US20070185333A1 - Process for the Preparation of 4-(Benzimidazolylmethylamino)-Benzamides and the Salts Thereof - Google Patents

Process for the Preparation of 4-(Benzimidazolylmethylamino)-Benzamides and the Salts Thereof Download PDF

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US20070185333A1
US20070185333A1 US11/614,304 US61430406A US2007185333A1 US 20070185333 A1 US20070185333 A1 US 20070185333A1 US 61430406 A US61430406 A US 61430406A US 2007185333 A1 US2007185333 A1 US 2007185333A1
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substituted
alkyl group
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Georg Zerban
Arndt Hausherr
Kerstin Schlarb
Rainer Hamm
Gunter Koch
Bjoern Weyell
Heinz-Peter Schmitt
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Boehringer Ingelheim International GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to a process for preparing an optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidine, wherein
  • the 4-(benzimidazol-2-ylmethylamino)-benzamidine thus obtained may subsequently be converted into a salt.
  • the invention relates to a process for preparing a salt of an optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidine, wherein
  • the main types of indication for the compound of chemical formula I are the postoperative prevention of deep vein thrombosis and the prevention of stroke (prevention of stroke due to atrial fibrillation, SPAF for short).
  • the aim of the present invention was to indicate an alternative method of preparing the substituted (4-benzimidazol-2-ylmethylamino)-benzamidines, by which this technologically complex step could be avoided.
  • the 4-(benzimidazol-2-ylmethylamino)-benzamidine thus obtained may subsequently be converted into a salt.
  • the 4-(benzimidazol-2-ylmethylamino)-benzamidine thus obtained may if desired subsequently be converted into a salt, particularly into a pharmaceutically acceptable salt, in another step (c).
  • Another preferred process for preparing a salt of an optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidine of formula (I) wherein R 1 to R 3 are as hereinbefore defined comprises the following steps:
  • Preferred salts are the methanesulphonate, chloride, maleate, tartrate, salicylate, citrate and malonate of the compound of formula (I).
  • a particularly preferred salt is the methanesulphonate.
  • step (A) The condensation of step (a) is carried out in the presence of an inert diluent and a water-binding agent.
  • the correspondingly substituted diaminobenzenes of formula (II) are known e.g. from International Patent Application WO 98/37075, e.g. from Example 25 (Steps a and b), or may be prepared analogously to those described therein.
  • the solvent used may be, for example, toluene, isopropanol, triethylamine, ethanol, butyl acetate, ethyl acetate, methanol or mixtures of these solvents.
  • the hydrogenation is carried out under a hydrogen pressure of 1 to 20 bar, but higher pressures are also possible.
  • the concentration of the aromatic nitrogen compound (educt) is conveniently 10 to 40 wt. %; it is more preferably present in a concentration of 20 to 30 wt. %.
  • the catalyst used may be for example 5-10% palladium on charcoal, while preferably 2-20 wt. % of wet charcoal-palladium catalyst is used, based on the aromatic nitrogen compound, which corresponds to about 0.05-1 wt. % palladium based on the aromatic nitrogen compound.
  • 3-amino-4-methylaminobenzoic acid amides are used, particularly 3-amino-4-methylaminobenzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide.
  • 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.
  • the aprotic apolar solvents used are preferably branched or unbranched C 5 -C 8 aliphatic alkanes, C 4 -C 10 cycloalkanes, C 1 -C 6 aliphatic haloalkanes, C 6 -C 10 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-butyl-methylether or dimethoxyethylether or amides such as, for example, dimethylformamide, or lactams such as N-methylpyrrolidone, for example.
  • Water-binding agents which may be used are hygroscopic salts, inorganic or organic acids or the acid chlorides thereof, anhydrides of inorganic or organic acids, anhydrides of alkanephosphonic acids, molecular sieves or urea derivatives. 1,1′-carbonyldiimidazoles and alkanephosphonic anhydrides are preferred, while alkanephosphonic anhydrides are particularly preferred.
  • 1,1′-carbonyldiimidazole is suspended in THF and heated. 2-[4-(1,2,4-Oxadiazol-5-on-3-yl)-phenylamino]-acetic acid is added. The correspondingly substituted diaminobenzene is added to THF. The reaction mixture is stirred at about 50° C. and subsequently, after the addition of acetic acid, evaporated down and mixed with water and the solid substance is filtered off, washed and dried.
