WO2014049512A2

WO2014049512A2 - Novel process for preparation of azilsartan medoxomil

Info

Publication number: WO2014049512A2
Application number: PCT/IB2013/058766
Authority: WO
Inventors: Shahid Akhtar Ansari; Hitin Maganbhai HIRPARA; Nikhil Shashikant BHATT; Reenaben Ratansing Baria; Ashok Keshavlal YADAV; Manishkumar Baldevlal PATEL
Original assignee: Lupin Limited
Priority date: 2012-09-26
Filing date: 2013-09-23
Publication date: 2014-04-03
Also published as: WO2014049512A3

Abstract

The present invention provides novel process for preparation of azilsartan medoxomil (II) comprising coupling of azilsartan (I) and 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (VII) in presence of carbonyl compound, R₃COR₄, wherein substituents R₃ and R₄ represent a heterocyclic ring selected from imidazole, benzimidazole, triazole; or in presence of carbodiimides and base wherein carbodiimide is selected from dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-[3-(dimethyl-amino) propyl]-N'- ethylcarbodiimide. The present invention further provides novel Form I of azilsartan kamedoxomil.

Description

NOVEL PROCESS FOR PREPARATION OF AZILSARTAN MEDOXOMIL FIELD OF INVENTION

The present invention provides novel process for preparation of azilsartan (I) and azilsartan medoxomil (II).

BACKGROUND OF THE INVENTION

Azilsartan,represented by formula (I), is a selective ATI subtype angiotensin II receptor antagonist and used for the treatment of hypertension. Azilsartan (I) is administrated as azilsartan medoxomilwhich is a prodrug and chemically known as (5-methyl-2-oxo-l,3- dioxol-4-yl)methyl-2-ethoxy-l-{ [2'-(5-oxo-4,5-dihydro-l,2,4-oxodiazol-3-yl)biphenyl-4- yl]methyl}-lH-benzimidazole-7-caboxylate and represented by formula II.

Azilsartan (I) was first disclosed in US 5,354,766 while azilsartanmedoxomil (I) and its salts were disclosed in patents US 7,157,584. The patent US 5,354,766 provides process for preparation of azilsartan ester (VI; Ri=Me) as depicted in scheme 1, wherein oxime compound (III;Ri=Me) is reacted with ClCOOR₂(IV; R₂=Et) to give oxime derivative (V; Ri=Me; R₂=Et) followed by cyclization in xylene at reflux temperature.The crude azilsartan ester (VI; Ri=Me) is purified by column chromatography and obtained in 23% yield. Pure azilsartan ester (VI; Ri=Me) is hydrolyzed with lithium hydroxide to give azilsartan (I).

(VI)

Scheme 1: Process for preparation of azilsartan (I) as given in US 5,354,766

The patent US 5,354,766also provides alternate process for preparation of azilsartan ester (VI; Ri=Me) wherein the cyclization of oxime derivative(V; Ri=Me; R2=Et) is carried out in presence of a base DBU and solvent ethylacetate followed bycrystallization from chloroform-ethyl acetate mixturein 45% yield.

Another reference Kohara et al, Bioorganic & medicinal chemistry letters, 5, 17, 1903- 1908, 1995, describes similar processes for preparation of azilsartan (I), as depicted in scheme 1.

Example 2 of US 7,572,920 provides reaction of azilsartan (I) and 4-hydroxymethyl-5- methyl-l,3-dioxol-2-one (VII) in presence of triethylamine, 2,4,6-trichlorobenzoyl chloride in THF to give azilsartan medoxomil (II) in a yield of 50%. Example 1 of US 7,572,920 describes reaction of disodium salt of azilsartan and 4-chloromethyl-5-methyl- l,3-dioxol-2-one in DMF to give azilsartan medoxomil (II) in a 14% yield after purification using column chromatography.

