WO2006044754A2 - Process for preparing telmisartan - Google Patents
Process for preparing telmisartan Download PDFInfo
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- WO2006044754A2 WO2006044754A2 PCT/US2005/037185 US2005037185W WO2006044754A2 WO 2006044754 A2 WO2006044754 A2 WO 2006044754A2 US 2005037185 W US2005037185 W US 2005037185W WO 2006044754 A2 WO2006044754 A2 WO 2006044754A2
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- methyl
- propyl
- biphenyl
- benzimidazol
- carboxylate
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- 0 *c(cccc1)c1-c1ccc(C(Br)Br)cc1 Chemical compound *c(cccc1)c1-c1ccc(C(Br)Br)cc1 0.000 description 1
- BBGMMSJWUWGPGE-UHFFFAOYSA-N CCCC(Nc(c(N)c1)c(C)cc1C(Nc(cccc1)c1NC)=O)=O Chemical compound CCCC(Nc(c(N)c1)c(C)cc1C(Nc(cccc1)c1NC)=O)=O BBGMMSJWUWGPGE-UHFFFAOYSA-N 0.000 description 1
- RMMXLENWKUUMAY-UHFFFAOYSA-N CCCc1nc(c(C)cc(-c2nc3ccccc3[n]2C)c2)c2[n]1Cc(cc1)ccc1-c(cccc1)c1C(O)=O Chemical compound CCCc1nc(c(C)cc(-c2nc3ccccc3[n]2C)c2)c2[n]1Cc(cc1)ccc1-c(cccc1)c1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 1
- XVWHGXBWUBIPAA-UHFFFAOYSA-N CCCc1nc(c(C)cc(C(O)=O)c2)c2[n]1Cc(cc1)ccc1-c(cccc1)c1C(O)=O Chemical compound CCCc1nc(c(C)cc(C(O)=O)c2)c2[n]1Cc(cc1)ccc1-c(cccc1)c1C(O)=O XVWHGXBWUBIPAA-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
Definitions
- the present invention relates to processes for preparing telmisartan, telmisartan salts, and intermediates thereof.
- Telmisartan is chemically known as 4'-[[(2-n-propyl-4-methyl-6-(1- methylbenzimidazol ⁇ -yO-benzimidazol-i-ylJ-methyO-biphenyl ⁇ -carboxylic acid, and has the following structural Formula I.
- Telmisartan is an angiotensin-ll receptor antagonist, useful in the treatment of hypertensive diseases, heart diseases, heart strokes and bladder diseases and is commercially available in tablets sold using the brand name MICARDISTM.
- U.S. Patent No. 5,591 ,762 discloses telmisartan and its pharmaceutically acceptable salts, along with pharmaceutical compositions. This patent also discloses a process for the preparation of telmisartan by hydrolysing the tertiary- butyl ester precursor of telmisartan with trifluoroacetic acid in dimethylformamide.
- the invention provides a process for the preparation of telmisartan. In another aspect, the invention relates to a process for proficiently preparing telmisartan substantially free of residual solvent.
- the invention relates to a process for proficiently preparing telmisartan substantially free of ash content.
- the invention provides telmisartan and intermediates of telmisartan substantially free of impurities.
- the invention provides polymorphic forms of methyl-4'-[[(2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2yl)-benzimidazol-1-yl]- methyl]-biphenyl-2-carboxylate and it's hydrochloride salt, and process for the preparation thereof.
- the invention provides a process for preparing telmisartan, comprising: a) reduction of methyl 4-butyramido-3-methyl-5-nitrobenzoate to form methyl 3-amino-4-butyramido-5-methylbenzoate,which on subsequent hydrolysis followed by ring closure forms 2-n-propyl-4-methyl-benzimidazole-6- carboxylic acid; b) condensation of 2-n-propyl-4-methyl-benzimidazole-6-carboxylic acid with N-methyl-o-phenylenediamine hydrochloride to form 2-n-propyl-4-methyl-6- (1 -methyl benzamidazole-2-yl) benzamidazole; c) condensation of 2-n-propyl-4-methyl-6-(1 -methyl benzamidazole-2-yl) benzamidazole with methyl 4'-(bromomethyl)biphenyl-2-carboxylate in the presence of a base to form methyl-4'
- the process of the present invention provides alternative methods for the preparation of 2-n-propyl-4-methyl-6-(1 -methyl benzamidazole-2-yl) benzamidazole of Formula IV.
