IMPROVED PROCESS FOR MANUFACTURING ANHYDROUS (E)-3-[2N-BUTYL-l-
{(4-CARBOXYPHENYL)METHYL}-lH-IMIDAZOLE-5-YL]-2.(THIENYL)
METHYL-2-PROPENIOC ACID METHANE SULFONATE
Field of the Invention
The present invention relates to a simple efficient and cost effective process for coinmercial manufacture of (E)-3-[2n-butyl-l-{(4-carboxyphenyl) methyl}-lH-imidazole-5-" yl]-(2-thienyl)methyl-2-propenioc acid and its conversion to substantially pure anhydrous mesylate salt as shown in Formula I, with a purity level of 99.85% and single individual impurity of less than 0.10 %.

Background of the Invention
Eprosartan mesylate is known to be angiotensin II receptor antagonist and is useful in regulating hypertension induced by angiotensin II and in the treatment of congestive heart failure, renal failure and glaucoma.
US5185351 describes the process for preparation of imidazole compoimds one amongst them being Eprosartan .The process comprises condensation of valerimidine methyl ester with dihydroxyacetone to give a diacetate which was treated with 4-carboxymethylbenzyl alcohol in the presence of trif lic acid to give 2n-butyl-5-acetoxymethyl-l-(4-carboxyphenyl)-methyl-lH-imidazole. Thus obtained compound on further oxidization with manganese dioxide and thereafter condensation with methyl-3-(3-(2-theinyl)-propionate in the presence of n-butyl hthium at -78°C gives an ester which is hydrolysis gives Eprosartan. Eprosartan is further converted to its desired salt form. The form of the product obtained here is anhydrous in nature. The process can be best represented by Scheme I shown below;


The process has the following drawbacks, use of hazardous reagents such as n-butyl lithium, DBU and triflic acid which are not suitable to use at manufacturing scale because of their high cost and safety reasons. The temperature of the reaction has to be maintained at - which is difficult to achieve and maintain all the time at manufacturing scale moreover the overall yields are also very low about 40%.
US6172237 (EP0970073) discloses the condensation of 4-[(2-n-butyl-5-formyl-lH-imidazol-l-yl)methyl]benzoic acid or the bisulfite addition compound of 4-[(2-n-butyl-5-formyl-1 -yl-imidazol-1 -yl)methyl]benzoic acid and 2-(thienylmethyl)propanedioic acid(Scheme II) or 2-(thienylmethyl)propanedioic acid monoethyl ester(Scheme III) at reflux temperature in toluene imder reduced pressure 9-13 inches Hg in presence of piperidine as a catalyst followed by hydrolysis of the intermediate ethyl ester to give Eprosartan which is further converted to its desired salt form, best represented by Scheme II shown below, the form of the product obtained here is anhydrous form;


The major drawbacks of this processes are, the condensation is done at reduced pressure of 9-13 inches Hg which is very difficult to maintain all the time at higher scale of production, the reaction is time consuming and when used as potassium or sodium salts gives low yield.
US6458963 (EP973769) discloses regioselective protection of nitrogen of the 2-n-butyl-4-formyl-lH-imidazole ring followed by treatment with (2-thienylmethyl)propanedioic acid, mono methyl ester under reduced pressure treatment with methyl-4-bromomethyl-benzoate and hydrolysis of the ester, followed by deprotection to give Eprosartan which is converted to its suitable salt form as shown in Scheme TV below,


Alternatively US6458963 (EP973769) also discloses another process as in Scheme V whereby 2-n-butyl-4-fonnyl-1 H-imidazole is first condensed with (2-thienylmethyl) propanedioic acid, mono methyl ester then the product is regioselectively protected condensed and deprotected to give Eprosartan which is converted to its suitable salt form,

The drawbacks of these processes as in Scheme IV and V are that there is frequent protection followed by deprotection which leads to lower yield, use of costlier reagents like DBU is not advisable at manufacturing scale. The condensation is carried out under reduced pressure which is difficult to maintain all the time at higher scale of production.
. Med. Chem. (1991), 34, 1514-1517 discloses a process for the preparation of Eprosartan in which the condensation of the aldehyde with (2-thienylmethyl) propanedioic acid monomethyl ester in the presence of piperdine using toluene as solvent wherein the reported yield was only 40%.
US6517871 (EP1098634) disclose and claims amorphous ammonium salt of Eprosartan and process of preparation which comprises dissolving Eprosartan or Eprosartan mesylate in ammonium hydroxide in the presence of crystallization inhibitor(polvinyl pyrrolidine).
EP889880 (US2001003187) discloses Eprosartan methanesulfonate dihydrate and the process of preparation thereof from anhydrous Eprosartan methanesulfonate.