(VII)

The patent US 7,572,920 alsomentions condensation of azilsartan (I) and compound (VII) in presence of 1-3 moles of condensing agent like DCC, in anorganic solvent at about - 30°C to refluxing temperature for about half an hour to 24 hours, however enabling disclosure is not provided.In our hand, when this process was employed for condensation of azilsartan (I) with compound (VII) using DCC in ethyl acetate at 25-30°C for 3.5 to 20 hours, product formation was negligible and the reaction was incomplete along withvery high impurity formation. When we carried out this reaction in presence of base surprisingly we observed that reaction was complete and impurities were controlled.

The PCT application WO 2012/107814 provides process for preparation of azilsartan ester (VI; Ri=Me) wherein oxime compound (III; Ri=Me) is reacted with a carbonyl source such as carbonyldiimidazole, dialkyl carbonate, phosgene equivalents etc followed by in-situ cyclization of the intermediate. The application also provides preparation of azilsartan medoxomil (II) wherein azilsartan (I) reacts with 4-hydroxymethyl-5-methyl- l,3-dioxol-2-one (VII) in presence of p-toluoylsulfonylchloride, 4-dimethylaminopyridine and potassium carbonate in dimethylacetamide.

Another PCT application WO 2012/090043 provides various crystalline forms,J₂ to J₉, amorphous forms of azilsartan medoxomil and process for their preparation.

The present invention provides novel process for preparation of high purityazilsartan medoxomil (II) and azilsartan kamedoxomil which is simple and economical. BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

Figure 1 : X-ray powder diffraction pattern of azilsartan.

Figure 2: X-ray powder diffraction pattern of azilsartan kamedoxomil crystalline Form I.

SUMMARY OF THE INVENTION The present invention provides novel process for preparation of azilsartan (I) comprising cyclization of oxime derivative of formula (V) to azilsartan ester (VI)

whereinRi and R₂ are protecting group, selected from alkyl, aralkyl, phenyl, substituted phenyl etc., in presence of a base without a solvent and followed by hydrolysis.

The present invention also relates to novel process for preparation of azilsartan medoxomil (II) comprising reaction of azilsartan (I) anddioxolonecompound (VII)

(I) (II) (VI I) in presence of carbonyl compound R₃COR_4i wherein R₃ and R₄ could be same or different andrepresent a heterocyclic ring which can be optionally substituted;or carbodiimides such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-[3-(dimethyl-amino) propyl] -N'-ethylcarbodiimide etc.

DETAILED DESCRIPTION OF THE INVENTION

In a preferred embodiment the present invention provides process for preparation of azilsartan (I) comprising cyclization of compound (V) to azilsartan ester (VI) wherein Ri and R₂ are protecting group, selected from alkyl, aralkyl, phenyl, substituted phenyl etc., in presence of a base without a solvent and followed by hydrolysis.

The base is an organic base selected from DBU, DBN, pyridine, dimethylaminopyridine,dibutyl amine, triethyl amine, tributyl amine etc., preferably dibutylamine.

The reaction is carried out at a temperature of 0-150°C, preferably50-150°C, most preferably 80-120°C.

The azilsartan ester (VI) is hydrolyzed using inorganic base like alkali or alkaline earth metals hydroxides selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide etc.

Hydrolysis is carried out in a solvent selected from water or polar solvent selected from nitriles such as acetonitrile, propionitrile etc.; ether such as tetrahydrofuran, dioxan etc.; alcohols such as methanol, ethanol, propanol etc.; ketones such as acetone, methyl ethyl ketone etc., amides such as dimethylformamide, dimethylacetamide, N-methyl pyrrolidone etc., or mixtures thereof.

Hydrolysis is carried out at a temperature of 0-100°C, preferably 50-70°C.

Azilsartan (I) obtained by the present invention exhibit an X-ray powder diffraction patternas depicted inFigure 1. It shows characteristic peaks at 9.17, 12.78, 18.72, 19.39, 21.51, 23.58 ±°2Theta. In another embodiment, the present invention provides novel process for preparation of azilsartanmedoxomil (II) comprising coupling of azilsartan (I) and dioxolonecompound (Vll)in presence of carbonyl compound R₃COR_4, wherein substituents R₃ and R₄ could be same or different andrepresent a heterocyclic ring which can be optionally substituted; the heterocyclic ring system could be selected from imidazole, benzimidazole, triazole etc.; preferably imidazole;

In yet another embodiment, the present invention provides novel process for preparation of azilsartanmedoxomil (II) comprising coupling of azilsartan (I) anddioxolone compound (VII) in presence of carbodiimides and base.

