Field of the Invention

The present invention relates to an improved process for preparing Eprosartan.

Background of the Invention

Eprosartan is a potent and selective angiotensin II subtype 1 receptor antagonist. Angiotensin II (formed from Angiotensin I in a reaction catalyzed by Angiotensin -converting enzyme kininase II), a potent vasoconstrictor, is the principal pressor agent of the rennin-angiotension system. Angiotensin II also stimulates aldosterone synthesis and secretion by the adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system, and smooth muscle cell growth. Eprosartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues. There is also an AT2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. By inhibiting the binding, Eprosartan disrupts the vasoconstriction mediated by AT1 receptors and thus helps patients with hypertension. In addition, by reducing the pressure against which the heart must pump blood, candesartan reduces the work of the heart and is useful in patients with heart failure.

The chemical name of Eprosartan is (E)-2-butyl-1-(p-carboxybenzyl)-a-(2-thienylmethyl) imidazole-5-acrylic acid, monomethanesulfonate.

Processes for the preparation of Eprosartan and related compounds were disclosed in U.S. Patent No. 5,185,351; 6,172,237 and PCT publication No. WO2008/078330.

According to the U.S. Patent No. 5,185,351, methyl 4-[[2-butyl-5-formyl-1H-imidazol-1-yl]methyl]benzoate is reacted with ethyl 2-carboxy-3-(2-thienyl)propionate, in the presence of a base, such as piperidine, in a suitable solvent, such as toluene, at a temperature of 80°C to 110°C, preferably at 100°C, to give ethyl (aE)-a-[[2-n-Butyl-1-[[4- (methoxycarbonyl)phenyl]methyl]-1H-imidazol-5-yl]methylene-2-thiophene propionate, which is then hydrolyzed to give Eprosartan, which is further converted to Eprosartan mesylate.

According to U.S. Patent No. 6,172,237, Eprosartan is prepared by reacting 4-[[2-butyl-5-formyl-1H-imidazol-1-yl]methyl]benzoic acid or the bisulfite addition compound of 4-[[2-butyl-5-formyl-1 H-imidazol-1-yl]methyl]benzoic acid with (2-thienylmethyl)-propanedioic acid, mono-ethyl ester in a solvent (and/or solvent systems) selected from the group consisting of toluene, cyclohexane, cyclohexane:dichloroethane (12:5 or 1 :1), cyclohexane:pyridine (12:5), and cyclohexane:ethyl acetate: pyridine (8:3:1) in the presence of piperidine as catalyst at reflux temperature at reduced pressure followed by hydrolysis of the intermediate ethyl ester (ethyl (a£)-o>[[2-n-butyl-1-[[4-(methoxycarbonyl) phenyl]methyl]-1 H-imidazol-5-yl]methylene-2-thiophene propionate). It is difficult

to maintain the reaction at reflux under vacuum. The vacuum creates loss of solvent from reaction medium.

According to WO2008/078330, Eprosartan is prepared by reacting methyl-4-[[2-butyl-5-formyl-1H-imidazol-1-yl]methyl]benzoate with (2-thienylmethyl)-propanedioic acid, monoethyl ester in a solvent selected from cylcohexane and n-hexane in the presence of piperidine as catalyst at reflux temperature followed by hydrolysis.

The disadvantage of the prior art process is the difficultly in condensation reaction of compound of formula (a) with compound of formula (b) in presence of reduced pressure or carrying the reaction at higher temperature which leads to the formation of impurities. Thus requires extensive purification procedures to obtain the required quality of the product, which lowers the yield and there by increasing the operational cost of the product.

Still there is a need for an improved and commercially viable process of preparing pure Eprosartan, which will be suitable for large-scale preparation, in terms of simplicity, chemical yield and purity of the product.

Object of the invention

The main object of the present invention relates to an improved process for the preparation of Eprosartan and its pharmaceutical acceptable salts.

Another object of the present invention relates to an improved process for the preparation of Eprosartan Mesylate.

Summary of the Invention

In accordance with main aspect of the present invention, there is provided an improved process for the preparation of Eprosartan comprising the steps of:

a) condensing the compound of formula (a) with a compound of formula (b) in presence of a catalyst and in a solvent selected from chlorinated C1-5 alkyl, chlorinated benzene, n- heptane, n-butanol or mixtures thereof to get a compound of formula (c);

or

condensing the compound of formula (a) with a compound of formula (b) in presence of a catalyst and dehydrating agent such as molecular sieves to get a compound of formula
(c);

b) hydrolyzing the compound of formula (c) to get a compound of formula (I)

c) optionally converting compound of formula (I) into a pharmaceutically acceptable acid addition salt.

