FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION (See section 10, rule 13)
"PROCESS FOR THE PREPARATION OF TELMISARTAN”

CIPLA LIMITED
289 Bellasis Road, Mumbai Central, Mumbai 400 008, India

The following specification particularly describes the invention and the manner in which it is to be performed.

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PROCESS FOR THE PREPARATION OF TELMISARTAN
The present invention relates to a process for the preparation of telmisartan [4' - [2-n-propyl-4-methyl-6-(l-methyl-ben2imidazol-2-yl) benzimidazol-1-yl methyl] biphenyl-2-carboxylic acid] in a "one pot" synthesis, which is thus simple and cost effective, and produces telmisartan with high product yield and quality.
Telmisartan is known from EP 0502314B and has the following chemical structure of formula (I)

COOH
S/1

(i)
Telmisartan is an angiotensin II receptor antagonist, which by virtue of its pharmacological properties is particularly useful in the treatment of hypertension and cardiac insufficiency.
Chinese Patent CN 1344172 discloses the preparation of telmisartan in two steps: namely condensation and hydrolys's.
US 5591762 discloses the preparation of telmisartan from its tertiary butyl ester. Hydrolysis is carried out using trifluoro acetic acid in dimethyl fomramide at room temperature and maintained for !about 12 hours. The crude product obtained is purified over a silica gel column and finally crystallized from acetone.

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US 2002/0094997 is a divisional application of US 6358986. US 2002/0094997 discloses polymorphs of telmisartan, particularly polymorphic form B, polymorphous mixtures and their preparation. Accordingly, telmisartan Form A is dissolved in a mixture of solvents consisting of water, formic acid and an organic solvent that is miscible therewith; the solution is heated followed by distillation and telmisartan containing Form A and Form B is precipitated from the mixture by addition of a base. The disclosure further refers to advantages of the polymorphic Form B mixture, for example it is easily filterable and has a low tendency to electrostatic charging. The disclosure still further refers to the fact that Form A, which is obtained according to the basic patent, is difficult to filter, is characterized by a very long drying time and exhibits a strong tendency to electrostatic charging. The two telmisartan polymorphs of Form A and B as characterised by US 2002/0094997 differ considerably in their melting point Form B melts at 183°C (determined by DSC), Form A at' 269°C (determined by DSC). The polymorphs A and B also differ in their IR spectrum. Pure polymorph A has a characteristic band at 815 cm"1 in the IR spectrum. In polymorph B, this oscillation is shifted to 830 cm"1.
In all the prior art processes, telmisartan is prepared in two or three steps, which is time consuming, product is lost during intermediate isolation, and as such there is a resulting low yield of the final product. It is also suggested in the prior art that the use of
dimethyl forrnamide and alkali metal carbonates as solvent resulted in dimer formation,
which also contributed to low yield.
The aim of the present invention is, therefore, to provide an improved process for
the preparation of telmisartan. In particular, it is an aim of the present invention to prepare
telmisartan in a one step process, thereby increasing the yield, decreasing the cost and
avoiding filtration and drying problems.
Surprisingly, it has been found according to the present invention that telmisartan
can be synthesised in one step from intermediates [1H - Benzimidazole - 2- n-propyl-4-
methyl-6-(1 '-methyl benzimidazo!e-2'-yl)] and methy!-4-(bromomethyl) biphenyl-2-
carboxylate.
According to the present invention, therefore, there is provided a process for the
preparation of telmisartan of formula (I), or a pharmaceutically acceptable salt thereof

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characterised in that lH-Benzimidazole-2-n-propyl-4-methyl-6-(l '-methyl benzimidazole-2'yl) of formula (II), and methyl-4-(bromomethyl) biphenyl-2-carboxylate of formula (III), are subjected to condensation and hydrolysis in a single step (in other words, a "one pot" synthesis)

Intennediate compounds of formulae (II) and (III) are preferably reacted according to a process of the present invention in a polar aprotic solvent in the presence of a base. Polar aprotic solvents are well known- in the art and can include, for example, dimethyl acetamide, dimethyl formamide, dimethyl sulphoxide, and the like, with the use of dimethyl formamide

