This application claims priority to Indian patent application numbered 2243/CHE/2011 filed on Jul 01, 2011 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of intermediate compounds of Candesartan and its further conversion to Candesartan Cilexetil. In particular, the present invention relates to a process for the preparation of 3-(2'-substituted biphenyl-4-ylmethyl)-2-ethoxy-3H-benzimidazole-4-carboxylic acid derivatives.

BACKGROUND OF THE INVENTION:

Candesartan Cilexetil, the prodrug of Candesartan, is a potent, long lasting, selective ATI subtype angiotensin II receptor antagonist. The chemical name of Candesartan Cilexetil is: (±)-1 -Hydroxyethyl 2-ethoxy-l-\p-(p-\Htetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate, and has the following structure.
Several processes were known in the prior art to prepare Candesartan.

The product patent EP 0459136B1 discloses a process, wherein Candesartan is prepared by the alkylation of one molar proportion of 2-ethoxy-3H-benzimidazole-4-carboxylic acid derivative with 1 to 3 moles of 4'-halomethyl-biphenyl-2-carbonitrile compound in presence of 1 to 3 moles of a base. The reaction was conventionally conducted in solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile.

tetrahydrofuran, acetone, ethylmethylketone, and the like. Also the bases used include Sodium hydride, Potassium t-butoxide, Potassium carbonate and sodium carbonate.

The EP 0459136B1 also discloses an alternative process to prepare candesartan, in which ethyl 3-amino-2-N-[2'-cyanobiphenyl-4-yl)methyl]aminobenzoate is reacted with ethyl ortho carbonate in acetic acid to produce ethyl l-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate which on treatment with trimethyltin azide in toluene gives Candesartan.

EP 1764365B1 patent discloses preparation of candesartan, which involves cross coupling reaction of 2-cyano phenyl boronic acid with p-halo benzyl-IH-imidazole derivatives in presence of a transition metal catalyst and an organic or inorganic base.

The resulting cyano compound was later converted to its tetrazole derivative to form Candesartan.

WO 2006015134 patent application discloses an alternative process, which involves protection of tetrazole group of candesartan with trialkyl silyl halide and condensation of the protected compound with Cyclohexyl 1-haloethyl carbonate, to give trialkyl silyl protected Candesartan Cilexetil followed by deprotection to yield Candesartan Cilexetil.

Though there are exists several processes to prepare candesartan, still there is a need to develop a commercially viable process.

OBJECT AND SUMMARY OF THE INVENTION:

The main object of the present invention is to provide a novel process for the preparation of intermediate compounds of Candesartan.

Another object of the present invention is to provide, a novel process for the preparation of 3-(2'-substituted biphenyl-4-ylmethyl)-2-ethoxy-3H-benzimidazole-4-carboxylic acid derivatives.

Yet, another object of the present invention is to provide an improved process for the preparation of Candesartan Cilexetil.

In achieving the above objects of the present invention, a process was developed for the preparation of 3-(2'-substituted biphenyl-4-ylmethyl)-2-ethoxy-3H-benzimidazole-4-carboxylic acid derivatives by condensing 2-ethoxy-3H-benzimidazole-4-carboxylic acid derivative with 2-substituted 4'-halomethyl-biphenyl compounds in presence of phase transfer catalyst, and a base in an organic solvent.

DETAILED DESCRIPTION OF THE INVENTION:

The invention can be more readily understood through reading of the following detailed description of the invention and study of the included examples.

One aspect of the present invention provides a process for the preparation of 3-(2'-substituted biphenyl-4-ylmethyl)-2-ethoxy-3H-benzimidazole-4-carboxylic acid derivatives.

Accordingly, one aspect of the present invention provides a process for the preparation of 3-(2'-substituted biphenyl-4-ylmethyl)-2-ethoxy-3H-benzimidazole-4-carboxylic acid derivatives, by condensing 2-Ethoxy-3H-benzimidazole-4-carboxylic acid derivative with 2-substituted 4'-halomethyl-biphenyl compounds in presence of phase transfer catalyst, and a base in an organic solvent as depicted in Scheme I.

