FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10, rule 13)
"PROCESS FOR THE PREPARATION OF ANGIOTENSIN RECEPTOR BLOCKERS AND INTERMEDIATES THEREOF"
Glenmark Pharmaceuticals Limited an Indian Company, registered under the Indian company's Act 1957 and having
its registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. SawantMarg, Chakala, Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

1

PRIORITY
[0001] This application claims the benefit under Indian Provisional Application No.
305/MUM/2005, filed on March 21, 2005, and entitled "PROCESS FOR THE PREPARATION OF TELMISARTAN AND INTERMEDIATES THEREOF", the contents of each of which are incorporated by reference herein.
BACKGROUND OF THE INVENTION
1. Technical Field
[0002] The present invention generally relates to an improved process for the
preparation of angiotensin receptor blockers ("ARBs") and intermediates thereof.
2. Description of the Related Art
[0003] The present invention is directed to an improved process for the preparation of
biphenyl-containing compounds such as, for example, ARBs and intermediates thereof.
Generally, the ARBs of the present invention are angiotensin II receptor (type AT])
antagonist. Angiotensin II is formed from angiotensin I in a reaction catalyzed by
angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor
agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation
of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium.
ARBs block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by
selectively blocking the binding of angiotensin II to the AT| receptor in many tissues, such as
vascular smooth muscle and the adrenal gland. Its action is therefore independent of the
pathways for angiotensin II synthesis. ARBs are indicated for the treatment of hypertension.
[0004] Representative examples of ARBs include telmisartan, candesartan, losartan,
irbesartan, and valsartan. Telmisartan (also known as 4,-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-r-yl)methyl]-[l,!'-biphenyl]-2-carboxylic acid) is represented by the structure of formula I.
2

CH3
(I)

Telmisartan is sold under the trade name MICARDIS®. See. e.g., The Merck Index,
Thirteenth Edition, 2001, pp. 1628-29, monograph 9209; and Physician's Desk Reference,
"Micardis," 58th Edition, pp. 1011-1013 (2004).
[0005] Candesartan (also known as (±)-1 -hydroxyethyl-2-ethoxy-1 -|p-(o-1H-
tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester)) is
represented by the structure of formula II.

Candesartan is sold under the trade name Atacand . See, e.g., The Merck Index, Thirteenth
Edition, 2001, p. 1749, monograph 1747; and Physician's Desk Reference, "Atacand," 58th
Edition, pp. 600-602 (2004).
[0006] Losartan (also known as 2-butyl-4-chloro-l-[p-(o-lH-tetrazoI-5-
ylphenyl)benzyl]imidazole-5-methanol monopotassium salt) is represented by the structure
of formula III.
,C!
OH
NQN K+
(III)
3

Losartan is sold under the trade name Cozaar . See, e.g., The Merck Index, Thirteenth
Edition, 2001, p. 1000, monograph 5604; and Physician's Desk Reference, "Cozaar," 58th
Edition, pp. 1952-1957(2004).
[0007] Irbesartan (also known as 2-butyl-3-[p-(o-lH-tetrazol-5-ylphenyl)benzyl]-
l,3-diazaspiro[4,4]non-l-en-4-one) is represented by the structure of formula IV.


(IV)
Irbesartan is sold under the trade name Avapro . See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 914, monograph 5100; and Physician's Desk Reference, "Avapro," 58th Edition, pp. 1042-1045, 3011-3014 (2004).
[0008] Valsartan (also known as N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-L-valine) is represented by the structure of formula V.
H3C CH3

(S) *COOH

Valsartan is sold under the trade name Diovan . See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 1767, monograph 9982; and Physician's Desk Reference, "Diovan," 58th Edition, pp. 2244-2246 (2004).
4

[0009] U.S. Patent No. 5,591,762 ("the '762 patent"), herein incorporated by
reference, discloses a process for preparing telmisartan. The process of the '762 patent includes reacting of l,4'-dimethyl-2'-propyl[2,6'-bi-lH-benzimidazole] (1) with 4'-(bromomethyl)[l,l'-biphenyl]-2-carboxylic acid 1,1-dimethylethyl ester (2) in a solvent optionally in the presence of an acid binding agent to produce the intermediate 4,-[(l,4'-dimethyl-2'-propyl[2,6'-bi-lH-benzimidazol]-r-yl)methyl]-[l,1-biphenyl]-2-carboxylic acid 1,1-dimethylethyl ester (3). The intermediate is further hydrolyzed to provide telmisartan (I). This reaction is shown generally below in Scheme 1.
SCHEME I

