WO2009116089A2

WO2009116089A2 - Novel intermediates and method for synthesis of 4'-[(1,4'-dimethyl-2'-propyl-[2,6'- bi-1hbenzimidazol]-l-yl)methyl]-1,1-biphenyl]-2-carboxylic acid.

Info

Publication number: WO2009116089A2
Application number: PCT/IN2009/000176
Authority: WO
Inventors: Ashok Kumar; Suneel Yeshwant Dike; Pramikumar Mathur; Yogesh Mohanbhai Patel
Original assignee: Ipca Laboratories Limited
Priority date: 2008-03-14
Filing date: 2009-03-13
Publication date: 2009-09-24
Also published as: WO2009116089A3

Abstract

Disclosed herein is a method for synthesis of 4'-[(1,4'-dimethyl-2'-propyl-[2,6'-bi- 1H]benzimidazol]-l-yl)methyl]-[1,1-biphenyl]-2-carboxylic acid or its derivatives, and novel intermediate compounds useful in the synthesis.

Description

Novel intermediates and method for synthesis of 4'-[(I ,4'-dimethyl-2'-propyl-[2,6'- bi-lH]benzimidazoI]-l-yl)methyl]-[l,l-biphenyl]-2-carboxylic acid.

Field of invention.

The present invention relates to a novel method for synthesis of 4'-[(I ,4'-dimethyl-2'- propyl-[2,6 '-bi- lHJbenzimidazol]- 1 -yl)methyl]-[ 1 , 1 -biphenyl]-2-carboxylicacid, commonly known as Telmisartan. The invention further relates to novel intermediate compounds useful in the synthesis of Telmisartan, and process for their preparation.

Background of the invention

Telmisartan is an angiotensin II receptor antagonist developed for the treatment of hypertension and other medical indications as disclosed in EP502314. It is a non-peptide Angiotensin II blocker, which is chemically named either as 4'-[(I ,4'-dimethyl-2'-propyl- Pjo'-bi-lHjbenzimidazolJ-l-yOmethylJ-tlJ-biphenylJ^-carboxylic acid or 4'-[2-n- propyl-4-methyl-6-( 1 -methylbenzimidazol-2-yl)-benzimidazol- 1 -ylmethyl]-bipheny 1- carboxylic acid. Its empirical formula is C33Η30N4O2, and its structural formula is

Formula I

The pharmaceutical application of telmisartan and various preparative methods for obtaining Telmisartan are described in EP502314. It exemplified hydrolysis of a tertiary butyl ester of Telmisartan.

Further improvements or other synthetic methods are disclosed in following literature: CN 1344712 discloses a method for preparing telmisartan by condensation ot Z-propyi-4- methyl-6-(r-methylbenzimidazol-2'-yl)benzimidazole with bromobiphenyl 2-carboxylic acid ester, followed by hydrolysis.

WO2003059890 describes preparation and purification of intermediate l,7'-dimethyl-2'- propyl-2,5'-bis-lH-benzimidazole, useful for preparing telmisartan, by reaction of 2- propyl-4-methyl-lH-benzimidazole-6-carboxylic acid, or its salts, with N-Methyl-o- phenylenediamine.

WO2004087676 describes preparation of Telmisartan by reaction of 2-propyl-4-methyl- 6-(r-methylbenzimidazol-2'-yl)benzimidazole (I) with biphenyl cyano derivative, followed by hydrolysis of cyano intermediate to provide telmisartan. Similar process is disclosed in CN1412183 also.

WO2005108375 discloses preparation of Telmisartan by condensation of IH- benzimidazole-2-n-propyl-4-methyl-6-( 1 '-Methylbenzimidazole-2'-yl) and Methyl-4- (bromomethyl)biphenyl-2-carboxylate, followed by hydrolysis in a single step. Similar route of synthesis is mentioned in WO2006044648

WO2006044754 discloses preparation of various intermediates and their use in the process for preparation of Telmisartan.

WO2006050509 discloses alkali salts of telmisartan and their polymorphic forms. WO2006050921 also discusses alkali salts of Telmisartan and polymorphs made there from.

Polymorphs of Telmisartan are disclosed in WO2000043370. US2006111417 discloses process for amorphous form of Telmisartan.

