WO2015132794A1 - Procédés améliorés pour la préparation de dabigatran étexilate au moyen de nouveaux intermédiaires - Google Patents

Procédés améliorés pour la préparation de dabigatran étexilate au moyen de nouveaux intermédiaires Download PDF

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WO2015132794A1
WO2015132794A1 PCT/IN2014/000147 IN2014000147W WO2015132794A1 WO 2015132794 A1 WO2015132794 A1 WO 2015132794A1 IN 2014000147 W IN2014000147 W IN 2014000147W WO 2015132794 A1 WO2015132794 A1 WO 2015132794A1
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acid
amino
formula
addition salt
pyridyl
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PCT/IN2014/000147
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Dodda Mohan Rao
Aadepu Jithender
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Symed Labs Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Definitions

  • the present invention relates to novel, commercially viable and industrially advantageous processes for the preparation of Dabigatran or a salt thereof, in high yield and purity, using novel intermediates.
  • U.S. Patent No. 6,087,380 discloses a variety of disubstituted bicyclic heterocycle derivatives and their pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof.
  • These compounds have valuable pharmacological properties, particularly a thrombin-inhibiting activity and the effect of extending thrombin time, and are useful for the prophylaxis or treatment of venous and arterial thrombotic diseases such as deep leg vein thrombosis, reocclusion after a bypass operation or angioplasty, occlusion in peripheral arterial disease, pulmonary embolism, disseminated intravascular coagulation, coronary thrombosis, stroke, and the occlusion of a shunt or stent.
  • venous and arterial thrombotic diseases such as deep leg vein thrombosis, reocclusion after a bypass operation or angioplasty, occlusion in peripheral arterial disease, pulmonary embolism, disseminated intravascular coagulation, coronary thrombosis, stroke, and the occlusion of a shunt or stent.
  • Dabigatran etexilate mesylate chemically named ethyl 3-[[[2- [ [ [4- [[ [(hexyloxy)carbonyl] amino] iminomethyljphenyl] aminojmethyl] - 1 -methyl- 1 H- benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propanoate mesylate salt, is a direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF).
  • Dabigatran etexilate mesylate is represented by the following structural formula:
  • Dabigatran etexilate mesylate is marketed by Boehringer Ingelheim under the brand name PRADAXA ® , and it is orally administered as capsules containing 75 mg and 150 mg of Dabigatran etexilate mesylate.
  • Dabigatran etexilate was first described in the US 6087380.
  • Various processes for the preparation of Dabigatran etexilate, its intermediates, and pharmaceutically acceptable salts thereof are apparently described in U.S. Patent Nos. US 7202368, US 7932273, US 81 19810, US 8394961, US8394962, US 8399678, US 8471033; U.S.
  • Dabigatran chemically named l-methyl-2-[N-(4- amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide is prepared by the following sequence of reaction steps:
  • step-(a) the nitro-compound obtained in step-(a) is then hydrogenated in ethanol and dichloromethane in the presence of palladium/charcoal to produce 3-amino-4- methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide;
  • step-(b) the amino-compound obtained in step-(b) is then condensed with N-(4-cyanophenyl)- glycine in the presence of ⁇ , ⁇ '-carbonyldiimidazole in tetrahydrofuran to produce a reaction mass, followed by treating with glacial acetic acid and then subjecting to usual work up methods and column chromatographic purifications to produce 1 -methyl -2- [N-(4-cyanophenyl)-aminomethyl]-benzimidazole-5-yl-carboxylic acid-N-(2-pyridyl)- N-(2-ethoxycarbonylethyl)-amide (hereinafter referred to as the cyano-benzimidazole intermediate); d) the cyano-benzimidazole intermediate obtained in step-(c) is then reacted with saturated ethanolic hydrochloric acid and subsequently with ammonium carbonate followed by usual work up and column chromatographic purifications to produce Dabig
  • l-methyl-2- [N-(4-(N-n-hexyloxycarbonylamidino)phenyl)-aminomethyl]-benzimidazol-5-yl- carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (Dabigatran Etexilate) is prepared, analogously to the example 90, by reacting l-methyl-2-[N-(4-amidinophenyl)- aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl ethyl)-amide hydrochloride salt (Dabigatran hydrochloride) with n-hexyl chloroformate in the presence of potassium carbonate in a solvent medium comprising tetrahydrofuran and water, followed by isolation using column
  • the preparation of l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]- benzimidazole-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide as described in the prior art involves the use of 15 volumes of acetic acid with respect to 3- amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide, whereas the process of the present invention requires the use of 0.25 to 0.3 volumes of acetic acid.
