TELMISARTAN PART 3/3

PART 1........http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-13.html

PART 2........http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html

                   OR  http://newdrugapprovals.org/2015/04/06/telmisartan-part-23/

PART3......   http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-33.html

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PAPER

Journal of Organic Chemistry (2015), 80(3), 1915-1919

J. Org. Chem., 2015, 80 (3), pp 1915–1919

DOI: 10.1021/jo5025333

http://pubs.acs.org/doi/abs/10.1021/jo5025333?source=chemport&journalCode=joceah

A direct and efficient total synthesis has been developed for telmisartan, a widely prescribed treatment for hypertension. This approach brings together two functionalized benzimidazoles using a high-yielding Suzuki reaction that can be catalyzed by either a homogeneous palladium source or graphene-supported palladium nanoparticles. The ability to perform the cross-coupling reaction was facilitated by the regio-controlled preparation of the 2-bromo-1-methylbenzimidazole precursor. This convergent approach provides telmisartan in an overall yield of 72% while circumventing many issues associated with previously reported processes.

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PAPER

International Journal of Research in Pharmaceutical and Biomedical Sciences (2013), 4(1), 293-295

telmisartan1. [Yield 87%, Purity 99.97% by HPLC.M.P. 260 – 262°C, Sulphated ash < 0.01%].

1H NMR (DMSO-d6): δ 0.98-1.03 (t,3H), 1.73- 1.86 (m, 2H), 2.5 - 2.63 (s, 3H), 2.90-2.95 (s, 2H),3.82 (s, 3H), 5.62 (s, 2H), 7.16-7.34 (m,7H), 7.40-7.59 (m,4H), 7.68-7.70 (m, 3H), 12.86 (s, 1H).

M/Z: 515.50 [M + H]+

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PATENT

WO 2014027280

http://www.google.com/patents/WO2014027280A1?cl=en

Scheme 1 given below: Formula .

Example 1: 4'-[2-n^ropyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-ylmeth^ carboxylic acid In a 2 litre reaction flask was added 400 ml methylene chloride, followed by 100 gm of 2- cyano-4' -methyl biphenyl. The reaction mass was stirred to get a clear solution and cooled to 20 °C. Chlorine gas was sparged into the reaction mass for a period of 15 hours till completion of the reaction. The reaction was monitored by TLC using mobile phase n-hexane: ethyl acetate (8:2). The excess chlorine from the reaction mass was removed by flushing with nitrogen. The solvent was distilled out completely by distillation at atmospheric pressure and removal of the final traces under vacuum. To the residual mass, 500 ml of methyl isobutyl ketone was added. The reaction mass was stirred and washed with a solution of 300 ml of 5% sodium bicarbonate solution.
The lower aqueous layer was separated and the upper organic layer was washed with 300 ml water. The lower aqueous layer was separated. To the organic layer containing 4-chloromethyl-2'-cyanobiphenyl, the compound 2-n-propyl-4-methyl-6-(l'- methylbenzimidazol-2'-yl)benzimidazole was added, followed by a solution of 40 gm sodium hydroxide in 300 ml water.
 The reaction mass was stirred for 10 minutes and 10 gm of tetrabutyl ammonium hydrogen sulphate was added. The reaction mass was heated to 80 ^UC and maintained at 80 to 85 °C for 4 hours. The completion of the reaction was monitored by TLC using mobile phase chloroform: methanol (9: 1). After completion of reaction, the lower aqueous layer was separated.
The solvent was distilled out till mass temperature 120 °C and final traces were removed completely under vacuum. To the residual mass, 50 ml of n-butanol was added and the solvent distilled out under vacuum below 100 °C to remove all traces of methyl isobutyl ketone. The residue was dissolved in 750 ml of n-butanol and 83 gm sodium hydroxide added. The reaction mass was heated to reflux and maintained for 24 hours at 123 to 126 °C. The completion of the reaction was monitored by TLC using mobile phase chloroform: methanol (9: 1). The solvent was distilled out at atmospheric pressure till the mass temperature reached 140 C.
The residual mass was cooled to 100 °C and 300 ml water was added. The solvent was distilled out azeotropically till the mass temperature reached 120 °C. To the reaction mass 750 ml of water was added, the solution warmed to 80 °C. The pH of the reaction mass was adjusted to 8.0 with hydrochloric acid. Finally the pH was adjusted to 6.0 with acetic acid, and the reaction mass maintained at 80 to 85 °C for one hour. The product obtained was filtered, washed with water and dried to yield 120 gm of 4'-[2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl-2-carboxylic acid, which can be purified as per the procedure described mentioned in Example 5.