The carbodiimide is selected from dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-[3-(dimethyl-amino) propyl]-N'-ethylcarbodiimide and the like.

The base is an organic base selected from DBU, DBN, pyridine, dimethylaminopyridine, dibutyl amine, triethyl amine, tributyl amine etc., or an inorganic base selected sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate etc.

The coupling reaction can be carried out in solvent is selected form esters such as ethyl acetate, butyl acetate etc.; chlorinated hydrocarbons such as dichlorome thane, chloroform, ethylene dichloride etc.; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone etc., nitriles such as acetonitrile, propionitrile etc.; ether such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxan etc.; alcohols such as tert- butyl alcohol etc.; amides such as dimethylformamide, dimethylacetamide, N-methyl pyrrolidone etc.; dimethyl sulfoxide, sulfolane; aromatic hydrocarbons such as benzene, toluene, xylene etc.; or mixtures thereof; preferably ethylacetate anddichloromethane.

The coupling reaction is carried out at a temperature of 0 to 100°C, preferably 10-50°C.

In the coupling reaction, the dioxolonecompound (VII), carbonyl compoundR₃COR₄or carbodiimidecan be employed in the range of 1.0 to 2.0 molar equivalent of azilsartan (I), preferably in the range of 1 to 1.5 molar equivalent. In an embodiment the invention provides a process for preparation of Form I of azilsartan kamedoxomil comprising the steps of a) dissolving azilsartan medoxomil in acetone by heating, b) cooling the solution of step (a) to 0-5°C, c) adding a solution of potassium source in acetone, d) stirring the mixture at 0-5°C, and e) isolation of Form I of azilsartan kamedoxomil. Azilsartan medoxomil (II) can be converted to its corresponding potassium salt by treating with potassium source like potassium hydroxide, potassium carbonate, potassium acetate, potassium 2-ethyl hexanoate etc.

Azilsartan (I), azilsartan medoxomil (II) and azilsartan kamedoxomil can be isolated from the reaction mixture by techniques known in art like filtration, concentration, evaporation of the solvent etc.

Azilsartan kamedoxomil obtained by the present invention exhibit an X-ray powder diffraction patternas depicted in Figure 2 and is referred as Form I.

The X-ray diffraction pattern of Form I shows characteristic peaks at 5.99, 6.28, 13.44, 14.14, 14.57, 14.82, 16.08, 18.80, 20.38, 22.85, 23.87 ±°2Theta. The IR spectrum of Form I exhibit following bands: 1821, 1709, 1668, 1617, 1552, 1457, 1429, 1393, 1324, 1279, 1248, 1229, 1213, 1153, 1128, 1039, 1009, 992, 870, 801, 754, 738 and 687 cm^"1.

The Differential Scanning Calorimetry of Form I exhibit two endothermic peaks at 209 and 233°C. The present invention provides azilsartan kamedoxomil with purity of > 99.5%, with azilsartan (I) content of less than 0.25% and any other individual impurity less than 0.1% by HPLC.

The manufacture of azilsartan medoxomil (II) as per the process of present invention has the following advantages over the prior art methods: 1. Simple process, 2. Cost-effective,

3. Provides azilsartan medoxomil and azilsartan kamedoxomil with high purity.

The present invention is further illustrated by the following representative examples and does not limit the scope of the invention. EXAMPLES

The X-ray diffraction pattern was measured using PANalytical, X'pert PRO machine with following parameters:

Scan axis: Gonio

Step size: 0.0083°

Scan mode: continuous

Anode material: Cu

Radiation type" K-alpha 1

Scan angle (°): 3.5 to 39.98.

