FIELD OF THE INVENTION
The present invention relates to an industrially advantageous process for the preparation of bibenzimidazole derivative, particularly 4-methyl-6-(l-methylbenzimidazole-2-yl)-2-n-propylbenzimidazole of formula I,
(Formula Removed)
Formula I
a key intermediate in the preparation of telmisartan.
BACKGROUND OF THE INVENTION
Telmisartan and its physiologically acceptable salts are useful as angiotensin antagonists, particularly an angiotensin-II-antagonist and is chemically known as 4'-[[4-methyl-6-(l-methyl-2-benzimidazolyl)-2-n-propyl-l-benzimidazolyl]-methyl]-2-biphenylcarboxylic acid.
(Formula Removed)
It may be used to treat hypertension, cardiac insufficiency, to treat ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), to prevent the progression of cardiac insufficiency after myocardial infarction, to treat diabetic neuropathy, glaucoma, gastrointestinal diseases and bladder diseases.
Various methods for the synthesis of telmisartan are known in prior art. A number of the known synthetic routes to telmisartan proceed via the key intermediate, 4-methyl~6-( 1 -methylbenzimidazole-2-yl)-2-n-propylbenzimidazole of formula 1.

(Formula Removed)
Formula I
Several processes are known in art for the preparation of bibenzimidazole derivative of formula I. Some of them are provided herewith for reference.
J. Med. Chem. 1993, 36, 4040-51 discloses a process for the preparation of 4-methyl-6-(l-methyl benzimidazole-2-yl)-2-«-propylbenzimidazole of formula I. The process comprises acylating methyl 4-amino-3-methylbenzoate with butyryl chloride in chlorobenzene and reacting the resulting amide with fuming nitric acid in sulfuric acid to form methyl 4-(butyrylamino)-3-methyl-5-nitrobenzoate which is then reduced with palladium-carbon. The resulting amino compound is then cyclized using glacial acetic acid to form methyl 2-n-propyl-4-methyl~l//-benzimidazole-6-carboxylate which is then treated with sodium hydroxide in methanol to form the corresponding acid, followed by reaction with TV-methyl-o-phenylenediamine in the presence of phosphoric acid to form the desired intermediate, 4-methyl-6-(l -methyl benzimidazole-2-yl)-2-n-propylbenzimidazole of formula I.
The above process suffers from several drawbacks like the use of chlorobenzene which is a hazardous chemical, thereby rendering it unsuitable for commercial manufacturing.
U.S. patent 6,770,762 discloses a process for the preparation of 4-methyl-6-(l-methyl benzimidazole-2-yl)-2-«-propylbenzimidazole by reacting 2-n-propyl-4-mefhyl-1 H-benzimidazole-6-carboxylic acid with N-methyl-o-phenylenediamine in the presence of methanesulfonic acid and phosphorus pentoxide. The process can be represented by the following scheme:

(Formula Removed)
U.S. Application Publication 2007/0037986 discloses a process for preparing 4-mefhyl-6-(l-methyl benzimidazole-2-yl)-2-«-propylbenzimidazole by condensing 7V-methyl-o-phenylenediamine or its salts with 2-n-propyl-4-methyl-l//-benzimidazole-6-carboxylic acid or its salts in the presence of substituted halogenated -1,3,5-triazine and a tertiary amine through corresponding amide intermediate. This process involves the use of substituted halogenated-1,3,5-triazines, which are toxic and costly and hence not advisable to use at industrial scale.
U.S. Application Publication,. 2007/0287840 provides a process for preparing 4-methyl-6-(l-methyl benzimidazole-2-yl)-2-«-propylbenzimidazole by initially reducing methyl 4-butyramido-3-methyl-5-nitrobenzoate using palladium, on charcoal in methanol to give methyl 3-amino-4-butyramido-5-methylbenzoate which on subsequent hydrolysis followed by ring closure gives 2-«-propyl-4-methyl-benzimidazole-6-carboxylic acid which on condensation with /V-mefhyl-o-phenylenediamine hydrochloride affords 4-methyl-6-( 1 -methylbenzimidazole-2-yl)-2-n-propylbenzimidazole. The process is shown in the scheme below:

(Formula Removed)
The application further discloses a process for preparing for the preparation of 4-methyl-6-(l-methyl benzimidazole-2-yl)-2-n-propylbenzimidazole involving the condensation of 3-amino-4-butyramido-5-methyibenzoic acid with iV-methyl-o-phenylenediamine in the presence of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine to give 3-amino-4-(butyramido)-5-methyl-iV-(2-(methylamino)phenyl)benzamide followed by cyclization in the presence of a suitable agent like inorganic acid such as polyphosphoric acid, organic acid such as acetic acid, butyric acid, p-toluene sulphonic acid, methane sulphonic acid and phosphorus pentoxide and the like or mixture thereof. The process is represented by the following scheme:


(Formula Removed)
The above patent application discloses the use of toxic reagents like DCC. Additionally, DCC is an expensive reagent and its by-product dicyclohexyl urea (DCU) is also difficult to remove from final drug substance. Also, the process results in low yield (24%) of the product obtained.
Most of the processes reported in literature teach the process for preparing bibenzimidazole derivative of formula I by hydrolysing methyl 3-amino-4-butvramido-5-methylbenzoate to the corresponding acid and conversion thereof to bibenzimidazole derivative of formula I in several steps. However, none of the prior art reference teaches the direct conversion of 3-amino-4-butyramido-5-methylbenzoate to bibenzimidazole derivative of formula I.
The above mentioned drawbacks calls for an alternative and improved process for the preparation of highly pure bibenzimidazole derivative of formula I, that is cost
effective, commercially viable, reproducible on industrial scale and meets the needs of regulatory agencies.
It is, therefore, desirable to provide an economically excellent; less hazardous and eco-friendly process for the preparation of bibenzimidazole derivative of foraiula I, wherein use of toxic and expensive reagents is avoided and the process is convenient to operate on a commercial scale.
OBJECT OF THE INVENTION
One object of the present invention provides an improved one pot process for the preparation of bibenzimidazole derivative of formula I from 3-amino-4-butyramido-5-methylbenzoate wherein coupling and cyclization for double benzimidazole ring formation takes place in one step only, without isolating the intermediates in solid form, thus reducing the number of steps and hence is a time and cost saving process.
One another object of the present invention provides facile process for the preparation of bibenzimidazole derivative of formula I directly from 3-amino-4-butyramido-5-methylbenzoate in better yield and better purity by avoiding the use of toxic and expensive reagents.
SUMMARY OF THE INVENTION
The present invention relates to an industrially advantageous one pot process for the preparation of bibenzimidazole derivative, particularly 4-methyl-6-(1-methyl benzimidazole-2-yl)-2-n-propylbenzimidazole of formula I, a key intermediate in the preparation of telmisartan,
(Formula Removed)
Formula 1
which comprises:
condensing 3-amino-4-butyramido-5-methylbenzoate of formula II
(Formula Removed)
Formula II
wherein Rj denotes a straight-chained or branched C1-C8-alkyI group, a C1-C8 -alkyl aryl group, a C5-C7 cydoalkyl group, an aryl group optionally substituted with atleast one group consisting of a C1-C8 alleyl, an alley I aryl or an alkoxy alkyl,
with TV-methyl-o-phenylenediamine of formula III or salt thereof
(Formula Removed)
Formula III
in the presence of a suitable reagent.
In another embodiment, the present invention provides a process for the preparation of 4-methyl-6-(l -methyl benzimidazole-2-yl)-2-«-propyl benzimidazole of formula I which comprises:
a. cyclizing 3-amino-4-butyramido-5-methylbenzoate of formula II in the presence of a suitable reagent to form 7-methyl-2-o-propyl-3H-benzoimidazole-5-carboxylate of formula IV; and(Formula Removed)

Formula IV wherein R1 is as defined above,

b. reacting compound of formula IV with Af-methyl-o-phenylenediamine of formula III or salt thereof in the presence of a suitable reagent to form 4-methyl-6-(l-methylbenzimidazole-2-yl)-2-«-propylbenzimidazole of formula I.
DETAILED DESCRIPTION OF THE INVENTION
One embodiment of the present invention relates to an one pot process for the preparation of bibenzimidazole derivative, particularly 4-methyl-6-( 1-methylbenzimidazole-2-yl)-2-n-propyl benzimidazole of the formula I by condensing 3-amino-4-butyramido-5-methylbenzoate of formula II

(Formula Removed)

FormulaII

wherein R2 denotes a straight-chained or branched C1-C8 -alkyI group, a C1-C8 -alleyI aiyl group, a C5-C7 cycloalkyl group, an aryl group optionally substituted with at least one group consisting of a C1-C8 alky I, an alky I aryl or an alkoxy alley
with 7V-methyl-o-phenylenediamine of formula III or salt thereof
(Formula Removed)
Formula HI
in the presence of a suitable reagent in high yield and purity.
3-Amino-4-butvramido-5-methylbenzoate of formula II and a suitable reagent are stirred together, followed by the addition of JV-methyl-o-phenyl diamine of formula III or salt thereof at a temperature of 110-150 °C. In a preferred embodiment, alkyl 3-amino-4-butyramido-5-methylbenzoate is reacted with N-methyl-o-phenyl diamine of formula HI or salt thereof. In most preferred