Example 2: 4-chloromethyl-2 '-cyanobiphenyl In a 1 litre reaction flask 400 ml of methylene chloride was added followed by 100 gm of 2- cyano-4' -methyl biphenyl. The reaction mass was stirred to get a clear solution and cooled to 20 °C. Chlorine gas was sparged into the reaction mass for a period of 15 hours at 20 to 25 °C till completion of the reaction. The reaction was monitored by TLC using mobile phase n- hexane: ethyl acetate (8:2). The excess chlorine from the reaction mass was removed by flushing with nitrogen. The solvent was distilled out completely by distillation at atmospheric pressure and removal of the final traces under vacuum. To the residual mass, 400 ml of n- heptane was added. The reaction mass was stirred and warmed to 60 °C. The clear solution obtained was cooled to 10 °C and the product precipitated was filtered, washed with n-heptane and dried. Further crystallization with n-heptane yielded 80 gm of pure 4-chloromethyl-2'- cyanobiphenyl. C 73.87%, H 4.41%, N 6.19%; m/z 192.25; 1H NMR DMSO d₆400 Mhz : 5ppm 4.84 (s, 2H) 7.32 - 7.66 (aromatic 8H).

Example 3: 2-cyano-4^,-(2^,,-n-propyl-4^,,-methyl-6^,,-{V"-methylbenzim ylmethyl) biphenyl In a 2 litre reaction flask 500 ml of methyl isobutyl ketone was added followed by 100 gm of 2-n-propyl-4-methyl-6-( -methylbenzimidazol-2'-yl)benzimidazole. The reaction mass was stirred and a solution of 40 gm sodium hydroxide in 300 ml water was added. To this solution, 10 gm tetra butyl ammonium hydrogen sulphate and 80 gm of 4-chloromethyl-2'- cyanobiphenyl was added. The reaction mass was warmed to 80 °C and maintained for 4 hours at 80 to 85 °C. The completion of the reaction was monitored by TLC using mobile phase chloroform : methanol (9:1). After completion of the reaction, the mass was cooled to 20 °C, maintained 3 hours at 15 to 20 °C. The product which precipitated out was filtered, washed with methyl isobutyl ketone, followed by water to yield 126 gm of 2-cyano-4'-(2"-n-propyl-4"-methyl- 6"-(r"-methylbenzimidazol-2"'-yl)benzimidazol-l"- ylmethyl) biphenyl, melting at 196 - 198 °C. C 80.53%, H 5.70%, N 14.20%; m/z = 496.64 ^lH NMR DMSO d₆ 400 Mhz : 5ppm 0.96 - 0.99 (t, 3H) 1.75 - 1.84 (m, 2H) 2.62 (s, 3H) 2.89 - 2.93 (t, 2H) 3.80 (s, 3H) 5.67 (s, 2H) 7.18 - 7.92 (m, 14H)


 Example 4: 4'-[2-n^ropyl-4-methyl-6-(l-methylbenzi idazol-2-yl)benzi idazol-ylmethyl]bipheny carboxylic acid 126 gm of 2-cyano-4'-(2"-n-propyl-4"-methyl-6"-(l "'-methylbenzimidazol-2"'-yl) benzimidazol-1"- ylmethyl) biphenyl was dissolved in 750 ml of n-butanol and 83 gm sodium hydroxide added. The reaction mass was heated to reflux and maintained for 15 hours at 123 to 126 °C. The completion of the reaction was monitored by TLC using mobile phase chloroform: methanol (9: 1). The solvent was distilled out at atmospheric pressure till the mass temperature reached 140 °C. The residual mass was cooled to 100 °C and 300 ml water was added. The solvent was distilled out azeotropically till the mass temperature reached 120 °C. To the reaction mass 750 ml of water was added, the solution warmed to 80 °C. The pH of the reaction mass was adjusted to 8.0 with hydrochloric acid. Finally the pH was adjusted to 6.0 with acetic acid, and the reaction mass maintained at 80 to 85 °C for one hour. The product obtained was filtered, washed with water and dried to yield 120 gm of 4'-[2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl-2-carboxylic acid.


Example 5: Purification of 4'-[2-n^ropyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l- ylmethyl]biphenyl-2-carboxytic acid In a 3 litre reaction flask, 1000 ml of methanol was added followed by the addition of 120 gm of 4'-[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl- 2-carboxylic acid obtained by procedure described in Example 4. The solution was warmed to 50 °C and pH adjusted to 10.0 to 10.5 with 100 ml of a 10% methanolic potassium hydroxide solution. The reaction mass became a clear solution, and 6 gm activated carbon was added. The mass was maintained at 50 to 55 °C for one hour and filtered through hyflo supercel to remove the activated carbon. The clear filtrate obtained was collected and its pH adjusted to 6.0 to 6.5 with 130 ml of acetic acid, maintaining the temperature between 50 to 55 °C. The mass was cooled to 15 °C and maintained one hour at 10 to 15 °C. The product which precipitated out was filtered, washed with 50 ml of methanol followed by 500 ml of water. The wet product was dried to yield 107 gm of 4'-[2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl-2-carboxylic acid. C 76.49%; H 5.74%, N 11.02%; m/z 515.45.; 1H NMR DMSO d₆ 400 Mhz : 5ppm 0.97 - 1.01 (t, 3H) 1.76 - 1.85 (m, 2H) 2.62 (s, 3H) 2.90 - 2.94 (t, 3H) 3.81 (s, 3H) 5.61 (s, 2H) 7.15 - 7.71 (14H aromatic); Melting point of purified telmisartan: 269 °C.

