Description:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL/COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
AN IMPROVED PROCESS FOR PREPARING 2-(4-{[4-METHYL-6-(1-METHYL-1H-1,3-BENZODIAZOL-2-YL)-2-PROPYL-1H-1,3-BENZODIAZOL-1-YL]METHYL}PHENYL)BENZOIC ACID

2. APPLICANT(S):
a. NAME: LASA SUPERGENERICS LTD.
b. NATIONALITY: INDIA
c. ADDRESS: C-105, MIDC, MAHAD, DIST. RAIGAD, MAHARASHTRA, INDIA. PIN 402309

3. PREAMBLE TO THE DESCRIPTION:


FIELD OF INVENTION
Present invention relates to a process for preparing 2-(4-{[4-Methyl-6-(1-methyl-1H-1,3-benzodiazol-2-yl)-2-propyl-1H-1,3-benzodiazol-1-yl]methyl}phenyl)benzoic acid. More particularly it relates to the preparation of high purity telmisartan in safe, efficient and ecofriendly manner.

BACKGROUND OF THE INVENTION:
Telmisartan is known from EP 0502314B and has the following chemical structure of formula (I):

(Formula 1)

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. Telmisartan has also been found to have activity against a variety of cancers in vitro, including prostate, renal, colon, leukemia, and ovarian cancer. According to a study with 18 patients, telmisartan can replace valsartan and candesartan for hypertensive patients with have also diabetes type II because telmisartan has additional advantages of insulin sensitivity and antiatherosclerosis through probably its effects on PPAR-y.

US20060264491 has disclosed following route of synthesis for telmisartan. In this route, the cyano group of 4'-Methyl-2-cyanobiphenyl is converted to amide group and then by brominating, 4'-Bromomethyl-2'-cyanobiphenyl is obtained. It is reacted with 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl) benzimidazole and treated with KOH to get telmisartan.

US7193089 disclosed a method of preparation which involve reaction of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl)benzimidazole with 4'-Bromomethyl-2-cyanobiphenyl, and subsequently hydrolyzing the nitrile function to obtain the acid function.

US8691999 disclosed a process for preparing telmisartanb Form A in which 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl) benzimidazole and methyl-4-(bromomethyl)biphenyl-2-carboxylate are subjected to condensation and hydrolysis in dimethyl sulphoxide in the presence of a base in a single step. After completion of reaction, pH is adjusted using an aqueous acid. Product is extracted into dichloromethane and then isolated from acetone to get telmisartan Form A.

However, there is further need of a process which will be safe, efficient and eco-friendly.

Although earlier attempts were made in developing methods for preparing telmisartan, there were many problems associated with those. The processes yielded the slimy and viscous residue of telmisartan which was difficult to filter affecting the overall yield and quality. Current invention provides a simple yet efficient process for manufacturing telmisartan which is economic and high yielding product. The process is speedy and product obtained is highly pure.

SUMMARY OF INVENTION:
The process of preparing telmisartan i.e. 2-(4-{[4-Methyl-6-(1-methyl-1H-1,3-benzodiazol-2-yl)-2-propyl-1H-1,3-benzodiazol-1-yl]methyl}phenyl)benzoic acid comprises
a) adding methyl-4-(bromomethyl)biphenyl-2-carboxylate to the reaction mixture containing 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl) benzimidazole and a base in a solvent at a temperature range between 0 to 10°C;
b) maintaining temperature between 0 to 10°C for one hour and gradually increasing the temperature till 20°C under stirring within next 1-2 hours;
c) heating at reflux for 1-3 hours;
d) cooling the reaction mixture to 15-25°C, acidifying with alcohol-acid mixture or dry acid gas;
e) cooling to 0°C for 6 to 10 hours and filtering the precipitate of 2-(4-{[4-Methyl-6-(1-methyl-1H-1,3-benzodiazol-2-yl)-2-propyl-1H-1,3-benzodiazol-1-yl]methyl}phenyl)benzoic acid;
f) optionally subjecting the precipitate to distillation for recovery of solvent.

