PROCESS FOR PREPARING TELMISARTAN
RELATED APPLICATIONS
The present application claims the benefit of United States Provisional Patent
Application No. 60/619,563 filed on October 15, 2004.
FIELD OF THE INVENTION
The present invention is directed to processes for preparing a telmisartan
alkylester intermediate and further converting it to telmisartan. The present invention is
also directed to a process for the preparation of telmisartan in a single vessel.
BACKGROUND OF THE INVENTION
Telmisartan, 4'-[2-n-propyl-4-methyl-6-(l-methylbenzimid-azol-2-
yl)benzimidazol-l-ylmethyl]biphenyl-2-carboxylic acid, having the structure of Formula I
Mw 5 14.63
is a non-peptide angiotensin H receptor (type AT]) antagonist. The United States Food
and Drug Administration (FDA) approved it for the treatment of hypertension. It may be
used alone or in combination with other hypertensive agents, such as hydrochlorothiazf.de.
Boehringer Ingelheim markets telmisartan under the trade name Micardis® (telmisartan),
available as 40 and 80 mg tablets for oral administration. Two patents are listed in the
FDA's electronic Orange Book for telmisartan, U.S. Patent No. 6,358,986 ("the '986
patent") and U.S. Patent No. 5,591,762 ("the '762 patent").
The '986 patent discloses that telmisartan and the physiologically acceptable salts
thereof can also be used to- treat cardiac insufficiency, ischaemic peripheral circulatory
disorders, myocardial ischaemia (angina), diabetic neuropathy, glaucoma, gastrointestinal
diseases, bladder diseases, and to prevent progression of cardiac insufficiency after
myocardial infarct.
In addition to the above therapeutic applications of telmisartan, the '762 patent
discloses other therapeutic applications, including treating diabetic nephropathy,
pulmonary diseases, e.g., lung oedema and chronic bronchitis. It also discloses using
telmisartan to prevent arterial restenosis after angioplasty, thickening of blood vessel
walls after vascular operations, and diabetic angiopathy. The '762 patent further
discloses using telmisartan to alleviate central nervous system disorders, such as
depression, Alzheimer's disease, Parkinson Syndrome, bulimia, and disorders of
cognitive function in view of the effects of angiotensin on the release of acetylchloline
and dopamine in the brain.
The European Application No. EP 0502314 and its corresponding U.S. patent, the
'762 patent disclose preparing telmisartan by alkylation of l,7'-dimethyl-2'-propyl-lH,
3'H~[2,5'] bibenzoimidazolyl (referred to as BIM) with a 4'-[(bromomethyi)[l,rbiphenyl]-
2-carboxylic acid 1,1-dimethylethyl ester (referred to as a BMBP alkyl ester)
followed by hydrolysis.
Chinese patent application, CN 1344712A, filed July 2001 discloses a process to
prepare telmisartan by reacting l,7'-dimethyl-2'-propyl-lH, 3'H-[2,5']bibenzoimidazolyl
with 4'-bromomethyl-biphenyl-2-carboxylic acid methyl or ethyl ester to form a
telmisartan methyl or ethyl ester intermediate, which is converted to telmisartan by acid
or base hydrolysis.
BIM may be prepared by mixing 2-propyl-4-methyl-lH-benzimidazole-6-
carboxylic acid with N-methyl-o-phenylene-diamine dihydrochloride as disclosed in J.
Med. Chem. (1993), 36(25), 4040-51, International Patent Application WO 0063158, and
US Application No. 2003/0139608 and are hereby incorporated by reference for their
disclosure of processes for preparing BIM. US Application No. 2003/0139608 discloses
a process, which can be used on an industrial scale for preparing and purifying BM, in
which the crude product is subjected to charcoal treatment.
The BMBP alkylester, wherein the alkyl group is a C1-4 branched or straight chain
may be prepared as disclosed in EP Patent No. 253,310, Meyers et al., Tetrahedron 1985
vol. 41, 837-860, European Patent No 324,377, and Japanese Patent No. 06298684. Each
of these references is hereby incorporated by reference for their disclosure of processes
for preparing a BMBP alkylester.