Example 1: preparation of azilsartan ester (VI; Ri=Et): A mixture of ethyl 2-ethoxy-l-((2'-(N'-((ethoxycarbonyl)oxy)carbamimidoyl)-[biphenyl]- 4-yl)methyl)-lH-benzoimidazole-7-carboxylate (compound V; Ri= R2=ethyl) (5 g), and dibutyl amine (30 ml) was heated at 110-115°C for 2 hours. The reaction mixture cooled to 25-30°C and stirred for one hour. The solid was filtered, washed with ethyl acetate and dried. Yield: 4.3 g. Example 2: preparation of azilsartan (I):

A mixture of azilsartan ester (VI; Ri= Et) (25 g) and 0.4 N NaOH solution (380 ml) was heated at 70-75°C for 90 minutes. The reaction mixture was cooled to 10-15°C and the pH was adjusted to 2.5-3.0 with 2 N HC1. The mixture was stirred for 30 minutes at 10- 15°C. The solid was filtered, washed with water (100 ml) and dried under vacuum. Yield: 22.0 g;X-ray powder diffraction pattern as depicted in figure 1. Example 3: preparation of azilsartan medoxomil (II):

A mixture of azilsartan (I) (100 g), 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one (VII) (40.68 g ), Ν,Ν'- dicyclohexylcarbodiimide (45.20 g),dimethyl aminopyridine (1.0 g) in ethylacetate (1000 ml) was stirred at 15-20°C for 18-20 hours. The reaction mixture was filtered. The filtrate was washed with 5% sodium bicarbonate (500 ml) and was concentrated under vacuum. Acetonitrile (230 ml) was added to the residue and heated at 78-80°C for 30 minutes. The mixture was cooled to 5-10°C and stirred for 30 minutes. The solid was filtered, washed with acetonitrile and dried under vacuum. Yield: 92 g; HPLC purity: 99.43%. Example 4: preparation of azilsartan medoxomil (II):

A mixture of azilsartan (I) (5 g), 1, -carbonyldiimidazole (2.65 g) and dichloromethane (100 ml) was stirred at 25-30°C for 60 minutes. 4-(hydroxymethyl)-5-methyl-l,3-dioxol- 2-one (2.85 g) was added and stirred for 4 hours at 25-30°C. The reaction mixture was heated at 40-42°C for about 16 hours. The reaction mixture was cooled and 1% HC1 solution (25 ml) was added. The precipitated solid was filtered. The organic layer was separated and washed with 5% sodium bicarbonate solution. The organic layer was concentrated under vacuum and acetonitrile (10 ml) was added to the residue. The mixture was stirred for 30 minutes at 5-10°C. The solid was filtered, washed with acetonitrile and dried under vacuum to obtain azilsartan medoxomil. Yield: 1.2g. Example 5: preparation of azilsartan kamedoxomil:

A mixture of azilsartan medoxomil (II) (5 g) and acetone (91 ml) was heated at 45-50°C for 15 minutes and then cooled to 0-5°C. A solution of potassium 2-ethyl hexanoate (1.54 g) in acetone (18 ml) was added. The reaction mixture was stirred for 17 hours at 0-5°C. The solid was filtered and dried under vacuum. Yield: 3.2 g; HPLC purity: 99.57%; Melting point: 200-205°C; X-ray powder diffraction pattern as depicted in figure 2.

Example 6: preparation of azilsartan medoxomil (II) as described in US 7,572,920:

A mixture of azilsartan (I) (20 g), 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one (VII) (8.13 g )], Ν,Ν'- dicyclohexylcarbodiimide (9.94 g) in ethylacetate (200 ml) was stirred at 25-30°C for 18-20 hours.The reaction mixture was filtered. The filtrate was washed with 5% sodium bicarbonate (100 ml) and was concentrated under vacuum. Acetonitrile (18.5 ml) was added to the residue and heated at 78-80°C for 30 minutes. The mixture was cooled to 5-10°C. The solid was filtered, washed with acetonitrile and dried under vacuum. Yield: 7.8 g; HPLC analysis of the isolated solid indicates azilsartan medoxomil content upto 0.53% only.