WO2006103068 discloses intermediates for preparation of telmisartan and process for preparing the same. EP1719766 discloses a process for the preparation of telmisartan comprising building the biphenyl bond by substitution of mono-phenyl intermediate.

US2006264491 discloses preparation of Telmisartan by hydrolysis of 4'-[(l,4'-dimethyl- 2'-propyl[2,6'-bi-lH-benzimidazol]-r-yl)methyl]-[l,r-biphenyl]-2-carboxamide

JP2006321798 relates to crystalline Form A of telmisartan.

WO2006125592 describes process for the preparation of 2-alkyl l-((2-substituted biphenyl-4-yl)-methyl imidazole, dihydroimidazole or benzmidazole derivatives by boronic acid assisted building of biphenyl structure.

WO2007010558 discloses preparation of telmisartan comprising steps of (i) condensing 4-methyl-2-propyl-lH-benzimidazole-6-carboxylic acid with N-Methyl-o- phenylenediamine dihydrochloride to yield 4-methyl-6-(l-methylbenzimidazol-2-yl)-2- propyl-lH-benzimidazole; (ii) treating 4-methyl-6-(l-methylbenzimidazol-2-yl)-2- ^* propyl- lH-benzimidazole with 4'-(bromomethyl)-2-biphenyl-2-carboxylic acid ester; (iii) converting the resulting ester to telmisartan dihydrochloride; and (iv) finally converting telmisartan dihydrochloride to telmisartan.

US2007037986 discloses a preparative method for intermediate useful for synthesis of telmisartan by 2-chloro-4,6-dimethoxy-l,3,5-triazine mediated coupling of 2-amino-N- methylaniline phosphate and 4-methyl-2-propyl-6-benzimidazolecarboxylic acid.

CNlO 1024631 discloses a process for hydrolysis of intermediate 4'-[(l,4'-dimethyl-2'- propyl^jό'-bi-lH-benzimidazolJ-r-y^methylJ-fljl'-biphenylJ^-carboxylic ester to yield telmisartan.

CNl 01074213 discloses a method for producing intermediate 4-methyl-6-(l- methylbenzimidazol-2-yl)-2-propylbenzimidazole useful for the production of

Telmisartan

Thus, the search for a suitable manufacturing process for the synthesis of telmisartan from its discovery resulting in a satisfactory yield / purity of final product remains undoubtedly of interest. It is an objective of the present invention to discover an efficient and simpler process to synthesis telmisartan.

Summary of the invention.

Accordingly, the present invention provides new process for preparation of Telmisartan or its derivative of Formula IA, convertible into telmisartan

Formula IA wherein R stands for hydrogen, alkyl, or any N-protecting group; Rl stands for COOH; CHO; COOR2, wherein R2 stands for any alkyl or aralkyl ester group; CONR3R4, wherein R3 and R4 stands independently of hydrogen or alkyl group; and C(OR5)=NH, wherein R5 stands for hydrogen or alkyl group.

The process of the present invention comprises converting an intermediate mixture of Formula II & ILA into compound of Formula IA

Formula Il Formula HA wherein R is as defined above, preferably an alkyl group. The process comprises cyclizing a compound of Formula II or IIA or a combination thereof, to obtain a compound of formula III (wherein R is as defined before), followed by converging it to Telmisartan or its derivative of Formula IA by any conventional method or the method as described in the present invention. The cyclization reaction may be carried out in presence / absence of suitable reagent

The present invention also provides a method for preparation of novel intermediate compounds of formula II and IIA or a mixture of Formula II & IIA comprising the use of intermediates represented in the following scheme.

R6 is any ester forming group or H.

Formula IV

X is any leaving group Formula IX

Formula Vl Formula II/IIA

The intermediates of Formula V, Formula VI or its reactive acid derivatives are not reported in literature and are therefore novel. Preferably the process may be operated in a one-pot manner.

Thus, present invention provides a compound of general formula IHA for use in the preparation of telmisartan or a structural derivative of formula IA.

Formula IHA

H or subst. R¹ = aryl, alkyl

H₂N

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.

Detailed description of the invention.

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims. The present invention thus provides a process for preparing telmisartan or a suitable derivative of Formula IA which can be converted into telmisartan.

Formula IA

In the formula IA, R stands for hydrogen, alkyl, or any N-protecting group; Rl stands for COOH; CHO; COOR2, wherein R2 stands for any alkyl or aralkyl ester group; CONR3R4, wherein R3 and R4 stands independently of hydrogen or alkyl group; and C(0R5)=NH, wherein R5 stands for hydrogen or alkyl group.