SCHEME I

One embodiment of the present invention provides, condensation of compound of formula (I) wherein Ri is selected from Hydrogen, methyl, ethyl, tert-butyl, Cyclohexyl ethyl carbonate, preferably, ethyl with compound of formula (II), wherein R2 is selected from Cyano, tetrazol, triphenyl protected tetrazol, trialkyl silyl protected tetrazol, preferably, Cyano or triphenyl protected tetrazol in presence of a base. The base may be selected from organic or inorganic bases. Organic bases may include triethyl amine, diisopropylethylamine, pyridine, N,N-dimethylaniline, N-methyl-morpholine. Inorganic bases may include alkaline metal carbonates, alkaline earth metal carbonates, alkaline metal hydroxides, alkaline earth metal hydroxides. Alkaline metal carbonates may be selected from Lithium carbonate, sodium carbonate, potassium carbonate. Alkaline earth metal carbonates may be selected from. Magnesium carbonate. Calcium carbonate, Barium carbonate. Alkaline metal hydroxides may be selected from, Lithium hydroxide. Sodium hydroxide. Potassium hydroxide, preferably. Sodium hydroxide. Alkaline earth metal hydroxides may be selected from. Magnesium hydroxide. Calcium hydroxide, Barium hydroxide.

The condensation of compound of formula (I) with compound of formula (II) is carried out in a solvent. The solvent can be selected from polar and non-polar solvents or mixtures thereof. Polar solvents may include water, Methanol, Ethanol, 1-propanol, 2-propanol, butanol. Acetone, Acetonitrile, Ethyl acetate. Dimethyl formamide, Dimethyl sulfoxide, preferably water. Non-Polar solvents may include Toluene, Xylene, Benzene,
Cyclohexane, Hexane, preferably Toluene. The most preferable solvent system is a mixture of water and toluene. The condensation of compound of formula (I) with compound of formula (II) can also be carried out in presence of phase transfer catalyst.

The phase transfer catalyst may be selected from tetrabutylammonium bromide, tetrabutylammonium hydrogensulfate, benzyltriethylammonium chloride, tetra-n-butylammonium chloride, tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide, benzyltributylammonium bromide, benzyltriethylammonium bromide, tetramethylammonium chloride, preferably tetrabutylammonium bromide.

A particular embodiment of the present invention, provides process for the preparation of Candesartan Cilexetil from compound of formula (III), wherein Ri: is selected from methyl, ethyl, tert-butyl; R2:is selected from cyano; by the following scheme.

Compound of formula III, 3-(2'-cyano-biphenyl-4-ylmethyl)-2-ethoxy-3H-benzimidazol-4-carboxylic acid alkyl ester (formula III, wherein Ri is selected from methyl, ethyl, tert-butyl; R2 is cyano) is converted to Candesartan cilexetil by reacting with sodium azide and tributyltin chloride in presence of a solvent to produce 2-ethoxy-l-{[2'-(lH-tetrazol-5-yl) [1, r-biphenyl]-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid alkyl ester and subsequent hydrolysis followed by protection with Trityl chloride and reaction with Cyclohexyl 1-haloethyl carbonate and deprotection of Tetrazol group. The deprotection of Tetrazole group can be carried out by the prior art processes mentioned in EP 0459136B1,EP1685126BI.

One more embodiment of the present invention provides process for the preparation of Candesartan Cilexetil from compound of formula (III), wherein R\ is selected from methyl, ethyl, tert-butyl; R2 is selected from tetrazole, protected tetrazole; by hydrolyzing the ester group and treating with Cyclohexyl 1-haloethyl carbonate. In the sequence of these reactions, if desired, deprotection of the respective group can be deprotected for example the protected tetrazole group can be deprotected to tetrazole group to get the desired compound by following the prior art processes, as mentioned in EP 0459136BI, EP 1685126B1.

The starting materials of the present invention are prepared according to the following scheme.

In one embodiment of the present invention, 3-nitrophthalic anhydride was prepared from 3-nitrophthalic acid using acetic anhydride as per the process disclosed in WO 2007/006566.

In another embodiment of the present invention, 3-nitrophthalamic acid was prepared from 3-nitrophthalic anhydride using aqueous ammonia as per the process disclosed in WO 2007/006566.

In another embodiment of the present invention, 2-amino-3-nitrobenzoic acid was prepared from 3-Nitrophthalamic acid using bromine and potassium hydroxide as per the process disclosed in WO 2007/006566.

In another embodiment of the present invention, 2-amino-3-nitrobenzoic acid was treated with alcohol in presence of an acid to form 2-amino-3-nitro-benzoicacid ester. The acid may be selected from mineral acids such as Hydrochloric acid. Sulfuric acid. Nitric acid, preferably Sulfuric acid. The alcohol may be selected from Methanol, Ethanol, propanol, benzyl alcohol, preferably Ethanol.

