WO2012139535A1

WO2012139535A1 - A method of preparing 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl- 4-yl)methyl)-1h-benzo[d]imidazole-7-carboxylates and conversion thereof to azilsartan

Info

Publication number: WO2012139535A1
Application number: PCT/CZ2012/000030
Authority: WO
Inventors: Stanislav Radl; Jan Stach
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2011-04-11
Filing date: 2012-04-04
Publication date: 2012-10-18
Anticipated expiration: 2013-10-11
Also published as: HUP1300733A2; CZ303505B6; CZ2011208A3; HU230577B1

Abstract

An improved method of preparing alkyl 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3- yl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylates of formula (I), wherein R is either a branched or unbranched C₁-C₄ alkyl, ArCH_2, Ar₂CH, or Ar₃C, wherein Ar is a substituted or unsubstituted phenyl, and of conversion thereof to azilsartan of formula (II). This compound is an efficient angiotensin II AT1 receptor antagonist, which is used in the form of the prodrug azilsartan medoxomil of formula (III) in the treatment of hypertension.

Description

A method of preparing 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl- 4-yl)methyl)-lH-benzo[r/]imidazole-7-carboxylates and conversion thereof to azilsartan

Technical Field

The invention relates to an improved method of preparing alkyl 2-ethoxy- l-((2'-(5-oxo-4,5- dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH-benzo[i/]imidazole-7-carboxylates of formula I,

wherein R is either a branched or unbranched Ci-C₄ alkyl, ArCH₂, Ar₂CH, or Ar₃C, wherein Ar is a substituted or unsubstituted phenyl, and conversion thereof to azilsartan of formula II. This compound is an efficient angiotensin II ATI receptor antagonist, which is used in the form of the prodrug azilsartan medoxomil of formula III in the treatment of hypertension.

Background Art

Azilsartan of formula II is prepared, according to the published patents (US 5,583, 141 and EP 0 520 423) from the starting methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH- benzo[i ]imidazole-7-carboxylate of formula IVa. This compound, which is a well-known intermediate of synthesis of candesartan, is first converted, by reaction with hydroxylamine generated in situ from hydroxylamine hydrochloride, to methyl 2-ethoxy-l-((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)-lH-benzo[ii|imidazole-7-carboxylate (Va), which is then converted to methyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3- yl)biphenyl-4-yl)methyl)-lH-benzo[ii]imidazole-7-carboxylate of formula la, saponification of which produces azilsartan of formula II.

LiOH or NaOH

aq. MeOH

(II)

azlsartan In the above cited patents the conversion of the amidoxime of formula Va to la is performed by reaction with ethyl chloroformate in the presence of triethylamine in dichloromethane, followed by cyclization of the thus formed ethyloxycabonyl derivative of formula VI by boiling in xylene for 1.5 hrs. The product of formula la was then obtained from the mixture, after processing and chromatography, in 23% yield. In more recent publications the same authors (Kohara Y., Imamiya E., Kubo K., Wada T., Inada Y., Naka T.: Bioorg. Med. Chem. Lett. 1995, 5(7), 1903-1908; Kohara Y., Kubo K., Imamiya E., Wada T., Inada Y., Naka T.: J. Med. Chem. 1996, 39(26), 5228-5235) have used either methyl chloroformate or 3-exthylhexyl chloroformate instead of ethyl chloroformate. Cyclization of the intermediates of formula VI is again performed thermally, by boiling in xylene for 2 hrs. In the only working example presented in the cited reference of Kohara Y., Kubo K., Imamiya E., Wada T., Inada Y., Naka T.: J. Med. Chem. 1996, 39(26), 5228-5235, the product of formula la is obtained, using 3- octyl chloroformate, in 52% yield as colourless crystals with the melting point of 196-197 °C. The reference Kohara Y., Imamiya E., Kubo K., Wada T., Inada Y., Naka T.: Bioorg. Med. Chem. Lett. 1995, 5(7), 1903- 1908, mentions the possibility of cyclization of the intermediates of formula VI by the effect of DBU without quoting any details; being silent about the yield or the method of isolation of the intermediate of formula la, or information about the making up of the subsequent reaction without isolation of the compound of formula la.