  • alkanephosphonic anhydrides are added, in the presence of an organic base, preferably a tert. amine such as e.g. DIPEA, to a solution of 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid and correspondingly substituted diaminobenzene in THF.
  • the reaction mixture is stirred, preferably at temperatures between ⁇ 10 and 50° C., and subsequently, after the addition of acetic acid, evaporated down. It is combined with ethanol/water and optionally a filter aid, for example kieselguhr (e.g. Clarcel®), and filtered hot. Then the substance precipitated from the cooled solution is filtered off, washed and dried.
  • an organic base preferably a tert. amine such as e.g. DIPEA
  • step (B) The hydrogenation of step (b)i) or (b) is carried out in the presence of an inert diluent and a hydrogenation catalyst.
  • Particularly preferred is a process in which the hydrogenation is carried out in a temperature range from 0° C. to 100° C., preferably from 15° C. to 75° C., particularly from 30° C. to 60° C.
  • the inert diluents may be both protic solvents—such as e.g. alcohols, carboxylic acids and/or water, or aprotic polar solvents such as e.g. ethers and/or amides or lactams and/or mixtures thereof. Water may optionally be added to all the solvents.
  • the protic solvents used are preferably branched or unbranched C 1 -C 8 alkanols, C 1 -C 3 carboxylic acids or mixtures thereof Particularly preferably, lower alcohols such as methanol, ethanol, n-propanol and isopropanol, carboxylic acids such as formic acid, acetic acid and propionic acid or mixtures thereof are used.
  • aprotic solvents include polar ethers such as for example tetrahydrofuran, dioxane or dimethoxyethylether or amides such as for example dimethylformamide, or lactams such as for example N-methylpyrrolidone.
  • solvents with a low tendency to flammability are used.
  • Suitable hydrogenation catalysts are generally transition metals such as for example nickel, platinum or palladium or the salts or oxides thereof Raney nickel, platinum oxide and palladium on an inert carrier material, particularly palladium on activated charcoal (Pd/C) are preferred.
  • step (a) Processes in which the product of step (a) is used in a ratio by weight to the hydrogenation catalyst of 1:1 to 1000:1, preferably from 5:1 to 100:1 during hydrogenation are preferred.
  • step (b) the product of step (a) is taken up in ethanol and after the addition of acetic acid and at 2 bar hydrogen it is hydrogenated with water-moistened 10% Pd/C at ambient temperature.
  • the catalyst is filtered off and p-toluenesulphonic acid, dissolved in 90 ml of ethanol or in 90 ml of water, is added.
  • Preferably an aqueous p-toluenesulphonic acid solution is used.
  • the tosylate of the 4-(benzimidazol-2-ylmethylamino)-benzamidine obtained is precipitated, filtered off and washed with ethanol in several batches.
  • step (b) the product of step (a) is taken up in ethanol/water and at 4 bar hydrogen hydrogenated with water-moistened 10% Pd/C at 60° C.
  • the catalyst is filtered off and p-toluenesulphonic acid (solid or dissolved in 90 ml of ethanol or in 90 ml of water) is added.
  • p-toluenesulphonic acid solid or dissolved in 90 ml of ethanol or in 90 ml of water
  • solid p-toluenesulphonic acid is used.
  • the tosylate of the 4-(benzimidazol-2-ylmethylamino)-benzamidine obtained is precipitated, filtered off and washed with ethanol in several batches.
  • step (b)i) the product of step (a) is taken up in a mixture of THF and water (approx. 7:3 based on the volume) and hydrogenated at 4 bar hydrogen with water-moistened 10% Pd/C at approx. 40° C.
  • the hydrogenating solution is filtered and the filter is washed with THF/water (7:3).
  • the filtrate is diluted with THF and water and combined with potassium carbonate.
  • the carbonylation in step (b)ii) may be carried out directly.
  • the filtrate is combined with an auxiliary base and reacted with a carbonylation agent.
  • the carbonylation agents and bases which may be used as well as possible solvents and suitable temperature ranges are described in more detail under (E).
  • the reaction is preferably carried out with potassium carbonate and at temperatures between 10-50° C., preferably 10-20° C.
  • the suspension is heated to approx. 50° C., for example, so that a clear two-phase mixture is formed.
