FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION
[See section 10, rule 13]
PROCESS FOR PREPARING TELMISARTAN


APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD. 2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India

Indian Company incorporated under the Companies Act 1956
The following specification describes the invention.


TITLE
PROESS FOR PREPARING TELMISARTAN
TECHNICAL FIELD
The present invention is related to processes for preparing telmisartan alkylester intermediate and further converting it to telmisartan. The invention also relates to one-pot process for the preparation of telmisartan.
BACKGROUND AND PRIOR ART
Telmisartan, 4'-((l ,4'-dimethyi-2'-propyI-2,6'-bi(I H-benzo[d] imidazol)-1 '-
yl)methyl) biphenyl-2-carboxylic acid, with structural formula I,

Formula I
is a non-peptide angiotensin II receptor (Type ATi). Telmisartan is known from EP
0502314. Telmisartan is approved by the US FDA for the treatment of hypertension.
It is sold under the brand name Micardis® by Boehringer Ingelheim.
US 6,358,986 discloses telmisartan and pharmaceuticaliy accepted salts thereof and
its use in cardiac related diseases.
EP 0502314 and its US equivalent US 5591762 discloses preparation of telmisartan
from its t-butyl ester by alkylation followed by hydrolysis of the intermediate to get
telmisartan. Hydrolysis is carried out using trifluroracetic acid in dimethyl
formamide at room temperature and maintained for about twelve hours. Crude
telmisartan is purified by column chromatography and then crystallized from
acetone.
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The process disclosed in Organic Process and Research Development 2007, 11,81-85 (Dr. Reddy's Laboratories) discloses synthesis of telmisartan in two steps namely condensation and hydrolysis. The condensation is carried out using potassium hydroxide in the presence of acetone and the hydrolysis is carried out by using potassium hydroxide in the presence of acetonitrile at 80-85°C. GB 2414019 discloses the process wherein the condensation and hydrolysis are carried out in a single step. The reaction is carried out in a polar aprotic solvent in the presence of a base. The polar aprotic solvent is selected from dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide $nd the like. WO 2006/044648 discloses processes for the preparation of telmisartan. In two steps process, condensation is carried out using inorganic base in the presence of low boiling solvents like Ce-io aromatic hydrocarbon, ketone and ester and mixtures thereof, preferred solvent is toluene. In a single step process, the solvent used is a ketone solvent.
The prior art processes suffer from drawbacks like use of high boiling solvents such as dimethylformamide & dimethylsulfoxide. These solvents have boiling point of greater than about 150°C, difficult to remove from the reaction using various evaporation techniques known in the prior art. Prior art processes also uses of two different solvents for the two steps, or tedious work up procedures. These reaction conditions are less environment friendly & less efficient. Hence there is a need to develop process for synthesis of telmisartan which is simple, cost effective and produces telmisartan in high yield and purity.
The object of the present invention is to provide a process for the preparation of telmisartan which is economical, is high yielding and offers high purity product and avoids the use of high boiling solvents.
Inventors of the present invention have surprisingly found out that telmiartan can be prepared in high yield and purity by carrying out the steps of condensation of 2-n-pr0pyI-4-methyI-6-(I '-methyIbenzimidazoIe-2-yl) arid 4,-bromomethyIbiphenyI-2-carboxylic acid (alkyl) ester to get alkyl 4'-((l,4,'dimethyl-2'-propyl-2,6,-bi(lH-benzo[d]imidazol)-r-yl)methyl) biphenyl-2-carboxyIate and hydrolysis in a single
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solvent. In an embodiment of the invention telmisartan is prepared by carrying out the steps of condensation and hydrolysis of the in one-pot.
SUMMERY OF THE INVENTION
According to the present invention, there is provided a process for the preparation of
alkyl 4,-((l;4,-dimethyl-2,-propyl-256'-bi(lH-benzo[d]imidazol)-l,-yl)methyl)
biphenyl-2-carboxylate (herein after referred to as telmisartan alkylester intermediate) of formula II,