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or dimethyl sulphoxide being preferred, especially dimethyl sulphoxide. Preferred bases for use in a method according to the present invention are alkali metal hydroxides.
A process according to the present invention is preferably carried out at a temperature in the range of about 10 to 80°C, with a preferred temperature being in the range of about 25 to 50°C. The reaction time for a process according to the present invention is typically in the range of from about a few minutes to a few hours, depending on the exothermicity of the reaction. Telmisartan is then typically isolated from the reaction mass by adjusting the pH using aqueous acids, suitably for example the pH is adjusted to be in the range of about 3 to 4.5 using acetic acid, optionally followed by extraction in a water-immiscible solvent.
' Telmisartan can be isolated directly after pH adjustment by filtration without proceeding to extraction in a water-immiscible solvent. However, the use of the extraction phase is preferred because telmisartan as obtained directly after pH adjustment can be slimy in nature, thereby resulting in slow filtration properties. It is therefore preferable to extract telmisartan into a suitable solvent and isolate it from a non-solvent. A preferred water-immiscible solvent for extraction can be any of dichloromethane, ethyl acetate, chloroform or any other suitable water-immiscible solvent, with the use of dichioromethane being preferred. The organic layer is then suitably concentrated and isolated by addition of a suitable solvent, such as methanol, acetone, diisopropyl ether, acetonitrile or isopropyl acetate, with the use of acetone being preferred.
The present invention further provides telmisartan, or a pharmaceutically acceptable salt thereof, prepared by a process substantially as hereinbefore described. Telmisartan as prepared and isolated (typically employing acetone) by a process according to the present invention advantageously comprises free flowing polymorphic Form A, which can be similarly characterised by the melting point and IR properties as described above for Form A as defined in US 2002/0094997. Telmisartan Form A as provided by the present invention, however, is preferable over telmisartan Form A as prepared by prior-art'methods, in view of the free flowing properties of telmisartan as provided by the present invention compared to the poor flow characteristics of telmisartan Form A as provided by the prior art, for which the filtration rate can be very slow.

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Telmisartan Form A as prepared by a process according to the present invention
advantageously has a purity of at least about 97% and is typically obtained in a yield of about 80-88%.
The invention may also comprise further purification of telmisartan so as to achieve a highly pure compound. Preferably, telmisartan is subjected to purification by dissolving it in methanol and a methanolic ammonia mixture and isolating. Preferably, isolation is done by adjusting the pH using acetic acid, suitably to a pH of 3.5 - 4.0.
According to a preferred embodiment of the present invention, it may be desirable to isolate telmisartan as a pharmaceutically acceptable salt, such as the sodium or potassium salt of telmisartan. Telmisartan in salt form is suitably isolated from the reaction mass prior to pH adjustment.
Telmisartan, or a pharmaceutically acceptable salt thereof, has pharmaceutical utility as an angiotensin II receptor antagonist, and in view of the pharmacological properties thereof, telmisartan, or a pharmaceutically acceptable salt thereof, is suitable for the treatment of hypertension and cardiac insufficiency and also for treating ischemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency .after myocardial infarction and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases. In particular, telmisartan, or a pharmaceutically acceptable salt thereof, as provided by the present invention is useful for the treatment of hypertension.
Telmisartan, or a pharmaceutically acceptable salt thereof, as provided by the present invention is also suitable for treating pulmonary diseases, e.g. lung oedema and chronic bronchitis, for preventing arterial restenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy. In view of the effects of angiotensin on the release of acetyl-choline and dopamine in the brain, telmisartan, or a pharmaceutically acceptable salt thereof, as provided by the present invention is also suitable for alleviating central nervous system disorders, e.g. depression, Alzheimer's disease, Parkinson syndrome, bulimia and disorders of cognitive function.
The present invention further provides, therefore, a pharmaceutically acceptable

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composition for administering to a patient, suffering from, or susceptible to, a disease state
prevented, ameliorated or eliminated by the administration of an angiotensin II receptor
antagonist, which composition comprises a therapeutically effective amount of telmisartan,
or a pharmaceutically acceptable salt thereof, prepared according to the present invention,
together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
As used herein, the term "therapeutically effective amount" means an amount of
telmisartan, or a pharmaceutically acceptable salt thereof, which is capable of preventing,
ameliorating or eliminating a disease state for which administration of an angiotensin II
receptor antagonist is indicated.
By "pharmaceutically acceptable composition" it is meant that the carrier, diluent or
excipient is compatible with telmisartan, or a pharmaceutically acceptable salt thereof, and
not deleterious to a recipient thereof. For this purpose, telmisartan, or a pharmaceutically
acceptable salt thereof, optionally in conjunction with other active substances, such as
hypotensives, diuretics and/or calcium antagonists, may be incorporated together with one
or more inert conventional carriers and/or diluents, for example with corn starch, lactose,
glucose, microcrystailine cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid,
tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene-glycol,
propylene-glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as
hard fat or suitable mixtures thereof, in conventional pharmaceutical preparations such as
plain or coated tablets, capsules, powders, suspensions or suppositories.
The pharmaceutical compositions of the present invention may be prepared by
conventional methods known in the art. For example, tablets may be prepared by mixing
telmisartan, or a pharmaceutically acceptable salt thereof, according to the present
invention, with known adjuvants and/or diluents and subsequently compressing the
mixture in a conventional tabletting machine. The particular dosage form of telmisartan, or
a pharmaceutically acceptable salt thereof, required to treat a disease state prevented,
ameliorated or eliminated by the administration of an angiotensin II receptor antagonist as
described herein ifiiia-patient, will depend on the particular disease stateior condition, and
the symptoms and severityi-thereof Dosage, routes of administration, and frequency of
dosing are best decided by an attending physician.