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PAPER

Journal of Organic Chemistry (2014), 79(21), 10568-10580

http://pubs.acs.org/doi/abs/10.1021/jo501665e

J. Org. Chem., 2014, 79 (21), pp 10568–10580

DOI: 10.1021/jo501665e

On the basis of our recently reported aniline aqueous borylation, molecular diversity was achieved in a one-pot process by combining other reactions such as esterification, Suzuki–Miyaura coupling, hydrogenolysis, or Petasis borono-Mannich.

TELMISARTAN IS COMPD 9

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PATENT

US 20150031768

(EN)

Methods of halogenating a carbon containing compound having an sp3 C—H bond are provided. Methods of fluorinating a carbon containing compound comprising halogenation with Cl or Br followed by nucleophilic substitution with F are provided. Methods of direct oxidative C—H fluorination of a carbon containing compound having an sp3 C—H bond are provided. The halogenated products of the methods are provided.

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  PATENT

WO 2014067237

http://www.google.com/patents/WO2014067237A1?cl=en

Telmisartan Preparation: 12 Examples The title compound (III, R = COOCH ₃₎ (52.8g, O. lmol) of Example 11 with glacial acetic acid (200ml) and concentrated hydrochloric acid (250ml) mixing, 100 ° C to react for 5 to 6 hours. Evaporated to most mixed acid, residue slowly poured into crushed ice, under ice cooling with saturated K ₂ CO ^ solution to adjust the pH to neutral, solid precipitation, filtration, filtrate was washed with water, was for Mischa Tan crude, recrystallization telmisartan (40.1g), liquid purity greater than 99%. Example 13: Preparation of telmisartan of formula I compound (0.62g, leq) was added to acetonitrile (10ml). After stirring evenly, the KOH (0.14g, 1. leq) was slowly added, after stirring for 10 plus minutes, the title compound of Example 10 of the embodiment (11, R = COOCH ₃₎ (0.5g, leq) was slowly added, stirred for 3-4 hours, TLC the reaction was complete, the direct addition of 50% ethanol (30mL), reflux The reaction for 6 hours. After completion of the reaction by TLC, recovering the organic solvent under reduced pressure, the remaining solution was added dropwise hydrochloric acid (1: 1) to neutral pH. The precipitated solid was filtered, washed with water to give crude telmisartan, telmisartan recrystallized (yield 75.1%), the liquid phase is greater than 98% purity. Chloromethyl biphenyl -2- (II, R = CN) Preparation of 4'-nitrile:

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Journal of Pharmaceutical and Biomedical Analysis (2015), 108, 86-96.

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IN 262831/EP 1912975

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JP 2014201585

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 IN 2013KO00463/WO 2014174397

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PATENT

http://www.google.com/patents/CN1768044A?cl=en

Example 7: Telmisartan make 5.51 g telmisartan × HCl was dissolved in 50 ml of 40% acetic acid while refluxing. The brown solution was then filtered hot through 1.1 g of carbon, 2.5 ml of 40% acetic acid and washed, and at 80-90 ℃ 2.5 ml of 4N NaOH was added dropwise with stirring to light brown filtrate. Telmisartan crystallization, the suspension was diluted with 30 ml of water, and slowly cooled to ambient temperature. Telmisartan suction filtration, and washed with 50 ml of water. And dried in vacuo at 80 ℃ drying cabinet telmisartan. Yield: 4.80 g (93.3% of the theoretical yield).


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  PATENT http://www.google.com/patents/CN102731407A?cl=en Example 4 Preparation of telmisartan [0031] 2-n-propyl group as shown in Formula I-4-methyl-6- (benzimidazol-2-yl-methyl 1'_) benzimidazole (30. 4g, O. 10mol), 4_ bromomethyl-biphenyl-2-carboxylic acid (43. 6g, O. 15mol), three ko amine (12. Ig, O. 15mol) and ko ni ni ether 500ml alcohol were mixed and reacted at 100 ° C for 6 inches The reaction solution was poured into ice water, acidified with dilute hydrochloric acid and slowly adjusted PH2-3, to precipitate a solid. Filtration, 70 ° C drying crude, the resulting crude product ko ko acid ester 300ml heating beating again. Filtered, 70 ° C dry. Recrystallization from DMF telmisartan of formula III as shown in 25. Ig, yield: 50%.

