A process for preparation of 2-ethoxy-l-[(2,-[(hydroxyamino)iminomethyl]-biphenyl-4-yl)]methyl-lH-benzo[d]imidazole-7-carboxylic acid or it's inorganic salts
Technical field of the invention
The present invention relates to a process for preparation of 2-ethoxy-l-[[2'-[(hydroxyamino)iminomethy]]-biphenyl-4-yl)]methy|-]H-benzo[d]imidazole-7-carboxylic acid or its inorganic salts, of Formula (I), an intermediate compound of Aziisartan of Formula (II).

Wherein; R is H, Li, Na: K, Ca: Mg, Ba. Background of the invention
Aziisartan, chemically known as l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)[l,r-biphenyl]-4-yl]methyl]-2-ethoxy-lH-Benzimidazole-7-carboxylic acid, is an angiotensin II receptor antagonist used for treatment of hypertension. Aziisartan medoxomil having structural Formula (III) is a "prodrug" that is easily transformed to Aziisartan.


The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Azilsartan was first disclosed in US 5,583,141, This patent provides a process for preparation of azilsartan, depicted in scheme I, wherein methyl- l-[(2'-cyanobiphenyl-4-yl]methyl]-2-ethoxybenzimidazole-7-carboxylate of Formula (IV) is converted to an oxime of Formula (A) by reaction with hydroxylamine hydrochloride and sodium methoxide. The oxime of Formula (A), is then subjected to reaction with ethylchlorocarbonate followed by cyclization in xylene at reflux temperature to yield methyl ester of azilsartan of Formula (B) which on hydrolysis provides azilsartanof Formula (I). However, the intermediate formed in the process requires purification by column chromatography which is tedious, expensive, time consuming and hence the process is not viable on industrial scale.


Number of methods for preparation of Aziisartan are reported in literature but the simplest synthetic route is through formation of 2-ethoxy-l-[[2'-[(hydroxyamino)iminomethyl]-biphenyl-4-yI)]methyl-lH-benzo[d]imidazole-7-carboxylic acid of Formula (I).
WO20I3114305, discloses a process for preparation of Aziisartan medoximil through formation of 2-ethoxy-l-[[2'-[(hydroxyamino)iminomethyl]-biphenyI-4-yl)]methyl-IH-benzo[d]imidazole-7-carboxylic acid of Formula (I), wherein later is formed by reaction of a cyano ester of Formula (IV) with hydroxylamine salt in presence of methanolic sodium hydroxide and dimethyl acetate as solvent, followed by hydrolysis

using sodium hydroxide. The intermediate of Formula (I) thus formed was isolated and was subjected to sequentially reaction with 4-(chloromethyl)-5-methy1-1,3-dioxol-2-one and ethyl chloroformate followed by cyclisation to obtain Azilsartan medoximil. Said process depicted in scheme II

WO2012119573, reports a process for preparation 2-ethoxy-l-[[2:-[(hydroxyamino)iminomethyl]-biphenyl-4-yl)]methyl-lH-benzo[d]irnidazole-7-

carboxylic acid or ils ester, by reacting a cyano ester with aqueous hydroxylamine in polar aprotic solvent. This process is said to have reduced the formation of desethyl impurity, however said patent application is silent about other impurities formed in the process. The process is depicted in scheme ill

By careful inspection of all said prior arts with intrinsic and extrinsic evidences, all the prior arts are silent over the amide impurity (formula VI) formed during the reaction. This is the common drawback in all said prior arts.
Inventors of present invention skillfully designed the process in such a way that, the conversion of compound of Formula (IV) to compound of Formula (I), without formation of impurities like desethyl impurity of Formula (VII) and amide impurity of Formula (VI).