embodiment, methyl 3-amino-4-butyramido-5-methylbenzoate is coupled with 7V-methyl-o-phenyl diamine of formula III or salt thereof.
Preferably hydrochloride salt of N-methyl-o-phenyldiamine of formula III is employed in the present context. A suitable reagent can be selected from inorganic acid such as polyphosphoiic acid and organic acid such as acetic acid, butyric acid, p-toluene sulphonic acid, methane sulphonic acid and phosphorus pentoxide and the like or mixture thereof. Preferably polyphosphoric acid is used. The reaction mixture is further stirred at a temperature of 130-185 °C for a period of 10-20 hours. Progress of the reaction is monitored by thin layer chromatography or high performance liquid chromatography. After completion of the reaction, temperature of the reaction mass is lowered to about 70-100 °C. Thereafter the reaction mixture is diluted with water and neutralized using base such as aqueous potassium hydroxide solution to a pH of 6-7 at a temperature of 60-70 °C to isolate 4-methyl-6-(l-methylbenzimidazole-2-yl)-2-n-propyl benzimidazole of the formula I. Specific illustrations of suitable isolation and separation procedures are described in the Examples section that follows. However, other equivalent separation or isolation procedures could, of course, also be used. Filtration, extraction and a combination of these procedures are the presently most preferred separation procedures.
The product can optionally further be purified by methods known in art like treatment with activated carbon or recrystallization from a suitable solvent like C1-C4 alcohols like isopropyl alcohol, ether like tetrahydrofuran, ketone like acetone, water and mixtures thereof.
Another embodiment of the present invention provides an alternate process for the
preparation of 4-methyl-6-( 1 -methylbenzimidazole-2-yl)-2-o-propyl
benzimidazole of the formula I which comprises the cyclization of 3-amino-4-butyramido-5-methylbenzoate of formula II in the presence of suitable reagent to form 7-methyI-2-«-propyl-3H-benzoimidazole-5-carboxyiate of formula IV and reacting the same with N-methyl-o-phenylenediamine of formula III or salt thereof in the presence of a suitable reagent to prepare 4-methyl-6-(l -methyl

benzimidazole-2-yl)-2-n-propylbenzimidazole of the formula I in high yield and purity. Suitable reagent can be selected from inorganic acid such as polyphosphoric acid and organic acid such as acetic acid, butyric acid, p-toluene sulphonic acid, methane sulphonic acid and phosphorus pentoxide and the like or mixture thereof. Preferably polyphosphoric acid is used.
Typically, 3-amino-4-butyramido-5-methylbenzoate of formula II (preferably wherein Ri = CH3) in mixture with suitable reagent is heated to a temperature of 80-120 °C for a period of about 1-5 hours. Progress of the reaction is monitored by thin layer chromatography or high performance liquid chromatography. After completion of the reaction, the reaction mass is cooled to a temperature of 70-95 °C followed by dilution with water. The pH of the reaction mass is adjusted to 7.0 at a temperature of 10-40 °C. The product is isolated by the methods known in prior art, preferably by filtration. The product is then dried under vacuum at a temperature of 50-60 "C to isolate 7-methyl-2--n-propyl~3W-benzoimidazole-5-carboxylate of formula IV (preferably wherein R/ = CHj).
7-Methyl-2-n-propyl-3//-benzoimidazole-5-carboxylate of formula IV so isolated is then converted to 4-methyl-6-( 1 ~methylbenzimidazole-2-yl)-2-«-propylbenzimidazole of the formula I by the process disclosed in the context of present invention. Preferably compound of formula IV in mixture with suitable reagent is heated at a temperature of 100-130 °C followed by the addition of N-methyl-o-phenyl diamine of formula III or salt thereof at the same temperature. Preferably compound of formula. IV is reacted with the dihydrochloride salt of compound of formula III. The reaction mass is then heated to at a temperature of about 150-170 °C for a period of about 16 hours and then cooled to a temperature of 90 °C. This is followed by the addition of water and pH of the reaction mass is then adjusted to 7.0 with a suitable base at a temperature of 50-80 °C. The product so obtained is isolated preferably by filtration and dried under vacuum to afford 4-methyl-6-(l-methyl benzimidazole-2-yl)-2-H-propylbenzimidazole of the formula I in high yield and purity.