US6262102 (EP991647) discloses Eprosartan methanesulfonate monohydrate and the process of preparation thereof for anhydrous Eprosartan methanesulfonate.
It is apparent from most of the prior arts that, the preparation of Eprosartan has certain disadvantages such as the use of hazardous and costly raw materials like n-butyl lithium, DBU and triflic acid, low reaction conditions like temperature below -78 which is difficult to maintain all the time at higher scale of production, steps of protection followed by deprotection and high impurity and low yields. Therefore, there is a continuing need for developing a new process for the preparation of substantially pure Eprosartan mesylate which is cost effective and industrially viable.
Detail description of the invention
The present invention relates to a simple efficient and cost effective process for commercial manufacturing (E)-3-[2n-butyl-1 - {(4-carboxyphenyl) methyl} -1 H-imidazole-5-yl]-2-(thienyl)methyl-2-propenioc acid and its conversion to the substantially pure anhydrous Eprosartan mesylate of Formula I,

The process for preparation of Eprosartan can be best described by the scheme VII discussed below, which comprises;


• reacting 2-n-butyl-4-formyl-1 H-imidazole with (2-thienylmethyl)propanedioic acid
monomethyl ester at atmospheric pressure in which (2-thienyhnethyl)propanedioic acid
monomethyl ester was added in lots to 2-n-butyl-4-fonnyl-l H-imidazole in a suitable
organic solvent over a period of 4-5 hrs to avoid decarboxylation of (2-
thienylmethyl)propanedioic acid to give a compound of Formula III as shown in step la
• treating the compound of formula II with methyl 4-(bromomethyl)benzoate to give a
compound of Formula III as shown in 2a or 2b
• hydrolyzing the compound of Formula III followed by acidification to give Eprosartan of Formula IV
• methane sulphonate salt formation of compound of formula IV in a suitable organic solvent to give substantially pure anhydrous form of Eprosartan mesylate Formula I as in step 4.
The reaction of 2-n-butyl-4-formyl-1 H-imidazole with (2-thienylmethyl) propanedioic acid mono methyl ester is carried out in an organic solvent selected froma group consisting of cyclohexane, toluene, dichloromethane, water or mixture thereof; most preferably cyclohexane and a suitable base as catalyst selected fi-om a group consisting of piperidine, pyridine, morpholine, N-methyl pyrolidine most preferably piperidine to give a compound (2E)-3-(2-butyl-4,5-dihydro-1 H-imidazol-5-yl)-2-(thiophen-2-ylmethyl)prop-2-enoic acid of formula II (as in step 1)
The reaction of the compound of formula II with methyl 4-(bromomethyl)benzoate can be carried out in an organic solvents selected from a mixture of toluene: water or dichloromethane: water most preferably mixture of toluene: water in presence of a suitable

base selected from sodium hydroxide or potassium hydroxide most preferably sodium hydroxide with a phase transfer catalyst selected from tetra-n-butyl ammonium bromide (TBAB) or tetra-n-butyl ammonium iodide; most preferably tetra-n-butyl ammoniumbromide (TBAB) to give compound of formula III as in step 2a of Scheme VII.
Alternatively the reaction of the compound of formula III with methyl 4-(bromomethyl) benzoate can also be carried out in an organic solvent selected from a group consisting of dimethylformamide, dimethylsulphoxide or tetrahydrofuran; most preferably dimethylformamide and a suitable base selected from potassium carbonate or sodium carbonate; most preferably potassiimi carbonate to give compound of formula III as in step 2b of Scheme VII.
The hydrolysis of the compound of Formula III can be carried out in an organic solvent selected from a group consisting of methanol, ethanol or isopropyl alcohol most preferably methanol with a suitable base selected from sodium hydroxide or potassium hydroxide; most preferably sodium hydroxide.
The reaction after hydrolysis is acidified in the presence of suitable acid selected from acetic acid or dilute hydrochloric acid; most preferably acetic acid to give compound of formula IV.
The methane sulphonate salt formation of the compound of formula IV is carried out in the presence of methane sulphonic acid in an organic solvent selected form acetic acid, isopropanol or ethanol; most preferably acetic acid to give a compound of Formula I.
Alternatively Eprosartan mesylate can also be manufactured as depicted below in Scheme VIII whose process comprises;