0)
[0010] This process has been found to have several disadvantages in the commercial
manufacture of a pharmaceutical. For example, this process is time consuming as column chromatography is required and consequently not as economical as the yield obtained is less and not eco-friendly as effluent generation is more.
[0011] Accordingly, there remains a need for an improved process for the
preparation of ARBs and intermediates thereof that is less time consuming and is a convenient and cost efficient process that can be performed on a commercial scale.
5

SUMMARY OF THE INVENTION
[0012] In accordance with one embodiment of the present invention, a process for
the preparation of a biphenyl containing compound of general formula VI:

wherein R1 is a C3.6 carbonyl containing compound; R2 is a C3.6 substituted or unsubstituted,
1 9
straight or branched alkyl group, or R and R together with the nitrogen atom to which they are bonded are joined together to form a heterocyclic group selected from the group consisting of substituted imidazoles, substituted benzimidazoles and substituted 1,3-diazaspiro[4,4]non-l-en-4-one; and R3 is a carboxylic acid ester, cyano, a substituted or unsubstituted IH-tetrazolyl group or a substituted or unsubstituted group which may be converted in vivo into a carboxy group, is provided, the process comprising reacting compound of general formula VII:

wherein Rl and R2 have the aforestated meanings with a compound of general formula VIII:

Wherein Z is a leaving group and RJ has the aforestated meaning in a biphasic solvent system and in the presence of a phase transfer catalyst.
6

ADVANTAGES OF THE INVENTION
1) Provide biphasic reaction system in order to avoid formation of unrequired isomer
2) Avoid use of toxic chemicals like potassium tert-butoxide, and tri fluoro acetic acid etc.
3) High yield compared to prior art procedure
4) Avoid tedious purification process i.e. column chromatography known in art
5) Easy to operate at commercial scale
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0013] In general, the present invention is directed to processes for producing
biphenyl containing compounds such as, for example, intermediates of ARBs. One embodiment of a process of the present invention involves at least reacting a compound of general formula VII:

with a compound of general formula VIII:
Z

(VIII)
in a biphasic solvent system in the presence of a phase transfer catalyst to provide a compound of general formula VI:

1
wherein R is a C3.6 carbonyl containing compound; R is a C3.6 substituted or unsubstituted, straight or branched alkyl group, or R and R together with the nitrogen atom to which they
7

are bonded are joined together to form a substituted heterocyclic group selected from the
group consisting of substituted imidazoles, substituted benzimidazoles and substituted 1,3-
diazaspiro[4,4]non-l-en-4-one; R3 is a carboxylic acid ester, cyano, a substituted or
unsubstituted 1 H-tetrazolyl group or a a substituted or unsubstituted group which may be
converted in vivo into a carboxy group and Z is a leaving group such as a halogen, e.g., a
chlorine, bromine or iodine atom, and the like.
[0014] Representative examples of biphenyl-containing compounds which can be
obtained from the process of the present invention include, but are not limited to,
telmisartan (also known as 4'-[(l,4,-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-l'-
yl)methyl]-[ 1,1 '-biphenyl]-2-carboxylic acid), candesartan (also known as (±)-1 -
hydroxyethyl-2-ethoxy-1 -[p-(o-1 H-tetrazol-5-ylphenyl)benzyl]-7-
benzimidazolecarboxylate, cyclohexyl carbonate (ester)), losartan (also known as 2-butyl-4-chloro-1 -[p-(o-1 H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt), Irbesartan (also known as 2-butyl-3-[p-(o-lH-tetrazol-5-ylphenyl)benzyl]-l,3-diazaspiro[4,4]non-l-en-4-one), valsartan (also known as N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl) [l,l'-biphenyl]-4-yl]methyl]-L-valine).
[0015] Suitable phase transfer catalysts include, but are not limited to, quaternary
ammonium salts substituted with a residue such as a straight or branched chain alkyl group
having 1-18 carbon atoms, phenyl lower alkyl group including a straight or branched chain
alkyl group having 1 to 6 carbon atoms which is substituted by an aryl group and phenyl
group, e.g., tetrabutylammonium chloride, tetrabutylammonium bromide,
tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide,
tetrabutylammonium hydrogen sulfate, tributylmethylammonium chloride,
tributylbenzylammonium chloride, tetrapentylammonium chloride, tetrapentylammonium
bromide, tetrahexylammonium chloride, benzyldimethyloctylammonium chloride,
methyltrihexylammonium chloride, benzylmethyloctadecanylammonium chloride,
methyltridecanylammonium chloride, benzyltripropylammonium chloride,
benzyltriethylammonium chloride, phenyltriethylammonium chloride, tetraethylammonium chloride, tetramethylammonium chloride and the like; phosphonium salts substituted with a
8

