WO2015128875A2 - A process for preparation of dabigatran etexilate mesylate and intermediates thereof - Google Patents

A process for preparation of dabigatran etexilate mesylate and intermediates thereof Download PDF

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Publication number
WO2015128875A2
WO2015128875A2 PCT/IN2015/000100 IN2015000100W WO2015128875A2 WO 2015128875 A2 WO2015128875 A2 WO 2015128875A2 IN 2015000100 W IN2015000100 W IN 2015000100W WO 2015128875 A2 WO2015128875 A2 WO 2015128875A2
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acid
formula
compound
solvent
methyl
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PCT/IN2015/000100
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English (en)
French (fr)
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WO2015128875A3 (en
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Vijayavitthal Thippannachar Mathad
Pavankumar Vrajlal Solanki
Sekhar Babu UPPELLI
Ganesh Gitaram SARODE
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Megafine Pharma (P) Ltd.
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Publication of WO2015128875A2 publication Critical patent/WO2015128875A2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to an improved process for preparation of l-methyl-2- [N-[4-(N-nhexyloxycarbonylamidino)phenyl]aminomethyl]benz imidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula (I) also known as dabigatran etexilate and its methane sulfonate salt compound of formula (la), represented by the following structural formulae:
  • the process of the present invention is an improved, commercially viable and industrially advantageous process for the preparation of Dabigatran etexilate mesylate wherein, the said process substantially eliminates the impurities formed during the preparation of Dabigatran etexilate mesylate.
  • the present invention also provides novel acid additions salts of ethyl N-[(2- ⁇ [(4-cyanophenyl)amino]methyl ⁇ - 1 -methyl- 1 -H-benzimidazol-5-yl0carbonyl]-N- pyridin-2-yl-beta-alaninate (DEM-III), preferably p-toluene sulfonic acid salt, represented by structural formula (V), an useful intermediate in the synthesis of highly pure compound (la).
  • DEM-III novel acid additions salts of ethyl N-[(2- ⁇ [(4-cyanophenyl)amino]methyl ⁇ - 1 -methyl- 1 -H-benzimidazol-5-yl0carbonyl]-N- pyridin-2-yl-beta-alaninate
  • V p-toluene sulfonic acid salt
  • Dabigatran etexilate mesylate is an oral anticoagulant from the class of the direct thrombin inhibitors.
  • Direct thrombin inhibitors are a class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin. It is used to help prevent strokes or serious blood clots in people who have atrial fibrillation (a condition in which the heart beats irregularly, increasing the chance of clots forming in the body and possibly causing strokes) without heart valve disease.
  • Dabigatran etexilate mesylate is approved in both US and Europe and commercially available under the brand name of Pradaxa.
  • Dabigatran etexilate mesylate is a double prodrug of the active substance, Dabigatran of formula (II). It is the pharmacologically active molecule formed through hydrolysis c
  • Dabigatran and process for its preparation was first disclosed in WO9837075 (henceforth ⁇ 75) disclosed process involves the reaction of l-methyl-2-[N- [4amidinophenyl] aminomethyl]benzimidazol-5 -yl-carboxylicacid-N-(2-pyridyl)- N- (2-ethoxycarbonylethyl)amide hydrochloride of formula (VI) with hexylchloroformate in presence of potassium carbonate in tetrahydrofuran/water to provide l-methyl-2-[N -[4-(N -n-hexyloxycarbonylamidino) phenyl Jaminomethyl Jbenzimidazol- 5-yl-carboxylicacid- N-(2-pyridyl)- N-(2-ethoxy carbonylethyl)amide (herein after referred as dabigatran etexilate) of compound of formula (I). But WO'075 does not discuss or
  • the key step of the disclosed process is the conversion of the nitrile of the Formula (V) into the amidine hydrochloride of formula (VI) by pinner reaction.
  • the low yields of the pinner reaction can be derived from the water sensibility of the reaction on the one hand while the realization of the reaction is rendered more difficult on the other by the fact that the ester as well as amide, function of the molecule is susceptible to hydrolysis.
  • Example 58b of said patent in an analogous manner to Example 25d 1.2 g of l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-5- benzimidazole-carboxylic acid-N-(2-pyridyl)-N-[2-(ethoxycarbonylethyl]-amide (V) is reacted with ethanol saturated with hydrochloric acid in large dilution.
  • the evaporated crude product is then converted to hydrochloric acid salt of l-methyl-2- [N-(4-amidinophenyl)-aminomethyl]-5- benzimidazole-carboxylic acid-N-(2- pyridyl)-N-[2-(ethoxycarbonyl)-ethyl]- amide compound of formula(VI) using ethanol and ammonium carbonate.
  • the disclosed process was not suitable for large scale production because of tedious workup procedures, less yield, low purity, separation by column chromatography, which in turn results in excessive production time and costlier process and less eco-friendly.
  • the purification step performed by using large dilutions and column chromatography makes scale up and commercialization of the process strongly limited. Hence, this process commercially viable.
  • Example 1 13 of WO'075 reveals the total yield of the final compound (I) is 22%.
  • J.Med.Chem. 2002, 45, 1757-1766 describes a process for preparation of compound of formula (III) as depicted in scheme -II.
  • dabigatran etexilate base compound of formula (I) is characterized by mass spectrum, 1H NMR and melting point (128-129°C).
