Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • 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
  • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
  • C07D235/26—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to a process for the preparation of azilsartan medoxomil or pharmaceutically acceptable salts thereof.
• the drug substance used in the drug product formulation is the potassium salt of azilsartan medoxomil, also known by the United States accepted name of azilsartan kamedoxomil, is chemically described as (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2- ethoxy- 1 - ⁇ [2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4yl]methyl ⁇ - 1 H- benzimidazole-7-carboxylate monopotassium salt of Formula I.
• Azilsartan medoxomil is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
• the present invention relates to a process for the preparation of azilsartan medoxomil or its potassium salt.
• a first aspect of the present invention provides a process for the preparation of potassium salt of azilsartan medoxomil which comprises:
• X is hydrogen, the protecting group selected from alkyl, benzyl, substituted alkyl, or substituted aryl with hydroxyl amine, or its salt to form the compound of Formula V or a salt thereof,
• X is hydrogen, the protecting group selected from alkyl, benzyl, substituted alkyl or substituted aryl;
• R 1 is selected from halogen or hydroxyl atom
• R is hydrogen, alkyl, substituted alkyl, or an aryl group, wherein the aryl group may be further substituted by a nitro or chloro group;
• a second aspect of the present invention provides a process for the preparation of azilsartan medoxomil which comprises:
• X is hydrogen, the protecting group selected from alkyl, benzyl, substituted alkyl, or substituted aryl with hydroxyl amine or its salt, to form the compound of Formula V or a salt thereof,
• X is hydrogen, the protecting group selected from alkyl, benzyl, substituted alkyl, or substituted aryl;
• R is selected from halogen or hydroxyl atom
• R is hydrogen, alkyl, substituted alkyl, or aryl group wherein the aryl group may be further substituted by a nitro or chloro group;
• a third aspect of the present invention provides a process for the preparation of the compound of Formula VII or Formula VIII which comprises:
• X is hydrogen, the protecting group selected from alkyl, benzyl, substituted alkyl, or substituted aryl with hydroxyl amine or its salt to form the compound of Formula V or a salt thereof,
• X is hydrogen, the protecting group selected from alkyl, benzyl, substituted alkyl, or substituted aryl;
• R is selected from halogen or hydroxyl atom
• R is hydrogen, alkyl, substituted alkyl, or aryl group, wherein the aryl group may be further substituted by a nitro or chloro group;
• a fourth aspect of the present invention provides a process for the preparation of the compound of Formula IX, which comprises:
• FORMULA IV wherein X is hydrogen, the protecting group selected from alkyl, benzyl, substituted alkyl, or substituted aryl with hydroxyl amine or its salt to form the compound of Formula V or a salt thereof,
• X is hydrogen, the protecting group selected from alkyl, benzyl, substituted alkyl, or substituted aryl;
• R is selected from halogen or hydroxyl atom
• a fifth aspect of the present invention provides the compound of Formula VIII,
• R is hydrogen, alkyl, substituted alkyl, or an aryl group, wherein the aryl group may be further substituted by a nitro or chloro group.
• a sixth aspect of the present invention provides the compound of Formula VII.
• a seventh aspect of the present invention provides the compound of Formula IX.
• An eighth aspect of the present invention provides the use of the compound of Formula VII for the preparation of azilsartan medoxomil or pharmaceutically acceptable salts thereof.
• a ninth aspect of the present invention provides the use of the compound of Formula VIII for the preparation of azilsartan medoxomil or pharmaceutically acceptable salts thereof.
• the compound of Formula IV may be reacted with hydroxyl amine in the presence of a base and solvent.
• Hydroxylamine may be used in the form of a salt, for example, hydrochloride salt.
• bases include hydroxide or alkoxide of alkali or alkaline earth metal or organic bases.
• Suitable alkoxides of alkali and alkaline earth metal include sodium methoxide or potassium methoxide.
• Suitable hydroxides of alkali and alkaline earth metals include sodium hydroxide or potassium hydroxide.
• Suitable organic bases include triethyl amine or tri-n-butyl amine.
• a preferable base may be sodium hydroxide.
• the solvent may be selected from the group consisting of alcoholic solvents, polar solvents, or mixtures thereof.
• Suitable alcoholic solvents include methanol, ethanol, 1 - butanol, or 2-butanol.
• Suitable polar solvents include dimethylformamide,
• a preferable solvent includes methanol, dimethylacetamide, or mixtures thereof.