In process for preparation of Azilsartan or its ester, if these impurities are not reduced/ removed in early stages, are carried forward along with compound of Formula (I), and effects purity of final compound. It is always desirable to prepare a pharmaceutical product of high purity and having minimal amount of impurities in order to reduce adverse side effects and to improve shelf life of active ingredients. Hence, multiple purifications of Azilsartan or its esters are required which leads to reduction of yield.
To avoid these shortcoming of the prior art. the inventors of present invention have skillfully developed a process to preparation of 2-ethoxy-l-[[2:-[(hydroxyamino)iminomethyIj-biphenyl~4-yI)]methyI-IH-benzo[d]imidazoIe-7-carboxylic acid or its inorganic salts, of Formula (I), which is substantially free of desethyl impurity of Formula (VII) and amide impurity of Formula (VI) by employing the suitable base in process.
Object of the invention
1. The main object of the invention is to provide a process for preparation of 2-ethoxy-l-[[2'-[(hydroxyamino)iminomethyl]-biphenyl-4-yl)]methyl-lH-benzo[d]imidazole-7-carboxylic acid or its inorganic salts, of structural Formula (I)

2. Another object of present invention is to provide 2-ethoxy-l-[[2'-[(hydroxyamino)irninomethyI]-biphenyl-4-yl)]methyl-lH-benzo[d]imidazoIe-7-carboxylic acid or its inorganic salts, of structural Formula (I) having HPLC purity of more than 99% in high yield.
3. Another object of the present invention is to provide 2-ethoxy-l-[[2'-[(hydroxyamino)iminomethyl]-biphenyl-4-yl)]methyl-lH-benzo[d]imidazole-7-carboxylic acid or its inorganic salts, of Formula (I) substantially free of desethy] impurity of Formula (VII) and amide impurity of Formula (VI)
4. Yet another object of the present invention to provide simple, economic and industrially scalable process for the preparation of 2-ethoxy-l-[[2'-[(hydroxyamino)iminomethyl]-bipheny!-4-yl)]methyl-lH-benzo[d]imidazole-7-carboxylic acid or its inorganic salts, of Formula (I)
Summary of the invention
It is an aspect of the present invention to provide a process for preparation of 2-ethoxy-l-[[2'-[(hydroxyamino)iminomethyl]-biphenyl-4-yl)]methyl-lH-benzo[d]imidazole-7-carboxylic acid or its inorganic salts, of Formula (I) by treating cyano ester of Formula (IV) with a metal hydroxide to form compound Formula (V), which further reacts with aqueous hydroxylamine either in-situ or after isolation, in presence of metal hydroxide and a polar aprotic solvent to obtain 2-ethoxy-l-[[2'-[(hydroxyamino)iminomethyl]-biphenyl-4-yl)]methyI-lH-benzo[d]imidazole-7-carboxylic acid or its inorganic salts, of Formula (I), which is substantially free from desethy] impurity (formula VII) and amide impurity (formula VI).


Wherein; R is H, Li, Na, K, Ca, Mg, Ba.
Detailed Description of the Invention
According to an aspect of the present invention, there is provided a process for the preparation of 2-elhoxy-l-[[2'-[(hydroxyamino)iminomethyl]-biphenyl-4-yl)]methyI-]H-benzo[d]imidazole-7-carboxylic acid of Formula (I) comprising:


wherein R is H, Li. Na, K, Ca, Mg, Ba.
a) treating cyano ester of Formula (IV) with a metal hydroxide at temperature ranging from 0°C to 80°C for 3-5 hours, optionally in presence of polar aprotic solvent to form compound Formula (V);

b) optionally, isolating compound of Formula (V);
c) reacting compound of Formula (V), with aqueous hydroxylamine in presence of a aqueous metal hydroxide in a polar aprotic solvent at 0°C to 100°C for 7 -9 hours to obtain 2-ethoxy-l-[[2'-[(hydroxyamino)iminomethyl]-biphenyl-4-yl)]methyl-lH-benzo[d]imidazote-7-carboxylic acid or its inorganic salts, of Formula (I)

According to an embodiment of present invention, the metal hydroxide used in step a) and step c) is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or barium hydroxide, but preferably lithium hydroxide is used.
According to another embodiment of present invention, the metal hydroxide used in step a) and step c) is aqueous metal hydroxide or optionalJy metal hydroxide.
According to another embodiment of present invention, the polar aprotic solvent used in step a) and c) is selected from dimethyl sulfoxide, tetrahydrofuran, ethyl acetate. acetone, water, dimethyl formamide, acetonitrile, but preferably dimethyl sulfoxide or water is used.
According to yet another embodiment of present invention, the compound of Formula (V) is optionally isolated.
According to yet another embodiment of present invention, step (a) and step (b) are carried out in-situ.
The inventors of present invention contemplated the use of number of bases in step a) and step c) to facilitate high purity and high yield of compound of Formula (1). An appropriate base for the present invention is the one that efficiently yields compound of Formula (1), substantially free of desethyl impurity of Formula (VII) and amide impurity of Formula (VI). The observations using different bases in step (a) and step (c) of the present invention are summarized in Table I