DETAILED DESCRIPTION OF INVENTION:
Current invention provide a process for preparing telmisartan i.e. 2-(4-{[4-Methyl-6-(1-methyl-1H-1,3-benzodiazol-2-yl)-2-propyl-1H-1,3-benzodiazol-1-yl]methyl}phenyl)benzoic acid by adding methyl-4-(bromomethyl)biphenyl-2-carboxylate to the reaction mixture containing 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl) benzimidazole and a base in a solvent at a temperature range between 0 to 10°C and maintaining temperature between 0 to 10°C for one hour and gradually increasing the temperature till 20°C under stirring within next 1-2 hours. The reaction mixture is heated at reflux for 1-3 hours and cooled to 15-25°C followed by acidification with alcohol-acid mixture or dry acid gas. Thereafter it is cooled to 0°C for 6 to 10 hours and the precipitate of 2-(4-{[4-Methyl-6-(1-methyl-1H-1,3-benzodiazol-2-yl)-2-propyl-1H-1,3-benzodiazol-1-yl]methyl}phenyl)benzoic acid is filtered and washed with the solvent. The solvent can be recovered by subjecting the precipitate to distillation.

Solvent used in this process is preferably a polar aprotic solvent or mixture of such solvents. Examples of such alcohols include but not limited to N-methylpyrrolidone, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide etc. More preferably dimethylformamide and acetone can be suitably employed for this process.

Any suitable base can be employed for this process. Alkali metal hydroxides are more preferably employed in this process. One such example of base is Sodium Hydroxide.

The acidification step of current invention plays a vital role in getting non-slimy and non-viscous precipitate. The mixture of alcohol and acid or a dry acid gas is used for this purpose. The pH of reaction mass is adjusted within 5 to 6 to get precipitate. Mixture of alcohol & acid can be prepared in various ratios as per the need. Alcohols for this purpose can be selected form primary or secondary straight chain and branched alcohols. Examples of such alcohols include but not limited to methanol ethanol, propanol, butanol, n-propyl alcohol, iso-propyl alcohol etc. Although any acid can be used for this purpose, mineral acids can be more suitably employed. Examples of such mineral acids include but not limited to Hydrochloric acid, Hydrobromic acid etc. Also, these acids can be used in their dry gaseous form.

The product i.e. telmisartan yield for the process of current invention is about 80% with purity above 99.0%. Moreover, the process is anhydrous, ecofriendly, scalable and economic too. The filtration speed is faster due to non-slimy and non-viscous nature of residue. The solvent can also be recovered and reused for next production cycles.

Hereinafter, the invention is explained in detail in the following examples, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention in any way.

EXAMPLES:
Example 1:
Under stirring, 245 gm of methyl-4-(bromomethyl)biphenyl-2-carboxylate was added to the reaction vessel containing 200 gm of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl) benzimidazole, 100 gm of NaOH and 1600 ml dimethylformamide at 0 to 4° C. After addition of contents the temperature was maintained between 0-4°C for 1 hour and then the temperature was gradually increased till 20°C in 2 hours and thereafter the reaction mixture was heated to 80°C for 3 hours. Finally the reaction mixture was cooled to 20°C and the pH was adjusted to 5.3 using 20% hydrochloric acid prepared in isopropyl alcohol. The mixture was cooled to 0°C for 6 hours and washed with dimethylformamide. The wet cake was dried to obtain 293 gm of telmisartan with purity 99.4%.