residue such as a straight or branched chain alkyl group having 1-18 carbon atoms, e.g., tetrabutylphosphonium chloride and the like; and pyridinium salts substituted with a straight or branched chain alkyl group having 1-18 carbon atoms, e.g., 1-dodecanylpyridinium chloride and the like.
[0016] Among these phase transfer catalysts, quaternary ammonium salts substituted
with a straight or branched chain alkyl group having 1-1-8 carbon atoms such as tetrabutyl ammonium chloride and the like are particularly preferred. As the salt-forming ions in these salts, hydroxy! ion, hydrogen sulfate ion and halogen ions are preferred, among which the chlorine ion is particularly preferred. If desired, sodium sulfite or the like may be added to the reaction system of the above-mentioned reaction for the purpose of preventing the coloration caused by oxidation, tetrabutyl ammonium bromide, tetrabutyl ammonium hydroxide, tetramethyl ammonium iodide, tetrabutyl ammonium sulphate and the like and mixtures thereof. The amount of the phase transfer catalyst employed can range from about 1.0% to about 10% and preferably from about 5.0% to about 10%.
The coupling of the compound of formula VII with the compound of formula VIII is advantageously carried out in a biphasic solvent system. Generally, a biphasic solvent system includes at least an aqueous phase and a water-immiscible phase, e.g., water and water-immiscible solvent. Water-immiscible solvents are generally those solvents which when allowed to stand and remain undisturbed, after being initially mixed with water, separate out into a distinct layer different from the water layer. The two layers (or phases) are typically visible to the naked eye. Suitable water-immiscible solvents include, but are not limited to, halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, aliphatic hydrocarbon solvents, ketone solvents, ether solvents, and the like and mixtures thereof. Exemplary water-immiscible solvents include, but are not limited to, methylene chloride toluene, methyl isobutyl ketone, tert-butyl methyl ether, heptane, cyclohexane, n-heptane, hexane, octanol, n-decane, decalene and mixtures thereof
[0017] The temperature of the reaction can ordinarily be carried out at a range of
from about 20°C to about 50°C. The reaction time can range from about 2 hours to about 10 hours. The compound of formula VIII is ordinarily present in an amount ranging from
9

about 1.0 to about 1.5 per mole of mole of the compound of formula VII and preferably
from about 1.0 to about 1.1 per mole of mole of the compound of formula VII.
[0018] If desired, the reaction can be carried out in the presence of an acid binding
agent. Suitable acid binding agents include, but are not limited to, alkali metal hydroxide,
e.g., sodium hydroxide and potassium hydroxide, alkali metal carbonate, e.g., sodium
carbonate, and the like and mixtures thereof. Generally, the acid binding agent can be
employed in an amount ranging from about 1.0 molar eq to about 5.0 molar eq In one
embodiment, a process of the present invention produces an intermediate of telmisartan
which includes at least reacting l,4'-dimethyl-2'-propyl[2,6'-bi-lH-benzimidazole] (1) with
methyl 4'-(bromomethyl)[l,r-biphenyl]-2-carboxylate (7) in a biphasic solvent system in
the presence of an acid binding agent and a phase transfer catalyst to provide intermediate
methyl 4,-[(l,4'-dimethyl-2,-propyl[2,6,-bi-lH-benzimidazol]-r-yl)methyl]-[l,r-
biphenyl]-2-carboxylate (8) as generally shown in Scheme 2:
SCHEME 2


CH,
COOMe
CH,
(1)
CH,

COOH
COOMe

(I)