The solvents previously used to prepare telmisartan, such as dimethylformamide
and dimethylsulfoxide, have a high boiling point of greater than about 150°C. These
solvents are difficult to remove from the reaction using various evaporation techniques
known in the art. These reaction conditions are less environmentally friendly, less
efficient, and harsher on the product, and therefore result in a lower yield of the
telmisartan alkylester intermediate product. Other previously used solvents to prepare
telmisartan are miscible with water and therefore cause difficulties in extracting the
organic telmisartan alkylester intermediate products from the reaction. Other solvents are
toxic or unsafe for other reasons. Also, processes previously disclosed use 1.5
equivalents of BIM for each equivalent of a BMBP alkyl ester, which is in excess of what
is theoretically required. The expense of the reagents in the preparation and isolation of
BIM results in a more expensive overall synthesis of telmisartan than should theoretically
be required.
Thus, there is a need for processes for the preparation of telmisartan alkylester and
telmisartan that are environmentally friendly, easy to practice, produce high yields of
telmisartan, less costly and that can be adapted to industrial scale.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for preparing a telmisartan
alkylester intermediate of formula n
comprising the steps of
(a) combining l?7'-dimethyl-2'-propyl-lH,3'H-[2,5']bibenzoimidazolyl (referred to
as BIM) of formula III,
Formula III
with a 4'bromomethyl-biphenyl-2-carboxylic acid alkyl ester (referred to as
BMBP alkyl ester) of formula IV
Formula IV
an inorganic "base and a low boiling point organic solvent to obtain a mixture;
(b) heating the mixture obtained in step (a) to a temperature of about 55°C to about
120°C;
(c) maintaining the mixture obtained in step (b) for about 1 hour to about 8 hours to
obtain a telmisartan alkylester of formula II; and
(d) recovering the tennis artan alkylester of formula II;
wherein,
R is a straight or branched chainC1-4 alkyl.
In another aspect, the present invention provides a process for preparing
telmisartan by converting a telmisartan alkylester intermediate of formula II described
above to telmisartan of formula I, preferably by a process of hydrolysis under acidic or
basic conditions.
In yet another aspect, the present invention provides a process for the preparation
of telmisartan of formula I
(Figure Removed)
in a single reaction vessel comprising the steps of
(a) combining BBVI of formula III, a BMBP alkyl ester of formula IV, an inorganic
base and a ketone solvent, to obtain, a mixture;
(b) heating the mixture obtained in step (a) to a temperature of about 55°C to about
120°C;
(c) maintaining the mixture obtained in step (b) for about 6 hours to about 24 hours to
obtain a telmisartan salt of formula "V;
(Figure Removed)
Formula V
(d) separating the organic phase containing a tehnisartan salt of formula V from the
aqueous phase;
(e) converting tehnisartan salt of formala V to telmisartan of formula I; and
(f) recovering telmisartan of formula I,
wherein,
R is a straight or branched chain C1-C4 alkyl, and
M is a metal atom.
In one aspect the invention provides pharmaceutical compositions comprising
telmisartan prepared according to the processes of the present invention and
pharmaceutically acceptable excipients.
In another aspect the present invention provides a process for preparing
pharmaceutical formulation comprising mixing telmisartan prepared according to
processes of the present invention, and a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "low boiling temperature" refers to a boiling temperature
between about 55°C to about 120°C.
As used herein, the term "PTC (phase transfer catalyst)" refers to an agent, which
is used in a small amount in a two phase reaction, for extractirig the reactant from one
phase to the other. Typical PTCs are for example, crown ethers and quaternary
ammonium salts.
As used herein, the term "base" refers to a substance that tends to accept a proton.
Typical bases are for example, alkaline hydroxide and amines. Hence, an inorganic base
is a substance, which contains a metal cation and does not contain an organic moiety, as
compared to an organic base, which is a substance that contains an organic moiety.
Typical inorganic bases are for example, metal hydroxide, sucli as sodium hydroxide and
potassium hydroxide, metal carbonates, such as sodium carbonate and potassium
bicarbonate.
As used herein, the term "acid" refers to a substance that tends to release a proton.
