FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10 and Rule 13]
PROCESS FOR THE PREPARATION OF
1,7'-DIMETHYL-2-PROPYL-2,5-B1-1H-
BENZIMIDAZOLE


Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification describes the invention:

PROCESS FOR THE PREPARATION OF 1,7-DIMETHYL-2''-PROPYL-2,5'-BI-
1H-BENZIMIDAZOLE
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of l,7'-dimethyl-2'-propyl-2,5'-bi-lH-benzimidazole which is the key intermediate for the preparation of Telmisartan and its pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
Telmisartan is an angiotensin II receptor antagonist which is useful in therapy as antihypertensive agent. Telmisartan is chemically known as 4'-[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl-2-carboxylic acid and can be depicted structurally as compound of formula (I),

l,7'-dimethyl-2'-propyl-2,5'-bi-lH-benzimidazole of formula (II),

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is used as an intermediate product in the large-scale synthesis of the pharmaceutical^ active substance telmisartan and its pharmaceutically acceptable salts..
Ries et al, J. Med. Chem. (1993), 36(25), 4040-51, describes the preparation of 1,7-dimethyl-2'-propyl-2,5'-bi-lH-benzimidazole by reacting 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid with N-methyl-o-phenylenediamine in the presence of polyphosphoric acid.
U.S. Pat. No. 6770762 describes the preparation of l,7'-dimethyl-2'-propyI-2,5'-bi-lH-benzimidazole by reacting 2-propyI-4-methyl-lH-benzimidazole-6-carboxylic acid with N-methyl-o-phenylenediamine in the presence of methanesulfonic acid and phosphorus pentoxide.
U.S. App. No. 2007037986 Al describes the preparation of l,7-dimethyI-2'-propyl-2,5'-bi-1 H-benzimidazole by reacting 2-propyl-4-methyl-lH-benzimidazole-6-carboxylic acid with N-methyl-o-phenylenediamine in the presence of a 2-chloro-4,6-disubstituted-1,3,5-triazine and a tertiary amine.
We surprisingly found an improved process for the preparation of l,7'-dimethyf-2'-propyl-2,5'-bi-lH-benzimidazole. The present invention provides a process for the preparation of l,7'-dimethyl-2'-propyl-2,5'-bi-lH-benzimidazole in a good yield and purity, without generating a thick, potentially yield-reducing paste and foam. The process is simple, industrially feasible, economical, requires short reaction time and gives better yield and purity.
SUMMARYOF THE INVENTION
In one of the embodiment, the specification discloses a process for the preparation of 1,7'-dimethyl-2'-propyl-2,5'-bi-1 H-benzimidazole of formula (II),
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comprising.
reacting N-methyl-o-phenylenediamine of formula (III) or the salts thereof,

with 2-propyl-4-methyl-lH-benzimidazole-6-carboxylic acid of formula (TV) or the salts thereof,

in the presence of polyphosphoric acid and orthophosphoric acid.
In another embodiment, the specification discloses the process for the preparation of 1 ,T-dimethyl-2--propyl-2,5'-bi-lH-benzimidazole of formula (II) in high yield and purity.
In yet another embodiment, the specification discloses the use of 1, 7'-dimethyl-2'-propyl-2.5'-bi-lH-benzimidazole of formula (II) for the preparation of telmisartan and its pharmaceutically acceptable salts thereof. The process comprises,
(a) condensing l,7'-dimethyl-l'-propyl-2,5'-bi-lH-benzimidazole of formula (II) obtained according to the present invention,
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with 4' bromomethyl-biphenyl-2-carboxylic acid alkyl ester of formula (V),

to obtain telmisartan alkylester intermediate of formula (VI),

(VI) wherein, R is a straight or branched chain C1-C4 alkyl;
(b) hydrolyzing intermediate of formula (VI) to obtain telmisartan or its pharmaceutically acceptable salt.
DETAILED DESCRIPTION OF THE INVENTION
In one of the embodiment, the specification discloses a process for the preparation of l,7'-dimethyl-2'-propyl-2.5'-bi-1H-benzimidazole of formula (II),
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comprising,
reacting N-methyl-o-phenylenediamine of formula (III) or the salts thereof,

with 2-propyl-4-methyl-lH-benzimidazole-6-carboxylic acid of formula (IV) or the salts thereof,