[0019] Following the formation of the intermediate of formula 8, the intermediate
can then be hydrolyzed to provide telmisartan. The hydrolysis can be carried out in the
10

presence of a base such as, for example, an alkali metal hydroxide or carbonate, e.g., sodium hydroxide, potassium hydroxide, potassium carbonate, etc., and in a suitable solvent such as water, an alcohol, e.g., methanol, ethanol, isopropanol, and the like, and mixtures thereof, e.g., water/methanol. The temperature employed during hydrolysis can range from about 50°C to boiling temperature of the reaction mass.
[0020] The compounds obtained herein can be purified. For example, the
telmisartan obtained following hydrolysis can be purified in one or more solvents such as a halogenated hydrocarbon solvent, e.g., methylene chloride, a lower alcohol, e.g., methanol, and mixtures thereof. The process of the present invention advantageously provides compounds, e.g., telmisartan in relatively high purity, e.g., greater than about 98% and preferably greater than about 99%.
[0021] If desired, the compounds obtained herein such as telmisartan can thereafter
be converted to a pharmaceutically acceptable salt, e.g., telmisartan hydrochloride, by techniques known in the art. For example, after preparing the compound of Formula I corresponding to losartan, the compound Formula I will be further reacted with a suitable source of potassium to provide the potassium salt. The reaction to prepare the potassium salt is known to those skilled in the art.
[0022] Another aspect of the present invention is directed to pharmaceutical
compositions containing the biphenyl-containing compounds or pharmaceutically
acceptable salts thereof, particularly telmisartan, candesartan, losartan, irbesartan, and
valsartan. In addition to the active ingredient(s), the pharmaceutical compositions of the
present invention can contain one or more pharmaceutically acceptable excipients. The
selection of excipients and the amounts to use can be readily determined by the formulation
scientist based upon experience and consideration of standard procedures and reference
works in the field. For example, the most recent edition of Handbook of Pharmaceutical
Excipients, American Pharmaceutical Association, can be used as guidance.
[0023] Crude telmisartan can be purified in a in a solvent such as halogenated
hydrocarbon, amide, alcohol and mixtures thereof. Preferably N, N-dimethylformamide
11

The process of the present invention advantageously provides telmisartan in relatively high purity, e.g., greater than about 99.0% and preferably greater than about 99.5%.
[0024] Telmisartan further purified by addition of suitable base followed by addition
of suitable acid. Telmisartan can be dissolved in solvent which can be selected, but not limited to, alcohols or mixtures of alcohol, e.g., methanol, ethanol, 2-propanol, etc. The suitable base can be selected, but not limited to ammonia (gas or aq.solution), triethyl amine, diisopropyl amine, dimethyl amine, monomethyl amine (gas or aq.solution) diisopropyl ethyl amine; alkali metal hydroxides such sodium hydroxide, potassium hydroxide; sodium alcoholates such as sodium methoxide, sodium ethoxide or sodium isopropxide. The suitable acids can be selected, but not limited to, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid. The process of the present invention advantageously provides telmisartan in relatively high purity, e.g., greater than about 99.0% and preferably greater than about 99.5%.
[0025] The following examples are provided to enable one skilled in the art to
practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims.
EXAMPLE 1
[0026] Preparation of Methyl 4'-[(l, 4'-dimethyl-2'-propyl [2, 6'-bi-lH-
benzimidazol]-l'-yl) methyl]-[l, l'-biphenyl]-2-carboxylate
[0027] l,4'-dimethyl-2'-propyl[2,6'-bi-lH-benzimidazole] (40 g) in methyl isobutyl
ketone ("MIBK.", 160 ml) was placed in a vessel and a potassium hydroxide solution (36.8 g KOH in 200 ml water) was added. Methyl 4'-(bromomethyl)[l,r-biphenyl]-2-carboxyIate (44 g) and tetra- butyl ammonium bromide (4 g) were added. The reaction mixture was stirred for 2 hours at 25 to 30°C. The reaction mixture was filtered and washed with MIBK (40 ml). Dry the material at 60 to 65°C.Dry wt. 78 grams
12

