FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13) 1. TITLE OF THE INVENTION:
"Novel intermediates and method for synthesis of 4'-[(l ,4'-dimethyl-2'-propyl-[2,6'-bi-l/y]benzimidazol]-l-yl)methyl]-[1,1-biphenyl]-2-carboxylic acid."
2. APPLICANT:
(a) NAME: IPCA LABORATORIES LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West),
Mumbai-400067, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Field of invention:
The present invention relates to a novel method for synthesis of 4'-[(l ,4'-dimethyl-2'-
propyl-[2,6'-bi-l/f)benzimidazol]-l-yl)methyl]-[1,1-biphenyl]-2-carboxylic acid,
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'-[(l ,4'-dimethyl-2'-propyl-[2,6'-bi-l/H]benzimidazol]-l-yl)methyl]-[1,1-biphenyl]-2-carboxylic acid or 4'-[2-n-propyl-4-methyl-6-(l -methylbenzimidazol-2-yl)-benzimidazol-l-ylrnethyl]-biphenyl-carboxylic acid. Its empirical formula is C33H30N4O2, and its structural formula is CH3

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: CNI344712 discloses a method for preparing telmisartan by condensation of 2-propyl-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-l//-benzimidazole, useful for preparing telmisartan, by reaction of 2-propyl-4-methyl-l//-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-(l'-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 \H-benzimidazole-2-n-propyl-4-methyl-6-(r-Methylbenzimidazole-2'-yl) and Me 4-(bromomethyl)biphenyl-2-carboxylate, followed by hydrolysis in a single step. Similar route of synthesis is mentioned in WO 2006044648
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. WO 2006050921 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.
WO 2006103068 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,T-biphenyl]-2-carboxamide
JP2006321798 relates to crystalline Form A of telmisartan.


WO2006125592 describes process for the preparation of 2-alkyl 1 -((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.
CN101024631 discloses a process for hydrolysis of intermediate 4'-[(l,4'-dimethyl-2'-propyl[2,6'-bi-l//-benzimidazol]-l'-yl)methyl]-[l,r-biphenyl]-2-carboxylic ester to yield telmisartan.
CN101074213 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 derivative of Formula I A, convertible into telmisartan







Wherein R is H, alkyl or protecting group.
R1 is COOH, CHO, COOR', CONR3R4, C(OR5)=NH
Formula IA wherein R stands for hydrogen, alkyl, or any N-protecting group; Rl stands for CN, 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 & IIA into compound of Formula IA CH,

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



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

The intermediates of Formula V, Formula VI or its reactive acid derivatives are not reported in literature and are therefore novel.
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. CH,


Wherein R is H, alkyl or protecting group.
R1 is COOH, CHO, COOR', CONR3R4, C(OR5)=NH
Formula IA In the formula IA, R stands for hydrogen, alkyl, or any N-protecting group; Rl stands for CN, 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 according to the present invention comprises use of a novel intermediate combination of Formula II (wherein R group is as defined above)

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 or absence of a 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. Cyclization may be effected in the absence of a catalyst, by heating the intermediate in suitable condition, preferably in a solvent.
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 110 degrees. The reaction normally completes in a span of 5 - 10 hours.
The intermediate of Formula III obtained after the reaction of compound II may be optionally isolated & purified, if desired, before conversion to telmisartan or compound of Formula I A. 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 I A.


The process for preparation of Telmisartan or its suitable derivative of Formula 1A from compound of Formula 111 is accomplished by reaction 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 acids are sulphuric acid, hydrolchloric acid, trichloroacetic acid or trifluoroacetic acid.
The hydrolysis of cyano- group of compound 111 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 I A. 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 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 degree to reflux temperature of solvent, but preferably between 60 to 160 degrees. The reaction normally completes in a span of 10-15 hours.
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.[Pl. add solvent you think may be of use for purification]. 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, diemthylformamide, dimethyl acetamide, 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 11/111. The present compounds are










In this aspect the present invention provides process for preparation of said intermediates especially intermediate of Formula 11 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
,

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 phenelenediamine 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.
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 phenelenediamine 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).
The reactive derivative of compound of Formula is either an acid halide, or mixed anhydride as represented below:

Formula VIII 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"-yl methyl ]
biphenyl.
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 °C for 4-5 hrs. After completion of the reaction the methanol was distilled out under reduced pressure and residue was dissolve 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 %.
Example 2.
7-Methyl-N-(2-methylamino)-phenyl-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 78-80°C 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 5-7 °C. To this mixture, previously prepared acid chloride solution was added over a period of 30 minutes under nitrogen atmosphere maintaining the temperature 5- 10 °C. 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 °C, 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 %.
Example 3.
2-Cyano-4'-[2"-n-propyl-4"-methyl-6"-(r "-methyl benzimidazole-2'"-yl)
benzimidazole-l"-yI 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 °C for 4-5 hrs.. After completion of the reaction the toluene was distilled out under reduced pressure , water (l'00ml) followed by methylene di chloride (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 hrour, gradually cooled to 30-32 °C and then to 0-2 °C, maintained for 2 hrs. at 0-2 °C filtered, wet cake washed with 30 ml chilled toluene ,dried in oven at 65 °C to obtain 2-Cyano-4'-[2"-n-propyl-4"-methyl-6"-(r"-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 °C 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 °C 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 °C, 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 °C, the pH of the filtrate adjusted to 4- 4.5 with 50 % acetic acid , maintained for 30 minutes at 30 °C, cooled to 0-2 °C, 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 %.