Formula II comprising the steps of
a) Combining 2-n-propyl-4-methyl-6-( 1' -methylbenzimidazole-2-
yl)benzimidazole of Formula III,

Formula III with 4'-bromomethylbiphenyl-2-carboxylic acid, alkyl ester of Formula IV,
Formula IV a base and an alcohol solvent to obtain a mixture;
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b) stirring the reaction mixture of step a) till the compound of Formula III disappears on TLC;
c) recovering telmisartan alkylester of Formula II
In another aspect of the present invention, there is provided a process for converting the telmisartan alkylester intermediate of Formula II to telmisartan of Formula I by hydrolysis under basic conditions in an alcohol solvent comprising the steps of
a) making a slurry of the telmisartan alkylester of Formula II in an alcohol solvent;
b) adding a base to the above slurry and stirring;
c) heating the mixture obtained in step b) to the boiling point of the solvent;
d) stirring the mixture at the boiling point of the solvent for about 15 minutes to about 3 hours; till the disappearance of compound of Formula II
e) cooling the reaction mixture gradually to 25-30° C;
f) cooling to 0-5° C;
g) adjusting the pH with an acid;
h) stirring the mixture at 0-5° C to obtain solid;
i) filtering the solid to get telmisartan of Formula I In yet another aspect of the present invention there is a provided a one-pot process for the preparation of telmisartan of Formula I

comprising the steps of
a) combining 2-n-propyl-4-methyl-6-(l '-methylbenzimidazole-2-yl)
benzimidazole of Formula III, 4'-bromomethylbiphenyl-2-carboxyIic acid, alkyl ester of Formula IV, a base and an alcohol solvent to obtain a mixture;
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b) stirring the reaction mixture of step a) till the disappearance of the compound of Formula III on TLC;
c) heating the reaction mixture of step c) to the boiling point of the solvent
d) maintaining the temperature for about 15 minutes to about 5 hours; till the disappearance of compound of Formula II
e) cooling the reaction mixture gradually to 25-30° C;
f) cooling to 0-5° C;
g) adjusting the pH with an acid;
h) stirring the mixture at 0-5° C to obtain solid; i) filtering the solid to get telmisartan of Formula I
DETAILED DESCRIPTION
The present invention provides process for the preparation of telmisartan.
The processes of the present invention are disclosed in Scheme 1 and Scheme 2.
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Scheme 1: Two step process


Scheme 2: One-pot process

According to an aspect of the invention there is provided a process for the for the preparation of telmisartan alkylester intermediate of Formula II,

Formula II comprising the steps of
a) combining 2-n-propyl-4-methyI-6-(I '-methylbenzimidazole-2-yl)
benzimidazole of Formula III,
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with 4'-bromomethy]bipheny]-2-carboxylic acid, alky] ester of Formula IV,

a base and an alcohol solvent to obtain a mixture;
b) stirring the reaction mixture of step a) till the compound of Formula III disappears on TLC;
c) recovering telmisartan alkylester of Formula II;
wherein R is a straight chain or branched chain C1-C4; preferably R is methyl.
The base may be selected from inorganic bases or organic bases.
The inorganic bases may be selected from alkali & alkaline earth metal hydroxides,
carbonates, preferably alkali & alkaline earth metal hydroxides such as sodium
hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide calcium
hydroxide more preferably sodium hydroxide & potassium hydroxide
The solvent is selected from C1-C5 alcohol, preferably C3-C4 alcohol, more
preferably isopropyl alcohol & n-butanol.
The reaction mixture is stirred at a temperature range of 10-40° C, preferably at 15-
35° C, more preferably at 20-30° C.
The reaction mixture is stirred for 1 to 8 hours, preferably for 1 to 6 hours, more
preferably for 2 to 5 hours.

