yl-amino) ethyl propionate maleate was prepared according to the procedure described in example 1, in the place of succinic acid maleic acid was used. Yield: 85% HPLC: 95%.
  • Example-4 Preparation of ethyl 3-([2-[(4-cyanophenyl) amino)-methyI]-l- raethyl-lH-benzimidazole-5-carbonyl]-pyridin-2-yl-amino) propionate free base.
  • Example-5 Preparation of l-methyl-2-[N-(4-amidinophenyl)-aminomethyI]- benzimidazol-5-yI-carboxyIic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)- amide
  • Example-6 Preparation of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]- benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)- amide
  • Example-7 Preparation of N-[[2-[[[4-[[[[(Hexyloxy) carbonylj-amino] imino methyl] phenyl] amino] methyI]-l-methyl-lH-benzimidazol-5-yl] carbonyl]- N-2-pyridinyl - ⁇ - alanine ethyl ester.
  • Example 8 Process for the preparation of virtually crystalline form IC of N- [[2-[[[4-[[[[(Hexyloxy) carbonylj-amino] imino methyl] phenyl] amino] methyl]-l-methyl-lH-benzimidazol-5-yl] carbonyl]-N-2-pyridinyl - ⁇ - alanine ethyl ester
  • Example-9 Process for the preparation of DabigatranEtexilateMesylate from DabigatranEtexilate

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Abstract

L'invention concerne un procédé perfectionné pour la préparation d'etexilate mésylate de dabigatran et les procédés pour la préparation d'un promédicament individuel de dabigatran et d'etexilate de dabigatran.
EP13816563.4A 2012-07-12 2013-07-05 Procédé perfectionné pour la préparation d'etexilate mésylate de dabigatran et de ses intermédiaires Ceased EP2872500A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN2838CH2012 2012-07-12
IN4298CH2012 2012-10-15
PCT/IN2013/000413 WO2014009966A2 (fr) 2012-07-12 2013-07-05 Procédé perfectionné pour la préparation d'etexilate mésylate de dabigatran et de ses intermédiaires

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EP2872500A2 true EP2872500A2 (fr) 2015-05-20
EP2872500A4 EP2872500A4 (fr) 2016-03-30

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EP13816563.4A Ceased EP2872500A4 (fr) 2012-07-12 2013-07-05 Procédé perfectionné pour la préparation d'etexilate mésylate de dabigatran et de ses intermédiaires

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EP (1) EP2872500A4 (fr)
WO (1) WO2014009966A2 (fr)

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CN104892574A (zh) * 2014-03-04 2015-09-09 浙江海正药业股份有限公司 达比加群酯甲磺酸盐的晶型及其制备方法和用途
WO2015137680A1 (fr) * 2014-03-10 2015-09-17 동아에스티 주식회사 Composition pharmaceutique de traitement ou de prévention d'un accident vasculaire cérébral et de l'embolie systémique
CN104974137A (zh) * 2014-04-04 2015-10-14 江苏天士力帝益药业有限公司 达比加群酯甲磺酸盐新晶型及其制备方法
CN103951654B (zh) * 2014-05-13 2016-08-24 南京生命能科技开发有限公司 甲磺酸达比加群酯的晶体v及其制备方法
CN103965164A (zh) * 2014-05-13 2014-08-06 南京生命能科技开发有限公司 甲磺酸达比加群酯的晶体ⅵ及其制备方法
CN105348263B (zh) * 2015-12-15 2018-03-23 乐普药业股份有限公司 一种达比加群酯中间体的制备方法
CN108727334B (zh) * 2018-07-12 2020-10-30 江西国药有限责任公司 一种甲磺酸达比加群酯的生产工艺
WO2022006007A1 (fr) * 2020-06-29 2022-01-06 The General Hospital Corporation Procédés d'imagerie d'infections bactériennes
CN116041724B (zh) * 2023-02-23 2024-03-01 天津工业大学 一种多孔手性金属-有机框架材料及其制备方法和应用

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CN100509799C (zh) * 2005-12-16 2009-07-08 复旦大学 一种合成非手性，非肽类的抗凝血酶抑制剂的方法
DE102005061623A1 (de) * 2005-12-21 2007-06-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verbessertes Verfahren zur Herstellung von 4-(Benzimidazolylmethylamino)-Benzamidinen und deren Salzen
DE102006054005A1 (de) * 2006-11-16 2008-05-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Polymorphe von 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester
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
EP2522662A1 (fr) * 2011-05-11 2012-11-14 Medichem, S.A. Dabigatran etexilate et substances, procédés et compositions correspondants, et utilisation des substances en tant que standards de référence et marqueurs

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WO2014009966A2 (fr) 2014-01-16
EP2872500A4 (fr) 2016-03-30
WO2014009966A3 (fr) 2014-03-06

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