  • the cyano-benzimidazole intermediate obtained by the processes described in the prior art does not have satisfactory purity (Purity by HPLC: 50%) since unacceptable amounts of impurities are formed during the condensation reaction between 3-amino-4- methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and N-(4- cyanophenyl)-glycine in the presence of ⁇ , ⁇ '-carbonyldiimidazole, which are persistent impurities and cannot be removed completely.
  • Dabigatran or a salt or a derivative thereof can be prepared, in high purity and with high yield, by reacting N-(4-Cyanophenyl)-glycine with Carbonyldiimidazole to produce a novel intermediate compound 4-(2-imidazol-l-yl-2-oxo-ethylamino)-benzonitrile, which is then reacted with 3-Amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide to produce a novel intermediate compound 3-Amino-4-[N-[2- (4-cyano-phenylamino)acetyl]-N-methyl]amino]-benzoic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide, followed by converting it into Dabigatran or salt or a derivative thereof.
  • provided herein are efficient, industrially advantageous and environmentally friendly processes for the preparation of Dabigatran and its key intermediates l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazole-5-yl- carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide, in high yield and with high purity using novel intermediate compounds.
  • a novel intermediate compound 3-Amino-4- [N- [2- [(4-N-n-hexyloxycarbonylamidino) phenylamino] acetyl] -N-methyl] amino] -benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide, of formula VI:
  • the process avoids the use of excessive amounts of corrosive organic acids like acetic acid and toluenesulfonic acid;
  • the process avoids the use of additional and excess amounts of solvents, multiple isolation steps, column chromatographic purifications; vi) the processes involve easy work-up methods and simple isolation processes, and there is a reduction in chemical waste.
  • Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of solid state form of l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazole-5-yl-carboxylic acid-N-(2- pyridyl)-N-(2-ethoxycarbonylethyl)-amide acetate salt.
  • XRPD X-ray diffraction
  • Figure 2 is a characteristic infra-red (IR) spectrum of solid state form of 1 -Methyl -2-[N- (4-cyanophenyl)-aminomethyl]-benzimidazole-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide acetate salt.
  • the reaction in steps-(a) and (b) is, each independently, carried out in the presence of a reaction inert solvent.
  • exemplary inert solvents may include, but are not limited to, a chlorinated hydrocarbon solvent, an ether solvent, a hydrocarbon solvent, and mixtures thereof.
  • the solvent used in steps-(a) and (b) is, each independently, selected from the group consisting of dichloromethane, ethylene dichloride, chloroform, toluene, xylene and mixtures thereof, and a most specific solvent is dichloromethane or toluene.
  • the reaction in step-(a) is carried out at a temperature of about 25°C to the reflux temperature of the solvent used, specifically at a temperature of about 35°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used.
  • the reaction time may vary between about 2 hours to about 8 hours, and most specifically about 3 hours to about 5 hours.
  • reaction mass containing the 3-Amino-4-[N-[2-(4-cyano-phenylamino)acetyl]- N-methyl] amino] -benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide of formula III or an acid addition salt thereof obtained in step-(a) may be subjected to usual work up such as a washing, a filtration, an extraction, a pH adjustment, an evaporation, a layer separation or a combination thereof.
  • the reaction mass may be used directly in the next step to produce the compound of formula VIII, or the compound of formula III may be isolated and then used in the next step.
  • the compound of formula III is isolated from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
  • the solvent used to isolate the compound of formula III is selected from the group consisting of water, an alcohol, an ether, an ester, a hydrocarbon solvent, a chlorinated hydrocarbon, and mixtures thereof.
  • the solvent is selected from the group consisting of water, methanol, ethanol, iso-propanol, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-pentane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
  • a most specific solvent is methanol or toluene.
  • the reagent used in step-(b) is an acid.
  • the acid can be an organic acid or an inorganic acid or a combination thereof.
  • Exemplary acids used in step-(b) include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, 4-hydroxybenzoic acid, methanesulfonic acid, p-toluene sulfonic acid, or a combination thereof.
  • the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, p-toluene sulfonic acid, or a combination thereof; and a most specific acid is acetic acid.