• Treatment of the compound of Formula IV with hydroxylamine may be carried out at 60°C to 90°C, for example, at 70°C to 80°C.
• Treatment may be carried out for 10 hours to 48 hours, for example, 24 hours.
• the group X in the compound of Formula IV or Formula V may be selected from hydrogen, alkyl, benzyl, substituted alkyl, or substituted aryl.
• the alkyl group may be selected from methyl, ethyl, isopropyl, or a t-butyl group.
• a substituted aryl may be benzyl.
• the preferred group X in the compound of Formula IV or Formula V includes methyl.
• the protecting group in the compound of Formula V may optionally be hydrolyzed. The hydrolysis may be carried out using a base.
• a preferable base may be sodium hydroxide.
• the salts of the compound of Formula IV or Formula V include sodium or potassium salt.
• the salts of the compound of Formula V may be formed in-situ and used further without isolating.
• the compound of Formula IV or Formula V may be converted to its salt by reacting with a suitable alkali metal hydroxide or an alkali metal carbonate.
• a suitable alkali metal hydroxide includes sodium hydroxide or potassium hydroxide.
• a suitable alkali metal carbonate includes sodium carbonate or potassium carbonate.
• the compound of Formula V or its salt may be isolated by filtration, distillation, decantation, vacuum drying, evaporation, or a combination thereof.
• the compound of Formula V may be reacted with the compound of Formula VI in the presence of the solvent.
• the group R 1 in the compound of Formula VI may be selected from hydroxy or halogen atom.
• a suitable halogen atom includes chloro, bromo, or an iodo group.
• a preferable R 1 group includes a chloro atom.
• the solvent may be selected from the group consisting of polar solvents, halogenated hydrocarbon, or ketones.
• Suitable polar solvents include N, N-dimethylformamide, N, N-dimethylacetamide, or dimethylsulphoxide.
• Suitable halogenated hydrocarbon solvents include methylene chloride.
• Suitable ketonic solvents include acetone.
• a preferred solvent may be N,N- dimethylformamide.
• the treatment of the compound of Formula V with the compound of Formula VI may be carried out at - 10°C to 60°C, for example, at 0°C to 45°C.
• the treatment may be carried out for 20 hours to 30 hours, for example, 25 hours.
• the compound of Formula VII may be isolated by filtration, distillation, decantation, vacuum drying, evaporation, or a combination thereof.
• the compound of Formula VII may be optionally esterified in the presence of a base and solvent.
• the R group in the compound of Formula VIII may be selected from a group consisting of hydrogen, alkyl, substituted alkyl, or an aryl group wherein the aryl group may be further substituted by a nitro or a chloro group.
• the R group may preferably be a 4-nitro phenyl group.
• Examples of a base include an organic or inorganic base.
• the inorganic base may be selected from hydroxide or carbonates of alkali or alkaline metal.
• the organic base may be selected from various amines, for example, triethyl amine.
• a suitable base includes triethyl amine or sodium bicarbonate.
• the solvent may be selected from a group consisting of water, esters, halogenated hydrocarbon, ketone, ether, aromatic hydrocarbons, or mixtures thereof.
• the ester solvent may be, for example, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, or a mixture thereof.
• the halogenated hydrocarbon may be, for example, dichloromethane.
• the ketone solvent may be, for example, acetone.
• the ether solvent may be, for example, tetrahydrofuran.
• the aromatic hydrocarbon solvent may be, for example, toluene.
• the solvent may preferably be acetone, isobutyl acetate, or toluene.
• the esterifying agent may be selected from alkyl or aryl chloroformate, both substituted and unsubstituted.
• the alkyl chloroformate may be, for example, ethyl chloroformate.
• the aryl chloroformate may be, for example, phenyl chloroformate, 4-nitro phenyl chloroformate, or 4-chlorophenyl chloroformate.
• the esterifying agent may preferably be 4-nitrophenyl chloroformate.
• the esterification of the compound of Formula VII may be carried out at -10°C to 50°C, for example, at 0°C to 35°C.
• the treatment may be carried out for 2 hours to 4 hours, for example, 3 hours.
• the compound of Formula VIII may be isolated by filtration, distillation, decantation, vacuum drying, evaporation, or a combination thereof.
• the compound of Formula VII or Formula VIII may be cyclized in the presence of a solvent.
• the compound of Formula VII or Formula VIII may be used in the cyclization step in the solution form without isolating.
• the cyclization may be a thermal or chemical induced cyclization.