In another aspect of the present invention, there is provided a process for converting the telmisartan alkylester intermediate of Formula II to telmisartan of Formula I by hydrolysis under basic conditions in an alcohol solvent comprising the steps of
a) making a slurry of the telmisartan alkylester of Formula II in an alcohol solvent;
b) adding a base to the above slurry and stirring;
c) heating the mixture obtained in step b) to the boiling point of the solvent;
d) stirring the mixture at the boiling point of the solvent for about 30 minutes to about 3 hours; till the disappearance of compound of Formula II
e) cooling the reaction mixture gradually to 25-30° C;
f) cooling to 0-5° C;
g) adjusting the pH with an acid;
h) stirring the mixture at 0-5° C to obtain solid;
i) filtering the solid to get telmisartan of Formula I The alcohol solvent is selected from C1-C5 alcohol, preferably C3-C4 alcohol, more preferably isopropyl alcohol & n-butanol. Optionally water is added in step f) before cooling.
The pH in step g) is adjusted to 2 to 6, preferably to 4 to 6, more preferably to 5 to 6. The acid in step g) may be selected from organic acids such as acetic acid & inorganic acids may be selected from hydrochloric acid, sulphuric acid. The reaction mixture in step h) is stirred for about 1 to 4 hours, preferably for 1 to 2 hours.

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In yet another aspect of the present invention there is a provided a one-pot process for the preparation of telmisartan of Formula I

comprising the steps of
a) combining 2-n-propyl-4-methyl-6-(r-methylbenzimidazole-2-yl) benzimidazole of Formula III, 4'-bromomethylbiphenyl-2-carboxylic acid, alkyl ester of Formula IV, a base and an alcohol solvent to obtain a mixture;
b) stirring the reaction mixture of step a) till the disappearance of the compound of Formula III on TLC;
c) heating the reaction mixture of step c) to the boiling point of the solvent;
d) maintaining the temperature for about 15 minutes to about 5 hours; till the disappearance of compound of Formula II;
e) cooling the reaction mixture gradually to 25-30° C;
f) cooling to 0-5° C;
g) adjusting the pH with an acid;
h) stirring the mixture at 0-5° C to obtain solid;
i) filtering the solid to get telmisartan of Formula I wherein R is a straight chain or branched chain Ci-C4, preferably methyl. The base may be selected from organic bases or inorganic bases. The inorganic bases may be selected from alkali & alkaline earth metal hydroxides, carbonates, preferably alkali & alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide calcium hydroxide more preferably sodium hydroxide & potassium hydroxide The solvent is selected from C1-C5 alcohol, preferably C3-C4 alcohol, more preferably isopropyl alcohol & n-butanol.
The reaction mixture is stirred at a temperature range of 10-40° C, preferably at 15-35° C, more preferably at 20-30° C.
The reaction mixture in step b) is stirred for 1 to 8 hours, preferably for 1 to 6 hours, more preferably for 2 to 5 hours. Optionally water is added in step f) before cooling.
The pH in step g) is adjusted to 3 to 6, preferably to 4 to 6, more preferably to 5 to 6. The acid in step g) may be selected from organic acids such as acetic acid & inorganic acids may be selected from hydrochloric acid, sulphuric acid.
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The reaction mixture in step h) is stirred for about 1 to 4 hours, preferably for 1 to 2 hours.
THE INVENTION IS EXPLAINED BY THE NON-LIMITING EXAMPLES GIVEN BELOW.
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Scheme 1: Two step process


