FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION (See Section 10)
PROCESS FOR PREPARATION OF TELMISARTAN AND INTERMEDIATES
THEREOF
M/S AMOLI ORGANICS PVT. LTD, 407 DALMAL HOUSE, J.B.ROAD, NARIMAN POINT, MUMBAI-400021, INDIA, an Indian company incorporated under the
companies Act, 1956
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

The present invention relates to "A NOVEL PROCESS FOR THE PREPARATION OF TELMISARTAN AND INTERMEDIATES THEREOF"
Telmisartan is an angiotensin II receptor antagonist (ARB) used in the management of hypertension. Generally, angiotensin II receptor blockers (ARBs) such as telmisartan bind to the angiotensin II type 1 (ATI) receptors with high affinity, causing inhibition of the action of angiotensin II on vascular smooth muscle, ultimately leading to a reduction in arterial blood pressure. Recent studies suggest that Telmisartan may also have PPAR-gamma agonistic properties that could potentially confer beneficial metabolic effects, it is commercially developed by Boehringer Ingelheim Co., and marketed as Micardis®. Telmisartan is chemically described as 4'-[(l, 4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-1-yl)methyl]-[l,l'-biphenyl]-2-carboxylic acid. Its empirical formula is C33H30N4O2, its molecular weight is 514.63. and its structural formula is;

The process for preparation of Telmisartan has been described in various patents and to cite a few references, EP 0 502 314, EP 1 144 386, US 5,591,762, US 7,193,089, CN 1412183, WO 2004/087676, WO 2006/044648, WO 2007/010558 WO 2009/004064. Amongst the various processes described, the general process which has the possibility of scaling up to the Industrial scale is as below;

Reaction scheme step 1:



Reaction scheme step 3:
The acylation of 4-amino-3-methyIbenzdic acid methyl ester (I) with butyryl chloride (II) in hot chlorobenzene gives the corresponding amide (III), which is nitrated with HNO3/H2SO4 yielding 4-butyramido-3-methyl-5-nitrobenzoic acid methyl ester (IV). The hydrogenation of (IV) with H2 over Pd/C in methanol affords the expected amino compound (V), which is cyclized in refluxing acetic acid to 2-propyl-4-methylbenzimidazole-6-carboxylic acid methyl ester (VI). The hydrolysis of (VI) with NaOH in refluxing methanol/water affords the corresponding free acid (VII), which is cyclized with N-methyl-o-phenylenediamine (VIII) by means of polyphosphoric acid (PPA) at 150 C, giving 4-methyl-6-(l-methylbenzimidazol-2-yl)-2-propylbenzimidazole (IX). The condensation of (IX) with 4'-(bromomethyl)biphenyl-4-carboxylic acid tert-butyl ester (X) by means of potassium tert-butoxide in DMSO yields the tert-butyl ester (XI), which is finally hydrolyzed with trifluoroacetic acid.
As above mentioned information regarding prior art, which suffers from many operational and economical disadvantages, low yield and poor quality of the product as well as impracticability in large scale manufacturing procedure.
Thus, it is therefore an objective of the present invention to provide an improved and commercially viable process for the preparation of Telmisartan and intermediates thereof.

The present invention describes the process for the preparation of Telmisartan and its novel intermediates, in particular one of the embodiment of the invention describes the novel intermediate compounds of formula (3) and formula (5) as depicted in the following reaction schemes;
Reaction scheme 1:

The present invention describes preparation of a novel intermediate namely 4'-(bromomethyl)-N-hydroxybiphenyl-2-carboxamide, compound of formula (3) in above mentioned reaction scheme 1. This intermediate is obtained by refluxing methyl 4'-(bromomethyl)biphenyl-2-carboxylate compound of formula (2) in a polar protic solvent with hydroxyl amine as prepared in-situ, further treated with acetic acid to get the required intermediate.
Reaction scheme 2:

Present invention further provides a process for the preparation of penultimate intermediate namely 4'-(( 1,4'-dimethyl-2'-propyl-2,6'-bi( 1 /H-benzo[d]imidazol)-1 '-yl)methyl)-N-hydroxybiphenyl-2-carboxamide, compound of formula (5) as depicted in above reaction scheme 2. This intermediate is obtained by reacting 1,7'-dimethyl-2'-propyl-2,2',3,3'-etrahydro-2,5'-bi(lH-benzo[dimidazole) compound of formula (4) with

4'-(bromomethyl)-N-hydroxybiphenyl-2-carboxamide, compound of formula (3) as depicted in reaction scheme 2, in presence of alkali hydroxide solution in a polar aprotic solvent.
Reaction scheme 3:

The process is from the penultimate intermediate namely 4'-((l,4,-dimethyl-2'-propyl-2,6'-bi(lH-benzo[cf3imidazol)-r-yl)methyl)-N-hydroxybiphenyl-2-carboxamide, compound of formula (5) as depicted in above mentioned reaction scheme 3, is converted in to 4'-((l,4'-dimethyl-2'-propyl-2,6'-bi(lH-benzo[d]imidazol)-l,-yl)methyl)biphenyl-2-carboxylic acid compound of formula (1) by using alkali metal hydroxide in a polar protic solvent like methanol.
The distinct advantage of the present invention over the prior art can be summarized as below:
(1) The present process, which describes the manufacturing process of Telmisartan, an angiotensin II receptor antagonist, has the advantage of scaling up to the industrial level of production.
(2) The process uses novel intermediates in the process which makes it substantially free from impurities associated with prior art.
(3) The yields in the process are high which makes it a cost effective process.

The details of the invention are further illustrated in the following examples.
Example 1: Preparation of 4'-(bromomethyl)-N-hydroxybipheny 1-2-carboxamide
In a 1 liter 3-necked flask, equipped with stirrer, thermometer and reflux condenser, Hydroxyl amine hydrochloride (22.7 g, O.32moles) in Methanol (240 ml) was charged and heated to reflux for 10 minutes, similarly in another 1 liter 3-necked flask Potassium hydroxide (27.57 g, 0.491 moles) in methanol (140 ml) was charged and heated to 60°C until clear solution obtained, afterward both the samples were cooled to 30°-40°C., then alkali solution was slowly added to the Hydroxyl amine hydrochloride solution by stirring, and further reaction mixture was cooled to 5°-10°C, again reaction mixture was stir for 10-30 minutes. Add methyl 4'-(bromomethyl)biphenyl-2-carboxylate (50 g, 0.163moles) in above reaction mixture, the reaction mixture is filtered and washed with methanol (10 ml) and filtrate was allowed to precipitate overnight, then precipitates were collected washed with methanol and dried in air, dried precipitate was charged in 1.2 N Acetic acid (160 ml) and heated to 50°-55°C, till clear solution was observed, then solution was allowed to cool to room temperature and then chilled to 0°-5°C, and maintained for 30 minutes. Solid obtained was filtered and dried under vacuum of about lOmmHg and optionally purified by known method in the art. Product was weighed 25 -28g. (HPLC purity-95% and Yield 50%).
Example 2: Preparation of 4'-(( 1,4'-dimethyl-2'-propyl-2,6'-bi( 1H-benzo[d]imidazol)-1 '-yl)methyl)-N-hydroxvbiphenyl-2-carboxamide
In a 250 ml 3-necked flask, equipped with stirrer, thermometer and reflux condenser,
Acetone (102 ml) and l,7'-dimethyl-2'-propyl-2-2,,3,3'-tetrahydro-2,5'-bi(lH-
benzo[d]imidazole) (18 g, 59mmoles) was charged at 25°-30°C, powdered sodium hydroxide (2.69 g, 67mmoles) was added to the resultant reaction mixture, then it was stirred for 1 hour. To this reaction mixture 4'-(bromomethyl)-.N-hydroxybiphenyl-2-carboxamide (19.86 g, 64mmoles) [As prepared in Example 1] was added and resultant reaction mixture was stirred for 5-6 hours at 25°-30°C, reaction mixture was chilled to 0-