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  PATENT http://www.google.com/patents/WO2010146187A2?cl=en


 For example, WO 2004/087676 describes the hydrolysis of a compound with the chemical name 4 '-((1,7'- dimethyl-2 ' -propyl-lH, 3 'H-2, 5 ' -bibenzo [d] imidazol-3 ' -yl) - methyl) biphenyl-2-carbonitrile and having formula 2

which is hereinafter referred to as cyanotelmisartan . In par- ticular, the hydrolysis of cyanotelmisartan is carried out at elevated temperatures using strong alkaline conditions. Also, CN 1412183 discloses the hydrolysis of cyanotelmisartan. US 2006/0264491 Al discloses the hydrolysis of 4'-((l,7'- dimethyl-2 ' -propyl-lH, 3 'H-2, 5 ' -bibenzo [d] imidazol-3 ' - yl) methyl) biphenyl-2-carboxamide having formula 3

Example 2: Preparation and isolation of telmisartan Into a reaction vessel 20.5g (40 mmol) 4 ' - ( (1, 7 ' -dimethyl-2 ' - propyl-IH, 3 ' H-2 , 5 ' -bibenzo [d] imidazol-3 ' -yl) methyl) biphenyl-2- carboxamide and 20 ml (lδOmmol) H₂SO₄ (1:1) were added. The re- action mixture was heated to about 125°C and stirred at this temperature for 28 h. A sample of the reaction mixture was analyzed by Area% HPLC (starting compound below 0.1%, telmis- artan over 97%) . The reaction mixture was cooled below 80⁰C and 250 ml of water were added. Then, 200 ml of dichloro- methane were added and pH value of mixture was adjusted to 5.4 by addition of 6M NaOH. The mixture was stirred for approximately 5 min and then the phases were separated. The water phase was reextracted by 136 ml of dichloromethane . Collected organic phases were washed with water (2^χl36ml) and then treated with activated charcoal (5.3 g) . Subsequently, the organic phase was evaporated an oily residue (26g) . 264 ml of acetone were added. The mixture was stirred at room temperature for at least 6 hours. The precipitated product was sepa- rated and washed with fresh acetone and dried at 65°C under reduced pressure for 3 hours. Yield: 18.3g (89%) Area % HPLC: Telmisartan 99.80%

 Example 3: Isolation of telmisartan Into a reaction vessel 7.5g (15 mmol) of cyanotelmisartan, 30 ml of propylene glycol, 0.8 ml of water and 3g (45 mmol) of 85% KOH were added. The reaction mixture was heated to around 160⁰C to 170 ⁰C and stirred at this temperature for 24 h. The reaction mixture was cooled below 80⁰C and 75 ml of water were added. Then, pH value of the mixture was adjusted to 4.8 (by addition of 6M HCl) and then 150 ml of dichloromethane were added. The mixture was stirred for approximately 5 min and then the phases were separated. The water phase is reextracted by 50 ml of dichloromethane. Collected organic phases were washed with water (2^χ50ml) and then treated with activated charcoal (2 g) . After that the organic phase was evaporated to an oily residue (9.8g) . 100 ml of acetone were added. The mix- ture was stirred at room temperature for at least 6 hours. The precipitated product was separated and washed with fresh acetone and dried at 65°C under reduced pressure for 3 hours. Yield: 6.8g (88%) Area % HPLC: Telmisartan 99.60%



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  PATENT http://www.google.com/patents/CN1548421A?cl=en


Specific embodiments 14 'Example - [(1,4'-dimethyl-2'-propyl [2,6'- two-1H - benzoimidazol] 1'-yl) methyl] - [1, 1'-biphenyl] -2-carboxylic acid sodium salt in 250ml reaction flask, telmisartan 10g (0.0195mol), NaOH0.75g (0.0189mol) and water 100ml, stirred for 1 hour (30 ℃), filtered insoluble materials are removed and concentrated to a small volume, plus ethanol 30ml, concentrated, washed with 30ml of n-hexane, decanted, plus ethanol 30ml, concentrated, and then repeat again, and concentrated to dryness to obtain telmisartan sodium salt 9.9g yield 95.2%. Melting point: 223-225 ℃. Elemental analysis: C33H29N4O2Na · H2O Calcd: C71.48 H5.10 N10.11 Found: C71.42 H5.08 N10.22 