In another embodiment of the present invention, 2,3-diamino-benzoicacid ester was prepared from 2-amino-3-nitro-benzoicacid ester by hyrogenolysis. Hydrogenolysis is . carried out by passing hydrogen gas under inert atmosphere, in presence of catalysts such as Palladium-carbon, Raney Nickle, preferably Palladium-carbon. The reaction is carried out in presence of solvents selected from. Methanol, Ethanol, Propanol, Acetone, Methyl acetate. Ethyl acetate, Tetrahydrofuran, preferably Ethylacetate,

In another embodiment of the present invention, 2-ethoxy-3H-benzimidazol-4-carboxylic acid ester was prepared from 2,3-Diamino-benzoicacid ester using Tetraethyl ortho carbonate. The reaction is carrriedout in presence of an acid such as acetic acid. The reaction is carried at a temperature ranging from 15° C to 80*^ C, preferably in the range
25*0 to 35*0.

The following examples illustrate and explain the present invention and should be cited merely to illustrate embodiments and are not intended to limit the scope of the invention.

Examples:

Example 1: Preparation of 3-nitrophthalic anhydride

To a round bottomed flask, 3-nitrophthalic acid (100 g) and acetic anhydride (96.7 g) were added and refluxed for 30 minutes. The reaction mass was cooled to 70°C, 50ml toluene added and distilled under reduced pressure. Toluene (150ml) added and cooled to 25-30°C, filtered and dried to get 85g of 3-nitrophthalic anhydride with a melting point of l63-164°C.

Example 2: Preparation of 3-nitrophthalamic acid

To a round bottomed flask, ammonia solution (170ml) was added followed by addition of 3-nitrophthalic anhydride (lOOg) in portions. The reaction mass was maintained for Ihr at 0-5 °C. The reaction mass was filtered and the wet cake was taken into DM water (170ml). Con HCl (45ml) was added slowly at 50±2 °C, filtered and washed with water.

The product was dried to get 82g of 3-nitrophthalamic acid with a melting point of 214-216 °C.

Example 3: Preparation of 2-Amino 3-nitro benzoic acid (3-nitro anthranilic acid)

To a round bottomed flask, potassium hydroxide pellets (24 Ig) and purified water (1100 ml) were added at 30±5 °C and cooled the reaction mass to 0±5 °C. To the reaction mass bromine (76.2 g ) was added slowly followed by the addition of 3-nitrophthalamic acid (100 g). The reaction mass was maintained at 60±2 °C for 3hrs, cooled to room temperature and filtered. Water (400 ml) was added to the filtered material, stirred for Ihr at 65±3 °C, cooled to 20±2 °C, filtered, and dried to give 70g of 3-nitro anthranilic acid with a melting point of 208-209 °C.

Example 4: One pot preparation of 2-Amino 3-Nitro benzoic acid from 3-nitrophthalic acid

In a round bottomed flask 3-nitrophthalic acid (lOO.Og) and acetic anhydride (97.0g) were refluxed for 3hrs. The solvent was distilled off and the reaction mass was maintained at 85±5°C by adding toluene (150.0ml). The reaction mass was cooled and filtered off The wet cake was added to aqueous ammonia (150ml) and adjusted the pH at 50±2°C to pH 2.0 using dilute HCl. The reaction mass was filtered off. In another flask purified water (700ml) and potassium hydroxide (160gm) were cooled to 2±2°C and bromine was added followed by the addition of above wet cake. The reaction mass was maintained at 63±2°C for 3-4 hours. The reaction mixture was cooled to room temperature and maintain for 10-12 hours and filtered off. The wet cake was added to purified water (600ml) and pH was adjusted to pH: 1.0-2.0 using dilute hydrochloric acid.

The reaction mass was filtered off and dried to give 44gm of 2-Amino 3-Nitro benzoic acid from 3-nitrophthalic acid with a melting point of 208-209°C.

Example 5: Preparation of 2-Amino 3-nitro benzoic acid ethyl ester

To a round bottomed flask, ethanol (550 ml) and 3-nitro anthranilic acid (100 g) were added at 30±5 °C followed by slow addition of sulfuric acid (65 ml). The reaction mass was maintained at reflux temperature for 24 hrs. The reaction mass was cooled to room temperature and added to ammonia solution. The reaction mass was filtered, washed with ethanol and dried to get 90g of 2-amino-3-nitro benzoic acid ethyl ester with a melting range of 108-109°C.