  • the reaction in step-(b) is carried out at a temperature of about 35°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used while removing the water formed during the reaction through Dean- Stark apparatus.
  • the acid in step-(b) is used in a ratio of about 0.15 to 1 equivalents, specifically about 0.25 to 0.5 equivalents, with respect to the compound of formula III in order to ensure a proper course of the reaction.
  • reaction mass containing the compound of formula VIII or an acid addition salt thereof obtained in step-(b) may be subjected to usual work up, and then isolated and/or crystallized from a suitable solvent as per the methods described hereinabove.
  • the compounds of formulae III and VIII obtained in the above process steps-(a) and (b) may be collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.
  • the conversion of the acid addition salt of the compound of formula VIII into its free base is carried out by treating with a suitable base.
  • the base used in the above conversion is an organic or inorganic base, and specifically an inorganic base.
  • Exemplary inorganic bases include, but are not limited to, hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals, and ammonium hydroxide.
  • a most specific inorganic base is ammonium hydroxide.
  • the conversion is carried out in a suitable solvent selected from the group consisting of water, a chlorinated hydrocarbon solvent, a hydrocarbon solvent, and mixtures thereof. Specifically, the solvent is a mixture of water and dichloromethane.
  • Exemplary acid addition salts of the compound of formula VIII obtained by the process disclosed herein include, but are not limited to, hydrochloride, hydrobromide, dihydrochloride, dihydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, tartrate, and the like.
  • a most preferred acid addition salt of the compound of formula VIII obtained by the process disclosed herein is acetate salt.
  • the acetate salt of the compound of formula VIII obtained by the process disclosed herein is in the form of a solid state form.
  • the solid state form of the 1- Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazole-5-yl-carboxylic acid-N-(2- pyridyl)-N-(2-ethoxycarbonylethyl)-amide acetate salt obtained by the process exemplified in step-3 of example 1, is a crystalline form characterized by a powder X-ray diffraction pattern having peaks at about 7.73, 9.0, 10.07, 11.74, 12.07, 12.77, 15.48, 16.30, 16.67, 17.38, 17.74, 18.14, 18.37, 19.17, 19.52, 20.37, 20.86, 21.83, 23.53, 24.27, 24.99, 25.77, 26.77 and 27.14 ⁇ 0.2 degrees 2-theta substantially in accordance with Figure 1.
  • reaction between the N-(4-Cyanophenyl)-glycine of formula XI or a derivative thereof and carbonyldiimidazole is carried out in the presence of a reaction inert solvent.
  • a reaction inert solvent may include, but are not limited to, a chlorinated hydrocarbon solvent, an ether solvent, a hydrocarbon solvent, and mixtures thereof.
  • the reaction inert solvent is selected from the group consisting of dichloromethane, ethylene dichloride, chloroform, toluene, xylene and mixtures thereof. A most specific solvent is dichloromethane.
  • reaction between the N-(4-Cyanophenyl)-glycine of formula XI or a derivative thereof and carbonyldiimidazole is carried out at a temperature of about 25 °C to the reflux temperature of the solvent used, specifically at a temperature of about 35°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used.
  • reaction mass containing the compound of formula II obtained above may be subjected to usual work up, and then isolated and/or crystallized from a suitable solvent as per the methods described hereinabove.
  • Dabigatran or Dabigatran etexilate, or a pharmaceutically acceptable salt thereof, comprising:
  • step-(b) converting the compound of formula VIII obtained in step-(b) into Dabigatran, or Dabigatran etexilate, or a pharmaceutically acceptable salt thereof.
  • reaction steps-(a) and (b) are carried out by using the methods, conditions and reagents as described hereinabove.
  • the conversion of the acid addition salt of the compound of formula VIII into its free base in step-(b) is carried out by treating with a suitable base according to the methods as described hereinabove.
  • step-(c) The conversion of the intermediate compound of formula VIII into Dabigatran, or Dabigatran etexilate, or a pharmaceutically acceptable salt thereof in step-(c) can be carried out either as per the methods described in the prior art, for example, as per the processes described in the US Patent No. 6,087,380, or as per the processes described hereinafter. According to another aspect, there is provided a process for the preparation of Dabigatran, or Dabigatran etexilate, or a pharmaceutically acceptable salt thereof, comprising:
  • step-(c) converting the compound of formula IX obtained in step-(c) into Dabigatran, or Dabigatran etexilate, or a pharmaceutically acceptable salt thereof.