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The present invention further provides telmisartan, or a pharmaceutically acceptable salt thereof, prepared according to the present invention, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of an angiotensin II receptor antagonist as described herein.
The present invention also provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of an angiotensin II receptor antagonist in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of telmisartan, or a pharmaceutically acceptable salt thereof, prepared according to the present invention, substantially as hereinbefore described.
The present invention will now be further illustrated by the following Examples, which do not limit the scope of the invention in anyway.
Example I
Preparation of |"4'-r2-n-propvl-4-methvl~6-(1-methvl benzimidazol-2-vl) benzimidazol—1-vl
methvll biphenvl-2-carboxvlic acid!
50 gm of [1H — Benzimidazole-2-n-propyl~4-methyl-6-(1 'methyl benzimidazole-2 -yl)] was added to 200 ml dimethyl sulfoxide and 50 gm of potassium hydroxide. To this was added 60 gm of methyl-4-(bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30cC, then heated to 40-50°C and maintained for 2 hours. About 500 ml water was added to the reaction mixture at room temperature and acidified to pH 4 with acetic acid. The reaction mixture was filtered and washed with purified water, dried under reduced pressure at 50-60°C to give 80 gm (88 %) of the title product.
Example 2
Preparation of f4'-f2-n-propvi-4-methvl—6-(1-methvl benzimidazol-2-vl)benzimidazol —1-
yl methynbiphenyl-2-carboxylic acid!
50 gin of [1H — Behzimidazole-2-n-propyl-4-methy!-6-(1'- methyl behzimidazole-2'-yl)] was added to 200 ml dimethyl sulphoxide and 50 gm of potassium hydroxide. To this

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was added 60 gm of methyl-4- (bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30°C. The contents were heated to 40-50°C and maintained for 2 hours. About 500 ml water was added to the reaction mixture at room temperature and acidified with acetic acid to pH 3.8, extracted twice with 250 ml of dichloromethane and the combined extracts were concentrated and isolated by filtration after addition of 300 ml acetone, dried under reduced pressure at 50-60°C to give 75 gm (80 %) of the title product
Example 3
Preparation of f4' - r2-n-propyl—4-methyl-6-(1 -methyl benzimidazol-2-yl) benzimidazol — 1-yl
methvll biphenvl-2-carboxvlic acid!
50 gm of [1H — Benzimidazole-2-n - propyl-4-rnethyl-6-(1 '-methyl benzimidazole-2'-yl)] was added to 200 ml dimethyl sulfoxide and 50 gm of sodium hydroxide. To this was added 60 gm of methyl-4- (bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30°C and then heated to 40-50 and maintained for 2 hours. About 500 ml water was added to the reaction mixture and acidified with acetic acid to pH 4.2, extract4ed twice with 250 ml of dichloromethane and the combined extracts were concentrated and isolated by filtration after addition of 300 ml acetone, dried under reduced pressure at 50-60°C to give 75.0 gm (80%) of the title compound.
Example 4
Purification of 14' - f2-n-propyl-4-methyl-6-(1-methyl benzimidazol-2-yl) benzimidazol-1-yl
methyl] biphenyl-2-carboxviic acid]
50gm of [4' - [2-n-propyl~4-methyl-6-(1 -methyl benzimidazol-2-yl) benzimidazol-1-yl methyl] biphenyl-2-carboxylic acid] (obtained according to any of Examples 1, 2 or 3) was added to 500ml of methanol. To this was slowly added 50ml of methanolic ammonia (10-15%) at 25-30°C. The contents were stirred for 30 minutes at 25-30°C. About 3gm charcoal was added and stirred at 25-30°C for 30 minutes. The reaction mixture was filtered over hyflo, bed washed with methanol. The clear filtrate pH was adjusted to 3.5-4.0 using acetic acid. The contents were stirredi ;at 20-30° C for 1 hour. Pure telmisartan was isolated-by filtration, dried under reduced pressure:at/50-60°C to yield 45gm (90%) of the title product with HPLC purity of about 99.3%.