Table (I)

Sr. Base used Des-ethyl Amide Di-acid
No. 0 impurity of impurity of impurity of
Formula (VI) Formula (VII) Formula (IX)
01 LiOH Nil 1-2% Nil
02 Mg(OH)2 Nil 2-3 % Nil
03 Ca(OH)2 Nil 2-3 % Nil
04 NaOH 3-4 % 22-25 % 3-4 %
05 Triethyalamine (when R- C1-C3 alkyl; in formula V) 5-6 % 30-33 % Nil
06 NaOMe 3-4 % 22-25 % 3-4 %
07 NaHC03/Na2C03 3-5% 6-7% Nil
08 K2C03 3-5% 7-9% Nil
From above observations it can be concluded that use of metal hydroxides, in step (a) and step (c), controls formation of desethyl impurity of Formula (VII) and amide impurity of Formula (VI) to great extent.
Furthermore, intensive studies by inventors of present invention revealed that usage of strong alkali hydroxide like sodium hydroxide or potassium hydroxide, above 2 moJar concentrations with respect to formula (V) or at high temperature, in step a) and c) leads to formation of di-acid impurity of Formula (IX).


However, surprisingly use of lithium hydroxide in step a) and c) resulted in compound of Formula (I) with high yield and purity without leading to formation of di-acid impurity of Formula (IX) and hence, use of lithium hydroxide is preferred in step (a) and step (c).
It was surprisingly found that the metal hydroxide salt of compound of Formula (V) on treatment with aqueous hydroxylamine in presence of base do not allow hydrolysis on carboxylic acid site and hence, results in compound of Formula (I), substantially free from impurities. In converse to this, ester of compound of Formula (V) on treatment with aqueous hydroxylamine/ hydroxylamine HC1 in presence of base like triethylamine, sodium carbonate, sodium methoxide, potassium ter-butoxide, sodium bicarbonate etc. may allow hydrolysis on carboxylic acid site which change the reactivity of molecule and leads to formation of impurities like desethyl, amide and di-acid.
According to present invention, the process for preparation of compound of Formula (I), is depicted in Scheme IV


The detail of the invention provided in the following example is given by the-way of illustration only and should not be construed to limit the scope of the present invention.

Examples:
Example 1: Preparation of l-[(2'-cyanobiphenyl-4-yI)methyl]-2-ethoxy-lH-benzimidazole-7-carboxylic acid, compound of Formula (V)
A mixture of a cyano ester of Formula (IV) (5.9 g 0.012 mols) and aqueous lithium hydroxide (0.7649 g 0.018 mols) in dimethylsulfoxide was stirred at 50-80 °C for 5-S hours. After completion of reaction, the mixture was quenched in water and acidified with dilute Hydrochloric acid (60 ml) at 10-20 °C. Cooled to 10-20 °C and stirred for 1 hour. The precipitate obtained was filtered, washed with water (10 ml), and dried in a vacuum drier (35 °C/50 mbar) overnight to provide 4.6 g ofJ-[(2'-cyanobipheny]~4-yl)methyl]-2-ethoxy-lH-benzimidazo!e-7-carboxylic acid having HPLC purity of 99.7% (Yield: 98%)
Example 2: Preparation of l-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-lH-benzimidazole-7-carboxylic acid, compound of Formula (V)
The same procedure of example 1 was followed except that ethyl acetate was used instead of dimethyl sulphoxide. The process provided 4.5 g of J-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-lH-benzimidazole-7-carboxylic acid having HPLC purity of 99.7% (Yield: 97.7%). The same reaction as in example 3, with same reaction condition subject to boiling point of solvent are carried out in various solvent the result obtained is depicted in table

Example Solvent used for reaction (reaction condition remains same as in Example 01) Yield & Purity (%)
03 Tetrahydrofuran 96 % & 99%
04 Iso-propyl alcohol 97 % & 99%

