DESC:FIELD OF INVENTION
The present invention provides novel process for preparation of azilsartan medoxomil (I) and its salts. The present invention also provides novel intermediate compounds for synthesis of azilsartan medoxomil (I).
BACKGROUND OF THE INVENTION
Azilsartan medoxomil (I) is chemically known as (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2-ethoxy-1-{[2’-(5-oxo-4,5-dihydro-1,2,4-oxodiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimid azole-7-caboxylate and represented by formula I. It is marketed as azilsartan medoxomil potassium salt and is an angiotensin II receptor blocker indicated for the treatment of hypertension, to lower blood pressure.

Azilsartan medoxomil (I) and its salts were disclosed in patent US 7,157,584. Another patent US 7,572,920, in example 2, provides reaction of azilsartan (II) and 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (III) in presence of triethylamine, 2,4,6-trichlorobenzoyl chloride in tetrahydrofuran to give azilsartan medoxomil (I) in a yield of 50%. The process is depicted in scheme 1.

Scheme 1: Process for preparation of azilsartan medoxomil (I) as given in US 7,572,920.
Example 1 of patent US 7,572,920 describes reaction of disodium salt of azilsartan (II) and 4-chloromethyl-5-methyl-1,3-dioxol-2-one in dimethylformamide to give azilsartan medoxomil (I) in a 14% yield after purification using column chromatography.
Various routes involving multistep synthesis of Azilsartan Medoxomil are described in patent applications US 2013/317230, US 2014/113942, WO 2013/186792 and WO 2013/114305.
SUMMARY OF THE INVENTION
The present invention provides novel process for preparation of azilsartan medoxomil (I) which comprises:

a) reacting a nitro cyano compound (IV),

wherein R’ is H, alkyl, substituted alkyl, aryl, substituted aryl with hydroxylamine hydrochloride to form a nitro oxime compound (V)

b) cyclizing nitro oxime compound (V) to nitro oxadiazole compound (VI)

c) reducing nitro oxadiazole compound (VI) to amino oxadiazole (VII)

d) cyclizing amino oxadiazole compound (VII) to azilsartan ester (VIII)

e) converting azilsartan ester (VIII) to azilsartan (II) except when R’ is H, and

f) reacting azilsartan (II) with medoxomil compound (III), wherein R” is chloro, bromo, hydroxy or derivative thereof.

The process further comprises conversion of azilsartan medoxomil to its salts.
The present invention also provides novel compounds of formula (V), (VI) and (VII) for preparation of azilsartan medoxomil.