Typical acids are for example, mineral acids, such as HC1 and organic acids, such as
trifluoro acetic acid, and acetic acid. Hence, a weak acid refers to a substance that tends to
a partial dissociation in water. Typical weak acids are for example, acetic acid, paratoluenesulfonic
acid and
The present invention provides a process for preparing a telmisartan alkylester
intermediate of formula II
Formula II
comprising the steps of
(a) combining l,7'-dimethyl-2'-propyl-lH,3'H-[2,5']bibenzoimidazolyl (referred to
as B1M) of formula III,
(Figure Removed)
with a 4'bromomethyl-biphenyl-2-carboxylic acid alkyl ester (referred to as
BMBP alkyl ester) of forrrrula IV,
Formula IV
an inorganic base, and an a low boiling point organic solvent, to obtain a mixture;
(b) heating the mixture obtained in step (a) to a temperature of about 55°C to atiout
120°C;
(c) maintaining the mixture obtained in step (b) for about 1 hour to about 8 hours, to
obtain a telmisartan alkylester of formula II, and
(d) recovering a telmisartan alleylester of formula n,
wherein,
R is a straight or branched chain C1-C4 alkyl.
Preferably, the straight or branched chainC1-C4 alkyl is methyl.
The solvents used in the process of the present invention have a boiling
temperature less than about 120°C. Thus, these solvents are easy to remove from the
reaction using various evaporation techniques known in the art. Therefore, a lower
reaction temperature is applied. Moreover, almost all of the solvents used in the present
invention to prepare telmisartan are slightly to non-miscible with water and therefore do
not cause difficulties in extracting the organic telmisartan alkylester intermediate products
from the reaction. Also, these solvents are non-toxic, safe and environmentally friendly.
Preferably, the low boiling point solvent is selected from trie group consisting of
Ce-io aromatic hydrocarbon, ketone and ester and mixtures thereof". Preferably, the Ce-io
aromatic hydrocarbon is toluene. Preferably, the ketone is methylethylketone,
methylisobutylketone or acetone. A preferred ester is isobutylacetate.
The more preferred solvent is toluene.
Preferably, water can be added to the low boiling point organic solvent in step (a).
The process of the present invention uses about 0.9 to about 1 mole equivalents of
BIM per mole equivalent of a BMBP alkyl ester. Thus, allowing a facile separation of the
product from BIM and therefore, leading to a significantly less expensive and time
consuming process.
Preferably, the amount of BIM used in step (a) is of about 0.8 to about 1.5 mole
equivalents per mole equivalent of BMBP, more preferably, of about 0.9 to about 1 mole
equivalents per mole equivalent of BMBP.
The process of the present invention uses an inorganic base instead of an organic
base. Therefore, disposing of the base in the work-up stages is very simple and more
environmental friendly. Preferably, the inorganic base is selected from the group
consisting of a metal hydroxide and a metal carbonate. Preferably, the metal hydroxide is
sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide,
magnesium hydroxide, calcium hydroxide or strontium hydroxide. Preferablx, the metal
carbonate is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium
bicarbonate or cesium carbonate. Preferably the inorganic base is either potassium
carbonate or sodium hydroxide.
Preferably, an aqueous solution of an inorganic base is used in step (a.).
Optionally, water can be added to step (a) when a solid inorganic base is used.
When a two-phase system is formed, such as for example, when the solvent is
toluene, the reaction may occur at the interface between the two phases. Hence, the rate of
such an interfacial reaction may be greatly increased by use of a phase transfer catalyst
(PTC). Preferably, the PTC is selected from the group consisting of quaternary
ammonium compounds, crown ether and phosphonium compounds. A preferred
quaternary ammonium compound includes, tributylmethylammoniurn chloricie (Aliquat®
175), tetrabutylammonium bromide (TBAB), tetrabutylammonium hydrogen, sulphate
(TBAHS), benzyltriethylammonium chloride and tetrapropylammonium bromide
(TPAB).
Preferably, the temperature of step (b) is of about 78°C to about 110°C.
Telmisartan alkylester of formula II may be recovered by any method known in
the art, such as the steps of cooling the reaction mixture of step (c), filtering, washing the
organic phase with water and drying the organic phase, filtering and evaporating the
solvent.