The present invention is represented by the following scheme.

wherein R, and R2 are independently selected from CM alkyl.

Detailed description of the Invention

The present invention provides an improved process for the preparation of Eprosartan or its pharmaceutically acceptable salt comprising the steps of: condensing compound of formula (a) with compound of formula (b) in presence of a catalyst, in a solvent selected from chlorinated C1-5 alkyl, chlorinated benzene, n-heptane, n-butanol or mixtures thereof to get a compound of formula (c), and hydrolyzing the compound of formula (c) to get Eprosartan and optionally converting Eprosartan to its pharmaceutically acceptable salt. The present invention also relates to process for the preparation of compound of formula (c) by condensing compound of formula (a) with compound of formula (b) in presence of dehydrating agent.

One aspect of the present invention relates to an improved process for preparing Eprosartan of formula 1:

or a pharmaceutically acceptable salt thereof; which comprises:

a) reacting compound of formula (a):

wherein R1 is CM alkyl;

with a compound of formula (b):

wherein R2 is CM alkyl;

in the presence of a catalyst and in a solvent selected from chlorinated d.5 alkyl, chlorinated benzene, n-heptane, n-butanol or mixtures thereof to get diester intermediate of formula (c):

b) hydrolyzing the compound of formula (c) to obtain Eprosartan of formula (I)

c) optionally converting Eprosartan of formula (I) into a pharmaceutically acceptable acid addition salts of Eprosartan.

According to one embodiment of the present invention, catalyst used in condensation of compound of formula (a) with compound of formula (b) is selected from piperidine, morpholine, 1-methylpiperazine, pyrrolidine or their salts thereof; preferably piperidine or its salts such as Piperidinum acetate.

According to one more embodiment of the present invention, solvents used in condensation of compound of formula (a) with compound of formula (b) is selected from chlorinated C1-5 alkyl, chlorinated benzene, n-heptane, n-butanol or mixtures thereof; preferably n-heptane, dichloromethane or mixtures thereof more preferably heptane and dichloromethane mixtures in solvent ratio selected from 50:50, 70:30, 80:20, 90:10 and the like.

According to the present invention "chlorinated C1-5 alkyl" generally means, unless specified otherwise, chloro substituted alkanes such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like.

Typically the process is carried out by condensing 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid or its ester with (2-thienylmethyl)-propanedioic acid, mono-alkyl ester in a suitable solvent selected from chlorinated C1-5 alkyl, chlorinated benzene, n-heptane, n-butanol or mixtures thereof preferably heptane:dichloromethane mixture in the presence of a catalyst, for example piperidine with acetic acid, at a suitable temperature, such as at a temperature of about 75°C to about 100°C, preferably at a temperature of 80°C to 85°C

The resulted ester is hydrolyzed to the corresponding carboxylic acid of compound of formula (I) using base, such as aqueous sodium or potassium hydroxide. Thereafter, pharmaceuticaly acceptable salts may be prepared as per the procedure known in the art. Preferably Eprosartan Mesylate is formed by reacting Eprosartan with Methane sulphonic acid in presence of a solvent.

Acid addition salts of formula (I) are formed with the appropriate inorganic or organic acids by methods known in the art. Representative examples of suitable acids are maleic, fumaric, acetic, succinic, hydrochloric, hydrobromic, sulfuric, phosphoric or methanesulfonic. Preferably, the pharmaceutically acceptable acid addition salt for the formula (I) compound is the methanesulfonic acid addition salt.

According to one embodiment of the present invention, Eprosartan of formula (I) is further converted to its pharmaceutically acceptable salts preferably Mesylate salt by reacting Eprosartan of formula (I) with methane sulphonic acid in presence of a solvent to yield Eprosartan Mesylate.

According to one embodiment of the present invention, solvent used in the conversion of Eprosartan to Eprosartan Mesylate is selected from alcohols such as ethanol, methanol, isopropyl alcohol; ketones such as acetone, butanone; esters such as ethyl acetate, isopropylacetate; acids such as acetic acid or mixtures thereof.

One more aspect of the present invention relates to an alternative process for preparation of diester intermediate of compound of formula (c):

which comprises:

a) reacting compound of formula (a):

wherein R1 is CM alkyl;

wherein R2 is C1-4 alkyl;

in the presence of a catalyst and dehydrating agent such as molecular sieves to get diester intermediate of formula (c).