  • step-(a) is carried out by using the methods, conditions and reagents as described hereinabove.
  • the reagent used in step-(b) is ethanolic-HCl.
  • the reaction in step-(b) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 20°C to the 50°C, and more specifically at a temperature of about 25°C to the 35°C.
  • reaction mass containing the compounds of formula IV obtained in steps-(b) may be subjected to usual work up methods as described hereinabove.
  • the compound of formula IV obtained in step-(b) may be used directly in the next step to produce the compound of formula IX, or the compound of formula IV may be isolated by the methods described hereinabove and then used in the next step.
  • the reagent used in step-(c) is an organic or inorganic acid selected from the group as described hereinabove.
  • the reagent used in step-(c) is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, p- toluene sulfonic acid, or a combination thereof; and a most specific acid is acetic acid.
  • the reaction in step-(c) is carried out in the presence of a reaction inert solvent such as a chlorinated hydrocarbon solvent, an ether solvent, a hydrocarbon solvent, and mixtures thereof.
  • a reaction inert solvent such as a chlorinated hydrocarbon solvent, an ether solvent, a hydrocarbon solvent, and mixtures thereof.
  • the reaction in step-(c) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, specifically at a temperature of about 35°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used.
  • reaction mass containing the compound of formula IX obtained in steps-(c) may be subjected to usual work up methods as described hereinabove.
  • the compound of formula IX obtained in step-(c) may be used directly in the next step to produce Dabigatran or Dabigatran etexilate or a pharmaceutically acceptable salt thereof, or the compound of formula IX may be isolated and/or recrystallized by the methods described hereinabove and then used in the next step.
  • Dabigatran etexilate, or a pharmaceutically acceptable salt thereof in step-(d) can be carried out by the methods described in the prior art, for example, as per the processes described in the US Patent No. 6,087,380.
  • Dabigatran or Dabigatran etexilate, or a pharmaceutically acceptable salt thereof, comprising:
  • step-(d) optionally converting the compound of formula X or an acid addition salt thereof obtained in step-(d) into Dabigatran etexilate or a pharmaceutically acceptable salt thereof.
  • reaction steps- (a) and (b) are carried out by using the methods, conditions and reagents as described hereinabove.
  • the reagent used in step-(c) is ethanolic ammonia or ammonium carbonate. In another embodiment, the solvent used in step-(c) is ethanol.
  • the reaction in step-(c) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 20°C to the 50°C, and more specifically at a temperature of about 25°C to the 35°C.
  • reaction mass containing the compounds of formula V obtained in steps-(c) may be subjected to usual work up methods as described hereinabove.
  • the compound of formula V obtained in step-(c) may be used directly in the next step to produce the Dabigatran of formula X, or the compound of formula V may be isolated and/or recrystallized by the methods described hereinabove and then used in the next step.
  • the reagent used in step-(d) is an organic or inorganic acid selected from the group as described hereinabove for such purpose.
  • the reagent used in step-(d) is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, p-toluene sulfonic acid, or a combination thereof; and a most specific acid is acetic acid.
  • the reaction in step-(d) is carried out in the presence of a reaction inert solvent such as a chlorinated hydrocarbon solvent, an ether solvent, a hydrocarbon solvent, and mixtures thereof.
  • a reaction inert solvent such as a chlorinated hydrocarbon solvent, an ether solvent, a hydrocarbon solvent, and mixtures thereof.
  • the solvent used in step-(d) is selected from the group consisting of dichloromethane, ethylene dichloride, chloroform, toluene, xylene and mixtures thereof.
  • step-(d) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, specifically at a temperature of about 35°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used.
  • the reaction mass containing the Dabigatran of formula X or an acid addition salt thereof obtained in steps-(d) may be subjected to usual work up methods as described hereinabove.
  • the Dabigatran of formula X or an acid addition salt thereof obtained in step- (d) may be used directly in the next step to produce the Dabigatran etexilate, or the compound of formula X or an acid addition salt thereof may be isolated and/or recrystallized by the methods described hereinabove and then used in the next step.
  • step-(e) The conversion of the dabigatran of formula X or an acid addition salt thereof into dabigatran etexilate or a pharmaceutically acceptable salt thereof in step-(e) can be carried out by the methods described in the prior art, for example, as per the processes described in the US Patent No. 6,087,380.
  • the preparation of the compound of formula IV from the compound of formula III is carried out by using the suitable reagents, methods and conditions as described hereinabove.