The process according to the present invention comprises use of a novel intermediate combination of Formula II & HA (wherein R group is as defined above)

Formula Il Formula HA

In this aspect of the present invention, the process comprises treating compound of Formula II under suitable conditions to cyclize into a compound of Formula III, and followed by conversion of Formula III into telmisartan or a derivative of Formula IA, suitable for obtaining telmisartan in a known manner.

The cyclization of intermediate II into compound of formula III may be effected in presence / absence of suitable cyclizing agent. The cyclizing agent may be selected from an acid catalyst, organic or inorganic, for example acetic acid, sulphonic acid, sulphuric acid, or polyphosphoric acid. The sulphonic acid may be selected from methane sulphonic acid, p-toluene sulphonic acid, benzene sulphonic acid. The especially preferred agent is p-toluene sulphonic acid.

The cyclization reaction may be effected in the presence or absence of a solvent, but advantageously in presence of an inert solvent. The solvent may be selected from any inert organic solvents those are customarily used, for example, but not limited to, alcohols, ketones, amide, sulphoxides, hydrocarbons, chlorinated solvents, nitriles, and ethers or their mixtures. When sulphonic acid is used as cyclization agent, then the reaction is preferably carried out in presence of an organic solvent. Especially preferred solvent is toluene, and/or xylene,.

The cyclization reaction is preferably performed by heating the reactants in neat condition (solvent free) or in a suitable solvent and the preferred temperature for carrying out the reaction is from ambient condition to reflux temperature of solvent, but preferably between 50 to 115 degrees. The reaction normally completes in a span of 5 - 10 hours. The reaction may be effected under positive pressure in a pressure vessel.

The intermediate of Formula HI obtained after the reaction of compound II may be optionally isolated & purified, if desired, before conversion to telmisartan or compound of Formula IA. In this process, the work up and isolation of the compound III is carried out either by solvent elimination or filtration or extraction of the product into an organic solvent. The extraction may be performed by following an acid-base treatment to purify the product, and crystallization from a suitable solvent, which are known to a skilled artisan, or exemplified in the present invention. In another alternative the crude product may be directly subjected to the hydrolysis of cyano-group to telmisartan or its suitable derivative of Formula IA.

The process for preparation of Telmisartan or its suitable derivative of Formula IA from compound of Formula III is accomplished by reaction of compound of Formula III under suitable hydrolytic conditions. It can be seen that direct hydrolysis of Cyano group in Formula III may be effected in presence of acid or base. Acid may be selected from those are customarily used for hydrolysis of cyano group into carboxylic group or an amide group, or into a C(OR5)=NH group. Examples of acids are sulphuric acid, hydrochloric acid, trichloroacetic acid or trifluoroacetic acid.

The hydrolysis of cyano- group of compound III may be effected in presence of a base. Any base may be selected from those which are customarily used for hydrolysis of cyano group into carboxylic group. Examples of inorganic bases include alkali hydroxide. Examples of alkali metal hydroxides include sodium hydroxide and potassium hydroxide. Both the base and acid may be used in catalytic amount to molar excess related to the starting compound of Formula III.

In a further embodiment of the invention, the hydrolytic reaction may be carried out in the presence of a catalyst. The catalyst may be selected from among the phase-transfer catalyst or metal iodide. The selection or presence of said catalysts accelerate the reaction and reduces the time cycle. Sodium or potassium iodide is especially preferred among the metal iodides. As the phase transfer catalyst, mention can be made of, for example, quaternary ammonium salts.

The reaction is effected in presence of aqueous or organic solvent depending upon the specific compound targeted from the group of compounds of Formula IA. The process is advantageously carried out in an organic or aqueous solvent, such as those customarily used, for example, alcohols, chlorinated hydrocarbons, ethyl acetate, toluene, diethylether, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethyl acetamide, or N- methyl pyrollidone etc. The reaction may be done in presence of water or mixture of water miscible solvents. Alcohol may be selected from methanol, ethanol, propanol, butanol, and glycols. Especially preferred solvent is ethylene glycol and its mixture with water.