Bibenziraidazole derivative of formula I so fonned by the processes of present invention can be converted into telmisartan of following fomiula by the processes well known in prior art like those reported in U.S. 5,591,762; 6,770,762; 7,193,089; J. Med. Chem. 1993, 36 (25), 4041-4051; Zhongguo yiyao gongye zazhi, 2003, 34 (6), 262-264 etc.
(Formula Removed)
In general, bibenzimidazole derivative of formula I is condensed with substituted biphenyl derivative of fomiula V
(Formula Removed)
Formula V
wherein Ri denotes a straight-chained or branched Cj~Cs -allzyl group, a C/-Q -alkyl aryl group, a C^-Cy cycloalkyl group,, an aryl group optionally substituted with atleast one group consisting of a C/-Q alkyl, an alkyl aryl or an alkoxy alkyl,
Formula VI
II
in the presence of suitable solvent and base to give telmisartan ester derivative of fomiula VI
(Formula Removed)
wherein R2 is as defined above
which is then hydrolysed under appropriate acidic or basic conditions to form
telmisartan.
Specifically, bibenzimidazole derivative of formula I is condensed with substituted biphenyl derivative of formula V in the presence of a base, optionally in the presence of a phase transfer catalyst in a suitable solvent at a temperature of about less than 10 °C. Progress of the reaction is monitored by thin layer chromatography or high performance liquid chromatography and it takes about 20-30 hours for completion of reaction. Thereafter, telmisartan ester derivative of formula VI is isolated by any method known in the art, such as filtering and drying.
The suitable solvent can be selected from nitriles, aromatic hydrocarbons, alcohols, ethers, ketones, esters and the like. Preferably the reaction is conducted in the presence of acetonitrile, toluene, acetone, ethanol and the like. Generally, the base is selected from inorganic base such as a metal hydroxide, carbonate or bicarbonate. Preferably, the metal hydroxide can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide or strontium hydroxide and the like. While the metal carbonate or bicarbonate can be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or cesium carbonate and the like. Several classes of compounds are known to be capable of acting as phase transfer catalysts., such as quaternary ammonium compounds, phosphonium compounds or synthetic resins. Phase transfer catalysts include, but are not limited to, benzyltriethylammonium chloride, resin amberlite IRA-410, tetrabutylammonium bromide; tetrabutyl ammonium hydroxide; tricaprylylmethylammonium chloride, dodecyl sulfate, sodium salt, such as sodium lauryl sulfate; tetrabutylammonium hydrogensulfate; hexadecyl tributyl phosphonium bromide; or hexadecyltrimethylarnmonium bromide. Preferably, the phase transfer catalysts used is tetrabutylammonium bromide.
The above reaction can be carried out in biphasic system as well as in mono phasic system. It is preferable to conduct the reaction in mono phasic system even using phase transfer catalyst. By using a PTC, one can achieve faster reactions, obtain higher conversions or yields and fewer byproducts. In preferred embodiment of the present invention bibenzimidazole derivative of formula I is condensed with substituted biphenyl derivative of formula V wherein R2 is Ci-C4-alkyl and most preferably R2 is methyl.
Telmisartan ester derivative of formula VI is then hydrolysed to telmisartan under appropriate acidic or basic conditions. Suitable acid can be selected from inorganic or organic acids, preferably hydrochloric acid, sulfuric acid and the like. Suitable base can be selected from alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide or strontium hydroxide and the like. Typically, appropriate base is added to telmisartan ester derivative in suitable solvent and refluxed for a period of 2-30 hours. The solvent employed is preferably C1-C4 alcohol. After reaction completion, the solvent is distilled under vacuum and the reaction mass is diluted with water. The reaction mass is then treated with activated carbon, filtered and washed with dichloromethane. The reaction mass is then acidified with aqueous acid preferably hydrochloric acid to pH 4-5 at about ambient temperature. The precipitated solid was filtered to give telmisartan.
Telmisartan so formed can optionally be purified by treating telmisartan with a base in water or water miscible solvent to form a salt, and treating the salt so formed with an acid. Suitable bases include but are not limited to alkali metal hydroxides, alkali metal carbonates, ammonia and the like. Preferably ammonia is used. Suitable acids which can be used include, but are not limited to: inorganic acids like hydrochloric acid, hydrobromic acid; and organic acids like tartaric acid, acetic acid, citric acid and the like. Preferably hydrochloric acid is used.
1(Formula Removed)
Typically, telmisartan is dissolved in aqueous base and charcoalized. The solution is then filtered and the aqueous filtrate is washed with halogenated solvent like dichloromethane and acidified with acid to yield highly pure telmisartan.
If required purification process of telmisartan can be repeated by recrystallization in an organic solvent like halogenated solvent like dichloromethane, alcohol like ethanol, isopropanol, ketones like acetone, esters like ethyl acetate, hydrocarbon like tetrahydrofuran, and mixtures thereof.
The key starting material, 3-amino-4-butyramido-5-methylbenzoate of formula II useful in the process for the preparation of bibenzimidazole derivative of formula I can be formed by the methods known in the prior art such as those reported in J. Heterocyclic Chem. 40, 1107 (2003); J. Med. Chem. 1993, 36, 4040-4051 etc. or as incorporated herein for reference.
The process can be outlined by the scheme that follows:

(Formula Removed)
wherein R/ is as defined above
Preferably, 3-amino-4-butyramido-5-methylbenzoate of formula II (preferably wherein Rt = CH3) is prepared starting from 3-methyl-4-nitro-benzoic acid. Typically 3-methyl-4-nitro-benzoic acid is esterilied to the corresponding ester by reacting the same with suitable alcohol like methanol in the presence of acid, preferably sulfuric acid, hydrochloric acid and the like. The reaction mass is refluxed for a period of 10-30 hours. After completion of reaction, the reaction mass is cooled to a temperature of below 10 °C. The precipitated solid is filtered, washed with suitable alcohol and dried under vacuum to give methyl 3-methyl-4-nitro-benzoate.
3-Methyl-4-nitro-benzoate so formed is then hydrogenated to the corresponding amine derivative using hydrogen gas pressure in the presence of suitable catalyst and organic solvent. Catalyst can be selected from platinum oxide, Raney-nickel, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, etc., and the like, preferably palladium supported on carbon is used. Hydrogen gas is applied at a pressure of about 3 kg/cm to about 7 kg/cm . Organic solvent can be selected from alcohols preferably methanol, ethanol, isopropanol, butanol etc. The hydrogenation reaction is performed at a temperature of 25-34 °C for a period of 1-10 hours, preferably 2-3 hours. The reaction mass is then filtered and concentrated under vacuum to form 3-methyl-4-amino-benzoate which can be isolated from the reaction vessel using suitable non-polar solvent like cyclohexane, liexane, toluene, heptane, the like or mixtures thereof, followed by filtration.
3-Methyl-4-amino-benzoate so formed is then condensed with n-butyryl chloride in the presence of organic base like triethylamine in suitable solvent to form 4-butyrylamino-3-methyl- benzoate. Solvent used is preferably halogenated solvent such as dichloromethane and the like. The reaction is performed at a temperature of about 30-50°C with stirring. Completion of the reaction can be monitored by TLC. After completion of reaction, the organic layer is washed with water, aqueous base like alkali metal carbonate and solvent is evaporated to form 4-butyrylamino-3-methyl-benzoate which can be isolated from the reaction vessel using suitable non-polar solvent like cyclohexane, hexane, toluene, heptane, the like or mixtures thereof, followed by filtration.
4-Butyrylamino-3-methyl-benzoate is then treated with nitric acid at a temperature of below 0°C to form 4-butyrylamino-3-methyl-5-nitro-benzoate. The reaction mass is stirred at same temperature for 1-4 hours. Completion of the reaction can be monitored by TLC, After completion of reaction, the reaction is quenched preferably with chilled water or ice. The precipitated solid is filtered, washed with aqueous sodium bicarbonate to obtain 4-butyrylamino-3-methyl-5-nitro-benzoate. The product so formed can further be purified by recrystallization with ester
solvent preferably ethyl acetate to give pure 4-butyrylamino-3-methyl-5-nitro-benzoate having purity of 99.6% by HPLC.
4-Butyrylamino-3-methyl-5-nitro-benzoate is further hydrogenated to 3-amino-4-butyramido-5-methylbenzoate of formula II using hydrogen gas pressure in the presence of suitable catalyst and organic solvent. Catalyst can be selected from platinum oxide, Raney-nickel, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, etc., and the like, preferably palladium supported on carbon is used. Hydrogen gas is applied at a pressure of about 3 kg/cm" to about 7 kg/cm". Organic solvent can be selected from alcohols preferably methanol, ethanol, isopropanol, butanol etc. The hydrogenation reaction is perfomied at a temperature of 25-45 °C for a period of 1-5 hours. After reaction completion (monitored by TLC), the reaction mass is filtered and solvent is removed preferably by evaporation to form 3-amino-4-butyramido-5-methylbenzoate of formula II which is extracted with isopropyl ether at temperature of below 10 °C.
Yet another raw material, iV-methyl-o-phenyl-diamine an salt thereof can be procured from commercial source or prepared by the processes well known in art such as those reported in Organic Process Research Development 2007, 11, 81-85 or as exemplified herein for reference.
Typically, o-nitroaniline is methylated with dimethvlsulfate in the presence of suitable solvent like acef ne and base like potassium hydroxide at a temperature of 20-50 °C with stirring for a time sufficient to form the methylated product.. The reaction completion is monitored by TLC. The product is extracted with halogenated solvent like dichloromethane. The methylated product is then hydrogenated using hydrogen gas pressure of 2-7 kg/cm2 at a temperature of 20-50 °C in the presence of catalyst like palladium supported on carbon to form N-methyl-o-phenyl-diamine. TV-methyl-o-phenyl-diamine so formed can be converted to the corresponding dihydroehloride salt by reaction with stoichiometric amount of cone, hydrochloric acid. If required, /Y-methyl-o-phenyl-

diamine dihydrochloride can be purified by recrystaihzed from alcoholic solvent like isopropyl alcohol; nitrile like acetonitrile; ether like tetrahydrofuran.
By following the processes of the present invention telmisartan so formed is found to have low concentrations of following impurities:
a. 4'-{6~[2-(2-Dimethylamino-phenyl)-acetyl]-4-methyl-2-propyl-benzoimidazol-1 -ylmethyl} -biphenyl-2-carboxylic acid
(Formula Removed)