The present invention also provides a process for preparing telmisartan by
converting telmisartan alkylester intermediate of formula II described above -to
telmisartan of formula I, preferably according to the hydrolysis process undei acidic
conditions as disclosed in US patent NO. 5,591,762 or under basic conditions, as
disclosed in CN patent application NO. 1344712A.
Hydrolysis of a telmisartan alkylester of formula II to give telmisartan may be
conducted under acidic conditions or under basic conditions, as described above.
The process of the present invention can be done in a single vessel, by obtaining
the salt of telmisartan after hydrolysis of telmisartan alkylester. Because of the high
concentration of salts in the aqueous phase, the phases separate spontaneously and the
telmisartan salt, which is located in the organic phase, is then isolated by adding an acid
to the reaction vessel.
The present invention further provides a process for the preparation of telmisartan
of formula I
Formula I
in a single reaction vessel comprising the steps of
(a) combining BBVI of formula III, a BMBP alkylester of formula IV, an inorganic
base and a ketone solvent, to obtain a mixture;
(b) heating the mixture obtained in step (a) to a temperature of about 55°C to about
120°C;
(c) maintaining the mixture obtained in step (b) for 6 hours to about 24 hours, to
obtain telmisartan salt of formula V;
Formula V
(d) separating the organic phase containing telmisartan salt of formula V, from the
aqueous phase;
(e) converting telmisartan salt of formula V to telmisartan of formula I; and
(f) recovering telmisartan of formula I,
wherein,
R is a straight or branched chainC1-C4 alkyl;
M is a metal atom.
Preferably, the straight or branched cliain Ci-C4 alkyl is methyl.
Preferably, the metal atom is derived from the inorganic base.
The inorganic bases, BTM and their amounts are the same as those describ ed in the
process for the preparation of telmisartan alkylester of formula II.
Preferably, the ketone is methylethylketone, methylisobutylketone or acetone. The
more preferred solvent is acetone.
Preferably, water can be added to the ketone solvent in step (a).
The temperature of step (b) is the same as the temperature described in the process
for the preparation of a telmisartan alkylester of formula H
Preferably, a telmisartan salt maybe converted to telmisartan by adding an acid to
the organic phase obtained in step (d), containing a telmisartan salt of formula V,
preferably to obtain a pH of less than about 6, more preferably, of about 4 to about 6.
Preferably, the acid used is trifluoroacetic acid, sulfuric acid, or acetic acid. The more
preferred acid is acetic acid.
Telmisartan may be recovered by any method known in the art, such as filtering
and drying.
To conclude, the reaction conditions applied in the processes of the present
invention are more environmentally friendly., more efficient, and mild on the prod/uct,
leading to a much higher yield of the telmisartan alkylester intermediate product and thus,
can be adapted to an industrial scale.
The present invention provides pharmaceutical compositions comprising
telmisartan prepared according to the processes of the present invention and
pharmaceutically acceptable excipient.
The present invention further provides a process for preparing pharmaceutical
formulation comprising mixing telmisartan prepared according to processes of the present
invention, and a pharmaceutically acceptable carrier.
As used herein, the term "pharmaceutical compositions" includes tablets, pills,
powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection
preparations. Pharmaceutical compositions containing the telmisartan of the present
invention may be prepared by using diluents or excipients such as fillers, bulking agents,
binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
Various modes of administration of the pharmaceutical compositions of the invention can
be selected depending on the therapeutic purpose, for example tablets, pills, powders,
liquids, suspensions, emulsions, granules, capsules, suppositories, or injection
preparations.