• reacting 2-n-butyl-4-formyl-5-chloro-1 H-imidazole with methyl 4-
(bromomethyl)benzoate to give a compound of formula V as in step 1
• dehaloginating the compound of Formula V to give a compoundof formula VI as in
step 2
• condensation of the compound of Formula VI with a compound of Formula II imder reduced pressure to give a compound of Formula III as in step 3
• hydrolyzing the compound of Formula III followed by acidification to give Eprosartan of Formula IV as in step 4
• forming methane sulphonate salt of compound of formula IV in a suitable organic
solvent to give anhydrous Eprosartan mesylate of Formula I (as in scheme VII) as in
step 5

The reaction of the 2-n-butyl-4-formyl-5-chloro-lH-imidazole with methyl 4-(bromomethyl)benzoate can be carried out in an organic solvents selected from a mixture of toluene: water or dichloromethane: water most preferably mixture of toluene: water; in presence of a suitable base selected from sodium hydroxide or potassium hydroxide most preferably sodium hydroxide with a phase transfer catalyst selected from tetra-n-butyl ammoniumbromide (TBAB) or tetra-n-butyl ammonium iodide; most preferably tetra-n-butyl ammonium bromide (TBAB) to give compound of formula V as in step 1
The dehalogination of the compound of Formula V is carried out under reduced pressure in presence of palladiumcarbon or Raney Nickel in an organic solvent selected from methanol, ethanol or ethyl acetate; most preferably methanol to give a compound of Formula VI.
The reaction of the compound of formula VI with the compound of Formula II is carried out in the presence of suitable base selected from piperidine, pyridine, morpholine, N-methyl pyrolidine most preferably piperidine in an organic solvent selected from a group consisting of cyclohexane, toluene, dichloromethane, water or mixture thereof; most preferably tolueneunder reduced pressure to give a compound of formula III.
The hydrolysis of the compound of Formula III can be carried out in an organic solvent selected from a group consisting of methanol, ethanol or isopropyl alcohol; most preferably methanol with a suitable base selected from sodium hydroxide or potassium hydroxide most preferably sodium hydroxide.
The reaction after hydrolysis is acidified with suitable acid selected from acetic acid or dilute hydrochloric acid; most preferably acetic acid to give Eprosartan of formula IV.
Eprosartan of formula IV which has major XRD peaks at 7.89, 9.12, 10.02, 11.39, 13.22, 15.75, 15.90, 16.47, 16.93, 19.03, 20.06, 20.05, 21.01, 23.39, 24.75, 25.05, 27.17 and 30.09 at 2D values
The methane sulphonate salt formation of compound of formula IV is carried out in the presence of methane sulphonic acid in an organic solvent selected form acetic acid, isopropanol or ethanol; most preferably acetic acid to give a compound of Formula I
The present invention also provides a pharmaceutically acceptable active ingredient which is substantially pure with a purity level of 99.85% and impurity level of less than 0.10%.
Another embodiment of the present invention there is a process provided for the preparation of Eprosartan Mesylate which is substantially free from 4-(bromomethyl) benzoic acid

and (E)-3-[2-n-butyl-lH-imida2ole-5-yl]-2-(2-thienyl)methyl-2-propionic acid mono methanesulphonate of formula VII

Yet another embodiment of the present invention provides a process of synthesis of (E)-3-[2-n-butyl-lH-imidazole-5-yl]-2-(2-thienyl)methyl-2-propionic acid mono methanesulphonate of Formula VII which comprises;
reacting compoundof Formula II with methane sulphonic acid in the presence of suitable solvent
followed by the addition of suitable anti-solvent to precipitate the desired compound
purifying the compound with suitable solvent. The process wherein the reaction of compovmd of Formula II with methane sulphonic acid is carried out in the presence of acetic acid
The anti-solvent used to precipitate the compound is selected from isopropyl acetate The solvent used for the purification of the crude is acetic acid, ethanol or methanol most preferably acetic acid.
The invention is illustrated by the following example; the example is not intended to limit the scope of this invention as defined herein above and as claimed herein below.
EXAMPLE
Example 1: Preparation of(2E)-3-(2-butyl-4,5-dihydro-lH-imidazol-5-yl)-2'(thiophen-2-ylmethyl)prop-2-enoic acid of formula II
To cyclohexane (250mL) and piperidine (9.4g) together was added cone, hydrochloric acid in a dropwise manner for a period of 10 minutes at 25-30°C. The temperature was raised to 45-50°C and the content was stirred for 15-20mintues followed by the addition of 2-n-butyl-4-formyl-5-chloro-lH-imidazole (50g) [J.Org,Chem,(1997), 62, 8449-8454] and the stirring was continued