c. Impurity of the following formula:
17
b. 3-(2'-Carboxy-biphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid
(Formula Removed)
In the context of present invention, a "low concentration" refers to an amount of impurity not exceeding about 0.15 % area of telmisartan as determined by HPLC as recommended by United States, the Food and Drug Administration guidelines.
Major advantages realized in the present invention are high yield and purity of the product, which is achieved by involving reduced number of steps and thus time conserving. Further the process is simple, cost- effective and easy to operate on large-scale.
EXAMPLES
Example-1: Preparation of 4-methyl-6-(l-methvl benzimidazole-2-yi)-2-/i~ propylbenzimidazoie
Method A:
To a mixture of methyl 3-amino-4-butyrylamino-5-methyl-benzoate (80 g, 0.32 mol) and polyphosphoric acid (400 g) was added in lots A-methyl-o-phenyldiamine dihydrochloride (74 g, 0.38 mol) at 115-120°C. After complete addition, the reaction mass was stirred at 150-165°C for 18 hours. After completion of reaction (monitored by TLC), the reaction mass was cooled to 80-90°C, followed by dilution with water and basification with 50% aqueous potassium hydroxide solution to pH at 6.8 at 60-70°C. The precipitated solid was filtered, washed with hot water and dried to give crude product. The product was dissolved in isopropyl alcohol (480 ml) at 70-80°C and treated with activated carbon. The filtrate was diluted with water (720 ml) at 20-30°C and the precipitated solid was filtered to give 90 g of the title compound as solid having purity of 98.2% area by HPLC.(Yield - 88%)
Method B:
Step-1: Preparation of 7-methyl-2-n-propyl-3H-benzimidazole-S-earboxylate
A mixture of methyl 3-amino-4-butyramido-5-methylbenzoate (8 g, 0.03 mol) and polyphosphoric acid (24 g) was heated to 100 °C for 3 hours. Thereafter, the reaction mass was cooled to 90 °C followed by dilution with water. The pH of the reaction mass was adjusted to 7.0 with 50% aqueous potassium hydroxide
solution at 20-30°C. The solid, thus obtained, was filtered and dried under vacuum at 50-6Q°C to give 4.5 g of title compound as white solid having purity of 99.8% area by HPLC. (Yield - 61%)
Step-2: Preparation of 4-methyl-6-(l-methylbenzimidazole-2-vI)-2-«-propylbenzimidazoie
A mixture of 7-methyl-2-«-propyl-3H-benzimidazole-5-carboxylate (3 g, 0.013 mol) and polyphosphoric acid (15 g) was heated at 120 °C followed by addition of iV-methyl-o-phenyldiamine dihydrochloride (2.8 g, 0.014 mol) at the same temperature. After addition, the reaction mass was heated to 160 °C for 16 hours and then cooled to 90 °C. Reaction mass was diluted with water and pH was adjusted to 7.0 with 50% aqueous potassium hydroxide solution at 60-70 °C. The precipitated solid was filtered and dried under vacuum at 60-70 °C to give 3 g of title compound as solid.
Example-2: Preparation of telmisartan methyl ester
Method A:
A solution of methyl 4'-(bromomethyl)-biphenyl-2-carboxylate (82.8 g, 0.27 mol) in acetonitrile (225 ml ) was slowly added to a mixture of 4-methyl-6-(l-methylbenzimidazole-2-yl)-2-n-propylbenzimidazole (75 g, 0.23 mol), tetrabutylammonium bromide (0.78 g) acetonitrile (300 ml) and aqueous potassium hydroxide (55.3 g in 184 ml water) at -5 to 5°C. The reaction mass was stirred at 0-5 °C for 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered. The solid, thus obtained, was washed with aqueous acetonitrile and dried under vacuum at 50-60 °C for 12 hour to give 116 g of title compound as off white solid having purity of 98.3% area by HPLC (Yield - 89%)
Method B:
To a stirred suspension of 4-methyl-6-(l-methylbenzimidazole-2-yl)-2-«-propylbenzimidazole (10 g, 0.032 mol) in acetonitrile (60 ml), was added aqueous potassium hydroxide (7.4g in 28 ml water). The reaction mixture was cooled to 0 °C followed by the addition of methyl 4'-(bromomethyl)-biphenyl~2-carboxylate
(1 Ig) in acetonitrile (10 ml). The reaction mixture was stirred for 24 hours at the same temperature. After completion of reaction (monitored by TLC), the mass was filtered at 0 °C and the solid obtained was washed with acetonitrile-water mixture. The product was dried under vacuum at 60° C for 12 hrs to obtain title compound having purity of 98.77% area by HPLC (Yield 75%)
Exampie-3: Preparation of telmisartan
To a suspension of telmisartan methyl ester (95 g, 0.18 moi) in methanol (950 ml), was added sodium hydroxide (36 g) and stirred under reflux for 24 hours. After completion of the reaction, the solvent was distilled out under vacuum and the reaction mass was diluted with water and treated with activated carbon The reaction mass was filtered, washed with dichloromethane (110 ml) and acidified with 15% aqueous hydrochloric acid to pH 4.5 at 20-3Q°C. The precipitated solid was filtered to give the title compound as white solid which was again dissolved in aqueous ammonia followed by charcoalization. The aqueous filtrate was washed with dichloromethane and acidified with 15% hydrochloric acid to pH 6.2 to give 68 g of the pure title compound having purity of 99.77% area by HPLC. (Yield-73.5%)
Exampie-4: Preparation of methyi 3-methyl-4-nitro-benzoate
To a suspension of 3-methyl-4-nitro-benzoic acid (150 g, 0.83 mol) in methanol (600 ml), was added concentrated sulfuric acid (45 ml). The temperature of the reaction mass was raised and refluxed for 20 hours. After completion of reaction (absence of starting material in TLC), the reaction mass was cooled to 5°C. The solid, thus precipitated, was filtered, washed with chilled methanol and dried under vacuum to give 146 g of title compound as a crystalline solid having purity of 99.8% area by HPLC. (Yield - 90.3%)
Example-5: Preparation of methyl 4-amino-3-methvI-benzoate
A solution of methyl 3-methyl-4-nitro-benzoate (135 g, 0.69 mol) in methanol (1350 ml) was hydrogenated using hydrogen gas pressure of 4-5 Kg/cm2 for 2 hours at 25-35°C in the presence of 10% palladium on carbon. After completion of reaction, the catalyst was filtered off and the filtrate was concentrated under
vacuum to give solid product. The resulting solid was stirred with cyclohexane and filtered to give 108 g of the title compound as a crystalline solid having purity of 99.87% area by HPLC. (Yield - 94.70%)
Example-6;Preparation of methyl 4-butyrvlamimo-3-methyl-benzoate
To a suspension of methyl 4-amino-3-metfryl-benzoate (98 g, 0.59 mol) and triethylamine (119.90 g) in dichloro methane (600 ml) was added n-butyryl chloride (94.4 ml) at 35-40°C. The reaction mass was stirred for 1 hour (till completion of reaction) at the same temperature., After completion of reaction (monitored by TLC), water was added to the reaction mass and the layers were separated. The organic layer was washed with 5% aqueous potassium carbonate solution and concentrated to give a solid product which was stirred with cyclohexane to give 126 g of title compound as a white solid having purity of 99.8% area by HPLC (Yield - 90.3%)
Example-7:Preparatiom of methyl 4-butyrylaniino-3-methyl-5-nitro-benzoate
Methyl 4-butyrylamino-3-methyl-benzoate (115 g, 0.49 mol.) was added in small lots to fuming nitric acid (345 ml) at -15 to -2Q°C. The reaction mass was stirred at -15 to -20°C for 1 hour. After completion of reaction (monitored by TLC), the reaction mass was quenched with crushed ice. The precipitated solid was filtered, washed with 10% aqueous sodium bicarbonate solution (600 ml) to give 130 g of title compound having purity of 98.0%) area by HPLC. A small portion was recrystallized with ethyl acetate to give highly pure title compound having purity of 99.6% area by HPLC.
ExampIe-8: Preparation of methyl 3-amino-4-butyryiamino-5-methyl-benzoate
A solution of methyl 4-butyrylamino-3-methyl-5-nitro-benzoate (100 g, 0.357 mol.) in methanol (1500 ml) was hydrogenated using hydrogen gas pressure of 4-6 Kg/cm for 3 hours at 25-35 °C in the presence of 10% palladium on carbon. After completion of reaction (monitored by TLC), the catalyst was filtered off and the filtrate was concentrated under vacuum to give crude title compound. The resulting product was stirred with isopropyl ether at 0-5 °C, filtered and dried to