Any excipient commonly known and used widely in the art can be used in the
pharmaceutical composition. Carriers used include, but are not limited to, lactose, white
sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline
cellulose, silicic acid, and the like. Binders used include, but are not limited to, water,
ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions,
carboxymethyl cellulose, shelac, methyl cellulose, potassium pliosphate,
polyvinylpyrrolidone,, and the like. Disintegrating agents used include, but are not limited
to, dried starch, sodium alginate, agar powder, laminalia powder, sodium hydrogen
carbonate, calcium carbonate, fatty acid esters of polyoxyethylene sorbitan, sodium
laurylsulfate, monoglyceride of stearic acid, starch, lactose, and. the like. Disintegration
inhibitors used include, but are not limited to, white sugar, stearin, coconut butter,
hydrogenated oils, and the like. Absorption accelerators used include, but are not limited
to, quaternary ammonium base, sodium laurylsulfate, and the ILke. Wetting agents used
incluoe, out are not limited to, glycerin, starch, and the like. Adsorbing agents used
include, but are not limited to, starch, lactose, kaolin, bentonite, colloidal silicic acid,
the like. Lubricants used include, but are not limited to, purified talc, stearates, boric axid
powder, polyethylene glycol, and the like. Tablets can be further coated with commonly
known coating materials such as sugar coated tablets, gelatin film coated tablets, tablets
coated with enteric coatings, tablets coated with films, double layered tablets, and multilayered
tablets.
When shaping the pharmaceutical composition into pill form, any commonly
known excipient used in the art can be used. For example, carriers include, but are not
limited to, lactose, starch, coconut butter, hardened vegetable oils, kaolin, talc, and the
like. Binders used include, but axe not limited to, gum arabic powder, tragacanth gum
powder, gelatin, ethanol, and the like. Disintegrating agents used include, but are not
limited to, agar, laminalia, and the like.
For the ptirpose of shaping the pharmaceutical composition in the form of
suppositories, any commonly known excipient used in the art can be used. For example,
excipients include, but are not limited to, polyethylene glycols, coconut butter, higher
alcohols, and esters of higher alcohols, gelatin, and semisynthesized glycerides.
When preparing injectable pharmaceutical compositions, solutions and
suspensions are sterilized and are preferably made isotonic to blood. Injection
preparations may use carriers commonly known in the art. For example, carriers for
injectable preparations include, but are not limited to, water, ethyl alcohol, propylene
glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid
esters of polyoxyethylene sorbitan. One of ordinary skill in the art can easily determine
with little or no experimentation the amount of sodium chloride, glucose, or glycerin
necessary to make the injectable preparation isotonic.
Additional ingredients, such as dissolving agents, buffer agents, and analgesic
agents maybe added. If necessary, coloring agents, preservatives, perfumes, seasoning
agents, sweetening agents, and other medicines may also be added to the desired
preparations.
The amount of telmisartan or salt thereof contained in a pharmaceutical
composition for treating schizoplirenia should be sufficient to treat, ameliorate, or reduce
the symptoms associated with schizophrenia. Preferably, telmisartan is present in an
amount of about 1% to about 70% by weight, and more preferably from about 1% to
about 30% by weight of the dose.
The pharmaceutical compositions of the invention may b e administered in a
variety of methods depending on the age, sex, and symptoms of the patient. For example,
tablets, pills, solutions, suspensions, emulsions, granules and capsules may be orally
administered. Injection preparations may be administered individually or mixed with
injection transfusions such as glucose solutions and amino acid solutions intravenously.
If necessary, the injection preparations may be administered intramuscularly,
intracutaneously, subcutaneously or intraperitoneally. Suppositories may be administered
into the rectum.
The dosage of a pharmaceutical composition for treating schizophrenia according
to the invention will depend on the method of use, the age, sex, and condition of the
patient. Preferably, telmisartan is administered in an amount from about 0.1 mg/kg to
about 10 mg/kg of body weight/day. More preferably, about 1 mg to 200 mg of
telmisartan may be contained in a dose.
The invention also encompasses methods of making a pharmaceutical formulation
comprising combining telmisartan, and a pharmaceutically acceptable excipient. As used
herein, the term "pharmaceutical formulations" includes tablets, pills, powders, liquids,
suspensions, solutions, emulsions, granules, capsules, suppositories, or injection
preparations.
Having described the indention with reference to certain preferred embodiments,
other embodiments will become apparent to one skilled in the art from consideration of
the specification. The invention, is further defined by reference to the following examples
describing in detail the preparation of the compound of the present invention. It will be
apparent to those skilled in the ait that many modifications, both, to materials and
methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Example 1: Preparation of telmisartan aikylester of formula II
l,7'-dimethyl-2'-propyl-lH,3'H-[2,5']bibenzoimidazolyl (HIM) (4-g), Aliquat®
175 (1.36 ml), K2CO3 (8.19g), and toluene (50 ml) were added to a 250 ml round bottom
flask equipped with a magnetic stirring bar and reflux condenser. The mixture was heated
to reflux (about 85-90°C) until a clear brown organic solution was obtained.