The hydrolytic reaction may be accomplished at a temperature ranging from ambient temperature to reflux temperature of the solvent. The reaction is preferably performed under heating in a suitable solvent and the preferred temperature for carrying out the reaction is by maintaining the temperature above 50 degrees to reflux temperature of solvent, but preferably between 60 to 160 degrees. The reaction normally completes in a span of 10-15 hours. Reaction may be optionally carried out under a positive pressure to speed-up reaction rate..

On complete conversion, the telmisartan or compound of Formula IA is isolated by any conventional means: for example, solvent distillation, extraction, acid/base treatment, crystallization or recrystallization. If desired, the compound of Formula IA, where in Rl is not COOH group, may be converted into telmisartan by known means. Purification of crude telmisartan may be effected by first treating the crude product with an alkali, for example ammonia, in a polar protic solvent or aprotic dipolar solvent to form a solution, followed by precipitation of pure telmisartan with an acid. Crystallization solvents may be advantageously selected from alcohols, dimethylformamide, dimethyl acetamide, n- methyl pyrrolidone, acetonitrile, acetone or mixtures thereof.

In another aspect the present invention provides novel intermediates for preparation of telmisartan or compound of Formula IA. The present compounds are

Formul V

R, R6 are as previously defined. In this aspect the present invention provides process for preparation of said intermediates especially intermediate of Formula II/IIA or mixture thereof comprising the following reactions. The process according to the present invention comprises the following steps: a. Either by reaction of compound of formula IV with compound of Formula IX (wherein the groups are as defined in scheme below) under suitable conditions or by cyclization of an intermediate of Formula X under suitable condition

R6 is any ester forming group or H. Formula IV

X is any leaving group Formula IX

Formula V

Formula V optionally removing the R6 protection from resulting compound of Formula V to obtain compound of Formula VI; and b. reacting either compound of Formula V or VI or a reactive derivative of intermediate VI with phenylenediamine of Formula VII to obtain compound of Formula II.

In the formula II, III, IV, V, VI, VII, VIII, and IX , the groups R, R1-R6 are as defined previously.

In the Process step (a), the leaving group may be selected from halo, or tosyl, preferably the leaving group is bromine. The reaction may be effected in presence of a base, customarily used for this reaction. The base used in the reaction may be an inorganic or an organic base; examples of organic base include triethylamine, diisopropylethylamine, pyridine, morpholine, DBU (1,8-diazabicyclo- [5.4.0]-undec-7-ene), DBN (1,5- diazabicyclo-[4.3.0]- non-5-ene), 4-dimethylamino pyridine and mixtures thereof. Examples of inorganic bases include alkali metal carbonate, bicarbonate, hydroxide, alkoxides and mixtures thereof. Examples of alkali metal carbonates include sodium carbonate and potassium carbonate. Examples of alkali metal bicarbonates include sodium bicarbonate. Examples of alkali metal hydroxides include sodium hydroxide and potassium hydroxide. Organic bases are preferred for this application and especially suitable bases are amines, preferably triethylamine or N,N-diisopropylethylamine. The amount of base added to the reaction mixture is not very critical but should be adjusted with respect to the molar amounts of respective substrates or can be established by trial. The reaction may be effected in presence of catalyst also, especially preferred are metal iodide, or phase transfer catalyst. The reaction is performed in presence of a solvent, aqueous or organic or under biphasic conditions. Especially preferred solvents are dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, dimethyl sulphoxide, water, or mixture of water and a hydrocarbon, such as toluene. The reaction may be effected under heating. The reaction may be carried out in presence of a suitable catalyst, which may be selected from alkali metal halide or phase-transfer catalysts. Suitable catalysts are sodium iodide, potassium iodide, or tetrabutylammonium bromide.

Process Step (b), the R6 group may be alkyl or aralkyl group. When the R6 group is alkyl, the removal is effected under hydrolytic conditions, where as, when R6 is aralkyl, the deprotection is effected under hydrogenolysis conditions customarily used in such application.

Process Step c) may be effected by reaction of intermediate V or VI or a reactive derivative of formula VI with phenylenediamine of Formula VII in usual amide forming conditions such as in presence of a base or peptide coupling catalysts in suitable solvent. The base may be selected from known ones, illustrated for use in the step (a). The peptide coupling catalyst may be selected from dicyclohexyl carbodiimde (DCC) or any suitable agent.