EXAMPLE 2
[0028] Preparation of Telmisartan:
[0029] The methyl 4'-[(l, 4'-dimethyl-2'-propyl [2, 6'-bi-lH-benzimidazol]-l'-yl)
methyl]-[l, l'-biphenyl]-2-carboxylate (45 g) obtained in Example 1 in methanol (225 ml) were charged to a reaction vessel. A potassium hydroxide solution (19 g KOH in 55 ml water) was added and the reaction mass was heated to reflux for 3 hours. The reaction mass was cooled to 25°C and the pH was adjusted to 6 using dilute HC1. The solid obtained was filtered and dried (37 g). The dry solid was taken in a combination of dichloromethane and methanol (8 Vol. & 2 Vol) the insolubles were filtered and the reaction mass was concentrated in methylene dichloride and isolated the solid from methanol.
EXAMPLE 3 Purification of crude Telmisartan:
[0025] 30 grams of crude telmisartan were dissolved in 300 ml of N, N-dimethyl
formamide at 85 to 90 °C under stirring. The reaction mixture allowed to cool to room temperature. The solid obtained was filtered and dried at 60 to 65 °C.
Purity: > 99.50 %
EXAMPLE 4 Purification of Telmisartan
[0026] 20 gms of Telmisartan were dissolved in 100 ml methanol followed by the
addition of 4 ml of 25% aq.ammonia at 25 to 30°C, stirred the solution for 30 min. The solution obtained was filtered through hyflo bed and washed with 20.0 ml methanol, which is then neutralized with acetic acid (2.6 ml) by adjusting pH 6 to 7 and allowed to stirr for 30 min, followed by addition of 80-100 ml of distilled water in reaction mixture. The reaction mixture further stirred for 2 hrs at 25 to 30°C. The resulted solid was filtered and washed with 40 ml purified water and 40 ml of methanol. The solid obtained was dried at 60 to 65 °C under vacuum. HPLC Purity -99.6%
13

[0030] It will be understood that various modifications may be made to the
embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the features and advantages appended hereto.
14

WE CLAIM:
1. A process for the preparation of a biphenyl containing compound of general formula I:


^ a)
wherein R1 is a C3-6 carbonyl containing compound; R2 is a C3.6 substituted or unsubstituted, straight or branched alkyl group, or R and R together with the nitrogen atom to which they are bonded are joined together to form a substituted heterocyclic group selected from the group consisting of substituted imidazoles, substituted benzimidazoles and substituted 1,3-diazaspiro[4,4]non-l-en-4-one; and R3 is a carboxylic acid ester, cyano, a substituted or unsubstituted lH-tetrazolyl group or a substituted or unsubstituted group which may be converted in vivo into a carboxy group, the process comprising reacting a compound of general formula II:

wherein R1 and R2 have the aforestated meanings with a compound of general formula III:
Z

(III)
wherein Z is a leaving group and R3 has the aforestated meaning in a biphasic solvent system and in the presence of a phase transfer catalyst.
15

2. The process of Claim 1, wherein the biphasic solvent system comprises water and a water immiscible solvent.
3. The process of Claim 2, wherein the water immiscible solvent is selected from the group consisting of halogenated hydrocarbons, aromatic hydrocarbons, aliphatic hydrocarbons, ketones, ethers, and mixtures thereof.
4. The process of Claim 2, wherein the water immiscible solvent is selected from the group consisting of methylene chloride toluene, methyl isobutyl ketone, tert-butyl methyl ether, heptane, cyclohexane, n-heptane, hexane, octanol, n-decane, decalene and mixtures thereof
5. The process of Claims 1-4, wherein the phase transfer catalyst is selected from the group consisting of a quaternary ammonium phase transfer catalyst, a phosphonium phase transfer catalyst and a pyridinium phase transfer catalyst.
6. The process of Claims 1-4, wherein the phase transfer catalyst is a quaternary
ammonium phase transfer catalyst selected from the group consisting of
tricaprylylmethylammonium chloride, tetra-n-butylammonium bromide,
benzyltriethylammonium chloride, cetyltrimethylammonium bromide, cetylpyridinium
bromide, N-benzylquininium chloride, tetra-n-butylammonium chloride, tetra-n-
butylammonium hydroxide, tetra-n-butylammonium iodide, tetra-ethylammonium chloride,
benzyltri butyl ammonium bromide, benzyltriethylammonium bromide,
hexadecyltriethylammonium chloride, tetramethylammonium chloride, hexadecyltrimethyl
ammonium chloride, and octyltrimethylammonium chloride.
7. The process of Claims 1-4, wherein the phase transfer catalyst is selected from the
group consisting of tetrabutyl ammonium bromide, tetrabutyl ammonium hydroxide,
tetramethyl ammonium iodide, tetrabutyl ammonium sulfate and mixtures thereof.
16

8. The process of Claims 1-7, wherein the reaction is carried out in the presence of an acid binding agent.
9. The process of Claim 8, wherein the acid binding agent is selected from the group consisting of an alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate and mixtures thereof.