  • the lower, aqueous phase has a high inorganic load and can be separated off before the THF is distilled off and the solvent is exchanged for acetone, from which the compound of formula (I) is crystallised by the addition of water.
  • the solvent may be exchanged for butyl acetate.
  • the crystallisation of the compound of formula (I) is then carried out after aqueous extraction of the organic phase and azeotropic elimination of the residual moisture.
  • the inert diluents used may be both protic solvents—such as e.g. alcohols, and/or water—or aprotic polar solvents such as e.g. ethers and/or amides or lactams and/or mixtures thereof Water may optionally be added to all the solvents.
  • Protic solvents used are preferably water or branched or unbranched C 1 -C 8 alkanols or mixtures thereof Particularly preferably, water or lower alcohols such as methanol, ethanol, n-propanol and isopropanol or mixtures thereof are used. Most particularly preferably, ethanol is used as reaction medium, and this may optionally contain water.
  • Isopropanol optionally together with water, may also be used.
  • the most suitable solvent is water, however.
  • Suitable aprotic solvents are polar ethers such as for example tetrahydrofuran or dimethoxy-ethylether or amides such as for example dimethylformamide, or lactams such as for example N-methylpyrrolidone.
  • ethyl bromoacetate is metered into a suspension of 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-aniline and sodium carbonate in water/isopropanol or preferably in water/ethanol and stirred at 35-45° C.
  • the cooled suspension is suction filtered, washed with water and ethanol in several batches and dried.
  • the saponification is preferably carried out in a protic solvent with an alkali metal or alkaline earth metal hydroxide, particularly with lithium, sodium or potassium hydroxide.
  • 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid ester is suspended in water or preferably in water/ethanol and slowly combined with an aqueous solution of NaOH at ambient temperature.
  • the suspension changes into a solution and is heated to 45 to 75° C.
  • HCl is added to the solution thus obtained until a pH of about 5 or preferably pH 3 is achieved.
  • the solid is isolated and washed with cold water and cold ethanol and MtBE.
  • 4-aminophenyl-amidoxime may be prepared e.g. by reacting 4-aminobenzonitrile with hydroxylamine hydrochloride.
  • sodium methoxide or preferably sodium ethoxide is added at 65-75° C., preferably at 70-75° C., to a suspension of 4-aminophenyl-amidoxime in ethanol and rinsed with ethanol. After 15 min stirring diethyl carbonate or preferably dimethyl carbonate is added dropwise. After 2-4 hours reaction time the mixture is cooled and ethanol is distilled off at 120 mbar and 40° C. The residue is taken up in water and after heating adjusted to pH 10-12 using semi-conc. sodium hydroxide solution, then to pH ⁇ 6, preferably to pH ⁇ 4, particularly preferably to pH 2-3, by acidifying with conc. hydrochloric acid, and slowly cooled. The solution changes into a suspension, which is filtered and washed several times with cold water and ethanol.
  • X may represent a halogen such as for example chlorine or bromine or a p-toluenesulphonyl, methanesulphonyl or trifluoromethanesulphonyl group.
  • a halogen such as for example chlorine or bromine or a p-toluenesulphonyl, methanesulphonyl or trifluoromethanesulphonyl group.
  • n-hexylchloroformate for preparing a compound of formula (I) wherein R 3 denotes n-hexyl.
  • the reaction is preferably carried out at a temperature of 10 to 50° C., in particular at 10 to 20° C. in the presence of a base.
  • the base used may conveniently be an alkali metal carbonate such as for example potassium carbonate or sodium carbonate, an alkali metal hydrogen carbonate such as for example sodium hydrogen carbonate or potassium hydrogen carbonate or a tertiary amine such as for example triethylamine.
  • an alkali metal carbonate such as for example potassium carbonate or sodium carbonate
  • an alkali metal hydrogen carbonate such as for example sodium hydrogen carbonate or potassium hydrogen carbonate or a tertiary amine such as for example triethylamine.
  • potassium carbonate is used.
  • the reaction may for example be carried out in mixtures of water and acetone or water and THF; a water/acetone mixture is preferred.
  • a clear two-phase mixture may be formed by heating the suspension, e.g. to approx. 50° C., so that the aqueous phase, which contains a large proportion of the inorganic constituents, can easily be separated off.