  • WO 2008/059029 reports the melting point of 128 ⁇ 3°C for the anhydrous form-Ill.
  • W0' 158 discloses that according to WO2006/000353 dabigatran etexilate of formula (I) is prepared as described in Examples 5A and 5B by reacting the tosylate salt of (6) and hexylchloroformate in an acetone-aqueous medium, obtained product is dried at 45°C and is not characterized by analytical data.
  • dabigatran etexilate is prepared by crystallization from an acetone/water system (Example 5A) and in said process no drying agent or other dehydrating agent is used.
  • W0' 158 discloses that two anhydrous and tetrahydro form of dabigatran etexilate are described in WO 2006/131491.
  • no process is disclosed for preparation of dabigatran etexilate but reference is made rather to basic patent and hence the said new forms are obtained by recrystallization from ethyl acetate (anhydrous form-I and anhydrous II Examples 1 and 2) and a mixture of acetone and water (tetrahydrate form, example 3).
  • Example 6A is identical with Example 5A of WO 2006/000353, however in the working up method of new variants 6B and 6C an azeotropic distillation is employed using butyl acetate for dehydration. Accordingly in these cases actually the anhydrate of dabigatran etexilate (1) is formed and consequently the yield is lower (yield of 1 using ditosylate of 6).
  • WO 2010/045900 discloses the preparation of free base of dabigatran etexilate of formula (I), from oxalate salt of nitrile compound of formula (V) via monohydrochloride and dihydrochloride of the amidine of formula (VI). These salts are found to degrade and lead to the formation of impurities and thereby yield dabigatran etexilate with low purity. Thus making the process less favorable at industrial scale.
  • Dabigatran etexilate mesylate contain extraneous compounds or impurities that can come from many sources. They may be un-reacted starting materials, by-products of reaction, products ,of side reaction, and/or degradation products.
  • the primary object of the present invention is to provide an improved, economic, efficient, production friendly process for preparation of dabigatran etexilate mesylate of formula (la).
  • Yet another object of the present invention is to provide a novel process for the preparation of crystalline form-I of dabigatran etexilate mesylate compound of formula- la
  • Yet another object of the present invention is to provide a process for preparation of Dabigatran etexilate mesylate of formula (Ia);wherein the obtained Dabigatran etexilate mesylate of formula (la); is substantially free from impurities and thereby eliminating the required purification steps and further making the process cost effective and efficient.
  • Yet another object of the present invention is to provide an isolated acid addition salt of compound of formula (v).
  • Yet another object of the present invention is to provide a crystalline form of acid addition salt of compound of formula (v).
  • Another object of the present invention is to provide an improved process for the preparation of pure dabigatran etexilate mesylate wherein the overall yield and quality is consistent during production.
  • Figure 1 of the present invention illustrates X-ray powder diffraction (XRD) pattern of p-toluene sulfonate of compound of formula (V), prepared according to example h.
  • XRD X-ray powder diffraction
  • Figure 2 of the present invention illustrates Infrared spectrum (IR) pattern of p- toluene sulfonate of compound of formula (V), prepared according to example h. DETAILED DESCRIPTION OF THE INVENTION
  • Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations.
  • the described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.
  • solvent temperature means the temperature at which the solvent or the solvent system refluxes or boils at atmospheric pressure.
  • suitable solvents refers to solvents selected from “Ester solvents” like ethyl acetate, methyl acetate, isopropyl acetate, hexyl acetate, butyl acetate, Sec-butyl acetate, tert-butyl acetate; "Ether solvents” like tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, 1 ,4- dioxane, dimethoxy ethane, dimethoxy methane, diisopropyl ether, Di-tert-butyl ether _ and the like; "Hydrocarbon solvents” like toluene, xy
  • suitable bases refers to the bases selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert- butoxide, potassium tert-butoxide; titanium isopropoxide, titanium ethoxide, zirconium ethoxide, aluminium isopropoxide, tentalum ethoxide; alkali metal carbonates like sodium carbonate, potassium carbonate, and cesium carbonate; and alkali metal bicarbonates like sodium bicarbonate potassium bicarbonate, calcium bicarbonate and ammonium bicarbonate, ; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N- methyl morpholine, piper
  • the term "acid” herein the present invention is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; organic acids such as trifluoroacetic acid, acetic acid, methane sulfonic acid, 2,5- dihydroxy benzoic acid, ethanedisulfonic acid, p-toluene sulfonic acid (PTSA), benzene sulfonic acid, ethane disulfonic acid, ethane sulfonic acid, naphthalene disulfonic acid, naphthalene-2- sulfonic acid, camphor sulfonic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, oleic acid, malic acid, adipic acid, stearic acid, cinnamic acid, succinic acid, malonic acid, mandelic acid, palmitic acid, pamoic acid, ascor
  • substantially pure it generally means, unless specified otherwise, that the material is about 99% pure or more. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities and unreacted starting materials.
  • obtaining may include filtration, filtration under vacuum, centrifugation, and decantation to isolate product.
  • the product obtained may be further or additionally dried to achieve the desired moisture values.
  • the product may be dried in a hot air oven, tray drier, dried under vacuum and/or in a Fluid Bed Drier.
  • crystalizing herein means heating a "slurry” or “suspension” or “solution” of compound from about 25°C to about 10°C above or below of the reflux temperature of solvent, and optionally cooling to the ambient temperature to obtain crystalline form of compound.