for 15-20 minutes at 30-35°C to obtain a clear solution. The temperature of the reaction mixture was raised 50-55°C and to it was added 2-Carboxy-3-(2-thienyl)-propanoic acid (lOOg) in 4 lot, the temperature was further raised to 75°C followed by azeotropic removal of water with cyclohexane. To this reaction mixture 2-Carboxy-3-(2-thienyl)-propanoic acid was added after every Ihour at 50-55°C and the reaction mixture was refluxed at 75-80°C for at atmospheric pressure for 15-18hrs. Excess of cyclohexane was distilled off completely below 45T. The residue was taken in toluene at 25-30°C and water (lOOOmL) was added and stirring was continued for 20min. at 25-30°C, the two layers were separated. The organic layer is washed with sodium bicarbonate (IxlOOmL, 10% sodium metabisulphate (IxlOOOmL) and saturated NaCl solution (lx500mL)in a subsequent manner. The organic layer is separated, and evaporated under vacuum at 650-750mm Hg.(96gm, %Yield= 90) and dried to get the desired compound(96gm)
Example 2: Preparation of compound of formula III
The compound (50g) obtained jfrom the example 1 above was taken in toluene(lOOmL) at 25-30°C and stirred till dissolution, followed by the addition of water(200ml), sodium Hydroxide flakes(6.2gm), tetrabutylammonium bromide(17,5gm) and the stirring was continued for lOmin at 25-30°C. To this reaction mixture was added methyl-4-(bromomethyl)-benzoate and stirred for 18-24 hrs. at 25-30°C. The two layer are separated and the organic layer is washed with DM Water (500ml)and evaporated at 50-55°C under vacuum 650-750mm Hg to get the crude diester(64gm)
Example 3: Preparation of compound of formula IIL
The compound obtained from the example 1 above was taken in dimethylformamide and to it was added potassium carbonate and the reaction mixture was stirred for 30 minutes and cooled to followed by the addition of methyl-4-(bromomethyl)-benzoate (36g) dissolved in dimethylfonnamide(30mL). he reaction mixture was poured into water and extracted with ethyl acetate and the ethyl acetate layer was evaporated undervacuum, the dark brown oil was dissolved in hexane at 40°C, filtered and evaporated rot get the desired compound.
Example 4: Preparation ofEprosartan
The crude diester (64gm) is taken in methanol (192ml) at 25-30°C and stirred till dissolution
followed by the addition of water and sodium hydroxide and stirring was continued at 25-30°C

for 15min, the reaction mixture is heated at 57-60°C for 3 hrs. and the methanol layer is distilled off undervacuum. The residue was taken in water (500mL) and washed with toluene (2x500ml) and the pH is adjusted to 5.0-5.2 using glacial acetic acid at 20-25°C. The reaction mixture is stirred until the product separates out and cooled to 15-20°C and stirred for 2hrs at 15-20°C to allow complete precipitation of solid. The crude is filtered and dried undervacuum at 45"50°C for 2hrs to get yellow solid (40gm, %Yield= 68, HPLC=80%).
The crude eprosartan base(40gm) is takenin methanol (7.0V) at 25"30°C and stir till a slurry is obtained the temperature of the mixture is raised to 60-65°C and the stirring continued for 30 min., cool and stir for 6hrs at 25-30°C cool to 0-5°C and filter the product wash with hexane and dry at 45-50°C for 5-8 hrs to get pure yellowish-white solid product of eprosartan base (22gm, HPLC= 98%).
Example 5: Preparation of Eprosartan
The crude ester obtained form the example 5 above was taken in a mixture of water(20mL),
methanol(20m) and to it was added sodiimi hydroxide and heated to 60-65C for 2 hr. the
reaction mixture was cooled followed by the addition of 10% dilute hydrochloric
acid(14mL)imtil pH-5-5.2. The solid obtained is filtered and dried to get the desired
compound(2g)
Example 6: Preparation of Eprosartan
The crude ester (lOOg) was taken in methanol (300niL) or ethanol (300mL) and to it was added
sodium hydroxide dissolved in water. The contents were heated to reflux for 4 hrs and methanol
was evaporated under vacuum. The residue thus obtained was washed with toluene (20x2) and
the aq. layer was separated the pH was adjusted to 5-5.2 using acetic acid and stirred for 1 hr to
get yellowish colored solid which was filtered, washed with hexane and dried to get the desired
compound.
Example 7: Preparation of Eprosartan mono-methanesulphonate or Eprosartan
Mesylate
The eprosartan base(40gm) obtained fromthe example above was taken in glacial acetic
(160mL) acid at 25-30°C and to it was added methane sulphonic acid (10.8gm) at 25-30°C and
the content was heated to 75-80°C to get a clear solution, the temperature was decreased to 45°C