Example 6: Preparation of 2^-diamino benzoic acid ethyl ester

To a tightly closed reaction flask with nitrogen purging, ethyl acetate(1000 ml) and ethyl 2-amino-3-nitro-benzoate (100 g) were added at 30±5 °C followed by addition of Pd/C (10 g). Hydrogen gas was purged into the reaction mass for 5-6 hours. After the reaction completion, reaction mass was filtered and the solvent was distilled. To the crude, n-hexane (100ml) was added and maintained the reaction mass at to 3±2 °C for 30 minutes. Filtered, washed with n-hexane and dried under vacuum to give 75g of 2,3-diamino benzoic acid ethyl ester with a mehing point of 5 8-61 °C.

Example 7: Preparation of 2-ethoxy-3H-benzimidazol-4-carboxylic acid ethyl ester

To a round bottomed flask, acetic acid (362 ml) and ethyl 2,3-diamine benzoate (100 g) were added at 30±5 °C. Tetraethyl ortho carbonate was added to the reaction mass slowly at 3±2°C. The reaction mass was maintained at 30±5 °C for 3hrs. The reaction mass was again cooled to 3±2 °C and purified water was added. The reaction mass was maintained for 1hr, filtered and dried to give 110g of 2-ethoxy-3H-benzimidazol-4-carboxylic acid ethyl ester with a melting range of 95°-100°C.

Example 8: One pot preparation of 2-ethoxy-3H-benzimidazol-4-carboxylic acid ethyl ester from ethyl-2-amino 3-nitro benzoate

To a tightly closed reaction flask, ethyl-2-amino 3-nitro benzoate (lOOg), ethyl acetate (1000ml) and 5% Pd/C (lO.Og) were added at 30±5°C. Hydrogen gas was purged into reaction mass till reaction completion. The reaction mass was filtered off and distill off the filtrate. The reaction mass was cooled to 30±5°C and acetic acid (278ml) was added. The reaction mass was further cooled to 2±2°C and slowly added tetraethyl ortho carbonate (lOOg) under nitrogen atmosphere over a period of 30-60minutes. Reaction mass was maintained for 4 hours at 33±2°C. After the reaction completion, purified water (770.0ml) was added to the reaction mass at 2±2°C and stirred for one hour.Filtered off the product and and dried to get 90gm of 2-ethoxy-3H-benzimidazol-4-carboxylic acid ethyl ester from ethyl-2-amino 3-nitro benzoate with a melting range of 95-100°C.

Example 9: Preparation of 3-(2'-cyano-biphenyI-4-ylmethyl)-2-ethoxy-3H-benzimidazol-4-carboxylic acid ethyl ester

To a round bottomed flask, water (470 ml) and caustic soda flakes (16 g) were added at 30±5 °C. The reaction mass was cooled to 25±5°C and 2-ethoxy-3H-benzimidazoI-4-carboxylic acid ethyl ester (l00g) was added slowly followed by the addition of toluene (470 ml), 4'-bromomethyl-biphenyl-2-carbonitrile (l00g) and tetrabutyl ammonium bromide (6 g). The reaction mass was maintain for 3 hours at 43±2 °C. The reaction mass was cooled to room temperature and the organic layer was separated and distilled out.

Methanol (400 ml) was added to the remaining mass and maintained for 1 hr, filtered and
dried to get 110g of 3-(2'-cyano-biphenyl-4-ylmethyl)-2-ethoxy-3H-benzimidazol-4-carboxylic acid ethyl ester with an HPLC purity of > 99%.

Example 10: Preparation of 2-ethoxy-l-{[2'-(lH-tetrazol-5-yl) [1, l'-biphenyI]-4-yl]methyl}-lH-benziiiiidazole-7-carboxylic acid (Candesartan)

To a round bottomed flask water (165 ml), sodium azide (50 g) were added and stirred to dissolve. Tributyltin chloride (230 gm) was added to the above reaction mass over a period of 2-3 hours,.The reaction mass was cooled to 5-10°C and maintain for 2 hours. 0-xylene (600 ml) was added and the organic layer was seperated out. In a seperate round bottomed flask o-xylene(600 ml) and 3-(2'-cyano-biphenyl-4-ylmethyl)-2-ethoxy-3H-benzimidazol-4-carboxylic acid ethyl ester(lOOg) were taken and the above tin azide solution was added. Maintained the reaction mass for 20-24 hours at reflux temperature.