  • ambient temperature herein means temperature of about 20°C . or less.
  • the solvent used in step (a) is selected from ether solvents, hydrocarbon solvents, polar aprotic solvents, chlorinated solvents, nitrile solvents and the like; or mixtures thereof.
  • the base used in step (a) is an organic or inorganic base; organic bases selected from such as but not limited to 1, 8-diazabicyclo[5.4.0]undec-7-ene; 1,5- diazabicyclo[4.3.0]non-5-ene; primary amines such as but not limited to methylamine, propyl amine, 2-propyl amine, butyl amine, and the like; secondary amines such as but not limited to ⁇ , ⁇ -diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, morpholine, and the like; tertiary amines like triethylamine, ⁇ , ⁇ -dimethyl aniline, ⁇ , ⁇ -diisopropyl ethyl amine, trimethyl amine, pyridine or substituted pyridine such as but not limited to 2,6 lutidine, 2,4 lutidine, 3,5 lutidine and the like; pyrimidine,
  • the compound of formula (XII) can also be isolated and purified as per the conventional techniques known in the prior art like recrystallization, re-saltification, solvent purification, high vacuum distillation and the like;
  • the isolation of compound of formula (XII) comprises the steps of:.
  • step (a) i. treating the reaction mass of step (a) with water;
  • step (i) extracting the aqueous layer of step (i) with an organic solvent
  • step (iii) separating the organic layer of step (ii) followed by washing it with suitable aqueous base;
  • step (iii) removing the solvent from the organic layer of step (iii) to obtain the compound of formula (XII) as syrup/oil.
  • the organic solvent used in step (ii) is selected from the group comprising of aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbons such as dichloromethane and the like; carboxylic acid esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, di-methyl ether, methyl tertiary butyl ether and the like; substituted cyclic ether such as 2-methyltetrahydrofuran and the like; or mixtures thereof.
  • aromatic hydrocarbons such as toluene, xylene, and the like
  • aliphatic hydrocarbons such as hexane, heptane and the like
  • halogenated hydrocarbons such as dichloromethane and the like
  • the aqueous base used in step (iii) is selected from aqueous solution of alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates.
  • the solvent in step (iv) may be removed by the known techniques in the art like filtration, decantation, centrifugation, spray drying, evaporation and the like.
  • a process for the preparation of hexyl-4-nitrophenyl carbonate compound of formula (XII), comprising: a) Reacting hexyl chloroformate of formula (XIII) with p-nitro phenol of compound of formula (XIV) in a solvent and in presence of a base to provide hexyl-4-nitrophenyl carbonate compound of formula (XII);and optionally isolat
  • the solvent used in step (a) is selected from ether solvents, hydrocarbon solvents, polar aprotic solvents, chlorinated solvents, nitrile solvents and the like.
  • the base used in step (a) is an organic or inorganic base; organic bases such as but not limited 1, 8-diazabicyclo[5.4.0]undec-7-ene; l,5-diazabicyclo[4.3.0]non-5-ene; primary amines such as but not limited to methylamine, propyl amine, 2-propyl amine, butyl amine, and the like; secondary amines such as but not limited to N,N- diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, morpholine, and the like; tertiary amines like triethylamine, ⁇ , ⁇ -dimethyl aniline, ⁇ , ⁇ -diisopropyl ethyl amine, trimethyl amine, pyridine or substituted pyridine such as but not limited to 2,6 lutidine, 2,4 lutidine, 3,5 lutidine and the like; pyfimidine,
  • the isolation of compound of formula (XII) comprises the steps of:
  • step (a) i. treating the reaction mass of step (a) with water;
  • step (i) extracting the aqueous layer of step (i) with an organic solvent
  • step (iii) separating the organic layer of step (ii) followed by washing it with suitable aqueous base;
  • the organic solvent used in step (ii) is selected from the group comprising of aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbons such as dichloromethane and the like; carboxylic acid esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, di-methyl ether, methyl tertiary butyl ether and the like; substituted cyclic ether such as 2-methyltetrahydrofuran and the like; or mixtures thereof.
  • aromatic hydrocarbons such as toluene, xylene, and the like
  • aliphatic hydrocarbons such as hexane, heptane and the like
  • halogenated hydrocarbons such as dichloromethane and the like
  • the aqueous base used in step (iii) is selected from aqueous solution of alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates.
  • the solvent in step (iv) may be removed by the known techniques in the art like filtration, decantation, centrifugation, spray drying, evaporation and the like.
  • step (c) treating dabigatran etexilate (I) with an acid in an organic solvent to obtain acid addition salt of dabigatran etexilate (I); and d) isolating the acid addition salt of dabigatran etexilate (la) from reaction mixture of step (c).