10. The process of Claim 8, wherein the acid binding agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate and mixtures thereof.
11. The process of Claims 1-10, wherein the compound of formula I is methyl 4'-[(l, 4'-dimethyl-2'-propyl[2,6'-bi-lH-benzimidazol]-r-yl)methyl]-[l,r-biphenyl]-2-carboxylate.
12. The process of Claim 11, wherein the methyl 4'-[(l,4'-dimethyl-2'-propyl[2,6'-bi-lH-benzimidazol]-r-yl)methyl]-[l,r-biphenyl]-2-carboxylate is thereafter converted to telmisartan or a pharmaceutically acceptable salt thereof.
13. The process of Claims 12-16, further comprising purifying telmisartan or a
pharmaceutical^ acceptable salt thereof.
14. The process of Claim 13, wherein the telmisartan is purified in a solvent selected from the group consisting of a halogenated hydrocarbon, alcohol, and mixtures thereof.
15. The process of Claim 13, wherein the telmisartan is purified in a solvent selected from the group consisting of a halogenated hydrocarbon, alcohol methylene chloride, methanol and mixtures thereof.
17

16. A process for the preparation of methyl 4'-[(l)4'-dimethyl-2'-propyl[2,6'-bi-lH-benzimidazol]-r-yl)methyl]-[l,r-biphenyl]-2-carboxylate, the process comprising reacting a l54,-dimethyl-2'-propyl[2)6'-bi-lH-benzimidazole] with a methyl 4'-(bromomethyl)[l,r-biphenyl]-2-carboxylate in a biphasic solvent system in the presence of an acid binding agent and a phase transfer catalyst.
17. The process of Claim 16, wherein the biphasic solvent system comprises water and a water immiscible solvent.
18. The process of Claim 17, wherein the water immiscible solvent is selected from the group consisting of methylene chloride toluene, methyl isobutyl ketone, tert-butyl methyl ether, heptane, cyclohexane, n-heptane, hexane, octanol, n-decane, decalene and mixtures thereof.
19. The process of Claims 16-18, wherein the phase transfer catalyst is selected from the group consisting of a quaternary ammonium phase transfer catalyst, a phosphonium phase transfer catalyst and a pyridinium phase transfer catalyst.
20. The process of Claims 16-18, wherein the phase transfer catalyst is a quaternary ammonium phase transfer catalyst selected from the group consisting of tetrabutyl ammonium bromide, tetrabutyl ammonium hydroxide, tetramethyl ammonium iodide, tetrabutyl ammonium sulfate and mixtures thereof.
21. The process of Claims 16-20, wherein the acid binding agent is selected from the group consisting of an alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate and mixtures thereof.
18

22. The process of Claim 16-18, wherein the acid binding agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate and mixtures thereof.
23. The process of Claim 16, wherein the methyl 4'-[(l,4'-dimethyl-2'-propyl[2,6'-bi-lH-benzimidazol]-r-yl)methyl]-[l,r-biphenyl]-2-carboxylate is thereafter converted to telmisartan or a pharmaceutically acceptable salt thereof.
24. The process of Claims 16-23, further comprising purifying telmisartan or a
pharmaceutically acceptable salt thereof.
25. The process of Claim 24, wherein the telmisartan is purified in a solvent selected from the group consisting of a halogenated hydrocarbon, alcohol, and mixtures thereof.
26. The process of Claim 24, wherein the telmisartan is purified in a solvent selected from the group consisting of a halogenated hydrocarbon, alcohol methylene chloride, methanol and mixtures thereof.
27. Telmisartan prepared in accordance with the process of Claims 1-19 having a purity of greater than about 98%.
28. The process of Claims 1-10, wherein in the compound of formula I R1 and R2 together with the nitrogen to which they are bonded represent a substituted benzimidazole and R is a substituted or unsubstituted lH-tetrazolyl group.
29. The process of Claim 21, wherein the compound of formula I is candesartan of the formula
19

30. The process of Claim 1, wherein the compound of formula I is losartan of the
formula

31. The process of Claim 1, wherein the compound of formula I is irbesartan of the
formula

32. The process of Claim 1, wherein the compound of formula I is valsartan of the
formula
20

33. A pharmaceutical composition comprising the compound obtained from the process of Claims 1-30 and at least one pharmaceutically acceptable excipient.

21