  • Suitable solvents include for example ketones or esters such as MIBK, butyl acetate, ethyl acetate, propyl acetate, isopropyl acetate or isobutyl acetate. Particularly preferred are MIBK and butyl acetate.
  • the amount of solvent used for preparing the substrate solution may be increased. This allows clear filtration of the solution before the addition of the acid.
  • the working up of the individual reactions may take place in the conventional manner, for example, by separating off the reaction adjuvants, eliminating the solvent and isolating pure end product from the residue by crystallisation, distillation, extraction or chromatography.
  • the physiologically acceptable salts may be salts with inorganic or organic acids or, if the compound contains a carboxy group, with inorganic or organic bases.
  • acids for this purpose include methanesulphonic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • bases which may be used include sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the compound of formula (6) is preferably converted into its mesylate.
  • reaction vessel In the reaction vessel are placed 118.6 g (1 mol) 4-aminobenzonitrile and 68.9 g (0.65 mol) sodium carbonate in 500 ml of ethanol and 100 ml of water and the mixture is heated to 60° C. 76.4 g (1.1 mol) hydroxylamine-hydrochloride, dissolved in 100 ml of water, are slowly added dropwise to this suspension.
  • the mixture is subsequently stirred overnight at 60° C. During cooling to 0-5° C. the substance is precipitated, filtered off and washed several times with a total of 70 ml cold ethanol. Approx. 86 g moist product are obtained. This is further processed directly.
  • the ester (2A) (86.9 g; 0.33 mol) thus obtained is suspended in 400 ml of water and at RT 120 g of 45% NaOH are slowly added dropwise. The suspension goes into solution and is reddish (pH 12.5). It is heated to 60° C. and saponified for 1 h. The solution obtained is combined batchwise with HCl (37% or preferably with conc. HCl), until pH 5 is obtained. It is cooled to 0° C. The solid is suction filtered and washed in several batches with a total of 400 ml cold water as well as 40 ml cold ethanol and MtBE. 81.4 g moist dark substance are obtained. It is dried at 35° C. in vacuo.
  • the ester (2A) (86.9 g; 0.33 mol) thus obtained is suspended in 400 ml of water or preferably ethanol/water (1:1) and at RT 120 g of 45% NaOH are slowly added dropwise.
  • the suspension goes into solution and is reddish (pH 12.5). It is heated to ⁇ 60° C. and saponified for 1 h.
  • the solution obtained is combined batchwise with HCl (37% or preferably with conc. HCl), until a pH 3 is obtained. It is cooled to 0° C.
  • the solid is suction filtered and washed in several batches with a total of 400 ml cold water as well as 40 ml cold ethanol. 81.4 g moist substance are obtained. It is dried at 35° C. in vacuo.
  • Variant A Pd/C 5%
  • reaction mixture is stirred for approx. 18 h and subsequently, after the addition of 100 ml acetic acid, refluxed, so that the THF is distilled off. After approx. 1 h the mixture is combined with 400 ml of water and stirred.
  • Moist substance is obtained, which is dried in vacuo at 35° C.
  • Variant B Hydrogenation of (4) in Ethanol/Water
  • Moist substance is obtained, which is dried in vacuo at 35° C.
  • 30.0 g (45.3 mmol) (4) are dissolved in 90 ml THF/water (1:1) at ambient temperature, combined with 4 g water-moistened 10% Pd/C and hydrogenated at 4 bar and 60° C.
  • the catalyst is filtered off, washed with approx. 40 ml THF/water (1:1) and the filtrate is fed into the next step without working up or is isolated as described above by the addition of 13.6 g (72 mmol) PTSA, dissolved in 100 ml of water, and cooling.
  • Example 4 The compound obtained according to Example 4 is reacted with n-hexylchloroformate in the presence of a base in known manner.
  • the isolated substance is dried at 45° C. in vacuo.
  • the filtrate is combined successively with 56 ml THF, 260 ml of water and batchwise with 75.2 g (544 mmol) potassium carbonate at ambient temperature. Then 14.2 g (86 mmol) of n-hexylchloroformate are metered in over 40 min. After the conversion level has been checked a further 1.2 g (7.3 mmol) n-hexylchloroformate are metered in, so that all the starting material is reacted. The suspension is heated to approx. 45° C. A clear two-phase mixture is formed. The aqueous phase is discarded and the THF is largely distilled off. 150 ml acetone are added to the suspension, it is heated to 50° C. and filtered clear.