Thermal cyclization of the corresponding N-[(alkoxycarbonyl]oxy]imidamides, often carried out by boiling in high-boiling solvents, e.g. xylene, is a common and widely used method of synthesis of l ,2,4-oxadiazol-5(4H)-ones (e.g. Unangst P. C, Shrum G. P., Connor D. T., Dyer R. D., Schriert D. J.: J. Med. Chem. 1992, 55(20), 3691 -3698; Reichert A., Frohlich R., Ferguson R., Kraft A.: J. Chem. Soc, Perkin Trans. 1, 2001 , (1 1), 1321 - 1328; Assogba L„ Ahamada-Himidi A., Meddad-Bel Habich N., Aoun D., Boukli L., Massicot F., C. M., Huet J., Lamouri A., Ombetta J.-E., Godfroida J.-J., Dong C.-Z., Francoise Heymans F.: Eur. J. Med. Chem. 2005, 40(9), 850-861).

Disclosure of Invention

The invention relates to efficient, basically initiated cyclization of N-[(alkoxycarbonyl]- oxyjimidamides of formula VI,

This cyclization is carried out under more moderate conditions than the previously known thermal methods and minimizes production of impurities. The compounds of formula VI are subsequently hydrolyzed to azilsartan of formula II or its salts. The cyclization and hydrolysis can be done in one reaction step; such an arrangement makes the entire process more efficient.

Detailed description of the invention:

The invention relates to an improved method of preparing alkyl 2-ethoxy- l -((2'-(5-oxo-4,5- dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH-benzo[c ]irnidazole-7-carboxylates of formula I,

wherein R is either a branched or unbranched C 1 -C4 alkyl, ArC¾, Ar₂CH, or Ar₃C, wherein Ar is a substituted or unsubstituted phenyl; in a preferable embodiment, R being methyl, ethyl or benzyl; in which method the corresponding alkoxycarbonyl derivatives of formula VI,

wherein R' is a branched or unbranched, substituted or unsubstituted Ci-C₈ alkyl or substituted or unsubstituted phenyl, are cyclized by means of a base in a suitable solvent. A suitable solvent may include a polar aprotic solvent selected from the group of dimethyl sulfoxide (DMSO), N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide (DMAc), 1 - methyl pyrrolidone (NMP), 1 , 1 ,3,3-tetramethyl urea (TMU), 1 ,3 -dimethyl imidazolidin-2-one (DMI), l ,3-dimethyl-3 ,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), or hexamethyl phosphoramide (HMPA), preferably DMSO.

The cyclization is carried out at a temperature in the range from_0 °C to the boiling point of the solvent used.

The present method is performed by processing the reaction mixture by dilution with water or by pouring of the reaction mixture into water, acidification and subsequent isolation of the insoluble product by filtration or centrifugation. The purification method of the compounds of formula I, obtained by the present method, is carried out by crystallization from suitable solvents, including alcohols, e.g. methanol, ethanol, isopropanol, esters of aliphatic acids, e.g. methyl acetate, ethyl acetate, isopropyl acetate, amides, e.g. yV,N-dimethyl formamide, N,N- dimethyl acetamide, 1 -methyl pyrrolidone, ethers, e.g. dioxan, 1 ,2-dimethoxyethane, 1 - methoxy-2-(2-methoxyethoxy)ethane, or mixtures of these solvents.

Another object of the invention provides use of alkyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- l H-benzo[i/]imidazole-7-carboxylates of formula I, wherein R is either a branched or unbranched C i -C₄ alkyl, ArC¾, Ar₂CH, or Ar₃C, wherein Ar is a substituted or unsubstituted phenyl, for the preparation of azilsartan of formula II,

Another object provides a method of preparing azilsartan of formula II, consisting in basically initiated cyclization of the corresponding alkoxycarbonyl derivatives of formula VI

wherein said basically initiated cyclization of the alkoxycarbonyl derivatives of formula VI is carried out by stirring a solution of the starting compounds in a suitable solvent in the presence of a suitable base, and the primarily produced esters of formula I are directly converted, by the base used, to a salt of azilsartan and, after suitable processing, directly to azilsartan of formula H.

Preferable solvents that can be used in the method of preparing azilsartan of formula II include a dipolar aprotic solvent, most preferably DMSO or NMP.

Bases used include at least two molar equivalents of an alkali metal alcoholate R"OM, wherein R" is a branched or unbranched C 1 -C8 alkyl and M is an alkali metal.