According to one more embodiment of the present invention, condensation of compound of formula (a) with compound of formula (b) is carried out in the presence of a dehydrating agent such as molecular sieves.

As per the present invention, the process is carried out by condensing 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid or its ester with (2-thienylmethyl)-propanedioic acid, mono-alkyl ester in a suitable solvent, such as toluene, n-heptane or n-butanol, in presence of dehydrating agent for example Molecular sieves, along with a catalyst, for example piperidine with acetic acid, at a suitable temperature, such as at a temperature of about 75°C to about 100°C, preferably at a temperature of 80°C to 85°C.
According to one more aspect of the present invention, diester intermediate compound of formula (c) is further converted to Eprosartan of formula (I) or its pharmaceutically acceptable salts as per the procedures given above.

According to the present invention condensation reaction is carried out in absence of reduced pressure; and in a solvent medium which leads to the formation of diester intermediate in pure form in high yield. Without any further purification the diester intermediate is hydrolyzed to yield Eprosartan with high purity and high yield.

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

Examples

Example 1: Preparation of Eprosartan
A compound of methyl-4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl) methyl] benzoate (10 gms), was taken in a mixture of 135 ml of n-heptane and 15 ml of dichloromethane at room temperature. The reaction mixture was maintained at 70-80 °C for duration of 15-30 min by using Dean Stark apparatus. Then Piperidinum acetate catalyst (2.8 gms of Piperidine and 5.55 gms of acetic acid) in mixture of 8.5 ml of n-heptane and 1.5 ml of dichloromethane was added to the reaction mixture followed by addition of a compound of 2-thiophene-2-yl-methylmalonic acid monoethyl ester (17.3 gms). Reaction temperature was maintained at 70-80 °C for duration of -20 hrs. After reaction completion temperature was cooled to RT. Ethanol and DM water were added to the reaction mass and the pH was adjusted to 1.0 by using HCI. The layers were separated, and the aqueous layer was washed with n-heptane. Then pH of the aqueous layer was adjusted to 6.0 by using NaOH solution and resulted solution was extracted with toluene. The Combined organic layers were concentrated under vacuum. Resulted concentrated reaction mass was dissolved in ~ 130 ml of ethanol to this a solution of NaOH (13.5 gms of NaOH in 65 mL of water) was added and stirred for 1-2 hours. pH of the reaction mass was adjusted to 4.5 to 5.0 with HCI The resulted solid was filtered, washed with water and dried under vacuum to yield 11 gms of Eprosartan.

The reaction was also carried out by altering the solvents ratio and the obtained results were tabulated as shown bellow.

Example 2: Preparation of Eprosartan:

10 gms of Molecular sieves was added to 300 mL of toluene followed by methyl-4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoate (5 gms, 0.0166 moles) at room temperature (25-35 °C) in a 1 Lt round bottom flask. To this Piperidine (1.32 gms, 0.01552 moles) and acetic acid (10 mL) in 10 mL of toluene was added and slowly heated to 80°C. 2-Thiophen-2ylmethylmalonic acid monoethyl ester (4.38 gms in 12.5 mL of toluene) was added dropwise for a duration of 15-25 min and stirred at 80-85 °C for 60 min. 5 gms of 2-Thiophen-2ylmethylmalonic acid monoethyl ester in 12.5 mL of toluene was added dropwise for a duration of 15-25 min and stirred at 80-85 °C for 20 hrs. Again 1.4 gms of 2-thiophen-2ylmethylmalonic acid monoethyl ester in 12.5 mL of toluene was added dropwise for a duration of 15-25 min and stirred at 80-85 °C for 4 hrs. Reaction mass was cooled to room temperature and 50 mL of DM water was added and stirred for 10 min. Organic layer (Toluene) was separated and distilled under vacuum at below 60 °C. The concentrated mass cooled to room temperature. To this 40 mL of ethanol was added followed by 20 mL of KOH (4.66 gms, 0.0833 moles) solution. Slowly temperature was raised to reflux temperature and maintained for 4 hrs. Reaction mass was cooled to room temperature, pH was adjusted to 5.0-5.2 by adding 6N HCI and allowed to settle for 2 hrs. Then solid was filtered and washed with water followed by drying at 40-45 °C for 6 hrs under reduced pressure to yield 2.0 gms of Eprosartan.