DETAILED DESCRIPTION OF THE INVENTION
In a preferred embodiment the present invention provides novel process for preparation of azilsartan medoxomil (I) and its salts comprising, (a) reacting nitro cyano compound (IV) with hydroxylamine hydrochloride to obtain nitro oxime compound (V), (b) cyclizing nitro oxime compound (V) to nitro oxadiazole compound (VI), (c) reducing nitro oxadiazole compound (VI) to amino oxadiazole compound (VII), (d) cyclizing amino oxadiazole compound (VII) to azilsartan ester (VIII), (e) converting it to azilsartan (II) and (f) esterification of azilsartan (II) with medoxomil compound (III).
In another embodiment the present invention provides novel compounds (V), (VI) and (VII). The present invention provides novel compound (V), wherein R’ is ethyl. The compound is characterized by following absorption in FT-IR spectrum (KBr pellet method), 1496, 1527, 1579, 1602, 1660, 1689, 3366, and 3494 cm-1. The compound (V), wherein R’ is ethyl, has a melting point of 130-135°C.
The present invention further provides novel compound (VI), wherein R’ is ethyl. The compound is characterized by following absorption in FT-IR spectrum (KBr pellet method), 1492, 1527, 1575, 1600, 1691, 1764, 3296 and 3496 cm-1. The compound (VI), wherein R’ is ethyl, has a melting point of 196-198°C.
The present invention still further provides novel compound (VII), wherein R’ is ethyl. The compound is characterized by following absorption in FT-IR spectrum (KBr pellet method), 1600, 1684, 1768, 3337 and 3428 cm-1.Nitro cyano compound (IV) can be synthesized by methods known in literature for e.g. US 6,355,808 and medoxomil compound (III) can be synthesized by methods known in literature, for e.g. Synthetic Communications, 22(9), 1277-82, 1992; EP 0078413; JP 2003064076 and WO 2008012852.
In the step (a) the nitro cyano compound (IV) is reacted with hydroxylamine hydrochloride in presence of solvent and a base to form nitro oxime compound (V). Solvent can be selected from polar solvents like alcohols, dimethylacetamide, dimethyl sulfoxide or mixture thereof; alcohol can be selected from methanol, ethanol, propanol, butanol and mixture thereof. Base can be selected form organic or inorganic base; organic base can be selected form alkyl amines like triethyl amine or tributyl amine etc. inorganic bases include hydroxide, alkoxides or carbonates, bicarbonates of alkali or alkaline earth metal like sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium carbonate, potassium carbonate, sodium bicarbonate etc.
The reaction of nitro cyano compound (IV) with hydroxylamine hydrochloride can be carried out at a temperature of 0 to 150°C, preferably 40 to 100°C, more preferably 80-90°C.
After the reaction, nitro oxime compound (V) can be isolated form the reaction mixture by techniques known in the art.
In step (b) cyclization of nitro oxime compound (V) to nitro oxadiazole compound (VI) can be carried out in presence of “carbonyl” source and a base.
The "carbonyl" source can be selected from compounds which can provide carbonyl moiety, such as N,N-carbonyldiimidazole, dialkyl carbonate, ethyl chloroformate, phosgene equivalents, alkyl and aryl carbodimides such as N,N-diisopropylcarbodimide, N,N dicyclohexyl carbodimide, diphenyl carbodimide, ditolyl carbodiimide and the like, preferably N,N-carbonyldiimidazole.
Base can be selected from inorganic or organic base. Inorganic base can be selected from carbonates or bicarbonates of alkali or alkaline earth metal like sodium carbonate, potassium carbonate, sodium bicarbonate etc. Organic base can be selected from alkyl amines like tritely amine, diisopropyl amine etc.; cyclic amines like 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
Step (b) can be carried out at a temperature of 0 to 50°C, preferably 25 to 30°C. After the reaction, the nitro oxadiazole compound (VI) can be isolated from the reaction mixture by techniques known in the art.
In step (c) the reduction of nitro oxadiazole compound (VI) to amino oxadiazole compound (VII) can be carried out using suitable reducing agents. Suitable reducing agents can be selected from stannous chloride, iron/hydrochloride acid, sodium hydrosulfite, tin (II) chloride, titanium (III) chloride, hydrazine hydrate; preferably stannous chloride. Reduction can also be carried out by catalytic hydrogenation using platinum oxide, Raney nickel, palladium on carbon etc.
The reduction can be carried out in a polar solvent selected form alcohol like methanol, ethanol, isopropanol, water; or an acid like acetic acid; or a non-polar solvent selected from toluene, cyclohexane, dioxane, chlorinated hydrocarbons like chloroform, methylene dichloride; or mixtures thereof; preferably alcohols.