- Another aspect of the invention provides a crystalline potassium salt of telmisartan.
- Another additional aspect of the invention provides a crystalline telmisartan hydrogen sulphate.
- the invention provides processes for the preparation of compounds lib, IHb, IVa and Vl.
- the invention also provides telmisartan containing low concentrations of any one or more of: i) Methyl-(2-n-propyl-4-methyl-1 -hydroxy benzimidazole)-6- carboxylate; ii) (2-n-propyl-4-methy]-1 -hydroxy benzimidazole)-6-carboxylic acid; iii) N-methyl-2-nitroso aniline; iv) o-Phenylene diamine; v) N6-[2-(methyiamino)phenyl]-3-amino-4-methyl-2-propyl benzo diimidazoIe-6-carboxamide; vi) N1-[2-(methyIamino)phenyl]-3-amino-4-butyramino-5-methyl benzamide; vii) 2-n-propyl-4-methyl-6-(1-benzimidazole-2-yl) benzimidazole; viii) 2-n-propyl
- Fig. 1 is an X-ray powder diffraction ("XRPD") pattern for crystalline Form A of methyl-4'-[[(2 n-propyl-4-methyl-6-(1 -methylbenzimidazol-2-yl)-benzimidazol-1 - yl]-methyl]-biphenyl-2-carboxylate.
- Fig. 2 is an XRPD pattern for the crystalline hydrochloride salt of methyl-4 1 -
- Fig. 3 is an XRPD pattern for amorphous methyl-4'-[[(2 n-propyl-4-methyl- 6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate.
- Fig. 4 is an XRPD pattern for the amorphous hydrochloride salt of methyl-
- Fig. 5 is an XRPD pattern for the potassium salt of telmisartan.
- Fig. 6 is an XRPD pattern for the hydrogen sulphate salt of telmisartan.
- Fig. 7 is an XRPD pattern for telmisartan, prepared according to the invention.
- the invention provides a process for the preparation of telmisartan.
- the invention relates to a process for proficiently preparing telmisartan free of residual solvent. In a further aspect, the invention relates to a process for proficiently preparing telmisartan substantially free of ash.
- the invention provides telmisartan and intermediates of telmisartan substantially free of impurities.
- the present invention in one aspect, relates to a process for the preparation of telmisartan of Formula I comprising the steps of: a) reduction of the methyl 4-butyramido-3-methyl-5-nitrobenzoate compound of Formula II,
- Step a) involves hydrogenation of the methyl 4-butyramido-3-methyl-5-nitro benzoate compound of Formula Il with palladium on charcoal (containing about about 50% water) in methanol to give methyl 3-amino-4-butyramido-5- methylbenzoate of Formula lla, which on subsequent hydrolysis followed by ring closure with a suitable base in a suitable solvent gives 2-n-propyl-4-methyl- benzimidazole-6-carboxylic acid of Formula III.
- Suitable inorganic bases that can be used in the reaction include but are not limited to: hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like.
- Suitable solvents that can be used in the hydrolysis include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropanol, and the like; water; and their mixtures.
- the temperature for conducting the hydrolysis can range from 50-110° C, or 60-100° C, or at the reflux temperature of the solvent used.
- the intermediate compound of Formula Ha in step a) may or may not be isolated. The same can be converted in situ to the compound of Formula III. It has been found that the compound of Formula III is substantially free of methyl-(2n-propyl-4-methyl-1 -hydroxy benzimidazole)-6-carboxylate and contains low concentrations of 2-n-propyl-4-methyl-1 -hydroxy benzimidazole)-6-carboxylic acid, i.e., such as less than or equal to about 0.15 area-%, or less than about 0.12 area-%, as determined by high performance liquid chromatography ("HPLC").
- HPLC high performance liquid chromatography
- Step b) involves condensation of 2-n-propyl-4-methyl-benzimidazole-6- carboxylic acid of Formula III with N-methyl-o-phenylenediamine hydrochloride of Formula Ilia, in the presence of a suitable condensation reagent, to give 2-n- propyl-4-methyl-6-(1 -methyl benzamidazole-2-yl) benzamidazole of Formula IV.