• Chemical induced cyclization may be carried out using a cyclizing agent.
• a suitable cyclizing agent may include carbodiimidazole, phosgene, or triphosgene.
• the solvent may be selected from the group consisting of water, ketone, halogenated hydrocarbon, alcohols, ether, esters, or mixtures thereof.
• An ester solvent may be, for example, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, or a mixture thereof.
• a halogenated hydrocarbon may be, for example, dichloromethane.
• An ether solvent may be, for example, tetrahydrofuran.
• a ketone solvent may be, for example, acetone.
• An aromatic hydrocarbon solvent may be, for example, toluene.
• alcoholic solvents include ethanol, isopropanol, or isobutanol.
• the solvent may preferably be acetone, isobutyl acetate, or toluene.
• Cyclization of the compound of Formula VII or Formula VIII may be carried out at 10°C to 125°C, for example, at 20°C to 1 15°C. The treatment may be carried out for 10 hours to 15 hours, for example, 13 hours.
• the compound of azilsartan medoxomil of Formula II may be isolated by filtration, distillation, decantation, vacuum drying, evaporation, or a combination thereof.
• the compound of azilsartan medoxomil of Formula II may optionally be purified using various solvents.
• the solvent used for purification of the compound of azilsartan medoxomil of Formula II may be selected from the group consisting of ketone, halogenated hydrocarbon, alcohols, esters, or mixtures thereof.
• the ester solvent may be, for example, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, or a mixture thereof.
• the halogenated hydrocarbon may be, for example, dichloromethane.
• the ketone solvent may be, for example, acetone.
• the aromatic hydrocarbon solvent may be, for example, toluene. Examples of alcoholic solvents include ethanol, isopropanol, or isobutanol.
• the solvent may preferably be acetone.
• Azilsartan medoxomil may optionally be converted to potassium salt of azilsartan medoxomil by reacting with a potassium source in the presence of a solvent.
• the suitable potassium source may include potassium-2-ethylhexanoate.
• the solvent may be selected from the group consisting of ketone, aromatic hydrocarbon, or mixtures thereof.
• aromatic hydrocarbon solvents includes toluene.
• An example of ketone solvents includes acetone, methyl isobutyl ketone, methyl ethyl ketone, or methyl isopropyl ketone.
• Preferable solvents include acetone.
• the compound of potassium salt of azilsartan medoxomil of Formula I may be isolated by filtration, distillation, decantation, vacuum drying, evaporation, or a combination thereof.
• the compound of potassium salt of azilsartan medoxomil of Formula I, the compound of azilsartan medoxomil of Formula II, the compound of Formula VII, and the compound of Formula VIII may be further characterized by X-ray Powder Diffraction Pattern (XRPD) pattern.
• XRPD X-ray Powder Diffraction Pattern
• Methyl- l-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-lH-benzimidazole-7-carboxy late (100 g) was added to the reaction mixture at 25°C to 30°C and heated to 70°C to 75°C for 16 hours to 20 hours.
• the reaction mixture was cooled to 10°C to 15°C.
• the reaction mixture was added to deionized water (1000 mL) at 10°C to 25°C.
• the pH of the reaction mixture was adjusted to 0.8 to 1.2 using concentrated hydrochloric acid (150 mL).
• the reaction mixture was stirred for 30 minutes at 20°C to 30°C.
• the reaction mixture was filtered through celite and washed with deionized water (100 mL).
• the aqueous layer was washed with toluene (500 mL) at 25°C to 30°C and the pH of the aqueous layer was adjusted to 8.8 to 9.2 using 30% solution of sodium carbonate (500 mL) at 20°C to 30°C.
• the reaction mixture was stirred for 3 hours to 4 hours at 25°C to 30°C.
• the reaction mixture was filtered and washed with deionized water (100 mL) at 20°C to 30°C.
• Isobutanol 500 mL was added to the reaction mixture at 20°C to 30°C and the reaction mixture was heated to 90°C to 95°C. The reaction mixture was stirred for 2 hours at 90°C to 95°C, cooled to 25°C to 30°C, and stirred for 4 to 6 hours at 25°C to 30°C. The reaction mixture was filtered and washed with isobutanol (100 mL) at 20°C to 30°C. The reaction mixture was dried under vacuum for 30 minutes at 20°C to 30°C and then at 45°C to 50°C to obtain the title compound.
• the solid obtained was purified in 2-butanol (15 mL) at 90°C to 95°C for 4 hours and further cooled to 20°C to 30°C for 4 hours.