Example 24 '- [(1,4'-dimethyl-2'-n propyl [2,6'- two-1H - benzoimidazol] 1'-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid potassium salt in 250ml reaction flask, Telmisartan 10g (0.0195mol), KOH1.06g (0.0188mol) and water 100ml, stirred for 1 hour (30 ℃), filtered to remove insolubles, and concentrated to a small volume, ethanol 30ml, concentrated, hexane 30ml washed, decanted, plus ethanol 30ml, concentrated, and then repeat again, and concentrated to dryness to obtain telmisartan potassium 10.6g, yield 95.6%. Melting point: 203-205 ℃. Elemental analysis: C33H29N4O2K · H2O Calcd: C69.04 H5.40 N9.76 Found: C69.01 H5.28 N9.88 

Example 3 starting material and the mixed powder was sieved excipients, 5% polyethylene pyrrolidone was granulated and dried. After dried particles were sieved magnesium stearate was added mixed tabletted. mg / tablet of telmisartan sodium salt 20 Lactose 170 Sodium carboxymethyl starch 10 mg Magnesium stearate 8 meglumine 25% polyvinyl pyrrolidone solution q.s.


 Example 4 A mixed powder of raw materials and auxiliary materials sieved, added 5 % solution of polyvinylpyrrolidone is granulated and dried. After dried particles were sieved magnesium stearate was added mixed tabletted. mg / tablet telmisartan sodium Lactose 200 40 140 DCP sodium carboxymethyl starch 16 mg Magnesium stearate 45% povidone solution appropriate amount of 

Example 5 of this product, according to the dissolution assay (Chinese Pharmacopoeia 2000 edition Appendix II XC second method), phosphate buffer 900ml solvent, the speed of 75 revolutions per minute, operate according to the law, after 30 minutes, take the solution as spectrophotometry (Chinese Pharmacopoeia 2000 edition of the test solution, according to the spectrophotometric two Appendix IVA), absorbance was measured at 295nm wavelength. Another reference standard stock solution 10ml precise amount of determination under set 100ml flask, diluted with phosphate buffer to the mark, then the precise amount of 5ml, set 10ml volumetric flask, dilute to the mark with phosphate buffer , shake, the same method absorption, calculated for each piece of the dissolution of the limits of 80% scalar, should be specified. Dissolution test results in Table. Table dissolution test results Dissolution (%) telmisartan sodium 97.29 99.65 102.55 95.83 101.10 98.92 99.20 ± 2.45

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  PATENT http://www.google.com/patents/CN1412183A?cl=en

Example 5 4 '- [(1,4'-dimethyl-2'-propyl [2,6'- two -1H- benzimidazol] -1'-yl) methyl] - [1,1' - biphenyl] -2-carboxylic acid (III) IV (24.8g, 0.05mol) was added ethylene glycol (100ml) and water (150ml) (or other previously described a mixed solvent), sodium ethoxide (or as previously said other alcohols sodium) (13.6g, 0.2mol), was refluxed for 10 hours. After no starting material by TLC was cooled to room temperature, hydrochloric acid was added dropwise (1/1) to pH 5-6, the precipitated solid was filtered, washed with water to give III.


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  PATENT http://www.google.com/patents/CN101550107B?cl=en Example 3 [0047] 1) Preparation of telmisartan crude methyl ester Compound II into 50g in 500mL reaction flask, 200mL of methyl isobutyl ketone (MIBK), 25 ° C _30 ° C with stirring until dissolved, was added dropwise 35mL of triethylamine was added 55. Og After the completion of the compound III, 5 (T60 ° C or so for about 4_5 hours, TLC monitoring completion of the reaction, filtered and the filter cake washed with a small amount of MIBK, and then washed with water, dried to give 70. 3g of crude product. 81% yield, purity of about 98%. (TLC test conditions: ethyl acetate: methanol = 8: 1)  2) preparation of high purity methyl telmisartan  IOOOmL reaction flask, the input step to give the crude methyl ester telmisartan, add 500mL of isopropanol was heated to dissolve, 2gX 2 activated bleaching filtrate was heated to about 90 ° C, added dropwise with stirring 150mL 7jC insulation 0. 5~Ih, cooled slowly to room temperature with stirring. Filtered, and the filter cake washed sequentially with MIBK and water washing, and drying, the yield of about 82%, HPLC purity 99.5%, the single impurities less than 0.1%. 3) 

Preparation of telmisartan with high purity [0053] A reaction flask was put in a 500mL high purity 15g telmisartan ester, 3. Og sodium, 200mL of isopropanol, water, 80ml, was heated to reflux for 5 ~ 7 h, TLC monitoring of the reaction was complete, the distillation Isopropanol was removed, and water was added to completely dissolve the solid 40ml, 0. 5g of activated carbon bleaching, the filtrate was added 50ml of water, heated to 80 ° C, lmol / L of acetic acid to adjust the pH to 5. (Γ5. 5, filtered, and the filter cake dried to give 13. 14g of solid, yield 90%, HPLC purity 99.7%, the single impurities less than 0.1%. (TLC test conditions: ethyl acetate: methanol = 8: 1)