- the condensation reaction can also be carried out by using known methods, such as described by U. J. Ries et al., in Journal of Medicinal Chemistry, Vol. 36, pages 4040-4051 (1993), and U.S. Patent No. 6,770,762.
- the compound of Formula IV is substantially free of- N6-[2-(methylamino)phenyl]-3-amino-4-methyl-2-propyl benzodiimidazole-6- carboxamide, N 1 -[2-(methylamino)phenyl]-3-amino-4-(butyramino)-5-methyl benzamide, 2-n-propyl-4-methyl-6-(1 -methyl benzimidazole-2-yl)-1 -hydroxy benzimidazole, and contains low concentrations of 2-n-propyl-4-methyl-6-(1- benzimidazole-2-yl) benzimidazole, such as less than or equal to about 0.5 area- %, or less than about 0.28 area-%, by HPLC.
- Step c) involves condensation of 2-n-propyl-4-methyl-6-(1 -methyl benzamidazole-2-yl) benzamidazole of Formula IV with methyl 4'-(bromo methyl) biphenyl-2-carboxylate of Formula V in the presence of a suitable base in a suitable solvent to give methyl-4'-[[(2-n-propyl-4-methyl-6-(1 -methyl benzimidazol- 2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate of Formula Vl.
- Bases that are useful for the reaction include: inorganic bases like hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like, and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; and organic bases such as triethylamine, tributylamine, tripropylamine, and the like.
- inorganic bases like hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like, and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like
- organic bases such as triethylamine, tributylamine, tripropylamine, and the like.
- Solvents that can be used in the reaction include, without limitation: ketone solvents such as acetone, diethyl ketone, methyl isobutyl ketone (MIBK), and the like; nitrile solvents such as acetonitrile, propionitrile and the like; alcoholic solvents such as methanol, ethanol, propanol, butanol, and the like; tetrahydrofuran; and water; and mixtures thereof;
- Suitable temperatures for conducting the reaction can range from 0-100° C, or 10-50° C, or 20-30° C.
- the compound having Formula Vl can be converted to its acid addition salt, by reacting with an acidic reagent, such as with alcoholic or aqueous hydrochloric acid to form the hydrochloride salt.
- an acidic reagent such as with alcoholic or aqueous hydrochloric acid to form the hydrochloride salt.
- the compound of Formula Vl contains low concentrations of Methyl 4'-[2-n-propyI-4- methyl-6 -carboxylic acid - benzimidazol-1-yl] -methyl-biphenyl-2-carboxylate, 4'- [2-n-propyl-4-methyl-6- carboxylic acid-benzimidazol-1-yl] -methyl-biphenyl-2- carboxylic acid, and Methyl 4'-[2-n-propyl-4- methyl-6 ⁇ methyl -4"- (1 -methyl-biphenyl-2 carboxylate) benzimidazol-2-yl ⁇ -benzimidazol-1-yl] -methyl-biphenyl-2-carboxylate, such as less than or equal to about 0.1 area-%, or less than about 0.05 area-%, by HPLC.
- Step d) involves hydrolysis of methyl-4'-[[(2-n-propyl-4-methyl-6-(1- methylbenzimidazol-2-yl)-benzimidazol-1 -yl]-methyl]-biphenyl-2-carboxylate of Formula Vl, or its acid addition salt, in the presence of a suitable base in a suitable solvent to give telmisartan.
- Bases that are useful for the reaction include: hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like.
- Suitable solvents for the reaction include nitrile solvents such as acetonitrile, propionitrile, and the like. Temperatures for conducting the reaction can range from 0-150° C, or 50- 100° C 1 or at the reflux temperature of the solvent used.
- the potassium salt of telmisartan may or may not be isolated.
- the potassium salt of telmisartan can be isolated by filtration, centrifugation, decantation, and the like.
- the potassium salt of telmisartan can be further converted to telmisartan by heating the potassium salt of telmisartan in suitable solvents, followed by adjusting the pH using a suitable acid.
- Solvents that can be used include, but are not limited to, organic solvents such as nitrile solvents like acetonitrile, propionitrile, and the like; water; or mixtures thereof.
- Suitable acids can be aqueous.
- An example of a suitable acid is acetic acid.
- the pH can depend on the acid.
- a suitable pH range is typically 5-5.5. It has been observed that telmisartan obtained from the step d) frequently contains ash, in an amount about 3% w/w.