followed by the addition of isopropyl acetate ( 4V), the content was stirred for 2 hrs at 25-30°C and another lot of isopropyl acetate (4V) was added to it, the product precipitated out at 25-30°C and the mixture is stirred at 25-30°C for 5-6 hrs till complete precipitation. The product is filtered, washed with isopropyl acetate (2x20ml) and hexane (lx40nil) and dried at 45-50°C for 8-lOhrs. to get white solid of eprosartan mesylate (42gm, %Yield=89, HPLC=99.7%).
Example 8: Preparation of Eprosartan mono-methanesulphbnate or Eprosartan
Mesylate.
Eprosartan base (29.8g) was taken in acetic acid (120mL) and stirred for 15 minutes followed by the addition of methyl sulphonic acid (8.1g) to stir to get a clear solution. The reaction mixture was heated to 80°C stirred for lOmintues and cooled to room temperature gradually followed by the addition of isopropyl alcohol. The reaction mixture was further cooled to 20°C with stirring to get the product which was filtered undervacuum (33.5g)
Example 9: Preparation of (E)'3-[2'n-butyl'lH-imidazole-5-yl]-2-(2'thienyl)methyl-2' propionic acid mono methanesulphonate ofFORUMLA VIL
The compound obtained from the example 1 was taken in acetic acid and to it was added methyl sulphonic acid and the content was heated to 80°C for 2 hrs, cooled to 40-45°C and stirred at this temperature for l-2hrs followed by the addition of isopropyl acetic acid which yield to precipitation of the compound. The content were fiirther cooled to room temperature and to it was added isopropyl acetic acid and the stirring was continued for an hr. the reaction mixture was cooled , filtered and dried to get the crude compound. The crude was taken in acetic acid and heated to 80°C and gradually cooled to 45°C and stirred for 2hrs to get white crystals of the desired compound which was further filtered and dried under vacuum to get the desired compound. (1.5g)

We claim
1. An improved process for manufacturing Eprosartan mesylate which comprises reacting 2-n-butyl-4-formyl-1 H-imidazole

with (2-thienylmethyl)propanedioic acid monomethyl ester

wherein the (2-thienylmethyl)propanedioic acid monomethyl ester was added in lots to 2"n-butyl-4-formy1-1-H-imidazole over a period of 4-5 hrs to give (E)-3-[2-n-butyl-lH-imidazole-5-yl]-2-(2-thienyl)methyl-2-propionic acid a compound of Formula II

■ treating the compound of formula II with methyl 4-(bromomethyl)benzoate to give a
compound of Formula III

■ hydrolyzing the compound of Formula III followed by acidification to give Eprosartan
base of Formula IV


■ methane sulphonate salt formation of the compound of Formula IV in a suitable organic
solvent to give anhydrous Form of Eprosartan mesylate of Formula I.

2. An improved process for manufacturing Eprosartan mesylate which comprises
■ reacting 2-n-butyl-4-formyl-5-chloro-1 H-imidazole

with methyl 4-(bromomethyl)benzoate to give a compound of formula V

■ dehaloginating the compound of Formula V to give a compound of Formula VI

■ condensation of the compound of Formula VI with a compound of Formula II under
reduced pressure to give a compound of Formula III


■ hydrolyzing the compound of Formula III followed by acidification to give Eprosartan
of Formula IV

■ methane sulphonate salt formation of the compound of Formula IV with methane
sulphonic acid in suitable solvent to give Eprosartan mesylate of Formula I.