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  http://www.google.com/patents/CN101172968B?cl=en

Example 1 [0023] 1, 100gPPA, 21. 8g (0. Lmol) 2_ n-propyl _4_ _6_ carboxyl methyl benzimidazole and 21. 5gN- methyl-o-phenylenediamine added to the reaction flask in under N2 protection feeding, heated to IO (TC _1601 :, reaction 8-20 hours, down 70-80.C 200ml water was added and the reaction with hydrochloric acid to adjust ffl = 1~2, put charcoal 5_8%,, 8 (TC about 5 to 10 minutes, filtered, and the reaction repeated, the adjustment ra 12-14 with NaOH, for several hours, and filtered to give the crude intermediate 2-n-propyl -4-methyl-6- (benzimidazol-2-yl-methyl ) benzimidazole sodium salt. [0024] 2, the product of the previous step, 2-n-propyl -4-methyl--6_ (methyl benzimidazol-_2_ yl) benzimidazole sodium salt crude product was dissolved into 200 ml of ethanol , and dissolved by heating, cooling to room temperature, 400 ml 1N NaOH, to precipitate the compound 2-n-propyl -4-methyl-6- (methyl benzimidazol-2-yl) benzimidazole .50-8 ( TC dried in vacuo. [0025] 3, product of the previous step -4-methyl-2-n-propyl -6_ (methyl benzimidazol-_2_ yl) benzimidazole into 200 ml of dimethyl sulfoxide was stirred was added at room temperature and 4-bromomethyl - biphenyl-2-carboxylic acid methyl ester 33.55 g, was stirred for 14 hours, extracted with dichloromethane (200, 100, 100), and evaporated to dryness under reduced pressure, 300 ml of methanol and 10% potassium hydroxide (240 ml, 0. 6mo1) mixture was refluxed for 6 hours, cooled, washed with 80 ml of methylene chloride, adjusted with glacial acetic acid ffl = 6, a lot of white floc precipitated precipitate was filtered and dried to give a white Tilmicosin 49.6 g of crude product, the crude product was added 100 ml of chloroform was heated to reflux, activated carbon decolorization, crystallization, filtration, 8 (TC dried in vacuo to give a white pure telmisartan (HLPC> 99. 0%) 41 克, purification yield 82%. mp 261~263.C, H-NMR (d6-DMS0) S 1. 05t, 3H), 1. 83 (m, 2H), 2. 71 (s, 3H), 2. 94 (t, 2H), 3. 81 (s, 3H), 5. 57 (s, 2H), 7. 16-7. 83 (m, 14H) • C33H33N402 [0026] 

Example 2 Preparation of telmisartan  1, 100gPPA, 21. 8g (0. 1) 2_ [4-methyl-n-propyl-benzimidazole and _6_ 21. 5gN- carboxy-o-phenylenediamine added to the reaction flask in N2 Under the protection of feeding, heated to 100 ° C _160 ° C, the reaction for 8-20 hours, down 70-80. C, the reaction was added 200ml of water, adjusted with hydrochloric acid ffl = 1~2, into charcoal 5_8%, about 8 (TC 5_10 minutes filtered again reacted with K0H ra adjusted to 12-14 for several hours and filtered to give Intermediate crude 2-n-propyl -4-methyl-6- (benzimidazol-2-yl-methyl) benzimidazole potassium salt.

   2, the product of the previous step, 2-n-propyl -4-methyl--6_ (methyl benzimidazol-_2_ yl) benzimidazole potassium salt of the crude product into 200 ml of ethanol, and dissolved by heating, cooling to room temperature was added 400 ml 1N K0H, a precipitated compound is 2-n-propyl -4-methyl-6- (benzimidazol-2-yl-methyl) benzimidazole potassium salt. 50-8 (TC dried in vacuo.

 [0029] 3, 2-n-propyl prepared in the previous step -4-methyl-6- (benzimidazol-2-yl-methyl) benzimidazole potassium salt and 27.2 g of 4-bromomethyl-2-cyanobiphenyl, 10.4 g of triethylamine and DMF (DMA, dichloromethane, dichloroethane) were mixed and reacted for 5-10 hours at 35-40 °, TLC detection After no starting material the reaction mixture was poured into 600 g of ice water, extracted with ethyl acetate (300ml * 3), the combined organic phases were washed with water (300ml * 2), dried and desolvation, and then petroleum ether was added and stirred until a solid precipitated was The crude product was 45.6 g.