- telmisartan hydrogen sulphate is obtained wherein the acid is sulfuric acid and pH is less than 5.
- Step e) involves purification of telmisartan comprising the steps of : i) dissolving crude telmisartan in a solvent, and crystallizing; ii) crystallization in a mixture of solvents; and iii) recrystalization in an organic solvent.
- Step i) of e) involves dissolving crude telmisartan in a suitable solvent.
- a suitable solvent can be water.
- a suitable temperature range is from 50 to 80° C.
- the solution containing crude telmisartan can be cooled to 20 to 55° C, or 40-50° C for crystallization.
- the solid is then separated, such as by filtration followed by washing with a suitable solvent such as water.
- the obtained material is dried by using the technique known in art at 50 to 90° C over a period of 4 to 6 hours to afford telmisartan. It has been observed that telmisartan obtained from the step i) contains ash in an amount typically less than about 1% w/w.
- Step ii) of e) involves crystallization of telmisartan from step i) in a mixture of solvents.
- the solvents that can be used for this crystallization include halogenated hydrocarbons, alcohols, or mixtures thereof. Examples of halogenated solvents are dichloromethane, chloroform, ethylene dichloride, and the like.
- Useful alcoholic solvents include methanol, ethanol, isopropanol, butanol, and the like. It has been found that telmisartan obtained from step ii) is substantially free from extraneous matter, i.e. is substantially particle free, ash free, etc., but the residual solvent content can be high, such as more than about 6000 ppm of dichloromethane. It has been observed that telmisartan obtained from step ii) typically contains ash less than about 0.1% w/w.
- Step iii) of e) involves recrystallization of telmisartan in an
- Useful organic solvents include, but are not limited to, alcohol solvents such as methanol, ethanol, isopropanol, butanol, and the like.
- telmisartan obtained by the above process is substantially free from residual solvents such as dichloromethane, e.g., containing less than about 500 ppm, or less than about 150 ppm, or less than about 50 ppm of solvent, and contains less than about 0.1 % w/w of ash.
- solvents such as dichloromethane, e.g., containing less than about 500 ppm, or less than about 150 ppm, or less than about 50 ppm of solvent, and contains less than about 0.1 % w/w of ash.
- telmesartan subjected to step e) is substantially free of 4 ! -[2-n-propyl-4-methyl-6 ⁇ 4"-(1 -methyl-biphenyI-2 -carboxylic acid) benzimidazol ⁇ -ylJ-benzimidazol-i-yO -methyl-biphenyl ⁇ -carboxylic acid.
- the whole process can be represented by the following Scheme A:
- an alternative process for the preparation of 2-n-propyl-4-methyl-benzimidazole-6-carboxylic acid of Formula III comprising the steps of: a) hydrolysis of methyl 3-amino-4-butyramido-5-methylbenzoate of Formula Ha by reaction with an inorganic base in the presence of alcohol and water, to give 3-amino-4-butyramido-5-methylbenzoic acid of Formula lib; b) cyclisation of 3-amino-4-butyramido-5-methylbenzoic acid of Formula Hb in the presence of a dehydrating agent to give 2-n-propyl-4-methyl- benzimidazole-6-carboxylic acid of Formula III.
- a suitable inorganic base for use in step a) includes but is not limited to: hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonat ⁇ , potassium carbonate and the like; and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like.
- a suitable alcohol for use in the hydrolysis includes methanol, ethanol, isopropanol and the like.
- the temperature for conducting the reaction can range from 0-100° C, or 25-75° C, or 60-65° C.
- a suitable dehydrating agent for use in step b) includes acetic acid, polyphosphoric acid (PPA), methane sulfonic acid and the like.
- the process of the present invention provides an alternative method for the preparation of 2-n-propyl-4-methyl-6-(1 -methyl benzamidazole-2-yl) benzamidazole of Formula IV, without preparation of the compound of Formula III, comprising the steps of: a) condensation of 3-amino-4-butyramido-5-methylbenzoic acid of Formula lib with N-methyl-o-phenylenediamine of Formula Ilia, in the presence of a suitable condensation reagent in a suitable solvent to give 3-amino-4- (butyramido)-5-methyl-N-(2-(methylamino)phenyl)benzamide of Formula IHb; b) cyclisation of 3-amino-4-butyramido-5-methyl-N-(2-(methylamino) phenyl) benzamide of Formula 1Mb in the presence of a dehydrating agent to give the compound of formula IV.