The cyclization and conversion to the salt of azilsartan are carried out at a temperature from 0°C to the boiling point of the mixture, preferably at a temperature of 20 to 25°C.

Another embodiment includes carrying the method of preparing azilsartan of formula II, consisting in basically initiated cyclization of the corresponding alkoxycarbonyl derivatives of formula VI, out in one reaction step, i.e., performing the basically initiated cyclization of alkoxycarbonyl derivatives of formula VI by stirring a solution of the starting compounds in a suitable solvent, preferably in a dipolar aprotic solvent, most preferably in DMSO, in the presence of at least two molar equivalents of an alkali metal alcoholate R"OM, wherein R" is a branched or unbranched C 1 -C8 alkyl and M is an alkali metal, at a temperature in the range from 0°C to the boiling point of the solvent used, preferably at a temperature of 0°C to 50°C, most preferably at the room temperature.

The method of purification the compounds of formula II is carried out by crystallization from suitable solvents, including alcohols, e.g. methanol, ethanol, isopropanol, esters of aliphatic acids, e.g. methyl acetate, ethyl acetate, isopropyl acetate, amides, e.g. N,7V-dimefhyl formamide, /V-dimefhyl acetamide, 1 -methyl pyrrolidone, ethers, e.g. dioxan, 1 ,2- dimethoxyethane, l -methoxy-2-(2-methoxyethoxy)ethane, or mixtures of these solvents. Reproduction of the previously described thermal methods of the synthesis of formula la (see Examples 1-3) showed that besides the desired product the reaction mixture also contained the starting substance as well as several other impurities, including the desethyl derivative of formula Vila in spite of using anhydrous xylene.

Although the compound of formula Vila is formally a product of hydrolysis of the ethoxy group in position 2 of the benzimidazole skeleton of the corresponding derivative of formula la, it must be produced through a different mechanism. We have previously described a similar reaction in case of candesartan cilexetil, wherein deethylation and intermolecular ethylation of another molecule of candesartan cilexetil occurred (Havlicek J., Mandelova Z., Weisemann R., Stfelec I., Placek L., Radl S.: Collect. Czech. Chem. Commun. 2009, 74(2), 347-362).

In an effort to reduce the number of the above mentioned desethyl derivatives we have tried to use various other solvents (e.g. diphenyl ether, dimethyl sulfoxide, dimethyl sulfone, diglyme, PEG, toluene and others). Even these modifications, including the use of lower temperatures, did not lead to a substantial reduction of the content of these impurities. In addition, when lower temperatures were used, a considerable reduction of conversion occurred, while during prolonged heating the contents of secondary compounds increased.

The above mentioned findings indicate that the ethoxy group in position 2 of the benzimidazole skeleton is very sensitive to the reaction conditions used and is not compatible with the use of higher temperatures. Therefore, we have focused on the use of different procedures leading potentially to the production of l ,2,4-oxadiazol-5(4H)-ones. The essence of this invention is based on a quite surprising finding that with a suitable combination of the solvent and the base used this group is relatively stable and thus basically initiated cyclization of the corresponding N-[(alkoxycarbonyl]-oxy]imidamides can be used. We have used, as starting substances for the basically initiated cyclization, N- [(alkoxycarbonyl]-oxy]imidamides of formula VI,

wherein R is a branched or unbranched Ci-C₄ alkyl, ArCH₂, Ar₂CH, or Ar₃C, wherein Ar is a substituted or unsubstituted phenyl and R' is a branched or unbranched substituted or unsubstituted C _\ -C_$ alkyl or a substituted or unsubstituted phenyl. These starting substances are readily obtainable by reaction of the starting amidoximes of formula V with the corresponding alkyl chloroformate under conventional conditions, as previously described for the reaction of the amidoxime (Va) with alkyl chloroformates having, as R', methyl, ethyl, or 3-ethylhexyl. In extensive screening of various modifications of the basically initiated cyclization of the compounds (VI) we have used, as the base, various amines: triethylamine, diisopropylethylamine (DIPEA), 8-diazabicyclo[5.4.0.]undec-7-ene (DBU), 1 ,4- diazabicyclo[2.2.2]octane (DABCO), l ,8-bis-(dimethylamino)naphthalene, 1 - methylmorpholine, 1 -efhylpiperidine), or alcoholates: CH₃ONa, CH₃OK, C₂H₅ ONa, t- C₄H₉ONa, t-C₄H₉OK, t-AmONa, t-AmOK; alkali or alkaline earth metal carbonates (Na₂C0₃, 2C0₃, Cs₂C0₃), hydrogen carbonates (NaHC0₃, KHC0₃) and acetates (NaOAc, KOAc) in various solvents and their mixtures. In some cases, for example when alcoholates are used, compounds of formula V are formed under the above mentioned conditions. If the reaction was performed in alcohols, in particular in methanol or ethanol, the corresponding compounds of formula (V) were even the main products of the reaction. If the secondary products of formula V are contained as minority ones, they can be easily removed from the reaction mixture with regard to their considerable basicity either during the processing, which consists in pouring into water and subsequent acidification, or they can be removed by washing of the product with diluted acids on a filter, or by dissolution in a suitable solvent and shaking with diluted acids. A considerable reduction of formation of substances of formula V is achieved when weaker bases are used, e.g. potash. The reaction occurs at the room temperature, but it can also be performed at an elevated temperature.