Example 3: Preparation of Eprosartan Mesylate

10 gms of Eprosartan was dissolved in 150 ml of isopropyl alcohol at room temperature. 6.8 gms of methane sulfonic acid was added to the resulted clear solution and stirred for about 2 hours. The resulted solid was filtered, washed with isopropyl alcohol and dried to yield 10 gms of Eprosartan Mesylate.

Example 4: Preparation of Eprosartan Mesylate

10 gms of Eprosartan was dissolved in 150 ml of acetone at room temperature. 6.8 gms of methane sulfonic acid was added to the resulted clear solution and stirred for about 2 hours. The resulted solid was filtered, washed with acetone and dried to yield 10 gms of Eprosartan Mesylate.

Example 5: Preparation of Eprosartan Mesylate

10 gms of Eprosartan was dissolved in 150 ml of ethyl acetate at room temperature. 6.8 gms of methane sulfonic acid was added to the resulted clear solution and stirred for about 2 hours. The resulted solid was filtered, washed with ethyl acetate and dried to yield 10 gms of Eprosartan Mesylate.

Example 6: Preparation of Eprosartan Mesylate

10 gms of Eprosartan was dissolved in 50 ml of ethyl acetate at room temperature and 6.8 gms of methane sulfonic acid was added. Stirred the reaction mass for about 30-35 minutes and 30 ml of Acetic acid was added. Raised the temperature to about 75-80°C and stirred for 30-45 minutes. The resulted solid was cooled, filtered, washed with ethyl acetate and dried to yield 10 gms of Eprosartan Mesylate.

Example 7: Preparation of Eprosartan Mesylate

30 ml of acetic acid was added to 10 gms of Eprosartan and 6.8 gms of methane sulphonic acid. Heated the reaction mass to about 75-80°C and 10 gms of Carbon was added. Stirred the reaction mass for about 30-35 minutes, filter through high flow bed. Filtrate was cooled and 50 ml of ethyl acetate was added. Stirred the reaction mass for about 60 minutes and again 50 ml of ethyl acetate was added. Stirred the reaction mixture for about 5 hours and filtered. The solid was washed with ethyl acetate and dried to yield 10 gms of Eprosartan Mesylate.

Claims:

1. An improved process for the preparation of Eprosartan of Formula (I)

or a pharmaceutically acceptable salt comprising the steps of:

i) reacting compound of formula (a):

wherein R1 is C1-4 alkyl;

with a compound of formula (b):

wherein R2 is CM alkyl;

in the presence of a catalyst and in a solvent such as chlorinated C1-5 alkyl, chlorinated benzene, n-heptane, n-butanol or mixtures thereof, to get diester intermediate of formula (c):
ii) hydrolyzing the compound of formula (c) to obtain Eprosartan of formula (I) iii) optionally converting Eprosartan of formula (I) into a pharmaceuticaly acceptable acid addition salts of Eprosartan.

2. The process according to claim 1, wherein catalyst used in step (i) is selected from piperidine, morpholine, 1-methylpiperazine, pyrrolidine and a salt thereof.

3. The process according to claim 1, wherein solvent used in step (i) is selected from n-heptane, dichloromethane or mixtures thereof.

4. The process according to claim 1, wherein the solvent used in step (i) is n-heptane, dichloromethane mixture in the ratio 50:50 to 90:10.

5. The process according to claim 1, wherein the condensation of compound of formula (a) with compound of formula (b) is carried out at a temperature of about 75°C to about 100°C.

6. The process according to claim 1, wherein the hydrolysis of the compound of formula (c) is carried out in the presence of a base.

7. The process according to claim 6, wherein base is sodium hydroxide or potassium hydroxide.

8. An improved process for the preparation of Eprosartan of Formula 1

or a pharmaceutically acceptable salt thereof; i) by reacting compound of formula (a):
wherein R1 is C1-4 alkyl;

with a compound of formula (b):

wherein R2 is C1-4 alkyl;

in the presence of a catalyst and dehydrating agent to get diester intermediate of formula (c):

ii) hydrolyzing the compound of formula (c) to obtain Eprosartan of formula (I)

iii) optionally converting Eprosartan of formula (I) into a pharmaceutically acceptable acid

addition salts of Eprosartan.

9. The process according to claim 8 wherein the dehydrating agent used in step (i), is molecular sieves.

10. The process according to claim 1 and 8, wherein Eprosartan of formula (I) is converted to pharmaceutically acceptable acid addition salt preferably Eprosartan Mesylate.