05
Dimethyl formamide 97 % & 99.30%
06 Acelonitriie 97 % & 99%
07 water 98 % & 99.5%
Example 8: Preparation of l-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-lH-benzimidazole-7-carboxylic acid, compound of Formula (V)
The same procedure of example 1 was followed except that aqueous magnesium
hydroxide (1.059 g 0.0182 mols) was used instead of aqueous lithium hydroxide.
The process provided l-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-lH-
benzimidazole-7-carboxylic acid having HPLC purity of 99.7% (Yield: 97.7%)
Example 9: Preparation of l-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-lH-benzimidazole-7-carboxyIic acid, compound of Formula (V)
The same procedure of example 1 was followed except that aqueous calcium hydroxide (1.349 g 0.0182 mols) was used instead of aqueous lithium hydroxide. The process provided l-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-lH-benzimidazole-7-carboxylic acid having HPLC purity of 99.7% (Yield: 96.5%)
Example 10: Preparation of l-[(2'-cyanobiphenyI-4-yl)methyl]-2-ethoxy-lH-benzimidazole-7-carboxylic acid, compound of Formula (V)
The same procedure of example 1 was followed except that barium hydroxide (3.19 g 0.0182 mols) was used instead of aqueous lithium hydroxide. The process provided I -[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1 H-benzimidazole-7-carboxyl \c acid having HPLC purity of 99.7% (Yield: 96%)

Example 11: Preparation of l-[(2'-cyanobiphenyl-4-yl)methyll-2-ethoxy-lH-benzimidazole-7-carboxylicacid, compound of Formula (V)
The same procedure of example 1 was followed except that aqueous sodium
hydroxide (0.739 g 0.0162 mols) was used instead of aqueous lithium hydroxide.
The process provided 1 -[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-
benzimidazole-7-carboxylic acid having HPLC purity of 96% (Yield: 93%)
Example 12: Preparation of l-[(2'-cyanobiphenyl-4-yI)methyl]-2-ethoxy-lH-benzimidazole-7-carboxylic acid, compound of Formula (V)
A mixture of a cyano ester of Formula (IV) (5.09 g 0.0121 mols) and aqueous lithium hydroxide(0.7649 g 0.018 mols) without solvent was stirred at 50-80 °C for 5-8 hours. After completion of reaction, the mixture was quenched in dilute Hydrochloric acid at 10-20 °C. Then the mixture was again diluted with water (10 ml), slowly cooled to 10 °C and stirred for 1 hour. The precipitate obtained was filtered, washed with water (10 ml), and dried in a vacuum drier (35 °C/50 mbar) overnight to provide 4.5 g of l-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-lH-benzimidazole-7-carboxylic acid having HPLC purity of 99.6%. (Yield: 97.6%)
Example 13: Preparation of 2-Ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)-biphenyl-4-yI)methyl)-lH-benzirnidazole-7-carboxylic acid, compound of Formula (I)
A mixture of a compound of Formula (V) (5.09 g, 0.0125 mol), lithium hydroxide (1.05 g, 0.0251 mol). dimethyl sulfoxide (30 ml), and 50% aqueous hydroxylamine (16.69 g 0.251 mol) was stirred at 90 °C for 8 hours. Then the mixture was poured

into aqueous HC1 solution (18 mL), stirred for 30 min at 20 °C and was washed with MDC or toluene (10X2 ml). The aqueous layer obtained, was basified to yield a solid precipitate which was filtered, washed with water and dried to give 4.85 g of white precipitate containing 99 % of 2-Ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)-biphenyl-4-yl)methyl)-lH-benzimidazole-7-carboxylic acid, compound of Formula (I) according to HPLC. (Yield: 95%)
Example 14: Preparation of 2-Ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)-biphenyl-4-yl)methyl)-lH-benzimidazoIe-7-carboxylic acid, compound of Formula (I)
The same procedure of example 6 was followed except that sodium hydroxide (1.0 g 0.0251 mols) was used instead of lithium hydroxide. The process provided 4.3 g of white precipitate containing 99 % of 2-Ethoxy-1-((2'-(N,-hydroxycarbamimidoyl)-biphenyl-4-yl)methyl)-lH-benzimidazole-7-carboxylic acid, compound of Formula (I) according to HPLC. (Yield: 84%)
Example 15: Preparation of 2-Ethoxy-l-((2'-(N'-hydroxycarbamimidoy])-biphenyl-4-yl)methyl)-l H-benzimidazole-7-carboxylic acid, compound of Formula (I) (in-situ)
A mixture of a cyano ester of Formula (IV) (5.09 g 0.0121 mols) and aqueous lithium hydroxide (0.7649 g 0.0182 mols) in dimethylsulfoxide was stirred at 50-80 °C for 5-8 hours. After completion of reaction, 50% aqueous hydroxylamine (16.69 g 0.251 mol) was added and reaction mixture was stirred at 90 °C for 8 hours. The the mixture was poured into aqueous HC1 solution (22 mL), stirred for 30 min at 20 °C and was washed with MDC or toluene (10X2 ml). The aqueous layer thus formed,