- a condensation reagent useful for step a) is dicyclohexyl carbodiimide (DCC), optionally in combination with 1 -hydroxy benzotriazole (HOBT), and optionally in the presence of a catalytic amount of dimethylamino pyridine (DMAP).
- DCC dicyclohexyl carbodiimide
- HOBT 1 -hydroxy benzotriazole
- DMAP dimethylamino pyridine
- a suitable solvent for this step a) includes any solvent or mixture of solvents, in which required components are soluble. Examples include dimethylformamide (DMF); dimethylsulfoxide (DMSO); dimethylacetamide (DMAC); and the like; chlorohydrocarbon solvents having C- ⁇ -C 4- carbon atoms such as dichloromethane, ethylene dichloride, chloroform and the like; or mixtures thereof.
- DMF dimethylformamide
- DMSO dimethylsulfoxide
- DMAC dimethylacetamide
- chlorohydrocarbon solvents having C- ⁇ -C 4- carbon atoms such as dichloromethane, ethylene dichloride, chloroform and the like; or mixtures thereof.
- Suitable dehydrating agents that are useful in step b) include acetic acid, polyphosphoric acid (PPA), methane sulfonic acid and the like.
- the present invention provides an alternative process for the preparation of the compound of Formula IV, comprising the steps of; a) condensing 2-n-propyl-4-methyl-benzimidazole-6-carboxylic acid of Formula III with N-methyl-o-phenylenediamine of Formula Ilia, in the presence of a suitable condensation reagent, to give 7-methyl-N-(2- (methylamino) phenyl)-2-propyl-3H-benzodiimidazole-5-carboxamide of Formula IVa; and b) cyclisation of the compound of Formula IVa in the presence of a dehydrating agent giving the compound of Formula IV.
- a condensation reagent useful for step a) is dicyclohexylcarbodiimide (DCC), optionally in combination with 1 -hydroxy benzotriazole (HOBT), optionally in the presence of a catalytic amount of dimethylaminopyridine (DMAP).
- DCC dicyclohexylcarbodiimide
- HOBT 1 -hydroxy benzotriazole
- DMAP dimethylaminopyridine
- Suitable solvents for this reaction include any solvent or mixture of solvents, in which required components are soluble. Examples include, without limitation thereto, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMAC), and the like; Ci-C 4 chlorohydrocarbon solvents such as dichloromethane, ethylenedichloride, chloroform, and the like; or mixtures thereof.
- DMF dimethylformamide
- DMSO dimethylsulfoxide
- DMAC dimethylacetamide
- Ci-C 4 chlorohydrocarbon solvents such as dichloromethane, ethylenedichloride, chloroform, and the like; or mixtures thereof.
- a suitable dehydrating agent that is used in step b) includes acetic acid, polyphosphoric acid (PPA), methane sulfonic acid, and the like.
- a further aspect of the present invention relates to acid addition salts of methyl-4'-[[(2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]- methyl]-biphenyl-2-carboxylate of Formula Vl, and a process for preparation thereof.
- the acid addition salts include, without limitation, hydrochloride, hydrobromide, hydrogen sufate, tosylate, fumarate, maleate, tartrate, and methane sulfonate salts, and the like.
- the hydrochloride salt is well suited for commercial production of telmisartan with high purity, without further purification.
- the hydrochloride salt of the compound of Formula Vl exhibits a high degree of crystallinity with good flow properties and stability, making it easy to handle on a commercial scale.
- the hydrochloride salt of the compound of Formula Vl is prepared by reaction of the free base obtained by step c) of Scheme A, with hydrochloric acid in a suitable solvent.
- a suitable reagent for this purpose includes methanolic hydrochloric acid, isopropanolic hydrochloric acid, ethyl acetate hydrochloride, aqueous hydrochloric acid, and the like.
- the present invention relates to polymorphic forms of methyl-4'-[[(2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]- methyl]-biphenyl-2-carboxylate of Formula Vl and its hydrochloride salt, and processes for the preparation thereof.