  • the suitable base used in step (a) of the reaction is an organic or inorganic base; organic bases such as but not limited 1, 8-diazabicyclo[5.4.0]undec-7-ene; 1,5- diazabicyclo[4.3.0]non-5-ene; primary amines such as but not limited to methylamine, propyl amine, 2-propyl amine, butyl amine, and the like; secondary amines such as but not limited to ⁇ , ⁇ -diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, morpholine, and the like; tertiary amines like triethylamine, ⁇ , ⁇ -dimethyl aniline, ⁇ , ⁇ -diisopropyl ethyl amine, trimethyl amine, pyridine or substituted pyridine such as but not limited to 2,6 lutidine, 2,4 lutidine, 3,5 lutidine and the like; pyrimidine,
  • the solvent used in step (a) of the reaction is selected from but not limited to alcohols such as but not limited to methanol, ethanol, isopropanol, n-butanol, t- butanol; ketone selected from but not limited to acetone, methyl ethyl ketone; esters selected from but not limited to ethyl acetate, isopropyl acetate, butyl acetate; ethers selected from tetrahydrofuran, 2-methyl tetrahydrofuran; polar aprotic solvents selected from but not limited to dimethylformamide, dimethylacetamide, N- methylpyrrolidine, dimethylsulfoxide; hydrocarbons selected from but not limited to toluene, xylene; nitriles like acetonitrile and proprionitrile; water and mixtures thereof.
  • alcohols such as but not limited to methanol, ethanol, isopropanol, n-butanol,
  • the solvent used for crystallization in step (b) is selected from the group comprising of alcohols such as but not limited to methanol, ethanol, isopropanol, n-butanol, t- butanol; ketone selected from but not limited to acetone, methyl ethyl ketone; esters selected from but not limited to ethyl acetate, isopropyl acetate, butyl acetate; polar aprotic solvents selected from but not limited to dimethylformamide, dimethylacetamide, N- methylpyrrolidine, dimethylsulfoxide; hydrocarbons selected from but not limited to toluene, xylene; nitriles like acetonitrile and proprionitrile; water and mixtures thereof.
  • alcohols such as but not limited to methanol, ethanol, isopropanol, n-butanol, t- butanol
  • ketone selected from but not limited to acetone,
  • the acid addition salt of step (c) may be an organic or inorganic acid addition salt.
  • the organic acids is selected from but not limited to maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, camphor .
  • the solvent used for preparation of acid additions salt of step (c) is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as N,N-dimethylformamide, N,N- dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N-Methylpyrrolidinone and the Tike; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl
  • step (a) containing hexyl-4-nitrophenyl carbonate compound of formula (Xll)with l-methyl-2-[N-[4- amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2- pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula (VI) or its acid addition salt in a solvent and in presence of a base to provide Dabigatran etexilate of formula (I);crystallizing dabigatran etexilate of formula (I) in a suitable solvent to obtain substantially pure dabigatran etexilate of formula (I); and
  • dabigatran etexilate (I) optionally, treating dabigatran etexilate (I) with an acid in an organic solvent to obtain acid addition salt of dabigatran etexilate (I);
  • the solvent used in step (a) is selected from ether solvents, hydrocarbon solvents, polar aprotic solvents, chlorinated solvents, nitrile solvents and the like.
  • the base used in step (a) and (b) is an organic or inorganic base; organic bases such as but not limited 1, 8-diazabicyclo[5.4.0]undec-7-ene; l,5-diazabicyclo[4.3.0]non- 5-ene; primary amines such as but not limited to methylamine, propyl amine, 2- propyl amine, butyl amine, and the like; secondary amines such as but not limited to ⁇ , ⁇ -diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, morpholine, and the like; tertiary amines like triethylamine, N,N-dimethyl aniline, ⁇ , ⁇ -diisopropyl ethyl
  • the solvent used in (b) is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N- Methylpyrrolidinone and the like; nitriles such as acetonitrile, proprionitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether,
  • the solvent used for crystallization in step (b) is selected from the group comprising of alcohols such as but not limited to methanol, ethanol, isopropanol, n-butanol, t- butanol; ketone selected from but not limited to acetone, methyl ethyl ketone; esters selected from but not limited to ethyl acetate, isopropyl acetate, butyl acetate; polar aprotic solvents selected from but not limited to dimethylformamide, dimethylacetamide, N- methylpyrrolidine, dimethylsulfoxide; hydrocarbons selected from but not limited to toluene, xylene; nitriles like acetonitrile and proprionitrile; water and mixtures thereof.
  • alcohols such as but not limited to methanol, ethanol, isopropanol, n-butanol, t- butanol
  • ketone selected from but not limited to acetone,
  • the acid additions salt of step (c) may be an organic acid or inorganic acid addition salt.
  • the organic acids is selected from but not limited to fumaric acid, benzoic acid, ascorbic, acid succinic acid, oxalic acid, bis-methylenesalicylic acid, camphor sulfonic acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, maleic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzene sulfonic acid, theophylline acetic acids, 8-halotheophylline acid; inorganic acids such as but not limited to hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid; preferably selected from oxalic acid, methanesulfonic
  • the solvent used for preparation of acid additions salt of step (c) is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N-Methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl
  • the isolation of compound of formula (XII) comprises the steps of:
  • step (a) i. treating the reaction mass of step (a) with water;
  • step (i) extracting the aqueous layer of step (i) with an organic solvent
  • step (iii) separating the organic layer of step (ii) followed by washing it with suitable aqueous base;
  • step (iii) removing the solvent from the organic layer of step (iii) to obtain the compound of formula (XII) as oil.
  • the organic solvent used in step (ii) is selected from the group comprising of aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; carboxylic acid esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, di-methyl ether, methyl tertiary butyl ether and the like; substituted cyclic ether such as 2-methyltetrahydrofuran and the like; or mixtures thereof.