was basified to obtain solid product which was filtered, washed with water and dried to get4.89 g of compound of Formula (I) having HPLC purity of 99.5%. (Yield :92%)
Example 16: Preparation of 2-Ethoxy-l-((2'-(N'-hydroxycarbamimidoyI)-biphenyl-4-yl)methyl)-lH-benzimidazole-7-carboxylic acid, compound of Formula (I) (in-situ)
The same procedure of example 8 was followed except that sodium hydroxide (1.09 g 0.0251 mols) was used instead of lithium hydroxide . The process provided 4.59 g of compound of Formula (I) having HPLC purity of 98%. (Yield: 87%)
Referential example-1
Preparation of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazoIe-3-yl)
biphenyl-4-yl) mcthyl}-lH-benzo[d]imidazoJe-7-carboxyiic acid.
To the mixture of DMSO or THF (50ml) and sodium carbonate (3.7g, 0.0348 mol) was added 2-ethoxy-l-((2'-(N!-hydroxycarbamimidoyl) biphenyl-4-yl) methyl)-lH-benzo[d]imidazole-7-carboxylic acid (5.0g, 0.0116 mol) at 25-30°C. Cooled the reaction mass to 5-10°C and ethyl chloroformate (I.5g, 0.013 mol) was added and stirred the mixture at 25-30 C till completion. Quench with water, pH adjusted to 3-6, solid filtered washed with water followed by chloroform or MDC slurry wash to obtain crude product which on purification with methanol gives pure 3.5g 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) biphenyl-4-yl) methyl}-1H-benzo[d]imidazole-7-carboxylicacid.

We claim
1. A process for the preparation of 2-ethoxy-l-[[2'-[(hydroxyamino)iminomethyI]-biphenyl-4-yl)]methyl-lH-benzo[d]imidazole-7-carboxyIic acid of Formula (I) comprising:

Wherein; R is H, Li, Na, K, Ca, Mg, Ba.
a) treating cyano ester of Formula (IV) with a metal hydroxide at temperature ranging from 0°C to 80°C for 3-5 hours, optionally in presence of polar aprotic solvent to form compound Formula (V);

Wherein; R is same as defined above
b) optionally, isolating compound of Formula (V);

c) reacting compound of Formula (V), with aqueous hydroxylamine in presence of a metal hydroxide in a polar aprotic solvent to obtain 2-ethoxy-I-[[2'-[(hydroxyamino)iminomethyl]-biphenyl-4-yl)]methyl-lH-benzo[d]imidazole-7-carboxylic acid or its inorganic salts, of Formula (I).
2. The process as claimed in claim 1, wherein the metal hydroxide used in step a) and step c) is optionally aqueous metal hydroxide.
3. The process as claimed in claim 1, wherein the metal hydroxide used in step a) and step c) is selected from lithium hydroxide, calcium hydroxide, magnesium hydroxide or barium hydroxide.
4. The process as claimed in claim 1, wherein the metal hydroxide used in step a) and step c) is lithium hydroxide.
5. The process as claimed in claim 1, wherein polar aprotic solvent used in step a) and step c) is selected from dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, acetone, dimethyl formamide, acetonitrile, water or mixture thereof.
6. The process as claimed in claim 1, wherein polar aprotic solvent used in step a) and step c) is dimethyl sulfoxide.