If during the basically initiated cyclization of N-[(alkoxycarbonyl]-oxy]imidamides of formula VI alkali metal alcoholates are used in suitable solvents, e.g. in DMSO, NMP, THF, and other solvents, it is not only the cyclization to the corresponding esters of formula I that occurs, but the corresponding alkali metal salts of azilsartan are also produced, which are directly converted to azilsartan by processing with acidification. Thus, in a suitable embodiment, basically initiated cyclization of N-[(alkoxycarbonyl]-oxy]imidamides of formula VI can be directly carried out to azilsartan, thus achieving shortening of the reaction sequence by one reaction step. In this respect, the use of t-BuOK in DMSO, NMP, or other solvents is the most - preferable, thus obtaining high yields of azilsartan as after reacting at the room temperature for several hours.

The reactions were routinely monitored by HPLC in an HP 1050 instrument equipped with a Phenomenex Luna 5μ C I 8(2), 250 x 4.6 mm column with a 227nm UV detector. Phase A: 1 .2 g of NaH₂P0₄/l 1 of water (pH = 3.0; Phase B: methanol. The invention is elucidated in a more detailed way in the working examples below. These examples, which illustrate the improvement of the method according to the invention, have exclusively an illustrative character and do not limit the scope of the invention in any respect. Working Examples

Comparative Examples: Example 1

Methyl 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1 H- benzo[c/]imidazole-7-carboxylate of formula la - reproduction of the procedure (US

5,583, 141 ; EP 0 520 423).

A solution of ethyl choroformate (0.22 g, 2 mmol) in dichloromethane (2 ml) was added dropwise to a stirred mixture of methyl 2-ethoxy- l-((2'-((hydroxyamino)iminomethyl)- biphenyl-4-yl)methyl)-l -benzo[i ]imidazole-7-carboxylate of formula Va; 0.89 g, 2 mmol), dry THF (30 ml) and triethylamine (0.2 g) under cooling in a water-ice mixture and the mixture was stirred at the room temperature for 2 hours. The insolubles were aspirated and the filtrate was evaporated to dryness; the evaporation residue was diluted with ethyl acetate (5 ml), the insolubles were aspirated and the filtrate was evaporated again. The evaporation residue (1.0 g) contained 98.2% of the intermediate (of formula Vlab; R' = Et) according to HPLC.

A mixture of the evaporation residue and xylene (10 ml) was heated up to reflux for 1.5 hours. Ethyl acetate (25 ml) was added to the partially cooled reaction mixture; the solution was washed with water (2 x 10 ml) and then dried with MgS0₄. 0.9 g of an evaporation residue was obtained, containing 2.2 % of the intermediate (VI; R' = Et), 47.5 % of the product of formula la and 1 5.8 % of the compound of formula Vila according to HPLC. The total content of the product of formula la corresponds to a yield of 46 %. Example 2

Ethyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- l H- benzo[i ]imidazole-7-carboxylate of formula lb - modification of the procedure (US 5,583, 141 ; EP 0 520 423)

Using the procedure described in Example 1 , reacting the starting ethyl 2-ethoxy-l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H-benzo[(3 imidazole-7-carboxylate of formula Vb with ethyl chloroformate a mixture was obtained containing 96.4% of the corresponding intermediate of formula VI according to HPLC. This mixture was then cyclized by the procedure described in Example 1 providing a product containing 0.7% of the intermediate (of formula VI; R' = Et), 53.7 % of the product of formula lb and 33.2 % of the product of formula Vllb according to HPLC. The total content of the product of formula lb corresponds to a yield of 51 %.