• the solid obtained was filtered, washed with 2-butanol (6 mL), and dried to obtain the title compound.
• the temperature of the reaction mixture was increased to 45°C to 50°C and the reaction mixture was stirred for 8 to 10 hours. Tetrahydrofuran and the methanol mixture were recovered completely under vacuum.
• the reaction mixture was washed with toluene (100 mL) at 20°C to 30°C.
• the pH of the aqueous reaction mixture was adjusted to 4.0 to 4.5 using concentrated hydrochloric acid.
• the reaction mixture was filtered and washed with deionized water (2x40 mL). The reaction mixture was dried at 50°C to obtain the title compound.
• the solid obtained was filtered at 20°C to 30°C and washed with a solution of tetrahydrofuran (60 mL) and de-ionized water (60 mL). The solid material obtained was dried at 40°C to obtain the title compound.
• the temperature of the reaction mixture was raised to 20°C to 30°C and stirred for 20 hours.
• Deionized water 125 mL was added to the reaction mixture at 15°C to 25°C and stirred for 3 hours at 20°C to 30°C.
• the reaction mixture was filtered, washed with deionized water (25 mL), and dried at 45°C under vacuum to obtain the title compound.
• Example 5A Preparation of (5-Methyl-2-Oxo-1.3-Dioxol-4-Yl)Methyl 2-Ethoxy- l- (r2'- rN'-Hvdroxycarbamimidovf)Biphenyl-4-Yll-Methyl ⁇ - lH-Benzimidazole-7-Carboxylate (Formula VII)
• the reaction mixture was stirred at 45°C to 55°C for 6 to 8 hours.
• the reaction mixture was cooled to 15°C to 20°C.
• a solution of sodium bicarbonate (100 g) in water (2000 mL) was added to the reaction mixture.
• the solid obtained was filtered and washed with water (500 mL) and dried below 50°C to obtain the title compound.
• Example 5B Preparation of (5-Methyl-2-Oxo-1.3-Dioxol-4-Yl)Methyl 2-Ethoxy-l- (r2'- (N'-Hydroxycarbamimidoyl)Biphenyl-4-Yll -Methyl ⁇ - 1 H-Benzimidazole-7-Carboxylate (Formula VII)
• Tetrabutyl ammonium bromide (0.94 g), sodium iodide (0.44 g), and 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one (9.5 g) were added to the reaction mixture and stirred for 4 hours at 25°C to 30°C
• the reaction mixture was cooled to 5°C to 10°C.
• 2N Hydrochloric acid (50 mL) was added to the reaction mixture to adjust the pH to 1.5 to 2.0.
• De-ionized water (250 mL) was added to the reaction mixture and washed with toluene (50 mL).
• Example 8A Preparation of (5-Methyl-2-Oxo- L3-Dioxol-4-Yl)Methyl 2-Ethoxy-l- ir2'- (5-Oxo-4.5-Dihvdro-1.2.4-Oxadiazol-3-Yl)Biphenyl-4-Y11MethvU-lH-Benzimidazole-7- Carboxylate (Formula II)
• Example 8B Preparation of (5-Methyl-2-Oxo- 1.3-Dioxol-4-Yl)Methyl 2-Ethoxy-l- ⁇ r2'- i5-Oxo-4.5-Dihvdro-1.2.4-Oxadiazol-3-YnBiphenyl-4-Y11MethvU-lH-Benzimidazole-7- Carboxylate (Formula II)
• Example 8C Preparation of (5-Methyl-2-Oxo- 1.3-Dioxol-4-Yl)Methyl 2-Ethoxy-l- (r2'- i5-Oxo-4.5-Dihvdro-1.2.4-Oxadiazol-3-Yl)Biphenyl-4-YllMethyll-lH-Benzimidazole-7- Carboxylate (Formula II)
• Example 8E Preparation of (5-Methyl-2-Oxo-L3-Dioxol-4-Yl)Methyl 2-Ethoxy-l- ⁇ r2'- (5-Oxo-4.5-Dihvdro-1.2.4-Oxadiazol-3-Yl)Biphenyl-4-Y11MethvU-lH-Benzimidazole-7- Carboxylate (Formula II)
• the solid obtained was filtered and washed with isobutyl acetate (50 mL).
• the reaction mixture was dissolved in a solution of dichloromethane (400 mL), acetone (60 mL), and saturated sodium bicarbonate solution (250 mL) at 30°C to 35°C and stirred for 1 hour.