The reactive derivative of compound of Formula VI is either an acid halide, or an anhydride as commonly understood by a skilled artisan, and includes as represented below:

Formula VIII

All the above reaction steps may be conducted in a one-pot manner. One pot manner herein means the intermediate compounds are as such reacted without any purification steps in the same or different conditions. Preferably steps (a) to (c) and cyclization of intermediates of Formula II/IIA followed by hydrolysis are performed in one-pot manner.

Further details of the process of the present invention will be apparent from the examples presented below. The examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.

Example 1.

2-Cyano -4'-[2"-n-propyl-4"-methyl-6"-carboxylate-benzimidazole-l"-yI methyl ] bipbenyl.

2-Cyano-4'-[2"-n-propyl-4"-methyl-6"-methylcarboxylate-benzimidazole-l "-yl methyl ]-biphenyl (38 gm) was stirred with a mixture of methanol (380 ml), sodium hydroxide (7.2 gm), and water (53 ml) and heated to 70 ⁰C for 4-5 hrs. After completion of the reaction the methanol was distilled out under reduced pressure and residue was dissolved in water (380 ml). The aqueous layer was extracted with methylene dichloride and pH of aqueous layer adjusted to 3-4 with 3 % hydrochloric acid solution, stirred for 2 hrs. The precipitate obtained was filtered washed with water and dried to obtain 2-Cyano-4'-[2"- n-propyl-4"-methyl-6"-carboxylate-benzimidazole-l"-ylmethyl]biphenyl. Yield 36.2 gm (98.52 %of theory), HPLC purity 98 %. ESI-MS : 410 [M+l]⁺

¹H NMR (400 MHz, CDC13): δ 12.70 (blH), 7.19-7.95 (m, 10H), 5.68(s, 2H), 2.87- 2.90(t, 2H), 2.57 (s, 3H), 1.73-1.82 (q, 2H), 0.94-0.97 (t, 3H). Example 2.

7-Methyl-N-(2-methylamino)-phenyI-2-propyl-3-(2'-cyano-4"-ylmethyl biphenyl)- benzimidazole-5-carboxamide

2-Cyano-4'-[2"-n-propyl-4"-methyl-6"-carboxylate-benzimidazole-l "-ylmethyl]- biphenyl (60 gm) and thionyl chloride ( 180 ml) were heated to 78-8O⁰C for 4 hours under nitrogen atmosphere. Thionyl chloride was distilled out and reaction mass was stripped with toluene (100 ml) to remove thionyl chloride completely, the residue obtained was dissolved in methylene dichloride(600 ml). In another flask N- methyl ortho phenylenediamine ( 17.9 gm) was stirred with methylene dichloride ( 180 ml), and triethyl amine( 44.4 gm) and cooled to 5-7⁰C. To this mixture, previously prepared acid chloride solution was added over a period of 30 minutes under nitrogen atmosphere maintaining the temperature at 5- 10 ⁰C. After addition was complete, water (300 ml) was added to it, organic layer separated and washed with water (100 ml), activated carbon( 6 gm) was added to the organic layer and stirred for 1 hour at 30 ⁰C, filtered and filtrate concentrated under reduced pressure to get 7- Methyl-N-(2-methylamino)-phenyl- 2-propyl-3-(2'-cyano-4"-ylmethyl biphenyl)-benzimidazole-5-carboxamide.Yield 76.3 gm.(101 4 % of theory), HPLC purity 80 -85 %.

Mass Spectra for formula II and II A, wherein Rl = Methyl. ESI: MS 514 [M+l]⁺ 1H NMR (400 MHz. CDC13):

OFormula II (wherein R =Methyl): δ 8.15 (s, IH), 6.70-7.77 (m, 14H), 5.34 (s, 2H), 4.20 (s, IH), 2.83-2.87 (t, 2H), 2.77 (s, 3H), 2.69(s, 3H), 1.80-1.85 (q, 2H), 1.00-1.03 (t, 3H). ii)Formula HA (wherein R =Methyl): δ 6.48-7.81 (m, 14H), 5.11-5.28 (dd, 2H), 3.89 (s, 2H), 3.33 (s, 3H), 2.79-2.83 (t, 2H), 2.58(s, 3H), 1.73-1.80 (m, 2H), 0.98-1.02 (t, 3H)

Example 3.