Example 3

Methyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- l H- benzo[< ]imidazole-7-carboxyiate of formula la - reproduction of the procedure (J. Med. Chem. 1996, 39(26), 5228-5235)

2-ethylhexyl chloroformate (0.25 g, 2.6 mmol) was added to a stirred mixture of methyl 2- ethoxy- l -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H-benzo[i/]imidazole-7- carboxylate (of formula Va; 1.16 g, 2.6 mmol), dry DMF (5 ml) and pyridine (0.22 g) under cooling in a water-ice mixture and the mixture was stirred at the temperature of 0°C for 30 minutes. After dilution with water (20 ml) the mixture was extracted with ethyl acetate (4 x 10 ml), the extract was washed with water (4 x 5 ml) and dried with MgS0₄. The obtained evaporation residue ( 1.7 g) contained 92.2 % of the intermediate (of formula VI; R' = 2- ethylhexyl) according to HPLC.

A mixture of the evaporation residue and xylene (15 ml) was heated to reflux for 2 hours. The evaporation provided 0.9 g of an evaporation residue containing 0.9% of the intermediate (VI; R' = 2-ethylhexyl), 64.0 % of the product of formula la and 5.2 % of the product of formula Vila according to HPLC. The total content of the product of formula la corresponds to a yield of 64 %.

The evaporation residue was dissolved in a mixture of CHC1₃ (3 ml) and ethyl acetate (1 ml); an insoluble product started to separate after a short time. The mixture was left to stand at the room temperature; then the insolubles were aspirated. 0.55 g of ochre crystals was obtained containing 90.4% of the product of formula la and 8.6 % of formula Vila according to HPLC. The total content of the product of formula la corresponds to a yield of 40 %.

Working Examples of Basically Initiated Cyclization of the Compounds of Formula VI: Example 4 Methyl 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3 -yl)biphenyl-4-yl)methyl)- 1 H- benzo[<i]imidazole-7-carboxylate of formula la

0.05 g of the corresponding base was added to a mixture of 0.2 g of methyl 2-ethoxy- 1 -((2'- (A^-(methoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)-lH-benz[if]imidazole-7- carboxylate (of formula Vlaa; R' = Me) and 4 ml of the respective solvent, stirred in a reaction vial, and the mixture was stirred at the room temperature for 4 h. The collected samples were acidified with acetic acid and analyzed with HPLC. The results are summarized in Table I.

Table I - Yield and purity of the product of Example 4

Example 5

Ethyl 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1 H- benzo[c ]imidazole-7-carboxylate of formula lb

0.05 g of the corresponding base was added to a mixture of 0.2 g of ethyl 2-ethoxy- l -((2'-(N'- (ethoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)- l -benz[(i]imidazole-7- carboxylate (of formula VIbb; R' = Et) and 4 ml of the respective solvent, stirred in a reaction vial, and the mixture was stirred at the room temperature for 4 h. The collected samples were acidified with acetic acid and analyzed with HPLC. Table II - Yield and purity of the product of Example 5

Example 6

Methyl 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1 H- benzo[< ]imidazole-7-carboxylate (la) 2CO3 (0.5 g, 3.6 mmol) was added to a mixture of 1.0 g (2 mmol) of methyl 2-ethoxy- 1 -((2'- (A/'-(methoxycarbonyloxy)carbamimidoyl)-biphenyl-4-yl)methyl)-lH-benz[<^imidazole-7- carboxylate (of formula Vlaa; R' = Me) and 10 ml of DMSO and the mixture was stirred at the room temperature for 3 h. Then, the reaction mixture was poured into water (50 ml) and the resulting solution was acidified with acetic acid. 0.9 g (96.1 %) of a product of formula la with the melting point of 193- 197 °C was obtained containing 97.8 % according to HPLC. Ή NMR (500 MHz, DMSO) δ (ppm): 12.39 (s, 1 H, NH), 7.70 (dd, J = 7.9, 1.1 Hz, 1 H, Ar), 7.68- 7.63 (m, 2H, Ar), 7.55 (td, J = 7.4, 1.1 Hz, 1 H, Ar), 7.46 (m, 2H, Ar), 7.24 (d, J = 8.1 , 2H, Ar ), 7. 19 (t, J = 7.9 Hz, 1 H, Ar), 7.00 (d, J = 8.1 Hz, 2H, Ar), 5.54 (s, 2H, N-CH₂-Ar), 4.62 (q, J = 7.1 Hz, 2H, OCH₂CH3), 3.69 (s, 3H, OCH₃), 1.39 (t, J = 7.1 Hz, 3H, OCH₂CH3).