4'bromomethyl-biphenyl-2-carboxylic acid (BMBP) methyl ester (4.5 g) in toluene (24
ml) was added to the clear brown organic solution to form a reaction mixture. The
reaction mixture was stirred for about 6 hrs then cooled by ice bath and filtered forming a
cooled reaction mixture. The cooled reaction mixture was then extracted twice with water
(20 ml), dried over MgSO4, and evaporated forming telmisartan methyl ester (5.02 g),
which is about a 69% yield.
Example 2: Preparation of telmisartan alkvlester of formula II
l,7'-dimethyl-2'-propyl-lH33'H-[2,5']bibenzoimidazolyl (BIM) (4- g), NaOH
(4.26 g in 15 ml of water), and methylethyTketone (40 ml) were added to a 250 ml round
bottom flask equipped with a magnetic stirring bar and reflux condenser forming a
mixture. The mixture was heated to reflux: until a clear BIM solution was obtained. A
solution of 4bromomethyl-biphenyl-2-car"boxylic acid (BMBP) methyl ester (4.5 g) in
methylethylketone (16 ml) was added to th.e clear BIM solution forming a reaction
mixture- The reaction mixture was stirred for about 2 hrs then cooled to room
temperature. The cooled reaction mixture was then extracted with water (1 5 ml), dried
over MgSO4, and evaporated to obtain telmisartan methylester (5.76 g), which is about a
79% yield.
Example 3: Preparation oftehnisartan aikylester of formula II
l,7'-dimethyl-2'-propyl-lH,3IH-[2,5']bibenzoimidazolyl (BM) (4- g),
tetrabutylammonium hydrogensulphate (TBAHS) (0.45g) and NaOH (1.05 g), water (15
ml), and. toluene (40 ml) were added to a 250 ml round bottom flask equipped with a
magnetic stirring bar and reflux condenser forming a BIM mixture. The BUM mixture was
heated at reflux (80-90°C). A solution of 4'bromoniethyl-biphenyl-2-carboxylic acid
(BMBP) methyl ester (4.5 g) in toluene (16 ml) was added to the warm BIM mixture
forming a reaction mixture arxd the reaction mixture was stirred for 3.5 hrs then cooled to
room temperature. The cooled reaction mixture was then extracted with water (15 ml
forming an aqueous phase and organic phase. The organic phase was dried over MgSO4
then evaporated to obtain telmisartan methylester (7.41 g), which is about a 100% yield.
Example 4: Preparation of telmisartan alkylester of formula II
l,7'-dimethyl-2'-propyl-lH,3'H-[255']bibenzoimidazolyl (BIM) (4 g), Aliquat®
175 (0.47 ml), NaOH (4.85 g ), water (16 ml), and isobutylacetate (40 ml) were added to a
250ml round bottom flask equipped with a magnetic stirring bar and reflux condenser and
heated at reflux (80 °C) forming a warm BIM mixture. 4'bromomethyl-biphenyl-2-
carboxylic acid (BMBP) methyl ester (4.5 g) in isobutylacetate (16 ml) was added to the
warm BIM mixture to form a reaction mixture and the reaction mixture vvas stirred for
about one hour then cooled to room temperature. The cooled reaction mixture was then
extracted with water (20 ml) forming an aqueous phase and organic phase. The organic
phase was dried over MgSCU then evaporated to obtain telmisartan methylester (5.56 g),
which is about a 76% yield.
Example 5: Preparation of telmisartan
A 250-ml round bottom flask was loaded with BIM (4 g), methylethylketone (40
ml), and aqueous NaOH (22% or 19.26grams) to form a BEVI mixture. Tlie BIM mixture
was heated to 80°C and a solution of BMBP methylester (4 g.) in methylethylketone (16
ml) was added to the BIM mixture forming a reaction mixture. The reaction mixture was
stirred for about 24 hrs forming an organic phase and an aqueous phase. The two phases
were separated and the organic phase was divided into two portions. About 1 ml of glacial
acetic acid was added to one of the two portions until the pH was adjusted to about 4.7
forming a solution with a precipitate after a few minutes. The solution was stirred at room
temperature over night forming a product. The product was isolated by vacuum filtration
and dried in a vacuum oven at 50°C for 24 hr to obtain 2.7 g or 80% yield of Telmisartan.