• the layers obtained were separated and the dichloromethane layer was washed with de-ionized water (250 mL) at 20°C to 30°C.
• the layers obtained were separated and the dichloromethane layer was recovered under vacuum at 25°C to 35°C.
• the reaction mixture was dissolved in acetone (250 mL) at 55°C to 56°C and cooled to 0°C to 5°C for 4 hours.
• the residue obtained was filtered and washed with acetone (25 mL).
• the residue obtained was dried at 40°C under vacuum to obtain the title compound.
• dichloromethane (75 mL) was added to the reaction mixture at 20°C to 30°C and stirred for 1 hour. The layers obtained were separated and the organic layer was washed with de- ionized water (125 mL). Dichloromethane was completely recovered to obtain the solid material. Acetone (125 mL) was added to the reaction mixture and the temperature was increased to 55°C to 57°C. The reaction mixture was stirred for 12 hours, cooled to 20°C to 25°C, and stirred for 4 hours. The reaction mixture was filtered and washed with acetone (25 mL).
• the reaction mixture was dissolved in dichloromethane (500 mL), acetone (75 mL), and a solution of sodium bicarbonate (250 mL) at 35°C to 40°C and stirred for 1 hour.
• the layers obtained were separated and the dichloromethane layer was washed with de-ionized water (250 mL) at 20°C to 30°C.
• the layers obtained were separated and dichloromethane was recovered under vacuum at 25°C to 35°C.
• the solid material obtained was slurried in acetone (75 mL) at 20°C to 25°C for 4 hours.
• the solid obtained was filtered and washed with acetone (25 mL).
• the solid obtained was dried under vacuum at 40°C to obtain the title compound.
• Example 12A Preparation of Potassium Salt of (5-Methyl-2-Oxo-L3-Dioxol-4- YDMethyl 2-Ethoxy-l- ⁇ r2'-(5-Oxo-4,5-Dihvdro- l,2,4-Oxadiazol-3-Yl)Biphenyl-4-Y11 Methyl ⁇ - lH-Benzimidazole-7-Carboxylate (Formula I)
• Potassium-2-ethylhexanoate (30.44 g) was added to toluene (200 mL) at 20°C to 30°C under nitrogen atmosphere.
• the reaction mixture was heated to 100°C to 105°C and the toluene was azeotropically distilled to remove water and completely recovered.
• the reaction mixture was cooled to 40°C to 45°C under nitrogen and acetone (500 mL) was added to the reaction mixture.
• the reaction mixture was stirred and cooled to 20°C to 30°C.
• the reaction mixture was stirred for 3 hours to 4 hours at -5°C to - 10°C under nitrogen.
• the solid obtained was filtered at -5°C to -10°C under nitrogen.
• the reaction mixture was washed with acetone (100 mL x 2) under nitrogen and dried under vacuum at 35°C to 40°C to obtain the title compound.
• Example 12B Preparation of Potassium Salt of (5-Methyl-2-Oxo-1.3-Dioxol-4- YF)Methyl 2-Ethoxy-l- ir2'-i5-Oxo-4.5-Dihvdro- 1.2.4-Oxadiazol-3-YnBiphenyl-4- Y11Methyl ⁇ -lH-Benzimidazole-7-Carboxylate (Formula I)
• Acetone (1300 mL) was added to (5-methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl-2-ethoxy- 1 - ⁇ [2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl ⁇ -lH-benzimidazole-7-carboxylate (100 g) prepared in Example 9 at 20°C to 30°C. The reaction mixture was heated to 50°C to 55°C. The reaction mixture was filtered through celite and cooled to 0°C to 5°C.
• the acetone solution of potassiums- ethyl hexanoate prepared above was added to the reaction mixture at 0°C to 5°C and stirred for 3 to 4 hours.
• the solid obtained was filtered at 0°C to 5°C and washed with acetone (200 mL).
• the solid obtained was dried under vacuum at 20°C to 30°C to obtain the title compound.

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• 2013
  • 2013-01-30 IN IN6964DEN2014 patent/IN2014DN06964A/en unknown
  • 2013-01-30 EP EP13711960.8A patent/EP2814826A1/en not_active Withdrawn
  • 2013-01-30 US US14/375,389 patent/US20150011774A1/en not_active Abandoned
  • 2013-01-30 WO PCT/IB2013/050803 patent/WO2013114305A1/en active Application Filing

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