Example 7

Methyl 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3 -yl)biphenyl-4-yl)methyl)- 1 H- benzo[c/]imidazole-7-carboxylate of formula la

Using the procedure described in Example 6 methyl 2-ethoxy- 1 -((2'-(7V-(ethoxycarbonyloxy)- carbamimidoyl)biphenyl-4-yl)methyl)- l H-benz[ci]imidazole-7-carboxylate (of formula Vlab; R' = Et) was converted to methyl 2-ethoxy- l -((2'-(5-oxo-4, 5-dihydro- l , 2,4-oxadiazol-3- yl)biphenyl-4-yl)methyl)- l H-benzo[i ]imidazole-7-carboxylate of formula la. 94.3% of a substance containing 96.3%o of the product of formula la according to HPLC was obtained.

Example 8

Methyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- l H- benzo[c ]imidazole-7-carboxylate of formula la

K₂CO3 (0.5 g, 3.6 mmol) was added to a mixture of 1.8 g (3.2 mmol) of methyl 2-ethoxy- 1 - ((2'-(N'-(phenyloxycarbonyloxy)-carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzftf]- imidazole-7-carboxylate (of formula Viae; R' = Ph) and 15 ml of NMP and the mixture was stirred at the room temperature for 1 h. The reaction mixture contained 90.2% of the compound of formula la and 4.2 % of the starting compound according to HPLC (a mixture containing 96.4 % of the compound of the corresponding formula Viae according to HPLC. After stirring for another hour the reaction mixture was poured into water (75 ml) and the resulting solution was acidified with acetic acid. 1 .42 g (94.6 %) was obtained containing 100.0 % of a product of formula la according to HPLC. Example 9

Ethyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH- benzo[tf)imidazole-7-carboxylate of formula lb

Using the procedure described in Example 6 ethyl 2-ethoxy-l -((2'-(N'-(ethoxycarbonyloxy)- carbamimidoyl)biphenyl-4-yl)methyl)-lH-benz[i/]imidazole-7-carboxylate of formula VIbb; R' = Et) was converted to ethyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3- yl)biphenyl-4-yl)methyl)-l H-benzo[t/]imidazole-7-carboxylate of formula lb. 93.0% of a compound with the melting point of 179 to 182°C were obtained containing 97.8% of a product of formula lb according to HPLC. Ή NMR (500 MHz, DMSO) δ (ppm): 12.40 (s, lH, NH), 7.69 (dd, J = 7.9, 1.2 Hz, 1H, Ar), 7.50 (m, 1H, Ar), 7.44 (dd, J = 7.9, 1.2 Hz, 1H, Ar), 7.43-7.40 (m, 4H, Ar), 7.35 (d, J = 7.7 Hz, 1 H, Ar), 7.19 (t, J = 7.9 Hz, 1H, Ar), 6.95 (d, J = 8.3 Hz, 2H, Ar), 6.61 (bs, 2H, NH₂), 5.57 (s, 2H, N-CH₂-Ar), 4.60 (q, J = 7.1 Hz, 2H, COOCH₂CH₃), 4.18 (q, J = 7.1 Hz, 2H, OCH₂CH₃), 1.39 (t, J = 7.1 Hz, 3H, COOCH₂CH₃), 1.16 (t, J = 7.1 Hz, 3H, OCH₂CH₃).