  • aromatic hydrocarbons such as toluene, xylene, and the like
  • aliphatic hydrocarbons such as hexane, heptane and the like
  • halogenated hydrocarbons such as dichloromethane,
  • the aqueous base used in step (iii) is selected from aqueous solution of alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates.
  • step (iv) may be removed by the known techniques in the art like filtration, decantation, centrifugation, spray drying, evaporation and the like.
  • EMBODIMENT-5 the solvent in step (iv) may be removed by the known techniques in the art like filtration, decantation, centrifugation, spray drying, evaporation and the like.
  • step (c) adding a solution of methane sulfonic acid in suitable solvent to the obtained filtrate of step (c);
  • step (d) cooling the obtained suspension of step (d);
  • step (f) filtering the solid obtained in step (f) and washing with a solvent
  • the solvent used in (a), (d) and (f) is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N- Methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl
  • the compound of formula (VI) is used for preparation of dabigatran etexilate of formula (I) and its acid addition salt of formula (la).
  • the suitable solvent used in step (b) and step (c) is selected from alcohols such as methanol, ethanol, isopropanol, n-hutanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane, chloroform and the like; formamide such as ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N-Methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisoprop
  • the halogenating agent used in step (b) is selected from thionyl chloride, phosphorous trichloride, phosphorous pentachloride, phosphorus oxychloride, oxalyl chloride and the like.
  • the reaction step (b) may be performed in presence of catalytic amount of dimethylformamide.
  • the suitable base used in step (c) of the reaction is an organic or inorganic base; organic bases such as but not limited 1, 8-diazabicyclo[5.4.0]undec-7-ene; 1,5- diazabicyclo[4.3.0]non-5-ene; primary amines such as but not limited to methylamine, propyl amine, 2 -propyl amine, butyl amine, and the like; secondary amines such as but not limited to ⁇ , ⁇ -diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, morpholine, and the like; tertiary amines like triethylamine, ⁇ , ⁇ -dimethyl aniline, ⁇ , ⁇ -diisopropyl ethyl amine, trimethyl amine, pyridine or substituted pyridine such as but not limited to 2,6 lutidine, 2,4 lutidine, 3,5 lutidine and the like; pyrim
  • Compound of formula (IX) obtained in step (c) and compound of formula (III) obtained in step (d) can also be purified by the process like crystallization, recrystallization, re-saltification or by solvent purification.
  • the solvent used for isolation and crystallization of compound of formula (IX) obtained in step (c) and compound of formula (III) obtained in step (d) may be same or different and is selected from is selected from “Ester solvents” such as but not limited to ethyl acetate, methyl acetate, isopropyl acetate, hexyl acetate, butyl acetate, Sec-butyl acetate, tert-butyl acetate; "Ether solvents” such as but not limited to tetrahydrofuran, 2 -methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, 1,4- dioxane, dimethoxy ethane, dimethoxy methane, diisopropyl ether, and Di-tert-butyl ether; "Hydrocarbon solvents” such as but not limited to tol
  • the reducing agent used in step (d) is selected from but not limited to Sn/HCl, Fe HCl, Na 2 S 2 0 4 , sodium borohydride, lithium aluminium hydride, Raney nickel, Pd/C and Pt/C.
  • the solvent used in reduction step (d) is selected from the group comprising "Ester solvents” such as but not limited to ethyl acetate, methyl acetate, isopropyl acetate, hexyl acetate, butyl acetate, Sec-butyl acetate, tert-butyl acetate; "Ether solvents” such as but not limited to tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, 1,4- dioxane, dimethoxy ethane, dimethoxy methane, diisopropyl ether, and Di-tert-butyl ether; "Hydrocarbon solvents” such as but not limited to toluene, xylene, hexane, heptane, pentane, cyclohexane,
  • the process further includes removal of solvent from step (d) to obtain compound of formula (III).
  • the compound of formula (V) obtained in step (e) can be optionally converted into its acid addition salt before isolating and purifying the compound of formula (V).
  • the acid addition salt of (V) is further converted to its free base and further purified by crystallization process to obtain highly pure compound of formula (V).
  • the solvent used in step (e) is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane,.
  • dichloroethane and the like formamide such as N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N- Methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; or a mixture thereof.
  • the acid used in step (e) is selected from acetic acid, and halogenated acetic acid.
  • the coupling agent used in step (e) is selected from but not limited to Pivaloyl chloride, N,N'-dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3-dimethylaminoprpyl) carbodiimide (EDO) or its salts, ⁇ , ⁇ -carbonyldiimidazole (CDI), diphenylphosphorylazide (DPPA), diethylphosphoryl cyanide (DEPC), 3- (Diethoxyphosphoryloxy)-l ,2,3-benzotriazin-4(3H)-one (DEPBT), 4-(4,6- Dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), 1- [Bis(dimethylamino)methylene]- 1 H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), (0-(7
  • step (e) further comprises isolation of compound of formula (v) followed by purification of it; wherein the said process of isolation and purification comprises the steps of:
  • step (i) treating the residue of compound of formula (v) of step (i) with solvent and water; basifying the mixture obtained, separating the organic layer, followed by washing with water;
  • step (vi) optionally, drying the obtained wet solid of step (vi);
  • the solvent in step (i) may be removed by the known techniques in the art like filtration, decantation, centrifugation, spray drying, evaporation and the like.