2-Cyano-4 '-[2"-n-propyl-4"-methyl-6"-(l ' ' '-methyl benzimidazole-2" '-yl) benzimidazole-l"-yl methyl ] biphenyl

7- Methyl-N-(2-methylamino)-phenyl-2-propyl-3-(2'-cyano-4"-ylmethyl biphenyl)- benzimidazole-5-carboxamide (32.4 gm) was stirred with toluene (162 ml) to get a clear solution, para toluene sulphonic acid (10.9 gm) was added and heated to 85 ⁰C for 4-5 hrs.. After completion of the reaction the toluene was distilled out under reduced pressure , water (100ml) followed by methylene dichloride (100 ml) were added , stirred for 15 minutes, pH adjusted to 9-10 with liquor ammonia, separated organic layer, washed with water, stirred for 1 hour, filtered, filtrate concentrated under reduced pressure, and residue obtained was heated to with toluene (125 ml) for 1 hour, gradually cooled to 30- 32 ⁰C and then to 0-2 ⁰C, maintained for 2 hrs. at 0-2 ⁰C filtered, wet cake washed with^' 30 ml chilled toluene ,dried in oven at 65 ⁰C to obtain 2-Cyano-4'-[2"-n-propyI-4"-methyl- 6"-(l '"-methyl benzimidazole-2'"-yl) benzimidazole-l "-yl methyl ] biphenyl. Yield : 22.2 gms (70.92 % of theory) HPLC purity 98.9 %.

Example 4. Telmisartan

A mixture of 2-Cyano-4'-[2"-n-propyl-4"-methyl-6"-(r"-methylbenzimidazole-2'"- yl)benzimidazole-l"-yl methyl]-biphenyl ( 20 gms), ethylene glycol (180 ml), water (3.6 ml) and potassium hydroxide (17.3 gm) were heated to 150- 155 ⁰C for 12- 14 hrs. The completion of the reaction was monitored by TLC, after completion of the reaction the solvent was distilled out under reduced pressure, the concentrated mass was dissolved in 300 ml water, washed with methylene dichloride, pH of the aqueous phase adjusted to 4- 4.5 with 50 % acetic acid stirred for 2 hours, filtered, the wet cake washed with distilled water ( 3 x 100 ml), and dried in oven at 65 ⁰C to get telmisartan 20.5 gm ( 98.7% of theory), HPLC purity 99.24%.

Example 5. Purification

Crude Telmisartan ( 8.0 gm) and isopropyl alcohol (48 ml) were heated to 45 ⁰C, 20 % ammonium carbonate solution (12 ml) was added to make a solution, solution treated with activated carbon (0.8 gm), maintained for 1 hr, filtered, washed with isopropyl alcohol (2x8 ml), filtrate cool to 25-30 ⁰C, the pH of the filtrate adjusted to 4- 4.5 with 50 % acetic acid , maintained for 30 minutes at 30 ⁰C, cooled to 0-2 ⁰C, maintained for 2 hrs, filtered and wet cake washed with isopropyl alcohol followed by water, and dried. Yield 6.6 gm ( 82.5 %), HPLC purity 99.73 %.

Example 6.

2-Cyano -4'-[2"-n-propyl-4"-methyl-6"-methyIcarboxyIate-benzimidazoIe-l"-yl methyl ] biphenyl. lH-benzimidazole-6- methylcarboxylate-4-methyl -2-n-propyl (10.0 gm, 0.043 mol) was dissolved in DMF (30ml) and cooled to 20-25 ⁰C, potassium hydroxide (3.32 gm ), and 2- cyano-4'-bromomethyl biphenyl (12.8 gm 0.047 mol) were added and stirred at 30-32 ⁰C. After completion of the reaction (as monitored by TLC), the DMF was distilled out under reduced pressure at 50-55 ⁰C .The residue obtained was stirred with water for 30 minutes and filtered, washed with water, and dried in oven at 60-65 ⁰C to get 2-Cyano - 4'-[2"-n-propyl-4"-methyl-6"-methylcarboxylate-benzimidazole-l "-yl methyl ] biphenyl. Yield 18.6gm , ( 101.97 %) , HPLC purity 92.01 %.