  • the reagent used in the above reaction is ethanolic-HCl.
  • the preparation of the compound of formula V from the compound of formula IV is carried out by using the suitable reagents, methods and conditions as described hereinabove.
  • the reagent used in the above reaction is ethanolic ammonia or ammonium carbonate.
  • a most preferred acid addition salt of the compound of formula Va is 3-Amino-4- [N-[2-(4-amidino-phenylamino)acetyl]-N-methyl]amino]-benzoic acid-N-(2-pyridyl)-N- (2-ethoxy carbonyl ethyl)-amide hydrochloride salt of formula V.
  • the above reaction is carried out in the presence of a reaction inert solvent comprising water, an alcohol, a ketone, and mixtures thereof.
  • a reaction inert solvent comprising water, an alcohol, a ketone, and mixtures thereof.
  • the solvent is selected from the water, acetone, and mixtures thereof.
  • the base used in the above reaction is an organic or inorganic base, and specifically an inorganic base.
  • Exemplary inorganic bases include, but are not limited to, hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals.
  • a most specific inorganic base is sodium carbonate or potassium carbonate.
  • the above reaction is carried out at a temperature of below about 50°C, specifically at a temperature of about 0°C to the 35°C, and more specifically at a temperature of about lO°C to the 20°C.
  • a process for the preparation of Dabigatran etexilate or a pharmaceutically acceptable salt thereof comprising reacting 3- Amino-4-[N-[2-[(4-N-n-hexyloxycarbonylamidino)phenylamino]acetyl]-N-methyl] amino] -benzoic acid-N-(2-pyridyl)-N-(2-ethoxy carbonylethyl)-amide of formula VI:
  • the reagent used in the above reaction is an acid.
  • the acid can be an organic acid or an inorganic acid or a combination thereof selected from the group as described hereinabove. Specifically, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, methanesulfonic acid, p-toluene sulfonic acid, or a combination thereof; and a most specific acid is acetic acid.
  • the reaction is carried out in the presence of a reaction inert solvent.
  • exemplary inert solvents may include, but are not limited to, a chlorinated hydrocarbon solvent, an ether solvent, a hydrocarbon solvent, and mixtures thereof.
  • the solvent is selected from the group consisting of dichloromethane, ethylene dichloride, chloroform, toluene, xylene and mixtures thereof, and a most specific solvent is dichloromethane.
  • the reaction is carried out at a temperature of about 35°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used while removing the water through Dean-Stark apparatus.
  • the term "acid addition salt” as used herein, includes the salt that is derived from organic and inorganic acids.
  • the acid addition salt is derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, di-p-toluoyl-L-(+)- tartaric acid, malic acid, ascorbic acid, and the like.
  • a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glut
  • Exemplary acid addition salts of the compounds of formulae II, III, Va and VI include, but are not limited to, hydrochloride, hydrobromide, dihydrochloride, dihydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, tartrate, and the like.
  • Specific acid addition salts are hydrochloride, oxalate, methanesulfonate and p-toluenesulfonate.
  • a most specific acid addition salt is hydrochloride salt.
  • Exemplary pharmaceutically acceptable salts of Dabigatran or Dabigatran etexilate include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, and tartrate.
  • a most specific pharmaceutically acceptable salt of Dabigatran etexilate is methanesulfonate salt.
  • the novel intermediate compounds of Dabigatran disclosed herein are obtained as solid state forms in substantially pure form.
  • substantially pure refers to the compounds of formulae II, III, IV, IVa, V, Va and VI, or an acid addition salt thereof, disclosed herein, having a purity of greater than about 97 wt%, specifically greater than about 98 wt%, more specifically greater than about 99 wt%, and still more specifically greater than about 99.5 wt%.
  • the purity is preferably measured by High Performance Liquid Chromatography (HPLC).
  • HPLC High Performance Liquid Chromatography
  • the purity of the compounds of formulae II, III, IV, IVa, V, Va and VI, or an acid addition salt thereof obtained by the processes disclosed herein can be about 97% to about 99.9% as measured by HPLC.
  • the Dabigatran or Dabigatran etexilate, or a pharmaceutically acceptable salt thereof obtained by the processes disclosed herein has a purity of greater than about 98%, specifically greater than about 99%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC.
  • the compound of formula IVa can be prepared by reacting the compound of formula III or an acid addition salt thereof with ethanolic-hydrobromide analogously to the process for the preparation of compound of formula IV as described hereinabove.