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CLAIMS
1. A' process for the preparation of telmisartan of formula (I), or a pharmaceutically acceptable salt thereof

X^
COOH
V
(i)
characterised in that lH-Benzimida2ole-2-n-propyl-4-methyl-6-(lVmethyl benzimidazole-2'yl) of formula (E) and methyl-4-(bromomethyl) biphenyl-2-carboxylate of formula (HI) are subjected to condensation and hydrolysis in a single step
,Br

(II)


followed by pH adjustment using an aqueous acid.

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2. A process according to claim 1, wherein intermediate compounds of formulae (II) and (IE) are reacted in a polar aprotic solvent in the presence of a base.
3. A process according to claim 2, wherein said polar aprotic solvent is selected from the group consisting of dimethyl acetamide, dimethyl formamide and dimethyl sulphoxide.
4. A process according to claim 3, wherein said polar aprotic solvent is either dimethyl formamide or dimethyl sulphoxide.
5. A process according to claim 4, wherein said polar aprotic solvent is dimethyl sulphoxide.
6. A process according to any of claims 2 to 5, wherein said base is an alkali metal hydroxide.
7. A process according to any of claims 1 to 6, which is carried out at a temperature in the range of about 10 to 80°C.
8. A process according to claim 7, which is carried out at a temperature in the range of about 25 to 50°C.
9. A process according to any of claims 1 to 8, wherein said pH is adjusted to be in the range of about 3 to 4.5.
LO. A process according to any of claims 1 to 9, wherein said aqueous acid is acetic acid.
11. A process according to any of claims 1 to 10, wherein telmisartan, or a pharmaceutically acceptable salt thereof, is isolated by filtration directly after pH adjustment by said acid.

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12. A process according to any of claims 1 to 10, wherein further to pH adjustment telmisartan is extracted/into a suitable water-immiscible solvent and then isolated from a non-solvent.
13. A process according to claim 12, wherein said water-immiscible solvent is selected from the group consisting of dichloromethane, ethyl acetate and chloroform.
14. A process according to claim 13, wherein said water immiscible solvent is dichloromethane.
15. A process according to any of claims 12 to 14, wherein said non-solvent is selected from the group consisting of methanol, acetone, diisopropyl ether, acetonitrile and isopropyl acetate.
16. A process according to claim 15, wherein said non-solvent is acetone.
17. A process according to any of claims 1 to 16 wherein telmisartan is isolated as a free acid.
18. A process according to any of claims 1 to 17, wherein telmisartan is isolated as a pharmaceutically acceptable salt thereof.
19. A process according to claim 18, wherein telmisartan is isolated as the sodium or potassium salt thereof.
20. A process according to any of claims 1 to 19, which prepares telmisartan, or a pharmaceutically acceptable salt thereof, with a purity of at least about 97%.
21. A process according to any of claims 1 to 20, which prepares telmisartan, or a pharmaceutically acceptable salt thereof, in a yield of about 80-88%.

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22. A process according to any of claims 1 to 21, which prepares telmisartan, or a pharmaceutically acceptable salt thereof, as telmisartan Form A.
23. Telmisartan, or a pharmaceutically acceptable salt thereof, prepared by a process according to any of claims 1 to 22.
24. Telmisartan according to claim 23, which is telmisartan Form A.
25. Telmisartan according to claim 23 or 24, which has a purity of at least about 97%.
26. A pharmaceutically acceptable composition for administering to a patient, suffering from, or susceptible to, a disease state prevented, ameliorated or eliminated by the administration of an angiotensin II receptor antagonist, which composition comprises a therapeutically effective amount of telmisartan, or a pharmaceutically acceptable salt thereof, according to any of claims 23 to 25, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
27. Telmisartan, or a pharmaceutically acceptable salt thereof, according to any of claims 23 to 25, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of an angiotensin II receptor antagonist.
28. A method of treating a disease state prevented, ameliorated or eliminated by the administration of an angiotensin H receptor antagonist in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of telmisartan, or a pharmaceutically acceptable salt thereof, according to any of claims 23 to
25

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29. A process for the preparation of telmisartan, and telmisartan, or a pharmaceutically acceptable salt thereof, substantially as"'ft'ereiiibefore described with reference to the foregoing examples.
Dated this 10th day of November 2006.

(VIBHA SHUKLA)
Of K & S PARTNERS AGENT FOR THE APPLICANTS

ABSTRACT
"PROCESS FOR THE PREPARATION OF TELMISARTAN"

(I)


,COOCH3

(II)
An improved process for the preparation of telmisartan, or a pharmaceutical ly acceptable salt thereof, comprises subjecting lH-Benzimidazole-2-n-propyl-4-methyl-6-(l'-methyl benimidazole-2'yl) of formula (II) and methyl-4-(bromomethyl) biphenyl-2-carboxylate of formula (III) to condensation and hydrolysis in a single step.