- Form A The crystalline form (herein after referred to as "Form A") of methyl-4'-[[(2- n-propyl-4-methyl-6-(1 -methyl benzimidazol-2-yl)-benzimidazol-1 -yl]-methyl]- biphenyl-2-carboxylate of Formula Vl, is characterized by the XRPD pattern of Fig. 1 , wherein the most characteristic peaks are at about 7.8, 11.3, 12.2, 13.8, 14.4, 15.3, 17.2, 18.2, 18.9, 20.4, 20.9, 22.5, 23.3, 23.4, 23.8, 25.5, 25.8, 26.6, 29.0, 29.8 and 32.95 ⁇ 0.2 degrees two theta.
- a process for preparing crystalline Form A of the compound of Formula Vl comprises: a) heating a mixture of about 4 parts by weight methyl-4'-[[(2-n-propyl-4- methyl-6-(1 -methyl benzimidazol-2-yl)-benzimidazol-1 -yl]-methyl]-biphenyl- 2-carboxylate and about 40 parts by weight acetonitrile to reflux; b) stirring at reflux, such as for about 30-60 minutes, to form a solution; c) distilling off a portion of the solvent, such as about 50%, from the solution of step b) under reduced pressure; d) cooling the solution of step c) to 20-40 0 C and stirring as crystals form, such as for about 30-60 minutes; e) filtering the separated solid from step d) and washing with acetonitrile; and f) drying the obtained solid from step e) at about 45-60 0 C, such as for about 3-5 hours, to get the crystalline Form A of methyl
- a process for preparing the amorphous form of the compound of formula Vl comprises: a) heating methyl-4'-[[(2-n-propyl-4-methyl-6-(1 -methyl benzimidazol-2-yl)- benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and an alcoholic solvent such as methanol, ethanol, propanol, isopropanol, or a mixture of any two or more thereof, to reflux; b) stirring at reflux, such as for about 30-60 minutes, to form a solution; c) distilling off the alcohol from the solution of step b) under reduced pressure; and d) isolating the separated solid from step c), which is the amorphous form.
- Formula Vl methyl-4'-[[(2-n-propyl-4-methyl-6-(1 -methyl benzimidazol-2-yl)- benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate hydrochloride is characterized by the XRPD pattern of Fig. 2, wherein the most characteristic peaks are at about 6.1 , 12.3, 14.0, 14.5, 16.2, 19.8, 21.1 , 23.4, 23.7, 24.2, 24.6, 25.6 and 29.04 ⁇ 0.2 degrees two theta.
- a process for preparing the crystalline hydrochloride salt (methyl-4'-[[(2-n- propyl-4-methyl-6-(1 -methyl benzimidazol-2-yl)-benzimidazol-1 -yl]-methyl]- biphenyl-2-carboxylate hydrochloride) comprises: a) dissolving methyl-4'-[[(2n-propyl-4-methyl-6-(1 -methylbenzimidazol-2-yl)- benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate in a ketone solvent like acetone, propanone, methyl isobutyl ketone, or a mixture of any two or more thereof, at 25-3O 0 C; b) stirring the mixture, such as for about 15-30 minutes, at 25-3O 0 C to form a solution; c) adjusting the pH of the solution of step b) to 1-2 by slow addition of hydrochloric acid at 25-3O
- a process for preparing the amorphous form of methyl-4'-[[(2-n-propyl-4- methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2- carboxylate hydrochloride comprises: a) dissolving the hydrochloride salt of methyl-4'-[[(2-n-propyl-4-methyl-6-(1- methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate in methanol or acetonitrile; b) distilling off the solvent from the reaction solution of step a) under reduced pressure; c) isolation of separated solid from step b); d) drying the solid from step c) at 25-35 0 C, such as for about 1-2 hours, to get the amorphous form.
- An additional aspect of the invention provides telmesartan hydrogen sulphate.
- the present invention provides the compounds having Formulas lib, INb, and IVa, and the hydrochloride salt of the compound having Formula Vl.
- the invention provides processes for the preparation of compounds having Formulas lib, HIb, IVa, and the hydrochloride salt of the compound having Formula Vl.
- Compound IHb is prepared by process step (a) of the invention described with reference to Scheme C.
- Compound IVa is prepared by process step (a) of the invention described with reference to Scheme D.