Examples of Obtaining Azilsartan of Formula II: Example 10

2-Ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1 H- benzo[i/]imidazole-7-carboxylic acid - azilsartan of formula II

A mixture of methyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4- yl)methyl)-lH-benzo[< ]imidazole-7-carboxylate (of formula la; 4.7 g, 10 mmol), methanol (50 ml) and aqueous sodium hydroxide (2 g of NaOH in 10 ml of water) was stirred at the room temperature for 24 hours. Then, methanol was evaporated and the residue was diluted with 50 ml of water and acidified with 5% HC1. The insolubles were aspirated and washed with water. 4.4 g (96.4 %) of a product containing 97.8 % of azilsartan of formula II with the melting point of 208 to 21 1 °C according to HPLC was obtained. Example 11 2-Ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1 H- benzo[c/]imidazole-7-carboxylic acid - azilsartan of formula II

A mixture of ethyl 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4- yl)methyl)-l H-benzo[< ]imidazole-7-carboxylate (of formula la; 3.2 g, 6.6 mmol) and aqueous sodium hydroxide (0.8 g of NaOH in 50 ml of water) was stirred at the temperature of 70°C for 1.5 hours. After cooling to the room temperature the mixture was acidified with 10% HCl until pH 3 while being stirred and cooled. The insolubles were aspirated and washed with water. 2.6 g (86.2 %) of a product was obtained containing 97.2 % of azilsartan of formula II with the melting point of 208 to 21 1 °C according to HPLC. Ή NMR spectrum: Ή NMR (500 MHz, DMSO) δ (ppm): 13.17 (bs, 1H, OH or NH), 12.42 (bs, 1H, OH or NH), 7.70-7.60 (m, 3H, Ar), 7.57-7.50 (m, 2H, Ar), 7.50-7.44 (m, 1 H, Ar), 7.23 (d, J = 8.3 Hz, 2H, Ar), 7.18 (t, J = 7.9 Hz, lH, Ar), 7.05 (d, J = 8.3 Hz, 2H, Ar), 5.68 (s, 2H, N-CH₂-Ar), 4.58 (q, J = 7.1 Hz, 2H, OCH₂CH3), 1.38 (t, J = 7.1 Hz, 3H, OCH₂CH₃).

Example 12

2-Ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1H- benzo[( ]imidazole-7-carboxylic acid - azilsartan of formula II

A solution of ethyl chloroformate (2.7 g, 24.9 mmol) in dry DMF was added dropwise to a mixture of methyl 2-ethoxy-l -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)-l H- benzo[i ]imidazole-7-carboxylate (of formula Va; 10.6 g, 23.8 mmol), dry DMF (75 ml) and pyridine (2.25 g)under stirring in an ice-cold bath under nitrogen and the mixture was stirred under cooling under nitrogen for 6 hours. The reaction mixture was poured into a separation funnel containing water (150 ml) and the mixture was extracted with ethyl acetate (5 x 100 ml). The extract was dried with MgS0₄ and, after evaporation, 12.7 g of a solid yellowish substance were obtained. The evaporation residue was dissolved in DMSO (200 ml) and t- BuOK (8 g, 71.3 mmol) was added under stirring and cooling and the mixture was stirred at the room temperature for 5 h. Then, the reaction mixture was poured into water (750 ml) and the resulting solution was acidified with 5 % HCl. The separated product was aspirated, washed with water and air-dried. 1 1.2 g (the quantitative yield would be ca. 10.9 g) of a product containing 88.3 % of azilsartan of formula II according to HPLC was obtained. Crystallization from isopropanol provided 9.3 g (85.5%) of azilsartan of formula II with the HPLC content of 98.7% with the melting point of 205 to 208 °C.

Claims

C L A I M S

1. A method of preparing alkyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3- yl)biphenyl-4-yl)methyl)- l H-benzo[i/]imidazole-7-carboxylates of formula I,

wherein R is either a branched or unbranched C |-C₄ alkyl, ArCH₂, Ar₂CH, or . wherein Ar is a substituted or unsubstituted phenyl,

characterized in that the corresponding alkoxycarbonyl derivatives of formula VI,

wherein R' is a branched or unbranched, substituted or unsubstituted Ci-C₈ alkyl or substituted or unsubstituted phenyl,

are cyclized by means of a base in a solvent.