  • the acid addition salt of the compounds of formulae II, III, Va & VI is, each independently, derived from an organic or inorganic acid.
  • Specific acid addition salts of the compounds of formulae II, III, Va & VI include, but are not limited to, hydrochloride, hydrobromide, dihydrochloride, dihydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate and tartrate.
  • a most specific acid addition salt of the compounds of formulae II, III, Va & VI is hydrochloride salt.
  • reflux temperature means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
  • room temperature or "RT” refer to a temperature of about 15°C to about 35°C.
  • RT can refer to a temperature of about 20°C to about 30°C.
  • the X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X- ray powder diffractometer equipped with a Cu-anode (copper- ⁇ radiation). Approximately 1 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 38 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
  • FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer.
  • a Bruker vertex 70 spectrometer For the production of the KBr compacts approximately 5 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm “1 to 650 cm “1 .
  • DSC Differential Scanning Calorimetry
  • N-(4-Cyanophenyl)-glycine 133 g was added to dichloromethane (2000 ml) while stirring at room temperature and then stirred for 5 minutes to form a solution.
  • Carbonyldiimidazole 222 g was added to the resulting solution and the resulting mass was heated to reflux, followed by stirring the reaction mass at reflux for 2 to 3 hours. After completion of the reaction the reaction mass was cooled to 25-35°C and then stirred for 15 minutes at the same temperature.
  • Step-2 Preparation of 3-Amino-4-[N-[2-(4-cyano-phenylamino)acetyl]-N-methyl] amino] -benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyIethyl)-amide
  • Step-3 Preparation of l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazole- 5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide acetate salt
  • Toluene (2240 ml) was taken in a reaction flask equipped with Dean-Stark apparatus and then 3-Amino-4-[N-[2-(4-cyano-phenylamino)acetyl]-N-methyl]amino]-benzoic acid-N- (2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (220 g) was added into toluene at 25-30°C. The resulting mass was heated to reflux and then stirred for 30 minutes at reflux while removing the collected water through Dean-Stark apparatus. Acetic acid (61 ml) was slowly added to the reaction mass under reflux for 30 minutes.
  • P-XRD Data 7.73, 9.0, 10.07, 11.74, 12.07, 12.77, 15.48, 16.30, 16.67, 17.38, 17.74, 18.14, 18.37, 19.17, 19.52, 20.37, 20.86, 21.83, 23.53, 24.27, 24.99, 25.77, 26.77 and 27.14 degrees 2-theta.
  • Step-4 Preparation of l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazole- 5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyI)-amide free base
  • the resulting organic layer was separated, the aqueous layer was extracted with dichloromethane (200 ml), followed by combining the total organic layer.
  • the resulting organic layer was subsequently washed with water (400 ml) and 20% sodium chloride solution and then distilled the solvent under vacuum at 50°C to obtain a residue (wt. 59 g).
  • Ethyl acetate (176 ml) was added to the residue at 25-35°C, followed by stirring the mass for 30 minutes at the same temperature.
  • l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazole-5-yl-carboxylic acid-N-(2- pyridyl)-N-(2-ethoxycarbonylethyl)-amide (210 g, obtained in step-4) was added to saturated ethanolic hydrochloride solution (1000 ml) at 10-12°C, followed by slowly increasing the temperature of the reaction mass to 25-35 °C and then stirring the mass for 24 hours at the same temperature. Solvent was distilled from the reaction mass under vacuum at 40-45 °C to form a residue, followed by the addition of saturated ethanolic ammonia solution (2300 ml) at 25-35°C.
  • reaction mass was stirred for 10-12 hours at 25-35°C and then distilled the solvent under vacuum at 75-80°C to obtain a residue.
  • a solvent medium comprising ethyl acetate and ethanol (2:1) (1750 ml) was added to the above residue and then heated to reflux, followed by maintaining the reaction mass at reflux for 30 minutes.
  • the resulting mass was filtered and the mother liquor was distilled under vacuum to obtain a residue.
  • Isopropanol (2000 ml) was added to the resulting residue and then heated for 2 hours at 70°C.
  • the separated solid was filtered to produce 130 g of Dabigatran hydrochloride.
  • Ethanol 150 ml was taken into a reaction flask, followed by purging of hydrogen chloride gas into ethanol at 0-10°C until the weight of the ethanol increases to 80 to 90 g.