  • the filter is rinsed with 100 ml acetone.
  • the filtrate is cooled to ambient temperature and the product is precipitated by the slow addition of 100 ml of water.
  • the moist product is washed with 150 ml acetone/water (1:1) and 150 ml of water and dried in vacuo.
  • the precipitated product is isolated and washed with acetone.
  • reaction vessel 50.0 g (74.4 mmol) 5A and 63.0 g (446.6 mmol) potassium carbonate are suspended in 380 ml acetone and 248 ml of water and at 20° C. 13.48 g (81.9 mmol) of n-hexylchloroformate are metered in within 1 h. After 30 min further reaction the suspension is heated to approx. 50° C. A clear two-phase mixture is formed, into which another 0. 12 g (0.7 mmol) n-hexylchloroformate are metered after the conversion level has been checked, so that all the starting material is reacted.
  • the aqueous phase is separated off, the organic phase is filtered clear and the filter is washed with 50 ml acetone. Under a slight vacuum 300 ml acetone are distilled off and replaced by 250 ml MIBK. The aqueous phase that settles out is separated off and the organic phase is extracted at 50-60° C. with 50 ml of water. Then 300 ml solvent are distilled off and replaced by 500 ml acetone.
  • the reaction solution is cooled to 30-36° C., 7 seed crystals are added (obtained for example from an earlier reaction according to Example 7 or according to the method described in Example 3 of WO 03/074056) and a previously prepared solution of 6.44 g (67 mmol) methanesulphonic acid in 50 ml acetone is added dropwise.
  • the suspension is stirred for 20 min, the product is isolated by filtration and washed with 300 ml acetone.
  • the isolated substance is dried at 45° C. in vacuo.

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080119523A1 (en) * 2003-08-29 2008-05-22 Boehringer Ingelheim International Gmbh 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl) phenylamino]methyl}-1-methyl-1h-benzimidazol-5- carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as a medicament
US20100144796A1 (en) * 2006-11-16 2010-06-10 Boehringer Ingelheim Pharma Gmbh & Co.Kg New polymorphs of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino- methyl)-phenylamino]-methyl-1-methyl-1h-benzimidazole-5-carbonyl) -pyridin-2-yl-amino]-propionate
US20110118471A1 (en) * 2008-06-16 2011-05-19 Boehringer Ingelheim International Gmbh Method for producing an intermediate product of dabigatran etexilate
US20110123635A1 (en) * 2008-07-14 2011-05-26 Boehringer Ingelheim International Gmbh Method for manufacturing medicinal compounds containing dabigatran
US20110129538A1 (en) * 2008-03-28 2011-06-02 Boehringer Ingelheim International Gmbh Process for preparing orally administered dabigatran formulations
US8399678B2 (en) 2009-11-18 2013-03-19 Boehringer Ingelheim International Gmbh Process for the manufacture of dabigatran etexilate
US9073899B2 (en) 2012-02-23 2015-07-07 Esteve Química, S.A. Solid forms of dabigatran etexilate mesylate and processes for their preparation
US9260421B2 (en) 2011-05-11 2016-02-16 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Pharmaceutical intermediates and process for the preparation thereof
US9925174B2 (en) 2002-03-07 2018-03-27 Boehringer Ingelheim International Gmbh Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof
US11741771B2 (en) 2013-03-15 2023-08-29 Otsuka Pharmaceutical Co., Ltd. Personal authentication apparatus system and method

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102005061624A1 (de) * 2005-12-21 2007-06-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verbessertes Verfahren zur Herstellung von Salzen von 4-(Benzimidazolylmethylamino)-Benzamidinen
CZ305085B6 (cs) 2008-03-14 2015-04-29 Zentiva, K.S. Způsob přípravy dabigatranu
CZ2008669A3 (cs) * 2008-10-24 2010-05-05 Zentiva, A. S. Zpusob prípravy dabigatranu a jeho meziprodukty