Claims

WE CLAIM

1. A process for preparation of azilsartan medoxomil (II) comprising coupling of azilsartan I) and dioxolone compound (VII)

in presence of carbonyl compound R₃COR_4, wherein substituents R₃ and R4 could be same or different andrepresent a heterocyclic ring which can be optionally substituted.

2. A process according to claim 1, wherein the heterocyclic ring system could be selected from imidazole, benzimidazole, triazole.

3. A process for preparation of azilsartan medoxomil (II) comprising coupling of azilsartan (I) and dioxolone compound (VII) in presence of carbodiimides and base.

4. A process according to claim 3, whereincarbodiimide is selected from dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-[3-(dimethyl-amino) propyl] -N ' -ethylcarbodiimide .

5. A process according to claim 1 or 3, wherein coupling reaction can be carried out in solvent selected form ethyl acetate, butyl acetate, dichloromethane, chloroform, ethylene dichloride, acetone, methyl ethyl ketone, methyl isobutyl ketone,acetonitrile, propionitrile, diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxin,tert-butyl alcohol, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, dimethyl sulfoxide, sulfolane,benzene, toluene, xylene or mixtures thereof. 6. A process according to claim 5, wherein coupling reaction can be carried out inethylacetate or dichloromethane.

7. A process according to claim 3, whereincoupling reaction can be carried out inorganic base selected from DBU, DBN, pyridine, dimethylaminopyridine, dibutyl amine, triethyl amine, tributyl amine or inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate.

8. A process according to claim 1 or 3, wherein coupling reaction can be carried outat a temperature of 0 to 100°C.

9. A process according to claim 1 or 3, whereinin the coupling reaction, azilsartan (I) and carbonyl compound R₃COR₄ or carbodiimide can be employed in the range of 1.0 to 2.0 molar equivalent.

10. A process for preparation of Azilsartan (I) comprising cyclization of compound (V) to azilsartan ester (VI)

(V) (VI)

wherein Ri and R₂ are protecting group, selected from alkyl, aralkyl, phenyl, substituted phenyl;in presence of a base without a solvent and followed by hydrolysis.

The process according to claim 10, wherein the reaction is carried out in presence of base selected from DBU, DBN, pyridine, dimethylaminopyridine, dibutyl amine, triethyl amine, tributyl amine.

12. The process according to claim 10, wherein the reaction is carried out in presence of base dibutylamine.

13. The process according to claim 10, wherein hydrolysis of azilsartan ester (VI) is carried out using inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide.

The process according to claim 10, wherein hydrolysis of azilsartan ester (VI) is carried out in a solvent selected from water or polar solventselected from acetonitrile, propionitrile,tetrahydrofuran, dioxin, methanol, ethanol, propanol, acetone, methyl ethyl ketone, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone or mixtures thereof.

15. A process according to claim 1 or 3, further comprising reaction of azilsartan medoxomil (II) with potassium source to obtain azilsartan kamedoxomii. 16. A process according to claim 15, wherein potassium source is selected from potassium hydroxide, potassium carbonate, potassium acetate, potassium 2-ethyl hexanoate.

17. Form I of azilsartan kamedoxomii that exhibits an X-ray diffraction pattern as depicted in figure 2.

18. Form I of azilsartan kamedoxomii according to claim 17, wherein the X-ray diffraction pattern has characteristic peaks at 5.99, 6.28, 13.44, 14.14, 14.57,

14.82, 16.08, 18.80, 20.38, 22.85, 23.87 ±°2Theta.

19. A process for preparation of Form I of azilsartan kamedoxomii comprising:

f) dissolving azilsartan medoxomil in acetone by heating,

g) cooling the solution of step (a) to 0-5°C,

h) adding a solution of potassium source in acetone,

i) stirring the mixture at 0-5°C, and

j) isolation of Form I of azilsartan kamedoxomii.

20. A process according to claim 19, wherein potassium source is selected from potassium hydroxide, potassium carbonate, potassium acetate, potassium 2-ethyl hexanoate.