Example 7 Telmisartan

A mixture of 2-Cyano-4'-[2"-n-propyl-4"-methyl-6"-(r"-methylbenzimidazole-2'"- yl) benzimidazole-l"-yl methyl ] biphenyl (25 gms, 0.0505mol), ethylene glycol ( 225 ml), water (4.54 ml) and potassium hydroxide (21.6 gm) were heated to 150- 155 ⁰C for 24-26 hrs. The completion of the reaction was monitored by TLC, after completion of the reaction the solvent was distilled out under reduced pressure, the concentrated mass was dissolved in 300 ml water, extracted with 3x100 ml methylene dichloride, pH of the aqueous phase adjusted to 4-4.5 with 50% acetic acid, stirred for 2 hours, filtered, washed with water and dried in oven at 80 ⁰C to get crude telmisartan. Crude Telmisartan ( 24.0 gm) was heated with ethanol ( 144 ml) to 45 ⁰C, and 20 % ammonium carbonate solution and activated carbon (2.4gm) were added and heated to 50 ⁰C, maintained for 1 hour, filtered, washed with ethanol (2x8 ml), cool to 25-30 ⁰C, pH of the filtrate adjusted to 4- 4.5 with 50 % acetic acid, maintained for 2 hrs, filtered, washed with ethanol/water, and dried in oven at 80 ⁰C under vacuum. Yield -- 21.3gm ( overall yield 82%), HPLC purity 99.86 %.

Example 8

Methyl - 4 - butyramido - 3 - methyl - 5 - πitro benzoate ►

2-Cyano-4'-[2"-n-propyl-4"-methyl-6"-carboxylate-benzimidazole-l"-ylmethyl] biphenyl.

A mixture of Methyl-4-butyramido-3-methyl-5-nitrobenzoate (53 gm, 0.1892 mol), Raney Nickel, (2.65gm) and methanol (795 ml) were stirred in an autoclave with hydrogen pressure of 3.5-4.5 kg/cm2 for 4-5 hrs at 30-36 ⁰C. The completion of the reaction was monitored by TLC. After the completion of the reaction the catalyst was recovered by filtration and the filtrate was concentrated to dryness. Toluene( 470 ml), and Para toluene sulphonic acid ( 1.0 gm) were added and heated to reflux with dean stark arrangement for 4 -5 hrs.. After completion of the reaction, as monitored by TLC, toluene was distilled out completely and Dimethylformamide (132 ml ) was added and cooled to 20-25 ⁰C. Potassium hydroxide( 14.6 gm ) and 2-cyano-4'-bromomethyl biphenyl (56.6 gm) were added, and stirred at 5-10 ⁰C. After completion of the reaction (as monitored by TLC), DMF was distilled out under reduced pressure at 50-55 ⁰C and methanol ( 800 ml), sodium hydroxide ( 22.7 gm) dissolved in Water (170 ml) were added and heated to 55 ⁰C for 15-20 hrs. After completion of the reaction, as monitored by TLC, methanol was distilled out under reduced pressure and residue was dissolved in water, adjusted pH to 3-3.5 with 3 % hydrochloric acid solution, and stirred for 2 hrs. The precipitate obtained was filtered, washed with water and dried in oven at 65 ⁰C to obtain 2-Cyano-4'-[2"-n-propyl-4"-methyl-6"-carboxylate-benzimidazole-l "-yl methyl] biphenyl. Yield 80 gm.

Example 9

2-Cyano -4'-[2"-n-propyl-4"-methyl-6"-carboxylate-benzimidazole-l"-yl methyl ] bipheny ^►

2-Cyano-4'-[2"-n-propyl-4"-methyl-6"-(l'"-methyl benzimidazole-2'"-y-) benzimidazole-l"-yl methyl ] biphenyl