  4, the upper step of the solid 45.6 grams, was added 200ml of ethylene glycol, 150ml water, 12 g of sodium hydroxide, the reaction was refluxed for 10 hours, TLC detected no starting material and then cooled to room temperature, acidified with hydrochloric ra is 5 to 6, there is solid precipitation, filtration, washing, telmisartan was crude, DMF and recrystallized to give 44.5 g of telmisartan pure product (HLPC> 99. 0%) mp261~263 ° C. Force -NMR (de-DMS0) S 1. 05t, 3H), 1. 83 (m, 2H), 2. 71 (s, 3H), 2. 94 (t, 2H), 3. 81 (s, 3H ), 5. 57 (s, 2H), 7. 16-7. 83 (m, 14H) • C33H33N402 [0031] ............................

Citing Patent	Filing date	Publication date	Applicant	Title
CN100460396C	Mar 8, 2007	Feb 11, 2009	杭州盛美医药科技开发有限公司	Intermediate of telmisartan, preparation and use thereof
CN100506799C	Apr 19, 2007	Jul 1, 2009	北京理工大学	[(2-n-propyl-4-methyl-1H-Benzimidazole)6-radical] carboxamide-1-radical] methylbiphenyl compound, synthesizing method and usage
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CN101550107B	Apr 2, 2009	Jan 12, 2011	宁波九胜创新医药科技有限公司	Method for preparing telmisartan
CN101743228B	Jul 3, 2008	Jan 29, 2014	新梅斯托克尔卡托瓦纳兹德拉韦尔公司	Process for preparing telmisartan
CN101891735B	Nov 25, 2009	Jul 18, 2012	北京理工大学	Biphenyl sulfafurazole compound, synthesis method and application thereof
CN102093297B	Jan 28, 2011	Aug 1, 2012	海南美兰史克制药有限公司	Telmisartan compound and new preparation method thereof
EP1805146A2 *	Oct 18, 2005	Jul 11, 2007	Dr. Reddy's Laboratories Ltd.	Process for preparing telmisartan
EP2123648A1	May 20, 2008	Nov 25, 2009	Chemo Ibérica, S.A.	A process for the preparation of Telmisartan.
US7501448	Oct 13, 2005	Mar 10, 2009	Teva Pharmaceutical Industries, Ltd.	high yields, low cost process; easy solvent extraction; nontoxic, safe, environmentally friendly, low boiling point organic solvents; 1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bibenzoimidazolyl is reacted with 4'bromomethyl-biphenyl-2-carboxylic acid alkyl ester; industrial scale; hydrolysis
US8691999 *	May 10, 2005	Apr 8, 2014	Cipla Limited	Process for the preparation of telmisartan
WO2006044648A1 *	Oct 13, 2005	Apr 27, 2006	Teva Pharma	Process for preparing telmisartan
WO2007010558A1 *	Jul 19, 2006	Jan 25, 2007	Satyanarayana Chava	A process for the preparation of telmisartan
WO2009123483A1	Mar 30, 2009	Oct 8, 2009	Zaklady Farmaceutyczne Polpharma Sa	Process for preparation of telmisartan
WO2012028925A2	Aug 29, 2011	Mar 8, 2012	Ogene Systems (I) Pvt Ltd	An improved process for the preparation of telmisartan

CN1412183A	Oct 15, 2001	Apr 23, 2003	中国科学院上海药物研究所	New preparation method of timixatan
CN1620437A	Jan 15, 2003	May 25, 2005	贝林格尔英格海姆法玛两合公司	Method for the production and purification of 1, 7'-dimethyl-2'-propyl-2, 5'-bi-1h-benzimidazole
CN1768044A	Mar 26, 2004	May 3, 2006	贝林格尔·英格海姆国际有限公司	Process for manufacture of telmisartan
WO2005108375A1	May 10, 2005	Nov 17, 2005	Cipla Ltd	Process for the preparation of telmisartan

CN1344712A	Jul 30, 2001	Apr 17, 2002	中国科学院上海药物研究所	Synthesis path of Timisatem
CN1412183A	Oct 15, 2001	Apr 23, 2003	中国科学院上海药物研究所	New preparation method of timixatan
	US2006/0094883				Title not available
	WO03/059890A1				Title not available
	WO2005/108375A1				Title not available

US7501448	Oct 13, 2005	Mar 10, 2009	Teva Pharmaceutical Industries, Ltd.	high yields, low cost process; easy solvent extraction; nontoxic, safe, environmentally friendly, low boiling point organic solvents; 1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bibenzoimidazolyl is reacted with 4'bromomethyl-biphenyl-2-carboxylic acid alkyl ester; industrial scale; hydrolysis
WO2007147889A2 *	Jun 22, 2007	Dec 27, 2007	Krka Tovarna Zdravil D D Novo	Preparation of telmisartan salts
WO2010146187A2	Jun 21, 2010	Dec 23, 2010	Krka, Tovarna Zdravil, D.D., Novo Mesto	Process for the preparation of telmisartan
WO2012055941A1	Oct 26, 2011	May 3, 2012	Krka,Tovarna Zdravil, D. D., Novo Mesto	Multilayer pharmaceutical composition comprising telmisartan and amlodipine