2. The method according to claim 1 , characterized in that R is methyl, ethyl, or benzyl.

3. The method according to claim 1 , characterized in that the base is an organic base selected from the group consisting of triethylamine, diisopropylethylamine (DIPEA), 8-diazabicyclo[5.4.0.]undec-7-ene (DBU), l ,4-diazabicyclo[2.2.2]octane (DABCO), l ,8-bis-(dimethylamino)naphthalene, l -methylmorpholine, 1-ethylpiperidine); or an alcoholate selected from the group consisting of CH₃ONa, CH₃OK, C2H₅ONa, t- C₄H₉ONa, t-C₄H₉OK, t-AmONa, and t-AmOK; or an inorganic base selected from carbonates, hydrogen carbonates and acetates of alkali metals or alkaline earth metals. The method according to claims 1 to 3, characterized in that the solvent is a polar aprotic solvent selected from the group consisting of dimethyl sulfoxide (DMSO), N,N- dimethyl formamide (DMF), N,yV- dimethyl acetamide (DMAc), 1 -methyl pyrrolidone (NMP), 1 ,1 ,3,3-tetramethyl urea (TMU), 1 ,3 -dimethyl imidazolidin-2-one (DMI), 1 ,3- dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), and hexamethyl phosphoramide (HMPA), preferably DMSO.

The method according to claims 1 to 4, characterized in that the cyclization is carried out at a temperature in the range from 0°C to the boiling point of the solvent used.

The method according to claims 1 to 5, characterized in that the reaction mixture is processed by dilution with water or pouring the reaction mixture into water, acidification and subsequent isolation of the insoluble product by filtration or centrifugation.

A method of purifying compounds of formula I, obtained by the method according to claims 1 to 6, characterized in that said compounds are crystallized from suitable solvents selected from alcohols such as methanol, ethanol, isopropanol; aliphatic acid esters such as methyl acetate, ethyl acetate, isopropyl acetate; amides such as N,N- dimethyl formamide, N.N-dirnethyl acetamide, 1 -methyl pyrrolidone; ethers such as dioxan, 1 ,2-dimethoxyethane, l-methoxy-2-(2-methoxyethoxy)ethane; and mixtures of these solvents.

Use of alkyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4- yl)methyl)-lH-benzo[ci]imidazole-7-carboxylates of formula I, wherein R is either a branched or unbranched Ci-C₄ alkyl, ArCH₂, Ar₂CH, or Ar₃C, wherein Ar is a substituted or unsubstituted phenyl, for the preparation of azilsartan of formula II,

( ID

9. A method of preparing azilsartan of formula II, consisting in basically initiated cyclization of the corresponding alkoxycarbonyl derivatives of formula VI according to claims 1 and 2,

characterized in that said basically initiated cyclization of the alkoxycarbonyl derivatives of formula VI is carried out by stirring of a solution of the starting compounds in a suitable solvent in the presence of a suitable base and the primarily produced esters of formula I are converted by the base used directly to a salt of azilsartan and, after suitable processing, directly to azilsartan of formula II.

10. The method according to claim 9, characterized in that the solvent is a dipolar aprotic solvent, preferably DMSO or NMP.

1 1. The method according to claims 9 or 10, characterized in that the base is at least two molar equivalents of an alkali metal alcoholate R"OM, wherein R" is a branched or unbranched Ci-C₈ alkyl and M is an alkali metal.

12. The method according to claims 9 to 1 1 , characterized in that the cyclization and conversion to the salt of azilsartan are carried out at a temperature of 0°C to the boiling point of the mixture, preferably at a temperature of 20 to 25 °C.

13. A method of preparing azilsartan of formula II, consisting in basically initiated cyclization of the corresponding alkoxycarbonyl derivatives of formula VI according to claims 1 and 2, characterized in that the basically initiated cyclization of the alkoxycarbonyl derivatives of formula VI is carried out by stirring of a solution of the starting compounds in a suitable solvent, preferably in a dipolar aprotic solvent, most preferably in DMSO, in the presence of at least two molar equivalents of an alkali metal alcoholate R"OM, wherein R" is a branched or unbranched C i -C₈ alkyl and M is an alkali metal, at a temperature in the range of 0 °C to the boiling point of the solvent used, preferably at a temperature of 0° C to 50°C, most preferably at the room temperature.

14. A method of purifying azilsartan of formula II, characterized in that said compound is crystallized from a solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropanol; aliphatic acid esters such as methyl acetate, ethyl acetate, isopropyl acetate; amides such as vV,yV- dimethyl formamide, N,N-dimethyl acetamide, 1 -methyl pyrrolidone; ethers such as dioxan, 1 ,2-dimethoxyethane, 1 - methoxy-2-(2-methoxyethoxy)ethane; and mixtures of these solvents.