BRPI0921479A2 (pt) 2008-11-11 2016-01-12 Boehringer Ingelheim Int método para tratamento ou prevenção de trombose usando etexilato de dabigatran ou um sal do mesmo com aprimorado perfil de segurança em relação à terapia convencional com varfarina
HUP1000069A2 (en) * 2010-02-02 2012-05-02 Egis Gyogyszergyar Nyilvanosan M Kod Ruszvunytarsasag New salts for the preparation of pharmaceutical composition
EP2649060B1 (en) 2010-12-06 2017-04-05 MSN Laboratories Limited Process for the preparation of benzimidazole derivatives and its salts
EP2522662A1 (en) * 2011-05-11 2012-11-14 Medichem, S.A. Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers
CN102993175B (zh) * 2011-09-08 2014-08-13 天津药物研究院 达比加群的酯衍生物及其制备方法和用途
US9212166B2 (en) 2012-01-20 2015-12-15 Cadila Healthcare Limited Process for the preparation of dabigatran etexilate mesylate and polymorphs of intermediates thereof
WO2013150545A2 (en) 2012-04-02 2013-10-10 Msn Laboratories Limited Process for the preparation of benzimidazole derivatives and salts thereof
CN102850327B (zh) * 2012-06-19 2014-07-16 上海现代制药股份有限公司 一种制备达比加群酯的中间体及其制备方法和应用
CN102850325B (zh) * 2012-06-19 2014-03-26 上海现代制药海门有限公司 一种达比加群酯关键中间体的制备方法
CN102850326B (zh) * 2012-06-19 2014-04-09 上海现代制药股份有限公司 一种达比加群酯中间体及其制备方法和应用
EP2872500A4 (en) * 2012-07-12 2016-03-30 Rao Davuluri Ramamohan IMPROVED METHOD FOR THE PRODUCTION OF DABIGATRANETEXILATE MESYLATE AND INTERMEDIATE PRODUCTS THEREOF
CA2881947A1 (en) * 2012-08-31 2014-03-06 Ranbaxy Laboratories Limited Process for the preparation of crystalline form i of methanesulfonate salt of dabigatran etexilate
WO2014068587A2 (en) * 2012-10-29 2014-05-08 Biophore India Pharmaceuticals Pvt. Ltd. An improved process for the synthesis of dabigatran and its intermediates
US10077251B2 (en) 2012-10-29 2018-09-18 Biophore India Pharmaceuticals Pvt. Ltd. Process for the synthesis of Dabigatran Etexilate and its intermediates
EP2835370A1 (en) 2013-08-08 2015-02-11 Medichem, S.A. New crystals of dabigatran etexilate mesylate
CN104031031B (zh) * 2014-05-05 2017-01-11 南通常佑药业科技有限公司 一种制备达比加群酯的方法
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CN111595828B (zh) * 2019-02-21 2022-10-14 香港科技大学深圳研究院 一种纳米氧化锌溶出的监测方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6087380A (en) * 1949-11-24 2000-07-11 Boehringer Ingelheim Pharma Kg Disubstituted bicyclic heterocycles, the preparations and the use thereof as pharmaceutical compositions
US6248770B1 (en) * 1998-07-09 2001-06-19 Boehringer Ingelheim Pharma Kg Benzimidazoles having antithrombotic activity
US6451832B2 (en) * 1999-12-23 2002-09-17 Boehringer Ingelheim Pharma Kg Benzimidazoles with antithrombotic activity
US7202368B2 (en) * 2004-06-25 2007-04-10 Boehringer Ingelheim International Gmbh Process for the preparation of 4-(benzimidazolymethylamino) benzamidines

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE121699A1 (es) 1997-02-18 1999-12-08 Boehringer Ingelheim Pharma Heterociclos biciclicos disustituidos como inhibidores de la trombina
TWI248435B (en) * 1998-07-04 2006-02-01 Boehringer Ingelheim Pharma Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions
DE19962329A1 (de) * 1999-12-23 2001-06-28 Boehringer Ingelheim Pharma Benzimidazole, deren Herstellung und deren Verwendung als Arzneimittel
EA009664B1 (ru) * 2002-03-07 2008-02-28 Бёрингер Ингельхайм Фарма Гмбх Унд Ко. Кг Предназначенная для перорального применения лекарственная форма для этилового эфира 3-[(2-{[4-(гексилоксикарбониламиноиминометил)фениламино]метил}-1-метил-1h-бензимидазол-5-карбонил)пиридин-2-иламино]пропионовой кислоты и его солей
DE102005061624A1 (de) 2005-12-21 2007-06-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verbessertes Verfahren zur Herstellung von Salzen von 4-(Benzimidazolylmethylamino)-Benzamidinen
EP1956018A1 (de) 2007-02-06 2008-08-13 Boehringer Ingelheim Pharma GmbH & Co. KG Verfahren zur Herstellung eines Benzimidazolderivats