  • the solvent used in step (ii), (iv), (vi), (viii) and (x) may be same or different and is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane, chloroform and the like; formamide such as N,N- dimethylformamide, ⁇ , ⁇ -dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N-Methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofur
  • the base used in step (ii) and (viii) is an organic or inorganic base; organic bases such as but not limited 1, 8-diazabicyclo[5.4.0]undec-7-ene; 1,5- diazabicyclo[4.3.0]non-5-ene; primary amines such as but not limited to methylamine, propyl amine, 2-propyl amine, butyl amine, and the like; secondary amines such as but not limited to ⁇ , ⁇ -diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, morpholine, and the like; tertiary amines like triethylarnine, ⁇ , ⁇ -dimethyl aniline, ⁇ , ⁇ -diisopropyl ethyl amine, trimethyl amine, pyridine or substituted pyridine such as but not limited to 2,6 lutidine, 2,4 lutidine, 3,5 lutidine and the like;
  • the acid used in step (iv) may be selected from organic or inorganic acid, inorganic acids is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; organic acids such as trifluoroacetic acid, acetic acid, methane sulfonic acid, 2,5-dihydroxy benzoic acid, ethanedisulfonic acid, p-toluene sulfonic acid (PTSA), benzene sulfonic acid, ethane disulfonic acid, ethane sulfonic acid, naphthalene disulfonic acid, naphthalene-2- sulfonic acid, camphor sulfonic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, oleic acid, malic acid, adipic acid, stearic acid, cinnamic acid, succinic acid, malonic acid, mandelic acid, palmitic acid
  • the acid used in step (f) may be selected from organic or inorganic acid and is selected from but not limited to formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like.
  • the hydrochloric acid used in step - (f) may be aqueous hydrochloric acid, hydrochloric acid gas or solution of hydrochloric acid in a solvent like methanol, ethanol, isopropanol, acetone, ethyl acetate and the like.
  • alcoholic hydrochloric acid in alcoholic solvents like ethanol may be used.
  • the base used for basifying reaction mixture in step (f) is selected from ammonia gas, ammonium carbonate, ammonical solution in alcohols like methanol, ethanol, isopropanol, butanol and the like or mixture thereof.
  • the solvent used in step (f) is selected from "Ester solvents” such as but not limited to ethyl acetate, methyl acetate, isopropyl acetate, hexyl acetate, butyl acetate, Sec- butyl acetate, tert-butyl acetate; "Ether solvents” such as but not limited totetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, 1,4- dioxane, dimethoxy ethane, dimethoxy methane, diisopropyl ether, and Di-tert-butyl ether; "Hydrocarbon solvents” such as but not limited to toluene, xylene, hexane, heptane, pentane, cyclohexane, cycloheptan
  • the step (g) further comprises isolation of crude compound of formula (VI) followed by purification of it; wherein the said process of isolation and purification comprises the steps of:
  • step (f) i. removal of solvent from reaction mass of step (f) which comprises of filtering the reaction mass and evaporation of the solvent to obtain compound of formula (VI) or its acid addition salt as residue;
  • the solvent used for crystallization step (ii) is selected from "Ester solvents” such as but not limited to ethyl acetate, methyl acetate, isopropyl acetate, hexyl acetate, butyl acetate, Sec-butyl acetate, tert-butyl acetate; "Ether solvents” such as but not limited totetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, 1,4- dioxane, dimethoxy ethane, dimethoxy methane, diisoprop
  • the dabigatran etexilate mesylate of Formula (la) prepared by the process of present invention is crystalline form-I is substantially free from impurities.
  • the present invention provides an isolated acid addition salt of compound of formula (V).
  • the acid addition salt of compound of formula (V) may be prepared by using acid selected from organic or inorganic acid, inorganic acids is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; organic acids such as trifluoroacetic acid, acetic acid, methane sulfonic acid, 2,5- dihydroxy benzoic acid, ethanedisulfonic acid, p-toluene sulfonic acid (PTSA), benzene sulfonic acid, ethane disulfonic acid, ethane sulfonic acid, naphthalene disulfonic acid, naphthalene-2- sulfonic acid, camphor sulfonic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, oleic acid, malic acid, adipic acid, stearic acid, cinnamic acid, succinic acid, malonic acid, mandelic acid
  • the acid addition salt is p- toluenesulfonic acid.
  • Formula (V) According to another embodiment, the present invention provides a crystalline form of p-toluene sulfonate of compound of formula (V).
  • Figure 1 of the present invention illustrates X-ray powder diffraction (XRD) pattern of p-toluene sulfonate of compound of formula (V), prepared according to example h, exhibits the characteristic peaks at 4.78, 9.54, 14.85, 15.07, 15.32, 16.92, 17.24, 19.14, 19.57, 19.89, 22.69 and 24.
  • XRD X-ray powder diffraction
  • the X-ray diffractogram was measured on BrukerAxe, DS advance Power X-ray Diffractometer with Cu K alpha- 1 Radiation source having the wavelength 1.541 A°.
  • Figure 2 of the present invention illustrates Infrared spectrum (IR) pattern of p- toluene sulfonate of compound of formula (V), prepared according to example h.