To a mixture of 2-Cyano-4'-[2"-n-propyl-4"-methyl-6"-carboxylate-benzimidazole-l"- ylmethyl] biphenyl (20 gm, 0.0488 mol) in 200 ml methylenedichloride, thionyl chloride (14.52 gm 0.122 mol) and 0.1ml dimethylformamide were added and heated to 40- 42⁰C for 3 hours under nitrogen atmosphere. Methylene dichloride and thionyl chloride were distilled out and the residue obtained was dissolved in methylene dichloride( 250 ml) and was added to a solution of N- methyl orthophenylenediamine (6.5 gm 0.0531 mol), triethyl amine (14. 8 gm 0.1465 mol ) & dimethyl amino pyridine (0.3 gm) in methylene dichloride (100 ml) at temperature 0 ⁰C. After addition was complete the reaction mixture was further stirred for three hrs. at O⁰C , water (200 ml) was added to it, organic layer separated, washed with water, and concentrated under reduced pressure to get 7- Methyl- N-(2-methylamino)-phenyl-2-propyl-3-(2'-cyano-4"-ylmethyl biphenyl)-benzimidazole- 5-carboxamide. To this, Toluene ( 270 ml) was added and heated to reflux i.e 108-110 ⁰C for 7-8 hours. After completion of the reaction the toluene was distilled out under reduced pressure, methylene di chloride ( 250 ml) was added, stirred for 30 minutes, 2.5 gm activated carbon was added, stirred for 1 hour, filtered, filtrate washed with 3x 70 ml 5 % sodium hydroxide solution followed by water, organic layer concentrated under reduced pressure, residue obtained was heated to 95 ⁰C with toluene ( 120 ml) for 1 hr. , gradually cooled to 0-2 ⁰C, maintained for 2 hrs. at 0-2 ⁰C, filtered, wet cake washed with 30 ml chilled toluene, and dried in oven at 65 ⁰C to obtain 2-Cyano-4'-[2"-n-propyl-4"- methyl-6"-(r"-methylbenzimidazole-2'"-yl)benzimidazole-l"-ylmethyl] biphenyl. yield 18.8 gms (77 % of theory). HPLC purity = 99.43 % .

Claims

We claim,

1. A compound of the general formula IHA:

Formula IHA

H or subst.

NR¹

R' = aryl, alkyl

H₂N

2. Use of compounds according to claim 1 in the preparation of a compound of formula IA

Formula IA

Wherein, R stands for hydrogen, alkyl, or any N-protecting group; Rl stands for COOH; CHO; COOR2, wherein R2 stands for any alkyl or aralkyl ester group; CONR3R4, wherein R3 and R4 stands independently of hydrogen or alkyl group; and C(0R5)=NH, wherein R5 stands for hydrogen or alkyl group Use of compounds as claimed in claim 2, wherein the preparation of compound of formula IA comprises cyclization of at least one of the intermediate compounds of

subst.

or subst.

R' = aryl, alkyl Formula IIIA, wherein, n=0 and Y is

²

Use of compounds as claimed in claim 3, wherein the compound of formula IIIA is any one of the structure given below or their mixture:

Formula II Formula HA

5. Use of compounds as claimed in claims 3 to 4, wherein the cyclization is carried out in the presence of a catalyst.

6. Use of compounds as claimed in claim 5, wherein the catalysts is acetic acid, sulphonic acid, sulphuric acid, or polyphosphoric acid, methane sulphonic acid, p- toluene sulphonic acid, benzene sulphonic acid.

7. Use of compounds as claimed in claim 3 to 6, wherein the cyclization is in presence of a solvent.

8. Use as claimed in any one of the preceding claim, wherein the compound of formula IA is Telmisartan.

9. A process for preparation of compounds according to claim 1 comprises: a. Reacting a compound of formula IV and a compound of formula IX, wherein the groups as defined; and

R6 is any ester forming group or H. Formula IV

X is any leaving group Formula IX b. reacting the product of step a) with a reactive species of substituent Y as defined in claim 1.

10. A process for preparation of compounds IA according to claim 9 , wherein the preparation of compound of formula IA comprises: a. cyclizing a compound of formula X, wherein the groups as defined; and

Formula X

Formula V

b. optionally reacting the product of step a) with a reactive species of substituent Y as defined in claim 1, when n=0. 11. A process as claimed in claim 9 or 10, wherein the reactive species of substituent

or subst.

R' = aryl, alkyl

Y is as defined below:

12. A process as claimed in claim 9, wherein the reaction of compounds of formula IV and IX is in presence of a polar solvent.

13. A process as claimed in claim 10, wherein the reaction of compounds of formula IV and IX is in presence of a biphasic solvent medium.

14. A process as claimed in claim 12 to 13, wherein the reaction of compounds of formula IV and IX is in presence of a base and catalyst.

15. A process as claimed in claim 10, wherein the cyclization reaction is in presence of a catalyst.

16. A process as claimed in claim 10, wherein the cyclization reaction is in presence of solvent and absence of a catalyst.