US20120276206A1 (en) 2008-03-28 2012-11-01 Boehringer Ingelheim International Gmbh Method for manufacturing acid pellets
AU2009228795B2 (en) 2008-03-28 2014-02-13 Boehringer Ingelheim International Gmbh Process for preparing orally administered dabigatran formulations
WO2009153214A1 (en) 2008-06-16 2009-12-23 Boehringer Ingelheim International Gmbh Process for the manufacture of an intermediate in the synthesis of dabigatran
HUE025533T2 (en) 2008-06-16 2016-05-30 Boehringer Ingelheim Int A process for preparing an intermediate of dabigatran etexylate
BRPI0915942A2 (pt) 2008-07-14 2019-04-09 Boehringer Ingelheim International Gmbh método para produção de compostos medicinais contendo dabigatrana

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6087380A (en) * 1949-11-24 2000-07-11 Boehringer Ingelheim Pharma Kg Disubstituted bicyclic heterocycles, the preparations and the use thereof as pharmaceutical compositions
US6248770B1 (en) * 1998-07-09 2001-06-19 Boehringer Ingelheim Pharma Kg Benzimidazoles having antithrombotic activity
US6451832B2 (en) * 1999-12-23 2002-09-17 Boehringer Ingelheim Pharma Kg Benzimidazoles with antithrombotic activity
US7202368B2 (en) * 2004-06-25 2007-04-10 Boehringer Ingelheim International Gmbh Process for the preparation of 4-(benzimidazolymethylamino) benzamidines
US20070149589A1 (en) * 2004-06-25 2007-06-28 Boehringer Ingelheim International Gmbh Process for the Preparation of 4-(benzimidazolylmethylamino)benzamidines

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9925174B2 (en) 2002-03-07 2018-03-27 Boehringer Ingelheim International Gmbh Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof
US7932273B2 (en) 2003-08-29 2011-04-26 Boehringer Ingelheim International Gmbh 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl) phenylamino]methyl}-1-methyl-1H-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as a medicament
US20080119523A1 (en) * 2003-08-29 2008-05-22 Boehringer Ingelheim International Gmbh 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl) phenylamino]methyl}-1-methyl-1h-benzimidazol-5- carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as a medicament
US20100144796A1 (en) * 2006-11-16 2010-06-10 Boehringer Ingelheim Pharma Gmbh & Co.Kg New polymorphs of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino- methyl)-phenylamino]-methyl-1-methyl-1h-benzimidazole-5-carbonyl) -pyridin-2-yl-amino]-propionate
US20110129538A1 (en) * 2008-03-28 2011-06-02 Boehringer Ingelheim International Gmbh Process for preparing orally administered dabigatran formulations
US20110118471A1 (en) * 2008-06-16 2011-05-19 Boehringer Ingelheim International Gmbh Method for producing an intermediate product of dabigatran etexilate
US8471033B2 (en) 2008-06-16 2013-06-25 Boehringer Ingelheim International Gmbh Method for producing an intermediate product of dabigatran etexilate
US9089488B2 (en) 2008-07-14 2015-07-28 Boehringer Ingelheim International Gmbh Method for manufacturing medicinal compounds containing dabigatran
US20110123635A1 (en) * 2008-07-14 2011-05-26 Boehringer Ingelheim International Gmbh Method for manufacturing medicinal compounds containing dabigatran
US8399678B2 (en) 2009-11-18 2013-03-19 Boehringer Ingelheim International Gmbh Process for the manufacture of dabigatran etexilate
US8993770B2 (en) 2009-11-18 2015-03-31 Boehringer Ingelheim International Gbmh Process for the manufacture of dabigatran etexilate
US9260421B2 (en) 2011-05-11 2016-02-16 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Pharmaceutical intermediates and process for the preparation thereof
US9073899B2 (en) 2012-02-23 2015-07-07 Esteve Química, S.A. Solid forms of dabigatran etexilate mesylate and processes for their preparation
US11741771B2 (en) 2013-03-15 2023-08-29 Otsuka Pharmaceutical Co., Ltd. Personal authentication apparatus system and method

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