The second portion was evaporated forming a solid. The solid was dissolved in
absolute ethanol, or in methanol heated to reflux, and glacial acetic acid was added,
adjusting the pH to 5.5 forming an ethanol solution. After 40 minutes the ethanol solution
was cooled to room temperature and stirred for 24-hrs forming telmisartan precipitate.
The elrnisartan precipitate was isolated by vacuum filtration, waslied with ethanol and
dried in a vacuum oven at 50°C for 24 hr.
Example 6: Preparation of telmisartan
A 250-ml round bottom flask was loaded with BIM (8 g), Acetone (96 ml) and an
aqueous NaOH solution (35%, 20 ml) to form a BIM mixture, which was heated, at reflux.
BMBP methylester (8 g) in acetone (32 ml) was added to the warm BIM mixture forming
a reaction mixture. The reaction mixture was stirred at reflux for 24 hrs forming an
organic phase and an aqueous phase. The phases were separated and the organic phase
was divided into two portions. The first organic portion (48-ml) was heated to reflux and
glacial acetic acid (1 ml) was added, adjusting the pH to 5.5. The first organic portion was
then cooled to room temperature and stirred over night forming a precipitate. The
precipitate was isolated by vacuum filtration, washed with acetone (40 ml), and dried in a
vacuum oven at 50°C for 24 hrs to obtain 6.58 g of telmisartan (79% yield).
The second portion (48-ml) was evaporated forming a solid. The solid was
dissolved in absolute ethanol, or in methanol heated to reflux, and. glacial acetic acid
about 1 ml) was added, adjusting thepH to 5.5 forming an ethanol solution. After 40
minutes the ethanol solution was cooled to room temperature and stirred 24-hrs forming
telmisartan precipitate. The telmisartan precipitate was isolated by vacuum filtration,
washed with ethanol, (40 ml) and dried in a vacuum oven at 50°C for 24 hrs to obtain 4.92
g of telmisartan (71% yield).
Example 7: Preparation of telmisartan
A 100ml reactor was loaded with BBVI (4g), methylisobutylketone (48 ml) and an
aqueous NaOH solution (35%, 10 ml) forming a BIM mixture. The BIM mixture was
heated to 78°C and a solution of BMBP methylester (4 g) in methylisobutylketone (16 ml)
was added to the warmed BM mixture forming a reaction mixture. The reaction mixture
was stirred at reflux for 24 hrs forming a reaction mixture with an. organic phase and an
aqueous phase. The phases were separated and glacial acetic acid (2 ml) was added to the
organic phase. After 2 hrs the reaction mixture was cooled to room temperature and
stirred 3 hrs forming a telmisartan precipitate. The telmisartan precipitate was isolated by
vacuum filtration, washed with ethanol (40 ml), and dried in a vacuum oven at 50DC for 24
hrs to obtain 4.59 g of telmisartan (68% yield).

What is claimed is:
1. A process for preparing tehnisartan alkylester intermediate of formula II
comprising the steps of
(a) combining l,7'-dimeth.yl-2'-propyl-lH,3'H-[2,5']bibenzoimidazolyl (referred to
as HIM) of formula III,
(Figure Removed)
Formula III
with a 4'bromomethyl-biphenyl-2-carboxylic acid alkyl ester (referred to as
BMBP alkylester) of formula IV
Formula IV
an inorganic base and a low boiling point organic solvent, to obtain a mixture;
(b) heating the mixture obtained in step (a) to a temperature of about 55°C to about
120°C;
(c) maintaining the mixture obtained in step (b) for about 1 hour to about 8 hours, to
obtain telmisartan alkylester of formula II; and
(d) recovering telmisartan. alkylester of formula E3
wherein,
R is a straight or branched chain C1-C4 alkyl.