give 84 g of title compound as a off white solid having purity of 99.32% area by HPLC. (Yield - 94%)
Example-9: Preparation of N-inethyi-o-phenyI-diamine-dihydrochloride
To a suspension of o-nitroaniline (450 g, 3.26 mol) and potassium hydroxide (495 g) in acetone (900 ml), was slowly added dimethylsulfate (405 ml) at 25-40 °C and the reaction mass was stirred for 2 hours. After completion of reaction (monitored by TLC), the reaction mass was diluted with water and extracted with dichloromethane (4000 ml). The concentration of organic layer gave methylated product which was taken in ethanol (5000 ml) and was hydrogenated using hydrogen gas pressure of 4-5 Kg/cm at 25-40 °C in presence of 10% palladium on carbon. After completion of reaction, the reaction mass was filtered and acidified with cone, hydrochloric acid (2000 ml). The reaction mass was concentrated under vacuum to obtain solid product which was recrystallized from isopropyl alcohol to give 485 g of titled product having puiity of 99.2% area by HPLC. (Yield - 76%)

WE CLAIM
1. A one pot process for the preparation of bibenzimidazole derivative, 4-rnethyl-6-( 1 -methylbenzimidazole-2-yl)-2-H-propyl benzimidazole of formula

(Formula Removed)
Formula I which comprises the steps of: condensing 3-amino-4-butyramido-5-methylbenzoate of formula II
(Formula Removed)
Formula II
wherein R1 denotes a straight-chained or branched C1-C8 -alkyl group, a C1-C8 -alkyl aryl group, a C5-C7 cycloallcyl group, an aryl group optionally substituted with atleast one group consisting of a C1-C8 alkyl, an alkyl aryl or an alkoxv alkyl,,
with YV-methyl-o-phenylenediamine of formula III or salt thereof
(Formula Removed)
Formula III
in the presence of a suitable reagent.
2. The process according to claim 1, v/herein a suitable reagent is selected from inorganic acid such as poiyphosphoric acid, organic acid such as acetic acid,

butyric acid, p-toluene sulphonic acid, methane sulphonic acid and phosphorus pentoxide and the like or mixture thereof.
3. A process for the preparation of 4-methyl-6-(l-methylbenzimidazole-2-yl)-2-n-propylbenzimidazole of formula I,
(Formula Removed)
which comprises the steps of:
a. cyclizing 3-amino-4-butyramido-5-methylbenzoate of formula II
(Formula Removed)
Formula II
vvherein R2 denotes a straight-chained or branched C1-C8 -alkyl group, a C1-C8 -alkyl aryl group, a C5-C7 cycloalkyl group, an aryl group optionally substituted with atleast one group consisting of a C1-C8 alkyl, an alkyl aryl or an alkoxy alkyl,
in the presence of a suitable reagent to form 7-methyl-2-n-propyl-3i/-benzoimidazole-5-carboxylate of formula IV;
(Formula Removed)
Formula IV
wherein R1 denotes a straight-chained or branched C1-C8 -alleyI group, a C1-C8 -alkyl aryl group, a C1-C8 cycloal/tyl group, an aryl group