The reduction of nitro oxadiazole compound (VI) can be carried out at a temperature of 0 to 100°C., preferably 25 to 90°C. After the reaction, the amino oxadiazole compound (VII) can be isolated from the reaction mixture by techniques known in the art.
In step (d) cyclization of amino oxadiazole compound (VII) to azilsartan ester (VIII) can be carried out using reagent like tetraethyl ortho carbonate in presence of catalytic amount of organic acid and optionally in presence of a solvent.
Organic acid may be selected from acetic acid, propionic acid, butyric acid or benzoic acid; preferably acetic acid.
Solvent may be selected from non-polar solvent like xylene, toluene or mixture thereof; polar aprotic solvent like ethyl acetate, dimethylformamide, dimethyl sulfoxide or mixtures thereof.
The reaction can be carried out at a temperature of 0 to 100°C, preferably 30 to 60°C. After the reaction, azilsartan ester (VIII) can be isolated form the reaction mixture by techniques known in the art.
In step (e), azilsartan ester (VIII), wherein R’ is alkyl or substituted alkyl, is hydrolyzed to azilsartan (II). The hydrolysis can be carried out with a base in presence of a solvent. Base can be selected from hydroxides of alkali or alkaline earth metal like sodium hydroxide, potassium hydroxide, lithium hydroxide etc. Solvent can be selected from water, alcohols like methanol, ethanol, isopropanol or mixtures thereof.
The hydrolysis of azilsartan ester (VIII) can be carried out at a temperature of 0 to 100°C., preferably 40 to 60°C. After the reaction, azilsartan (II) can be isolated from the reaction mixture by techniques known in the art.
Conversion of azilsartan ester (VIII), wherein R’ is aryl or aralkyl, to azilsartan (II) can be carried out by catalytic hydrogenation using palladium, platinum, rhodium etc. Alternatively reagents like Lewis acids e.g. AlCl3/anisole, trifluoroacetic acid/anisole can be used.
In step (f), the condensation of azilsartan (II) and medoxomil compound (III) wherein R” is hydroxy can be carried out by the methods described below.
The condensation reaction can be carried out in presence of a condensing agent like N, N'-dicyclohexylcarbodiimide (DCC) in presence of base; triphenylphosphine along with diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) i.e. Mitsunobu reagents.
In an alternate method azilsartan (II) is treated with an acylating agent in presence of a base to obtain acylated azilsartan which is then reacted with medoxomil compound (III), in presence of base.
The acylating agent can be selected from acetyl chloride, pivaloyl chloride, ethyl chloroformate, tert-butyl chloroformate, ethyl chlorocarbonate, isobutyl chlorocarbonate, 2,4,6-trichlorobenzoyl chloride, 2,6-dichlorobenzoyl chloride, di-tert-butyl dicarbonate and the like.
In another method azilsartan (II) is reacted with oxalyl chloride or thionyl chloride and then esterified with medoxomil compound (III) in presence of base.
In step (f) base can be selected from inorganic or organic base. Inorganic base can be selected from carbonates or bicarbonates of alkali or alkaline earth metal like sodium carbonate, potassium carbonate, sodium bicarbonate; or sodium hydride, potassium tert-butoxide. Organic base can be selected from alkyl amines like triethyl amine, diisopropyl amine or DBU, dimethylaminopyridine.
The reaction of azilsartan (II) with medoxomil compound (III) can be carried out in an solvent selected from chlorinated hydrocarbon like dichloromethane, chloroform, 1,2-dichloroethane; hydrocarbon solvent like xylene, toluene; ethyl acetate, tetrahydrofuran, dioxane, dimethyl formamide, dimethylacetamide, dimethyl sulfoxide or mixtures thereof.
In step (f), the esterification of azilsartan (II) and medoxomil compound (III) wherein R” is bromo or chloro can be carried out by the method described below.
Azilsartan (II) is converted to its salt and reacted with medoxomil compound (III, R” is bromo or chloro) in a solvent. The salt is selected from sodium, calcium, potassium, magnesium, barium, lithium, strontium, argentum and the like. The solvent is selected form dimethyl formamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran or mixtures thereof.
After the reaction, Azilsartan medoxomil (I) can be isolated form the reaction mixture by techniques known in the art.