in the presence of polyphosphoric acid and orthophosphoric acid.
The process comprises reaction of N-methyl-o-phenylenediamine dihydrochloride of formula (III) with 2-propy]-4-methyl-lH-benzimidazole-6-carboxylic acid of formula (IV) in the presence of polyphosphoric acid and orthophosphoric acid. The reaction proceeds without generation of foam and thick, difficult to stir paste.
The reaction may be carried out at the temperature range of about 100°C to 150°C. The preferable temperature range is between 140°C to 150°C. The reaction may be accomplished over a time period of about 3 to 12 hours. The reaction mixture may be cooled at the temperature range of about 25-30°C which may be further neutralized by
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the addition of base, to obtain 1,7'-dimethyl-2'-propyl-2,5'-bi-1 H-benzimidazole of formula (II).
The purification of l,7'-dimethyl-2'-propyl-2,5'-bi-lH-benzimidazole of formula (II) may be carried out by the method known in the art. For example, the purification may be carried out by the process known in Ries et at., J. Med. Chem. (1993), 36(25), 4040-51.
1,7'-dimethyl-2-propyl-2,5-bi-1 H-benzimidazole of formula (II) obtained after purification is highly pure and gives high yield. The yield may be greater than 90% and the purity obtained by HPLC is greater than 97%.
l,7'-dimethyl-2'-propyl-2,5'-bi-lH-benzimidazole of formula (II) is used for the preparation of telmisartan and its pharmaceutically acceptable salts thereof. The process comprises,
with 4' bromomethyl-biphenyl-2-carboxylic acid alkyl ester of formula (V),
to obtain telmisartan alkylester intermediate of formula (VI),
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(a) condensing l,7l-dimethyl-2'-propyl-2,5,-bi-l H-benzimidazole of formula (II) obtained according to the present invention,




wherein, R is a straight or branched chain C1-C4 alkyl
(b) hydrolyzing intermediate of formula (VI) to obtain telmisartan or its pharmaceutically acceptable salt.
The condensation and hydrolysis may be carried out as per the method known in the art.
The following examples illustrate certain specific aspects and embodiments of the present invention in greater detail, and are not intended to limit the scope of the invention.
COMPARATIVE EXAMPLE:
2-n-propyl-4-methyl-6-caroxybenzimidazole (10.92 gm) was added to 130 gm of polyphosphoric acid (the mixture was not stirrable and formed thick paste). The mixture was heated to 150°C, slowly stirring was started then 9.76gm of N-methyl-o-phenylene diamine dihydrochloride was added slowly (high foaming was observed). The reaction mass was maintained for 20 hours at 150°C. The mixture was allowed to cool and 600 ml of water was added. The pH was adjusted to 9.0 by using ammonia solution. The precipitated solid was filtered and washed with water and dried. The dried material was taken in ethyl acetate and refluxed for (30 minutes) and cooled to 10-15°C. The precipitated solid was filtered and washed with diethyl ether. The material was dried.
Dry weight: 12.8 gm Yield: 84.09% mol/mol
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HPLC purity: 97.5%
EXAMPLE-1
15.0 ml orthophosphoric acid, 45.0 gm polyphosphoric acid and 10.0 gm 2-propyl-4-methyl-lH-benzimidazole-6-carboxylic acid were charged in round bottle flask at 25°C -30°C. N-methyl-o-phenylenediamine dihydrochloride was added to the reaction mass at 25-30°C. The reaction mass was heated upto 145-150°C. and maintained for 12.0 hours at 145-150°C. The sample was submitted for HPLC to check the completion of the reaction. The reaction mass was cooled at 25°-30°C. 60.0 ml of water was added to the reaction mass at 25°-30°C. NaOH solution (60.0 gm in 150.0 ml of water) was added to the reaction mass up to pH 7.0-7.5 at 25-30°C. The reaction mass was maintained for 1.0 hour at 25-30°C. The reaction mass was filtered, washed with water and suck dried for 30-40 minutes. 200 ml water and wet cake was charged into the reaction flask. The reaction mass was stirred for 1.0 hour at 25-30°C. The reaction mass was filtered, washed with water and suck dried for 30-40 minutes. 100 ml of ethyl acetate and wet solid were charged into the reaction flask. The reaction mass was heated upto reflux (70-75°C) and further stirred for 30.0 minutes at 80-90°C. The reaction mass was cooled at 25-30°C. and maintained for 1.0 hour at 25-30°C. The reaction mass was filtered, washed with ethyl acetate and suck dried. The wet solid was dried in hot air oven at 65-70°C for 10.0-12.0 hours.
Dry weight: 12.8 gm %yield: 92.0% HPLC purity: 98%
Dated this 24th day of October, 2008
....
for Torrent Pharmaceuticals Ltd, Praveen Chand Gandhi
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