  • the IR spectrum of p-toluene sulfonate of compound of formula (V) having characteristic peaks at 3277.1, 2977,2214.9, 1735.5, 1609.8, 1641.9, 1533.2, 1468.8, 1397.4, 1333.2, 1222.9, 1176.8, 1159.4 cm _1 .
  • the IR spectra of co-precipitates of the invention has been recorded on a Fourier Transform Infrared Spectroscopy, Perkin Elmer model 100 instrument using potassium bromide pellet method.
  • substantially free herein means dabigatran etexilate mesylate having about 99.0% purity.
  • dabigatran etexilate mesylate has about 99.50 % purity. More particular, dabigatran etexilate mesylate having about 99.81% purity, when measured by HPLC.
  • Dabigatran etexilate (I) or its acid addition salt (la) prepared according to any of the processes of the present invention has less than about 0.2% of the following impurities: 3-[[[2-[[(4-Cyanophenyl)amino]methyl]- 1 -methyl- 1 H-benzimidazol-5-yl] carbonyl]
  • step (a) 100 g (0.50mol) of 4-(methylamino)-3-nitrobenzoic acid as obtained in step (a) was suspended in 800 ml dichloromethane. To the obtained suspension was added of 200 ml of thionyl chloride diluted with 200 ml dichloromethane. Finally to the reaction mixture was added 2 ml of ⁇ , ⁇ -dimethylformamide. The mixture was stirred at reflux temperature for 4-5 hr. completion of reaction was monitored by TLC. Excess thionyl chloride was removed by vacuum distillation. The residue was dissolved in 100 ml of dichloromethane which was distilled under vacuum. Finally to the obtained residue was charged 700 ml of dichloromethane and solution was cooled to 0-5°C.
  • reaction mixture was then warmed to 25-30°C and stirred for 4-5 hr and completion of reaction was monitored by TLC. Upon completion of reaction, reaction mixture was quenched with 1.0 Lit purified water at 0-10°C and stirred for 30 min. Layers were then allowed to separate for 30 min.
  • reaction mixture 100 gm (0.292 mol) ethyl3- ⁇ [ ⁇ 2-amino-l- (methylamino)phen-4-yl ⁇ carbonyl](pyridyn-2-yl)amino ⁇ propanoate and stirred for 5 min at 0-5 °C.
  • reaction mixture 200 ml acetic acid and stirred for 10-15 min at 0-15°C.
  • Reaction mixture was then heated to 80-85°C and maintained the temperature for 2-4 hr. Completion of reaction was monitored by TLC. Upon completion of reaction, reaction mass was concentrated under vacuum at below 70°C to obtain residue. Obtained residue was cooled to 25-30°C.
  • the obtained solution was heated to 50-55°C and was charged with para toluene sulphonic acid solution prepared by using 55 gm paratoluenesulphonic acid and 100 ml ethanol, reaction mixture was stirred for 20-30 min. at 50-55°C and then cooled to 0-5°C. Precipitated solid was stirred at 0-5°C for around 60 min. and filtered.
  • 172 gm of p-toluene sulfonate salt of ethyl3- ⁇ [(2- ⁇ [(4-cyanophenyl)amino]methyl ⁇ - l-methyl-lh-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino ⁇ propanoate was suspended in mixture of 860 ml dichloromethane and 860 ml water. The obtained suspension was basified using aq. Ammonia to pH 8-10 and stirred for 20-25 min. Layers were then separated and aq. Layer was again extracted with 860 ml dichloromethane.
  • dichloromethane layers were combined and washed with 860 ml water, finally dichloromethane layer was distilled out under vacuum at below 45°C to obtain residue. Obtained reside was finally crystallized from mixture of ethyl acetate and acetone to obtain ethyl3- ⁇ [(2- ⁇ [(4-cyanophenyl)amino]methyl ⁇ -l- methyl-lh-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino ⁇ propanoate.
  • reaction mixture was then cooled to 0-5°C and was purged with ammonia gas till to achieve neutral pH.
  • ammonium carbonate 93 gm was added to the reaction mixture was added.
  • reaction mixture was warmed to 28-32°C and stirred for 10-12 hr. completion of reaction was monitored by HPLC.
  • Reaction mixture was filtered and the residue was washed with ethanol 465 ml. combined filtrate was concentrated under vacuum to obtain residue.
  • ethanol 465 ml and 930 ml ethyl acetate Mixture was refluxed for 30 min. and then cooled to 25-30°C. precipitated product was stirred for 60 min.
  • reaction mixture was then cooled to 0-5°C and was purged with ammonia gas till to achieve neutral pH.
  • 75 gm ammonium carbonate was added to the reaction mixture was added 75 gm ammonium carbonate and reaction mixture was warmed to 28-32°C and stirred for 10-12 hr. completion of reaction was monitored by HPLC.
  • Reaction mixture was filtered and the residue was washed with ethanol 500 ml. combined filtrate was concentrated under vacuum to obtain residue.
  • To the obtained residue was added 500 ml ethanol and 1000 ml ethyl acetate. Mixture was refluxed for 30 min. and then cooled to 25-30°C. precipitated product was stirred for 60 min. at 25-30°C and then filtered and dried at 40-45°C to obtain crude Ethyl3- ⁇ [(2- ⁇ [(4-)
  • reaction mixture was quenched with 1000 ml water. Organic layer was separated and aqueous layer was extracted with 500 ml dichloromethane. Combined dichloromethane layer was washed two times with 1000ml 0.5N NaOH solution. Finally dichloromethane layer was washed two times with 1000 ml purified water. Dichloromethane was removed under vacuum to obtain title compound.