Example 1
Preparation of methyl, 4'-((l,4,-dimethyl-2,-propyl-2,6'-bi(liy-benzo|(/|iniidazol) -r-yl)methyl)biphenyI-2-carboxylate (Telmisartan metbylester of Formula II):
To the stirred slurry of 2-n-propyl-4-methyl-6-(l '-methylbenzimidazole-2-yl) benzimidazole (50.0g, 0.1551moles) in isopropyl alcohol (200ml) was added aqueous solution of potassium hydroxide (10.41g, 0.186 moles + 30 ml of water) and stirred at 25-30° C for 10-15 minutes. Then 4'-bromomethylbiphenyl-2-carboxylic acid, methyl ester (56.76g, 0.186 moles) was added in lots over a period of 5-10 minutes at room temperature. Reaction progress was monitored by TLC (Ethyl acetate). After 3-4 hrs of stirring at RT, it showed absence of starting material. White solid precipitated was filtered out through Buchner funnel, washed with isopropyl alcohol (50 ml), and washed with water (2 x 100ml). Finally the crude product was dried under vacuum at 60-70° C for 3-5 hrs. Yield: 62.0g (75.6%); HPLC purity: >95%.
JH NMR in DMSO-d6 (5ppm): 7.82-7.78 (dd, 2H, ArH), 7.52-7.34 (m 5H ArH), 7.30-7.23 (m, 5H, ArH), 7.09 (d, 2H, ArH), 5.44 (s, 2H, ArCH?Nl 3.80 (s, 3H, -OCH3), 3.57 ( s, 3H, -NCHQ, 2.94 (t, 2H, ArCH2CH2), 2.77 (s, 3H, ArCHA 1.92-1.83 (m, 2H, -CH2CH2CH3), 1.06 (t, 3H, -CH2CH2CH3).
13C NMR in DMSO-d6 (8ppm): 168.81, 156.60, 154.83, 143.29, 143.05, 141.85, 141.25, 136.79, 135.20, 134.87, 131.51, 130.83, 130.67, 130.05, 129.58, 129.13, 127.52, 126.04, 124.04, 123.95, 122.61, 122.43, 119.68, 109.62, 1094.08, 52.01, 47.24, 31.96, 30.01, 22.01,17.03, 14.24.
IR (KBr): 3049.46, 2954.95, 2870.08, 1705.07, 1598.99, 1510.26, 1446.61, 1290.38, 1126.43, 920.05, 858.32, 759.95, 750.31 cm"1.
Example 2
Preparation of 4-((l,4'-dimethyl-2,-propyl-2,6,-bi(lbenzo[(/limidazol)-l,-
yl)metbyI)biphenyI-2-carboxylic acid (Telmisartan of Formula I):
To the stirred slurry of methyl, 4H(l,4'KlimethyI-2'-propyl-2,6'-bi(lH-benzo[d]imidazol)-r-yl)methyl) biphenyl-2-carboxylate (60.0g, 0.1135 moles) in isopropyl alcohol (240.0 ml) was added aqueous solution of potassium hydroxide
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(25.42g, 0.454 moles + 18 ml of water) at room temperature. Reaction mixture was then gradually heated to 80-85° C. Reaction progress was monitored by TLC (Ethyl acetate). After 30 minutes of heating reaction showed absence of starting material. Reaction mixture was allowed to cool gradually to room temperature. White solid precipitated out was dissolved by adding water (250ml) and cooled to 0-5° C. Reaction mixture pH was adjusted to 5-6 by using dilute acetic acid (100ml) & stirred at 0-5° C for 30 minutes. White solid precipitated was filtered out through Buchner funnel and washed with water (200 ml). Finally crude teimisartan was dried under vacuum at 60-70° C. Yield: 55g (94.5%); HPLC purity: >99%. *H NMR in DMSO-d6 (5ppm): 13.3-12.7 (brd, 1H, COOH), 7.73-7.67 (m, 3H, ArH), 7.60-7.58 (dd, 1H, ArH), 7.57-7.51 (ddd , 1H, ArH), 7.48 (s, 1H, ArH), 7.45-7.43 (ddd 1H ArH), 7.34-7.32 (dd, 1H, ArH), 7.30 (d, 2H, ArH), 7.27-7.21 (m, 2H, ArH), 5.63 (s, 2H, ArCH2N), 3.82 (s, 3H, -NCHO. 2.93 (t, 2H, ArO^CH2), 2.63 (s, 3H, ArCHA 1.82-1.79 (m, 2H, -CH2CH2CH3), 1.00 (t, 3H, -CH?CH7CHV). 13C NMR in DMSO-d6 (5ppm): 169.61, 156.26, 154.06, 142.73, 142.38, 140.55, 140.19, 136.62, 136.01, 134.75, 132.30, 130.93, 130.41, 129.18, 128.86, 128.28, 128.28, 127.38, 126.46, 123.27, 123.18, 122.14, 121.90, 118.71, 110.48, 109.39, 46.15, 31.82, 28.78, 20.82, 16.54,13.92.
IR (KBr): 3059.10-2868.15 (brd), 1693.50, 1598.99, 1462.04, 1409.96, 1382.96, 1267.23, 1230.58, 1128.36, 1008.77, 864.11, 813.96, 796.60, 758.02, 740.67, 705.95cm"1.
Example 3
Preparation of 4'-((l,4*-dimethyl-2'-propyl-2,6'-bi(l/T-benzo[rf|imidazol)-r-
yl)methyl)biphenyl-2-carboxyIic acid (Teimisartan of Formula I):
To the stirred slurry of methyl, 4'-((l,4'-dimethyl-2,-propyl-2,6'-bi(l^-benzo[d]imidazol)-r-yI)methyl) biphenyl-2-carboxylate (47.0g, 0,0888 moles) in n-butanol (188.0 ml) was added aqueous solution of potassium hydroxide (19.9g, 0.3553 moles + 14 ml of water) at room temperature. Reaction mixture was then gradually heated to 95-100°C. Reaction progress was monitored by TLC (Ethyl acetate). After 30 minutes of heating reaction showed absence of starting material. Reaction mixture was allowed to cool gradually to room temperature. White solid
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precipitated out was dissolved by adding water (250ml) and cooled to 0-5°C. Reaction mixture pH was adjusted to 5-6 by using dilute hydrochloric acid & stirred at 0-5° C for 30 minutes. White solid precipitated was filtered out through Buchner funnel and washed with water (2 x 100 ml). Finally crude telmisartan was dried under vacuum at 60-70° C. Yield: 42g (91.8%); HPLC purity: >99.0%.
Scheme 2: One-pot process