After the reaction completes, the reaction mass was cooled to 30±5°C and aqueous sodium hydroxide solution (50g Sodium hydroxide dissolved in 1000 ml of DM water)was added. Maintain 60±5°C for 3-4 hours. Cooled the reaction mixture and the organic layer was separated. Methanol (600ml) was added followed by char coal treatment. pH of the reaction mixture was adjusted to 4.5-5.5 with acetic acid (125-200 g) at 30±5°C. DM water(200 ml) was added to the reaction mass, filtered, washed with acetone and dried to get 95gm of candesartan.

Example 11: Preparation of 2-Ethoxy-3-[2'-(l-trityl-lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole'4-carboxylic acid (trityi candesartan)
Candesartan(l00g) and Triethylamine(28 gm) were taken in a round bottomed flask containing methylene chloride(600ml) and added trityl chloride (77g). The reaction mass was maintained for 4 hours under reflux temperature. The solvent was distilled off.

Toluene(300ml) was added followed by water(300ml) and stirred for two hours.

Filtered the material and dried to give 145g of trityl candesartan.

Example 12: Preparation of 2-Ethoxy-3-[2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmetliyl]-3H-benzoimidazole-4-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester (candesartan cilexetil)

In a round bottomed flask trityl candesartan(100 gm) was dissolved in dimethylsulfoxide(500ml) and potassium carbonate(25g) was added followed by the addition of potassium iodide(12g). The temperature was raised to 60-70°C and chloro cilexetil(36g) was added over a period of one hour and maintained for 4 hours. After the reaction completion toluene(300ml) and water(200ml) were added. The organic layer was separated and distilled off completely. Ethanol(500ml) was added and cooled to 20-22°C.

The wet cake was filtered off added into methano 1(1000ml). followed by DM water(6ml) and refluxed the mass till the clear solution obtained (10-14 hours). The Solvent was distilled completely and toluene(400ml) was added. The reaction mixture temperature was raised to 65-70°C and cooled to 25-30°C. The obtained crystals were filtered and wet cake was recrystallized in aqueous acetone (120ml of water and 300ml of acetone) to get 76g (85%) of candesartan cilexetil

1. A process for the preparation of 3-(2'-substituted biphenyl-4-ylmethyl)-2-ethoxy-3H-benzimidazole-4-carboxylic acid derivative of formula III, an intermediate of Candesartan cilexetil, comprising, reacting 2-Ethoxy-3H-benzimidazole-4-carboxylic acid derivative of formula I with 2-substituted 4'-halomethyl-biphenyl compound of formula II in presence of phase transfer catalyst.

2-Ethoxy-3//-benzoimidazole- 2-Substituted 4'-halomethyl- 3-(2'-substituted biphenyM-ylmethyl)-2-4-carboxyl.c acid denvafve biphenyl ethoxy-3H-benziinidazole-4-carboxylic

1. T, acid derivative

2. A process for the preparation of 3-(2'-cyano-biphenyl-4-ylmethyl)-2-ethoxy-3H-benzimidazol-4-carboxylic acid ethyl ester comprising, reacting 2-ethoxy-3H-benzimidazol-4-carboxylic acid ethyl ester with 4'-bromomethyl-biphenyl-2-carbonitrile in presence of phase transfer catalyst.

3. The process according to claims l or 2, wherein the phase transfer catalyst is selected from tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydroxide, tetrabutylammonium iodide, tetrabutylammonium hydrogensulfate, benzyltriethylammonium chloride, benzyltributylammonium bromide, benzyltriethylammonium bromide and tetramethylammonium chloride.

4. The process according to claim 3, wherein the phase transfer catalyst is tetrabutylammonium bromide.

5. The process according to claims 1 or 2, wherein the reaction is carried in presence of a base.

6. The process according to claim 5, wherein the base is an organic base selected from triethyl amine, diisopropylethylamine, pyridine, N,N-dimethylaniline and N-methyl-morpholine.

7. The process according to claim 5, wherein the base is an inorganic base selected from Sodium hydroxide, Potassium hydroxide, Lithium hydroxide, sodium carbonate, potassium carbonate. Magnesium carbonate and Calcium carbonate.

8. The process according to claims 1 or 2, wherein 3-(2'-cyano-biphenyl-4-ylmethyl)-2-ethoxy-3H-benzimidazol-4-carboxylic acid ethyl ester is further converted to Candesartan cilexetil.