3. A process for manufacturing Eprosartan mesylate as in claim 1, wherein the reaction of the
compound of formula II with methyl 4-(bromomethyl) benzoate can be carried out in an
organic solvent selected from a group consisting of dimethylformamide,
dimethylsulphoxide or tetrahydrofuran; most preferably dimethylformamide and a suitable
base selected from potassium carbonate or sodium carbonate; most preferably potassium
carbonate to give compound of formula III.
4. A process for manufacturing Eprosartan mesylate as in claim 1 and 2, wherein the reaction
of compound of (E)-3-[2-n-butyl-lH-imidazole-5-yl]-2-(2-thienyl)methyl-2-propionic acid
with methyl 4-(bromomethyl)benzoate as in claim 1 or 2-n-butyl-4-formyl-lH-imidazole
with methyl 4-(bromomethyl)benzoate as in claim 2 can be carried out in organic solvents

selected from a mixture of toluene: water or dichloromethane: water most preferably mixture of toluene: water, in a suitable base selected from sodium hydroxide or potassium hydroxide most preferably sodium hydroxide with a phase transfer catalyst selected from tetra-n-butyl ammonium bromide (TBAB) or tetra-n-butyl ammonium iodide; most preferably tetra-n-butyl ammonimnum bromide (TBAB) to give compound of formula III or formula V respectively.
A process for manufacturing Eprosartan mesylate as in claim 1 and claim 2, wherein the condensation of the 2-n-butyl-4-formyl-lH-imidazole with (2-thienylmethyl)propanedioic acid monomethyl ester as in claim or Formula VI with a compound of Formula II is carried out in atmospheric or under reduced pressure in an organic solvent selected from group comprising of cyclohexane, toluene, dichloromethane, water or mixture thereof; most preferably cyclohexane and a suitable base as catalyst selected from a group consisting of piperidine, pyridine, morpholine, N-methyl pyrrolidine most preferably piperidine to give (E)-3-[2-n-butyl-lH-imidazole-5-yl]-2-(2-thienyl)methyl-2-propionic acid a compound of Formula II or III respectively.
A process for manufacturing Eprosartan mesylate as in claim 1 and claim 2, wherein the hydrolysis of the compound of Formula III can be carried out in an organic solvent selected from a group consisting of methanol, ethanol or isopropyl alcohol most preferably methanol with a suitable base selected from sodium hydroxide or potassium hydroxide; most preferably sodium hydroxide.
A process for manufacturing Eprosartan mesylate as in claim 2, wherein the dehalogination is carried out in an organic solvent selected from methanol, ethanol or ethyl acetate; most preferably methanol; under reduced pressure in the presence of in presence of palladium carbon or Raney Nickel and to give a compound of Formula VI.
A process for manufacturing Eprosartan mesylate as in claim 1 and claim 2, wherein the acidification is carried out in the presence of suitable acid selected from acetic acid or dilute hydrochloric acid; most preferably acetic acid to give compound of formula IV. A process for manufacturing Eprosartan mesylate as in claim 1 and claim 2, wherein the methane sulphonate salt formation of the compoimd of formula IV is carried out in the presence of methane sulphonic acid in an organic solvent selected form acetic acid, isopropanol or ethanol; most preferably acetic acid to give a compound of Formula I. A process for the conversion of Eprosartan to Eprosartan mesylate comprising reaction of Eprosartan with methane sulphonic acid in presence of acetic acid.

11. An impurity of the compound of Formula VII and the process for preparation comprising

• reacting compound of Formula II with methyl sulphomc acid in the presence of suitable solvent selected from acetic acid and isopropanol, most preferably acetic acid.
• followed by the addition of suitable solvent to precipitate the desired compound, the solvent being selected from isopropyl and acetic acid
• purifying the compound with suitable solvent selected from acetic acid, methanol and ethanol most preferably acetic acid.
12. A process according to claim 1-10 wherein the Eprosartan mesylate formed is anhydrous in
nature.
13. Anhydrous Eprosartan mesylate of formula I substantially free from 4-(bromomethyl)
benzoic acid and (E)-3-[2-n-butyl-lH-imidazole-5-yl]-2-(2-thienyl)methyl-2-propionic acid
mono methanesulphonate of formula VII.
14. Substantially pure anhydrous form of Eprosartan mesylate of formula I, with purity level of
greater than 99.85% and single individual impurity less than 0.10%.