- Compound Vl is prepared by process step (d) of the invention described with reference to Scheme A, and the hydrochloride salt is prepared by reacting Compound Vl with aqueous hydrochloric acid or an alcoholic hydrochloric acid.
- the invention also provides telmisartan containing low concentrations of any one or more of the following impurities:
- a "low concentration" not associated with a specific numeric value is considered to be an amount of an impurity not exceeding about 0.1 area-%, or about 0.05 area-%, of the prepared intermediate, telmisartan, or telmisartan salt, as determined by HPLC.
- reaction mass 140 L of water was added to the reaction mass and pH was adjusted to 5.5-6 with 50% aqueous sodium hydroxide solution. Centrifuged the reaction mass and washed the solid with 35 L of water. Charged the wet cake and 70 L of water into a reactor. Reaction mass was heated to 70-80° C and stirred for 30-45 minutes. Cooled the reaction mass to 40- 45° C, centrifuged the solid and washed the cake with 35 L of water. Repeated the above water slurry process one more time, then dried the material at 70-75° C for 5-6 hours. Charged the dry material into a reactor containing 80 L of tetrahydrofuran under stirring. Heated the mass to reflux and stirred for 10 minutes.
- telmisartan obtained as above was charged into a clean reactor containing 450 L of methanol. Heated the reaction contents to 75-85°C under closed conditions and maintained at same temperature and the resulting pressure of 2 kg/cm 2 for 30-45 minutes. The clear solution thus obtained was passed through online and micro filters and the reactor was washed with 42.5 L of methanol. Cooled the filtrate and washings to 55-65 0 C and distilled off the methanol below 65 0 C under vacuum until 40-50% of the reaction mass volume remained. Then cooled the reaction mass to 5-10 0 C and stirred for 35-45 minutes. Centrifuged the mass and washed the solid with 4.5 L of methanol. Dried the solid at 75-80° C for 5-6 hours to get 4.0 kg of pure termisartan, having the XRPD pattern of Fig. 7.
- STEP B PREPARATION OF 2-n-PROPYL-4-METHYL-BENZIMIDAZOLE- 6-CARBOXYLIC ACID (FORMULA III)
- STEP B PREPARATION OF 2-n-PROPYL-4-METHYL-6- (1 -METHYL BENZAMIDAZOLE-2-YL) BENZAMIDAZOLE (FORMULA IV) 2 g of 7-methyl-N-(2-(methylamino) phenyl)-2-propyl-3H-benzodiimidazole-
- Example 12 25 g of methyl- (2-n-propyl-4-methyl-1 -hydroxy benzimidazole)-6- carboxylate of Example 12 was charged into a round bottom flask containing 250 ml methanol. Charged 7.5 g of sodium hydroxide flakes and heated the reaction mass to reflux. Stirred at reflux for 1-2 hours and then distilled the solvent completely. 250 ml of water was charged and the mass cooled to 25-35° C.
- the wet solid was charged into a flask and 50 ml of water was added. The contents were heated to 70-80° C and stirred for 30-45 minutes. Cooled to 25-35° C and stirred for 30-45 minutes. Filtered the solid and washed with 10 ml of water. Dried the solid at 50-55° C for 4-5 hours to afford 7.2 g of the title compound.
- the wet solid was charged into a flask and 50 ml of water was added. The contents were heated to 70-80° C and stirred for 30-45 minutes. Cooled to 25-35° C and stirred for 30-45 minutes. Filtered the solid and washed with 25 ml of water. Dried the solid at 50-55° C for 4-5 hours to afford 3.4 g of the title compound.
- the wet solid was charged into a flask containing 70 ml of acetonitrile at room temperature. Stirred for 30-45 minutes, filtered the solid and washed with acetonitrile (20 ml). Dried the solid at 25-35° C for 4-5 hours to get 10 g of the title compound.
- telmisartan potassium salt 15 g was charged into a round bottom flask containing 225 ml of methanol and stirred for 10-15 minutes. Filtered to remove undissolved solids and washed with 30 ml of methanol. 75 ml of water was added to the filtrate and stirred for 5-10 minutes at 25-35° C. Reaction mass pH was adjusted to 2-2.5 by adding a mixture of sulfuric acid (3 ml) and water (60 ml) and stirring for 10-15 minutes. Charged 150 ml of water to the mass and stirred for 30-45 minutes. Filtered the solid and washed with 75 ml of water. Dried the solid at 70-75° C for 4-5 hours to get 10.0 g of the title compound as a crystalline solid, having the XRPD pattern of Fig. 6.