  • reaction mixture Upon completion of reaction, reaction mixture was cooled to 0-5°C and stirred for 60 min. Precipitated product was filtered to obtain wet solid. To the obtained wet solid 1000ml purified water was added and stirred for 60 min to form slurry, filtered and dried at 50-55°C to obtain dabigatran etexilate.
  • Dabigatran etexilate obtained from the either of the variants as mentioned in example (1) was added to mixture of 500 ml ethyl acetate and 6 ml purified water. Crystallization mixture was then refluxed for 60 min. The obtain clear solution was then seeded with dabigatran etexilate dihydrate and cooled to 0-5°C. Precipitated product was stirred at 0-5°C for 60 min. filtered and dried at 40-45°C to obtain dabigatran etexilate. Moisture content of the dabigatran etexilate dihydrate was 5.5%.
  • Dabigatran etexilate obtained from the either of the variants as mentioned in example (1) was added to mixture of 700 ml acetone and 6 ml purified water. Crystallization mixture was then refluxed for 60 min. The obtain clear solution was then seeded with dabigatran etexilate dihydrate and cooled to 0-5°C. Precipitated product was stirred at 0-5°C for 60 min. filtered and dried at 40-45°C to obtain dabigatran etexilate. Moisture content of the dabigatran etexilate dihydrate was 5.9%.
  • Dabigatran etexilate obtained from the variant l. as mentioned in example (1) 100 gm Dabigatran etexilate obtained from the variant l. as mentioned in example (1) was added to mixture of 500 ml acetone, solution was heated to 45-50° C which was further stirred till clear solution was obtained. The solution was cooled to 25-30°C, to this 400 ml purified water was added slowly then stirred for 60 min at 25-30° Precipitated product was stirred at 0-5°C for 60 min. and then filtered and dried at 40-45°C to obtain dabigatran etexilate. Moisture content of the dabigatran etexilate dihydrate was 5.4%.
  • Dabigatran etexilate obtained from the variant 1 as mentioned in example (1) was dissolved in 800 ml acetonitrile at 65-70° C and was stirred for 15 min. The solution was cooled to 25-30°C, stirred for 60 min. The Precipitated product was filtered and dried at 40-45°C to obtain dabigatran etexilate. Moisture content of the dabigatran etexilate dihydrate was 5.4%.
  • the obtained methanesulfonic acid solution was added in to the solution of ethyl 3- [(2- ⁇ [4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl ⁇ - 1 -methyl- 1 H- benzimi-dazole-5-carbonyl)pyridin-2-ylamino]propionate base at 26° C. to 36° C. within 15 to 40 minutes. Then the mixture was stirred for 40 to 60 minutes at 26° C. to 33° C. It was then cooled to 17° C. to 23° C. and stirred for a further 40 to 80 minutes. The crystal suspension was filtered and washed 270 ml of acetone. The product was dried under vacuum at 45-50° C. for at least 4 hours.

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CN105732433A (zh) * 2016-04-13 2016-07-06 山东新华制药股份有限公司 达比加群酯中间体缩合物的精制方法
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
CN111690699A (zh) * 2020-05-19 2020-09-22 浙江工业大学 一种酶促在线合成3-（吡啶-2-氨基）丙羟肟酸的方法
CN114113346A (zh) * 2020-08-25 2022-03-01 石药集团恩必普药业有限公司 一种达比加群酯原料药或制剂中对甲苯磺酸乙酯、对甲苯磺酸异丙酯的检测方法
CN114716411A (zh) * 2022-04-29 2022-07-08 天方药业有限公司 一种从生产母液中回收制备甲磺酸达比加群酯的方法
CN115417855A (zh) * 2022-09-22 2022-12-02 安徽美诺华药物化学有限公司 一种达比加群酯甲磺酸盐的合成工艺

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CN105732433A (zh) * 2016-04-13 2016-07-06 山东新华制药股份有限公司 达比加群酯中间体缩合物的精制方法
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
CN111690699A (zh) * 2020-05-19 2020-09-22 浙江工业大学 一种酶促在线合成3-（吡啶-2-氨基）丙羟肟酸的方法
CN114113346A (zh) * 2020-08-25 2022-03-01 石药集团恩必普药业有限公司 一种达比加群酯原料药或制剂中对甲苯磺酸乙酯、对甲苯磺酸异丙酯的检测方法
CN114113346B (zh) * 2020-08-25 2024-01-12 石药集团恩必普药业有限公司 一种达比加群酯原料药或制剂中对甲苯磺酸乙酯、对甲苯磺酸异丙酯的检测方法
CN114716411A (zh) * 2022-04-29 2022-07-08 天方药业有限公司 一种从生产母液中回收制备甲磺酸达比加群酯的方法
CN114716411B (zh) * 2022-04-29 2024-03-15 天方药业有限公司 一种从生产母液中回收制备甲磺酸达比加群酯的方法
CN115417855A (zh) * 2022-09-22 2022-12-02 安徽美诺华药物化学有限公司 一种达比加群酯甲磺酸盐的合成工艺

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