Example 2:
Under stirring, 190 gm of methyl-4-(bromomethyl)biphenyl-2-carboxylate was added to the reaction vessel containing 160 gm of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl) benzimidazole, 75 gm of NaOH and 1200 ml acetone at 5 to 8° C. After addition of contents the temperature was maintained between 5-8°C for 1 one hour and then the temperature was gradually increased till 20°C under stirring within next 1 hour. Thereafter the reaction mixture was heated to 85°C for 1.5 hours. Finally the reaction mixture was cooled to 20°C and the pH was adjusted to 5.4 using 30% hydrobromic acid prepared in isopropyl alcohol. The mixture was cooled to 0°C for 8 hours and washed with dimethylformamide. The mixture was further subjected to simple distillation to recycle acetone.
The wet cake obtained was dried to get 214 gm of telmisartan with purity 99.3%.

Example 3:
Under stirring, 250 gm of methyl-4-(bromomethyl)biphenyl-2-carboxylate was added to the reaction vessel containing 210 gm of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl) benzimidazole, 100 gm of NaOH and 1600 ml dimethylformamide at 8 to 10° C. After addition of contents the temperature was maintained between 8 to 10°C for 1 hour and then the temperature was gradually increased till 20°C under stirring within next 2 hour. Thereafter the reaction mixture was heated to 80°C for 1.5 hours. Finally the reaction mixture was cooled to 20°C and the pH was adjusted to 5.6 by purging dry hydrochloric acid gas. The mixture was cooled to 0°C for 7 hours and washed with dimethylformamide. The mixture was further subjected to simple distillation to recycle dimethylformamide.
The wet cake obtained was dried to get 316 gm of telmisartan with purity 99.5%.

, Claims:CLAIMS
I/We claim:
1. A process of preparing telmisartan i.e. 2-(4-{[4-Methyl-6-(1-methyl-1H-1,3-benzodiazol-2-yl)-2-propyl-1H-1,3-benzodiazol-1-yl]methyl}phenyl)benzoic acid comprises
a) adding methyl-4-(bromomethyl)biphenyl-2-carboxylate to the reaction mixture containing 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl) benzimidazole and a base in a solvent at a temperature range between 0 to 10°C;
b) maintaining temperature between 0 to 10°C for one hour and gradually increasing the temperature till 20°C under stirring within next 1-2 hours;
c) heating at reflux for 1-3 hours;
d) cooling the reaction mixture to 15-25°C, acidifying with alcohol-acid mixture or dry acid gas;
e) cooling to 0°C for 6 to 10 hours and filtering the precipitate of 2-(4-{[4-Methyl-6-(1-methyl-1H-1,3-benzodiazol-2-yl)-2-propyl-1H-1,3-benzodiazol-1-yl]methyl}phenyl)benzoic acid;
f) optionally subjecting the precipitate to distillation for recovery of solvent.

2. The process as claimed in claim 1, wherein the solvent used in step a) is selected from a polar aprotic solvent or mixture of such solvents.

3. The process as claimed in claim 2, wherein the polar aprotic solvent is selected form N-methylpyrrolidone, ethyl acetate, acetone, dimethylformamide, acetonitrile and dimethyl sulfoxide.

4. The process as claimed in claim 1 to 3, wherein the solvent is dimethylformamide.

5. The process as claimed in claim 1 to 3, wherein the solvent is acetone.

6. The process as claimed in claim 1, wherein the base in step a) is selected from alkali metal hydroxides.

7. The process as claimed in claim 1, wherein in step d) the pH of reaction mass is adjusted within 5 to 6 by acidifying with alcohol-acid mixture or dry acid gas.

8. The process as claimed in claim 7, wherein the alcohol is selected form primary alcohols and secondary alcohols which can be straight chain or branched alcohols and any mixture thereof.

9. The process as claimed in claim 8, wherein the alcohol is selected from methanol ethanol, propanol, butanol, n-propyl alcohol and iso-propyl alcohol.

10. The process as claimed in claim 7, wherein the acid is selected from mineral acids.
Dated this 10th day of July, 2023
Signature: To be digitally signed by-
Name: Mr. Parag M. More
Partner, MORE & KADAM LEGAL ASSOCIATES
INTELLECTUAL PLATFORM®
Patent Agent for applicant
Patent Agent Regn. No. IN/PA-1688
On behalf of applicant