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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EP05812410A EP1805146A4 (en) | 2004-10-18 | 2005-10-18 | Process for preparing telmisartan |
US11/577,452 US7943781B2 (en) | 2004-10-18 | 2005-10-18 | Process for preparing telmisartan |
IL182919A IL182919A0 (en) | 2004-10-18 | 2007-05-02 | Process for preparing telmisartan and telmisartan derivatives prepared thereby |
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US61988104P | 2004-10-18 | 2004-10-18 | |
US60/619,881 | 2004-10-18 | ||
US62314004P | 2004-10-27 | 2004-10-27 | |
US60/623,140 | 2004-10-27 |
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WO2006044754A3 WO2006044754A3 (en) | 2006-12-14 |
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US (1) | US7943781B2 (en) |
EP (1) | EP1805146A4 (en) |
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Cited By (20)
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EP1779662A1 (en) | 2004-08-13 | 2007-05-02 | Industry Academic Cooperation Foundation Kyunghee University | Method and device for motion estimation and compensation for panorama image |
WO2007147889A2 (en) * | 2006-06-23 | 2007-12-27 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Preparation of telmisartan salts |
US7501448B2 (en) | 2004-10-15 | 2009-03-10 | Teva Pharmaceutical Industries, Ltd. | Process for preparing telmisartan |
WO2009006860A3 (en) * | 2007-07-09 | 2009-04-16 | Zentiva As | A method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan) |
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Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5614519A (en) | 1991-02-06 | 1997-03-25 | Karl Thomae Gmbh | (1-(2,3 or 4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls useful as angiotensin-II antagonists |
US6358986B1 (en) | 1999-01-19 | 2002-03-19 | Boehringer Ingelheim Pharma Kg | Polymorphs of telmisartan |
DE19901921C2 (en) | 1999-01-19 | 2001-01-04 | Boehringer Ingelheim Pharma | Polymorphs of telmisartan, process for their preparation and their use in the manufacture of a medicament |
CN1182122C (en) | 2001-07-30 | 2004-12-29 | 中国科学院上海药物研究所 | Synthesis path of Timisatem |
DE10153737A1 (en) | 2001-10-31 | 2003-05-28 | Boehringer Ingelheim Pharma | Crystalline sodium salt of telmisartan, process for its preparation and its use for the manufacture of a medicament |
US6737432B2 (en) | 2001-10-31 | 2004-05-18 | Boehringer Ingelheim Pharma Kg | Crystalline form of telmisartan sodium |
DE10201725A1 (en) | 2002-01-18 | 2003-08-14 | Boehringer Ingelheim Pharma | Process for the preparation and purification of 1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole |
US6770762B2 (en) * | 2002-01-18 | 2004-08-03 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for preparing and purifying 1,7′-dimethyl-2′-propyl-2,5′-bi-1H-benzimidazole |
DE10314702A1 (en) | 2003-03-31 | 2004-10-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for the preparation of telmisartan |
DE10319450A1 (en) * | 2003-04-30 | 2004-11-18 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical formulation of telmisartan sodium salt |
GB2414019A (en) | 2004-05-11 | 2005-11-16 | Cipla Ltd | One-step preparation of telmisartan by condensation and hydrolysis |
-
2005
- 2005-10-18 EP EP05812410A patent/EP1805146A4/en not_active Withdrawn
- 2005-10-18 US US11/577,452 patent/US7943781B2/en not_active Expired - Fee Related
- 2005-10-18 WO PCT/US2005/037185 patent/WO2006044754A2/en active Application Filing
-
2007
- 2007-05-02 IL IL182919A patent/IL182919A0/en unknown
Non-Patent Citations (1)
Title |
---|
See references of EP1805146A2 * |
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Also Published As
Publication number | Publication date |
---|---|
EP1805146A2 (en) | 2007-07-11 |
US7943781B2 (en) | 2011-05-17 |
IL182919A0 (en) | 2007-09-20 |
EP1805146A4 (en) | 2009-01-14 |
WO2006044754A3 (en) | 2006-12-14 |
US20070287840A1 (en) | 2007-12-13 |
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