5°C, and stirred for 2 hours, then it is filtered and wet cake was washed with acetone and further with water, residue was suck dry under vacuum of about 1 OmmHg. Dry product was weighed 17g. (HPLC purity-98% and Yield 94%).
Example 3: Preparation of 4'-((l,4'-dimethvl-2'-propyl-2,6'-bi(lH-benzo[d]imidazol)-1'-vl)methvl)biphenyl-2-carboxylicacid
In a 500 ml 3-necked flask, equipped with stirrer, thermometer and reflux condenser, methanol (200 ml), De-mineralized water (44 ml) and 4'-((l,4'-dimethyl-2'-propy 1-2,6'-bi(lH-benzo[d]|imidazol)-1'-yl)methyl)-N-hydroxybiphenyl-2-carboxamide (22 g, 41mmoles) [As prepared in Example 2] were charged at room temperature and stirred for 30 minutes. Gradually temperature was elevated to 65°-72°C, and reaction mixture was heated for 5-6 hours. Optionally the Charcoal treatment was given to the reaction mixture and filtered through the hyflow bed, then whole filtrate was transferred to 500 ml 3-necked flask, pH of the reaction mass was adjusted to 5,5-6.7 with the help of using Concentrated Hydrochloric acid. Reaction mixture was further washed with methanol and then with water, obtained wet cake was collected and dried under vacuum of about lOmmHg, at 55°-65°C. product was weighed 18-20g. (Melting point 261°-263°C, HPLC purity-99% and Yield 81%)

We claim:
1. The novel process for preparation of Telmisartan and intermediates thereof.
2. A said process of claim 1, comprises;

a) Refluxing methyl 4'-(bromomethyl)biphenyl-2-carboxyIate compound of formula (2) in hydroxyl amine in presence of acetic acid solution in polar protic solvent;
b) Condensing 4'-(bromomethyl)-N-hydroxybiphenyl-2-carboxamide compound of formula (3), as obtained in claim 2 (a) with l,7'-dimethyl-2'-propyl-2,2',3,3'-tetrahydro-2,5'-bi(lH-benzo[d]imidazole) compound of formula (4) in polar aprotic solvent in presence of alkali metal hydroxide solution;
c) Treating 4'-((l,4,-dimethyl-2'-propyl-2,6,-bi(lH-benzotd]imidazol)-r-yl)methyl)-N-hydroxybiphenyl-2-carboxamide as obtained in claim 2 (b) with alkali metal hydroxide in a suitable solvent at suitable pH range.

3. A process as claimed in claim 2 (a), wherein said polar protic solvent is selected from the group consisting of methanol, ethanol, n-butanol, n-propanol, water and mixture thereof, preferably the solvent is methanol.
4. A process as claimed in claim 2 (b), wherein said polar aprotic solvent is selected from the group consisting of Acetone, dimethylformamide, tetrahydrofurane, dichloromethane and mixture thereof, preferably the solvent is Acetone.
5. A process as claimed in claim 2 (c), wherein a suitable solvent is methanol.
6. A process as claimed in claim 2 wherein alkali metal hydroxide is selected from the Sodium hydroxide and potassium hydroxide, preferably it is potassium hydroxide.
7. A process as claimed in claim 2 (c), wherein pH adjusted to 5.5-6.7 with hydrochloric acid for recovering Telmisartan.
8. A novel intermediate of Telmisartan namely 4'-(bromomethyl)-N-hydroxybiphenyl-2-carboxamide compound of formula (3);


9. A novel intermediate of Telmisartan namely 4'-((l,4'-dimethyl-2'-propyl-2,6'-bi(lH/-benzo[d]imidazol)-l'-yl)methyl)-N-hydroxybiphenyl-2-carboxamide compound of formula (5);