Example 4
One-pot preparation of 4'-((l,4'-dimethyl-2'-propyI-2,6'-bi(lff-benzo[rf]
imidazoI)-l'-yl)methyl)biphenyl-2-carboxylic acid (Telmisartan of formula I):
To the stirred slurry of 2-n-propyl-4-methyl-6-(r-methylbenzimidazole-2-yl) benzimidazole (150.0g, 0.4654 moles) in isopropyl alcohol (600ml) was added aqueous solution of potassium hydroxide (39.0g, 0.6981 moles), water (30.0ml) and stirred at 25-30° C for 10-15 minutes. Then 4,-bromomethylbiphenyl-2-carboxylic acid, methyl ester (170.2g, 0.558 moles) was added in lots over a period of 5-10 minutes at room temperature. Reaction progress was monitored by TLC (Ethyl
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acetate). After 3 hrs of stirring at room temperature, it showed absence of starting material. To the reaction mixture was added potassium hydroxide (65.lg, 1.1635 moles) at room temperature. Reaction mixture was then gradually heated to 80-85° C. Reaction progress was monitored by TLC (Ethyl acetate). After 2.0-3.0 hrs of heating reaction showed absence of starting material (ester intermediate). Reaction mixture was allowed to cool gradually to room temperature. White solid precipitated out was dissolved by adding water (500ml) and cooled to 0-5°C. Reaction mixture pH was adjusted to 5-6 by using 50% aq. acetic acid & stirred at 0-5° C for 45-60 minutes. White colored product precipitated was filtered out through Buchner funneJ and washed with water (500 ml). Wet cake was taken in methanol (900ml) & heated to reflux for 1.0 hr. It was then allowed to cool to room temperature & stirred for 30 minutes. Solid was filtered out & dried under vacuum at 60-70° C. Yield: 172g (72.1% for two steps); HPLC purity: >98%.
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Note: Alcoholic solvents like methanol, ethanol, propanol, isopropanol, n-butanol, pentanol were also used for above alkylation as well as hydrolysis reaction.