optionally substituted with atleast one group consisting of a C1-C8 alkyl, an alkyl aryl or an alkoxy alkyl
h. reacting the compound of formula IV with Ar-methyl-o-phenyienediamine of formula III or salt thereof
(Formula Removed)
Formula III
in the presence of a suitable reagent to form compound of formula I; and
c. isolating compound of formula I.
4. The process according to claim 3, wherein a suitable reagent is selected from inorganic acid such as polyphosphoric acid, organic acid such as acetic acid, butyi'ic acid, p-toluene sulphonic acid, methane sulphonic acid and phosphorus pentoxide and the like or mixture thereof.
5. The process according to claims 1 and 3, wherein 3-ainino-4-but3'ramido-5-methylbenzoate of formula II is preferably alkyl 3-amino-4-butyramido-5-methylbenzoate and most preferably methyl 3-amino-4-butyramido-5-methylbenzoate
6. A process for the preparation of telmisartan of following formula
(Formula Removed)
which comprises: a. condensing 3-amino-4-butyramido-5-methylbenzoate of formula II
(Formula Removed)
Formula II
wherein Rj is as defined above
with iV-mefhyl-o-phenylenediamine of formula III or salt thereof
(Formula Removed)
Formula III
in the presence of suitable reagent to form bibenzimidazole derivative of formula I;
(Formula Removed)
Formula I
b. condensing compound of formula I with substituted biphenyl derivative of formula V
(Formula Removed)
Formula V
wherein R2 denotes a straight-chained or branched C1-C8-alkyl group, a C1-C8 -alkyl aryl group, a C5-C7 cycloalkyl group, an aryl group optionally substituted with atleast one group consisting of a C1-C8 alkyl, an a Hey I aryl or an alkoxy alkyl
in the presence of suitable solvent, base and optionally a phase transfer catalyst to give telmisartan ester derivative of formula VI; and

COOR,
(Formula Removed)
Formula VI
wherein R2is as defined above
c. hydrolysing telmisartan ester derivative of formula VI to form telmisartan;
d. isolating telmisartan thereof; and
e. optionally purifying telmisartan.
7. A process for the preparation of telmisartan of following formula
COOH
(Formula Removed)

which comprises: a. cyclizing 3-amino-4-butyramido-5-methylbenzoate of formula 11

(Formula Removed)
Formula II wherein Rj is as defined above in the presence of a suitable reagent to form a compound of formula IV,
(Formula Removed)

Formula IV
wherein R1 denotes a straight-chained or branched C1-C8 -alkyI group, a Ci-Cs -alkyI aiyl group, a C5-C7 cycloalkyl group, an aryl group optionally substituted with atleast one group consisting of a C1-C8 alkyl, an alkyl aryl or an alkoxy alkyl
b. reacting the compound of formula IV with Af-methyl-o-phenylenediamine of formula III or salt thereof
(Formula Removed)
Formula III
in the presence of suitable reagent to form compound of formula I;
(Formula Removed)
Formula I
c. condensing compound of formula I with substituted biphenyl derivative of formula
(Formula Removed)
wherein R2 denotes a straight-chained or branched C1-C8 -alkyl group, a C1-C8 -alkyl aryl group, a C5-C7 cycloalkyl group, an aryl group optionally substituted with atleast one group consisting of a C1-C8 alkyl, an alliyl aryl or an alkoxy alkyl,
in the presence of a base, and optionally a phase transfer catalyst in a suitable solvent, to give telmisartan ester derivative of formula VI; and

Formula VI (Formula Removed)
wherein R 2 is as defined above
d. hydrolysing telmisartan ester derivative of formula VI to form telmisartan;
e. isolating telmisartan thereof; and
f. optionally purifying telmisartan.
8. The process according to claims 6 and 7, wherein suitable reagent is selected
from inorganic acid such as polyphosphoric acid, organic acid such as acetic acid, butyric acid, p-toluene sulphonic acid, methane sulphonic acid and phosphorus pentoxide and the like or mixture thereof.
9. The process according to claims 6 and 7, wherein solvent is selected from
nitriles, aromatic hydrocarbons, alcohols, ethers, ketones, esters and the like
10. The process according to claims 6 and 7, wherein base is selected from a metal
hydroxide, a metal carbonate or bicarbonate and phase transfer catalyst is
selected from benzyltriethylammonium chloride, resin amberlite iRA-410,
tetrabutylammonium bromide; tetrabutyl ammonium hydroxide;
tricaprylylmethylammonium chloride, dodecyl sulfate, sodium salt, such as
sodium lauryl sulfate; tetrabutylammonium hydrogensulfate; hexadecyl
tributyl phosphonium bromide; or hexadecyltrimethylammonium bromide.