Azilsartan medoxomil (I) can be converted to its corresponding salts by techniques known in the art. Salts can be selected from alkaline or alkali earth metals like Lithium, sodium, potassium, calcium, magnesium, barium etc.
The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.
EXAMPLES:
Example 1: Preparation of ethyl 2-(((2'-(N'-hydroxycarbamimidoyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-nitrobenzoate [Nitro oxime compound (V; R’=Et)]:
A mixture of ethyl 2-(((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)amino)-3-nitrobenzoate (100 g), hydroxylamine hydrochloride (143.7 g) and sodium bicarbonate (211 g) in isopropanol (3000 ml) was heated at 80-85°C for 12-20 hours. The reaction mixture was cooled to 5-10°C, the solid was filtered, washed with water and suck dried. The solid was leached in water, filtered and dried under vacuum. Yield: 84.7 g.
Example 2: Preparation of ethyl 3-amino-2-(((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-yl)methyl)amino)benzoate [Nitro oxadiazole compound (VI; R’=Et)]:
A mixture of ethyl 2-(((2'-(N'-hydroxycarbamimidoyl)-[1,1'-biphenyl]-4-yl)methyl)amino)-3-nitrobenzoate (90 g) of example 1, N,N-carbonyldiimidazole (50.4 g) and DBU (47.3 g) in methylene dichloride (1080 ml) was stirred at 20-30°C for 1 hour. The reaction mixture was filtered and the filtrate was cooled to 10-15°C. The pH of the filtrate was adjusted to 0.5 to 1.0 by 1N HCl solution. The solid was filtered, washed with methylene dichloride and dried. The solid was leached in water, filtered and dried under vacuum. Yield: 66.6 g
Example 3: Preparation of 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzoimidazole-7-carboxylic acid [Amino oxadiazole compound (VII; R’=Et)]:
A mixture of ethyl 3-amino-2-(((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-yl)methyl)amino)benzoate (5 g) of example 2 and stannous chloride in isopropanol was stirred at 25-30°C for 1 hour and then heated to 80-85°C for 1 hour. The solvent was distilled out under vacuum and ethyl acetate (150 ml) was added to the residue, followed by addition of 2N NaOH solution (250 ml). The organic layer was separated and the aqueous layer was washed with ethyl acetate. The organic layers are combined and ethyl acetate was distilled out under vacuum. To the residue was added n-hexane (25 ml) and the mixture was stirred at 25-30°C for 15 mins. The solid was filtered, washed with n-hexane and dried under vacuum. Yield: 3.1 g.
Example 4: Preparation of ethyl 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzoimidazole-7-carboxylate [Azilsartan ester (VIII; R’=Et)]:
A mixture of 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzoimidazole-7-carboxylic acid (3 g) of example 3, tetraethyl orthocarbonate (7.5 ml) and acetic acid (0.58 ml) was heated at 50-55°C for 1 to 2 hours. To the reaction mixture was added ethyl acetate (15 ml) and cooled to 0-5°C. The solid was filtered, washed with cold ethyl acetate and dried under vacuum. Yield: 2.4 g.
Example 5: Preparation of Azilsartan (II):
A mixture of ethyl 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzoimidazole-7-carboxylate (2 g) and 0.4 N NaOH solution (30 ml) was heated at 70-75°C for 2 hours. The reaction mixture was cooled to 25-30°C and filtered. The filtrate was heated to 50-55°C and pH was adjusted to 2-3 using 0.5 N HCl solution. The mixture was cooled to 25-30°C, the solid filtered and washed with water and dried. The solid was leached in water, filtered and dried under vacuum. Yield: 1.4 g.
Example 5: preparation of azilsartan medoxomil (I):
A mixture of 2-ethoxy-1-[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl-1H-benzimidazole-7-carboxylic acid (200 g), DCC (90.4 g), dimethyl amino pyridine (2 g) and 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (57 g) in ethyl acetate (1800 ml) was stirred at 15-20°C for 20 hours. To the reaction mixture was added water (8 ml), cooled to 0-5°C and filtered. To the solid was added methylene dichloride (7000 ml) and heated to 35-40°C and then cooled to 25-30°C. The mixture was filtered and the filtrate was washed with 5% NaHCO3 solution (1000 ml) and then with water (1000 ml). The organic layer was distilled and to the residue was added acetonitrile (400 ml). The mixture was heated to 75-85°C for 30 minutes and then cooled to 25-30°C, filtered and the solid washed with acetonitrile. The solid was recrystallized from acetone. To the solid was added water (770 ml) and heated at 45-50° for 30 minutes, then cooled to 25-30°C, the solid was filtered, washed with water and dried under vacuum. Yield: 129.1 g.
,CLAIMS:1. A process for preparation of azilsartan (II) which comprises:

a) reacting a nitro cyano compound (IV),

wherein R’ is H, alkyl, substituted alkyl, aryl, substituted aryl with hydroxylamine hydrochloride to form a nitro oxime compound (V)

b) cyclizing nitro oxime compound (V) to nitro oxadiazole compound (VI)

c) reducing nitro oxadiazole compound (VI) to amino oxadiazole (VII)

d) cyclizing amino oxadiazole compound (VII) to azilsartan ester (VIII), and

e) converting azilsartan ester (VIII) to azilsartan (II) except when R’ is H.
2. The process according to claim 1 wherein, in step (a) nitro cyano compound (IV) is reacted with hydroxylamine hydrochloride in presence of solvent and a base.
3. The process according to claim 2 wherein, solvent is selected from polar solvents like alcohols, dimethylacetamide, dimethyl sulfoxide or mixture thereof; alcohol is selected from methanol, ethanol, propanol, butanol and mixture thereof.
4. The process according to claim 2 wherein, base is selected form organic or inorganic base; organic base is selected form alkyl amines like triethyl amine or tributyl amine; inorganic bases include hydroxide, alkoxides or carbonates, bicarbonates of alkali or alkaline earth metal like sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium carbonate, potassium carbonate, sodium bicarbonate.
5. The process according to claim 1 wherein, in step (b) cyclization of nitro oxime compound (V) to nitro oxadiazole compound (VI) is carried out in presence of “carbonyl” source and a base.
6. The process according to claim 5 wherein, "carbonyl" source is selected from compounds which can provide carbonyl moiety, such as N,N-carbonyldiimidazole, dialkyl carbonate, ethyl chloroformate, phosgene equivalents, alkyl and aryl carbodimides such as N,N-diisopropylcarbodimide, N,N dicyclohexyl carbodimide, diphenyl carbodimide, ditolyl carbodiimide.
7. The process according to claim 5 wherein, base is selected from inorganic or organic base; inorganic base is selected from carbonates or bicarbonates of alkali or alkaline earth metal like sodium carbonate, potassium carbonate, sodium bicarbonate; organic base is selected from alkyl amines like tritely amine, diisopropyl amine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
8. The process according to claim 1 wherein, in step (c) the reduction of nitro oxadiazole compound (VI) to amino oxadiazole compound (VII) is carried out using suitable reducing agents.
9. The process according to claim 8 wherein, reducing agents is selected from stannous chloride, iron/hydrochloride acid, sodium hydrosulfite, tin (II) chloride, titanium (III) chloride, hydrazine hydrate, catalytic hydrogenation using platinum oxide, Raney nickel, palladium on carbon.
10. The process according to claim 1 wherein, in step (d) cyclization of amino oxadiazole compound (VII) to azilsartan ester (VIII) is carried out using reagent tetraethyl ortho carbonate in presence of catalytic amount of organic acid and optionally in presence of a solvent.
11. The process according to claim 10 wherein, organic acid is selected from acetic acid, propionic acid, butyric acid or benzoic acid.
12. The process according to claim 10 wherein, solvent is selected from non-polar solvent like xylene, toluene or mixture thereof; polar aprotic solvent like ethyl acetate, dimethylformamide, dimethyl sulfoxide or mixtures thereof.
13. The process according to claim 1 wherein, in step (e), azilsartan ester (VIII), wherein R’ is alkyl or substituted alkyl, is converted to azilsartan (II) by hydrolysis.
14. The process according to claim 13 wherein, hydrolysis is carried out with a base in presence of a solvent.
15. The process according to claim 14 wherein, base is selected from hydroxides of alkali or alkaline earth metal like sodium hydroxide, potassium hydroxide, lithium hydroxide.
16. The process according to claim 14 wherein, solvent is selected from water, alcohols like methanol, ethanol, isopropanol or mixtures thereof.
17. The process of claim 1, further comprising:
f) reacting azilsartan (II) with medoxomil compound (III), wherein R” is chloro, bromo, hydroxy or derivative thereof, to obtain azilsartan medoxomil (I)

g) optionally converting azilsartan medoxomil (I) to its salts.
18. The process according to claim 17 wherein, reaction of azilsartan (II) with medoxomil compound (III), is carried out in presence of a condensing agent like N, N'-dicyclohexylcarbodiimide in presence of base; triphenylphosphine along with diethyl azodicarboxylate or diisopropyl azodicarboxylate.
19. The process according to claim 17 wherein, azilsartan (II) is treated with an acylating agent in presence to of a base, to obtain acylated azilsartan which is then reacted with medoxomil compound (III), in presence of base.
20. The process according to claim 19 wherein, acylating agent is selected from acetyl chloride, pivaloyl chloride, ethyl chloroformate, tert-butyl chloroformate, ethyl chlorocarbonate, isobutyl chlorocarbonate, 2,4,6-trichlorobenzoyl chloride, 2,6-dichlorobenzoyl chloride, di-tert-butyl dicarbonate .
21. The process according to claim 17 wherein, azilsartan (II) is reacted with oxalyl chloride or thionyl chloride and then condensed with medoxomil compound (III) in presence of base.
22. The process according to claims 18, 19 and 21 wherein, base is selected from inorganic or organic base; inorganic base is selected from carbonates or bicarbonates of alkali or alkaline earth metal like sodium carbonate, potassium carbonate, sodium bicarbonate; or sodium hydride, potassium tert-butoxide; organic base is selected from alkyl amines like triethyl amine, diisopropyl amine or DBU, dimethylaminopyridine.
23. The process according to claim 17 wherein, salt is selected from sodium, calcium, potassium, magnesium, barium, lithium, strontium or argentum.
24. A compound of formula (V), wherein R’ is ethyl.

25. A compound of formula (VI), wherein R’ is ethyl.

26. A compound of formula (VII), wherein R’ is ethyl.