  • 3-Amino- 4-[N-[2-(4-cyano-phenylamino)acetyl]-N-methyl]amino]-benzoic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide (30 g) was added to the ethanolic-HCl solution at 0-10°C and the temperature was raised to 25-35°C, followed by stirring the reaction mass at room temperature for 16 hours.
  • the combined organic layer was heated to reflux and the collected water was removed through Dean-Stark apparatus.
  • Acetic acid (8 ml) was added to the resulting organic layer at reflux.
  • the toluene layer reflux was continued until water collection is stopped from Dean-Stark apparatus.
  • the resulting toluene layer was initially cooled to room temperature, followed by further cooling to 0- 5°C.
  • the separated solid was filtered, washed with chilled toluene (50 ml) and then dried the material under vacuum at 60-65 °C to produce pure Dabigatran hydrochloride (Purity by HPLC: 99.95%).
  • Step-1 3-Amino-4-[N-[2-[(4-N-n-hexyloxycarbonylamidino) phenylamino] acetyl] -N- methyl] amino] -benzoic acid-N-(2-pyridyl)-N-(2-ethoxy carbonylethyl)-amide
  • reaction mass was cooled to room temperature and then water (250 ml) was added to the mass at the same temperature.
  • the resulting mass was further cooled to 10-15°C, followed by adjusting the pH of the mass to 8-9 with potassium carbonate.
  • the aqueous layer was separated and the organic layer was washed with water (200 ml), followed by distillation of dichloromethane solvent under vacuum at 50°C to produce 50 gm of Dabigatran Etexilate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux procédés, commercialement viables et industriellement avantageux, pour la préparation de dabigatran ou d'un sel de ce dernier, avec un rendement et une pureté élevés, au moyen de nouveaux composés intermédiaires. Ce nouveau procédé permet de résoudre les inconvénients associés aux procédés antérieurs et est commercialement viable pour la préparation de dabigatran et de sels ou dérivés de celui-ci.
PCT/IN2014/000147 2014-03-06 2014-03-06 Procédés améliorés pour la préparation de dabigatran étexilate au moyen de nouveaux intermédiaires WO2015132794A1 (fr)

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CN105153118A (zh) * 2015-09-24 2015-12-16 青岛黄海制药有限责任公司 一种甲磺酸达比加群酯制备过程中中间体的中控方法
CN105294651A (zh) * 2015-09-23 2016-02-03 烟台东诚药业集团股份有限公司 一种用于合成制备达比加群酯脒化中间体的方法
CN105732491A (zh) * 2016-03-28 2016-07-06 沈阳工业大学 达比加群的酯衍生物及其制备方法和用途
CN108658939A (zh) * 2018-07-16 2018-10-16 上海现代制药股份有限公司 一种甲磺酸达比加群酯关键中间体的合成方法
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
CN111334537A (zh) * 2020-04-01 2020-06-26 中山万汉制药有限公司 酶催化的达比加群酯中间体的合成方法
CN113933400A (zh) * 2020-06-29 2022-01-14 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基因毒性杂质的检测方法

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Cited By (10)

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CN105294651A (zh) * 2015-09-23 2016-02-03 烟台东诚药业集团股份有限公司 一种用于合成制备达比加群酯脒化中间体的方法
CN105153118A (zh) * 2015-09-24 2015-12-16 青岛黄海制药有限责任公司 一种甲磺酸达比加群酯制备过程中中间体的中控方法
CN105732491A (zh) * 2016-03-28 2016-07-06 沈阳工业大学 达比加群的酯衍生物及其制备方法和用途
CN105732491B (zh) * 2016-03-28 2018-01-02 沈阳工业大学 达比加群的酯衍生物及其制备方法和用途
CN108658939A (zh) * 2018-07-16 2018-10-16 上海现代制药股份有限公司 一种甲磺酸达比加群酯关键中间体的合成方法
CN108658939B (zh) * 2018-07-16 2021-07-20 上海现代制药股份有限公司 一种甲磺酸达比加群酯关键中间体的合成方法
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
CN111334537A (zh) * 2020-04-01 2020-06-26 中山万汉制药有限公司 酶催化的达比加群酯中间体的合成方法
CN113933400A (zh) * 2020-06-29 2022-01-14 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基因毒性杂质的检测方法
CN113933400B (zh) * 2020-06-29 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基因毒性杂质的检测方法

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