2. A process for the preparation of telmisartan in a single reaction vessel comprising the
steps of
(a) combining BIM of formula III, a BMBP alkylester of formula TV, an inorganic
base and a ketone solvent, to obtain a mixture;
(b) heating the mixture obtained in step (a) to a temperature of about 55°C about
120°C;
(c) maintaining the mixture obtained in step (b) for about 6 hours to about 24 hours,
to obtain telmisartan salt of formula V;
Formula V
(d) separating the organic phase containing telmisartan salt of formula V, from the
aqueous phase;
(e) converting telmisartan. salt of formula V to telmisartan of fornrula I; and
(f) recovering telmisartaa of formula I,
wherein,
R is a straight or branched chain C1-C4alkyl;
M is a metal cation.
3. The process of claims 1 and 2, wherein the straight or branched cb_ain C1-C4 alkyl is
methyl,
4. The process of claim 1, wlaerein the low boiling point solvent is selected from the
group consisting of C6.10 aromatic hydrocarbon, ketone, ester and mixtures thereof.
5. The process of claim 1, wfcerein water can be added to the low boiling point solvent in
step (a).
6. The process of claim 2, wherein water is added to the ketone solvent in step (a).
7. The process of claims 4, wherein the Cg-io aromatic hydrocarbon is toluene.
8. The process of claims 4 and 2, wherein the ketone is methylethylketone,
methylisobutylketone or acetone.
9. The process of claim 4, wherein the ester is isobutylacetate.
10. The process of claim 4, wherein the low boiling point organic solvent is toluene.
11. The process of claim 7, wherein the ketone is acetone .
12. The process of claims 1 and 2, wherein the amount of BIM used in step (a) is of about
0.8 to about 1.5 mole equivalent per mole equivalent ofBMBP.
13. The process of claim 12, wherein the amount of BIM used in step (a) is of about 0.9 to
about 1 mole equivalent per mole equivalent ofBMBP.
14. The process of claims 1 and 2, wherein the inorganic "base is selected from the group
consisting of a metal hydroxide and a metal carbonate.
15. The process of claim 14, wherein the metal hydroxide is sodium hydroxide, potassium
hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium
hydroxide or strontium hydroxide.
16. The process of claim 14, wherein the metal carbonate is sodium carbonate, sodium
bicarbonate, potassium carbonate, potassium bicarbonate or cesium carbonate.
17. The process of claim 14, wherein the inorganic base is either potassium carbonate or
sodium hydroxide.
18. The process of claims 1 and 2, wherein an aqueous solution of an inorganic base is
used in step (a).
19. The process of claim 1, wherein a PTC is used in step (a).
20. The process of claim 19, wherein the PTC is selected from the group consisting of
quaternary ammonium compounds, crown ether and phosphonium compounds.
21. The process of claim 20, wherein the said quaternary ammonium compound is
selected from the group consisting of tributylrnethylaxnmonium chloride (Aliquat®
175), tetrabutylarrunonium bromide (TBAB), tetrabutylamrnonium hydrogensulphate
(TBAHS), benzyltriethylammonium chloride and tetrapropylammonium bromide
(TPAB).
22. The process of claim 1 and 2, wherein the temperature of step (c) is of about 78°C to
about 120°C.
The process of claim 2, wherein the teknisartan salt of formula V is converted to
telmisartan by adding an acid to the organic phase obtained in step (d).
24. The process of claim 23, wherein the acid is added to obtain a pH of less than about 6.
25. The process of claim 24, wherein the acid is added to obtain a pH of about 4 to about
6.
26. The process of claim 23, wherein the acid is selected from the group consisting of
trifluoroacetic acid sulfuric acid and acetic acid.
27. The process of claim 26, wherein the acid is acetic acid.
28. The process of claims 1, wherein the telmisartan alkylester is converted to teknisartan
of formula I,
(Figure Removed)
Formula I
by a process of bydrolysis under acidic or basic conditions.
29. A pharmaceutical composition comprising telmisartan of formula I, prepared
according to the method of claims 1 and 2, and pharmaceiatically acceptable excipient.
30. A process for preparing pharmaceutical formulation comprising mixing teknisartan of
formula I prepared according to claims 1 and 2 and a pharmaceutically acceptable
carrier.