WO2003007876A2	Jun 25, 2002	Jan 30, 2003	Sumner H Burstein	N-fatty acid-amino acid conjugates and therapeutic uses
WO2003059327A1	Jan 16, 2002	Jul 24, 2003	Boehringer Ingelheim Pharma	Bilayer pharmaceutical tablet comprising telmisartan and a diuretic and preparation thereof
WO2004028505A1	Sep 18, 2003	Apr 8, 2004	Boehringer Ingelheim Int	Solid pharmaceutical formulations comprising telmisartan
WO2004087676A1	Mar 26, 2004	Oct 14, 2004	Boehringer Ingelheim Int	Method for the production of telmisartan
WO2004096215A1	Apr 27, 2004	Nov 11, 2004	Boehringer Ingelheim Int	Pharmaceutical formulation of the sodium salt of telmisartan
WO2005108375A1 *	May 10, 2005	Nov 17, 2005	Cipla Ltd	Process for the preparation of telmisartan
WO2006044754A2	Oct 18, 2005	Apr 27, 2006	Muthulingam Arunagiri	Process for preparing telmisartan
WO2006050509A2	Nov 3, 2005	May 11, 2006	Teva Pharma	Amorphous and polymorphic forms of telmisartan sodium
WO2006050921A2	Nov 9, 2005	May 18, 2006	Lek Pharmaceuticals	Preparation of telmisartan salts with improved solubility
WO2006063737A1	Dec 9, 2005	Jun 22, 2006	Boehringer Ingelheim Int	Combination therapy comprising telmisartan and hydrochlorothiazide
WO2006136916A2	Jun 20, 2006	Dec 28, 2006	Glenmark Pharmaceuticals Ltd	Substantially pure micronized particles of telmisartan and pharmaceutical compositions containing same
WO2007010559A2	Jul 19, 2006	Jan 25, 2007	Panacea Biotec Ltd	Novel pharmaceutical modified release dosage form cyclooxygenase enzyme inhibitor
WO2007060170A2	Nov 22, 2006	May 31, 2007	Boehringer Ingelheim Int	Bilayer tablet comprising telmisartan and diuretic
WO2007144175A2	Jun 14, 2007	Dec 21, 2007	Lek Pharmaceuticals	Pharmaceutical composition comprising hydrochlorothiazide and telmisartan
WO2007147889A2	Jun 22, 2007	Dec 27, 2007	Krka Tovarna Zdravil D D Novo	Preparation of telmisartan salts
WO2009004064A1	Jul 3, 2008	Jan 8, 2009	Krka Tovarna Zdravil D D Novo	Process for preparing telmisartan
CN1412183A	Oct 15, 2001	Apr 23, 2003	中国科学院上海药物研究所	New preparation method of timixatan
CN1548421A	May 22, 2003	Nov 24, 2004	上海医药工业研究院	Tilmisartan salt and its prepn
EP0502314A1	Jan 31, 1992	Sep 9, 1992	Dr. Karl Thomae GmbH	Benzimidazol, medicaments containing them and process for their preparation
EP1144386A1	Jan 7, 2000	Oct 17, 2001	Boehringer Ingelheim Pharma KG	Telmisartan polymorphs, methods for producing same and their use in the preparation of a medicament
EP1719766A2	Apr 18, 2006	Nov 8, 2006	Dipharma S.p.A.	A process for the preparation of telmisartan
US20060264491	Jun 8, 2006	Nov 23, 2006	Chemagis Ltd.	Telmisartan production process

CN101172968B	Nov 1, 2006	May 12, 2010	浙江天宇药业有限公司	2-propyl-4 methyl-6-(tolimidazole-2group) benzoglioxaline salt and method for producing the same
CN101743228B	Jul 3, 2008	Jan 29, 2014	新梅斯托克尔卡托瓦纳兹德拉韦尔公司	Process for preparing telmisartan
CN102015690B	Mar 19, 2009	Apr 30, 2014	力奇制药公司	Catalyzed carbonylation in the synthesis of angiotensin II antagonists
CN102036937B	Mar 19, 2009	Jun 4, 2014	力奇制药公司	2'-halobiphenyl-4-yl intermediates in the synthesis of angiotensin ii antagonists
WO2014067237A1 *	Oct 31, 2013	May 8, 2014	Topharman Shanghai Co., Ltd.	Telmisartan preparation method and intermediate thereof

WO2010018441A2 *	Aug 10, 2009	Feb 18, 2010	Cadila Pharmaceuticals Ltd.	An improved process for the preparation of substantially pure telmisartan
WO2010146187A2 *	Jun 21, 2010	Dec 23, 2010	Krka, Tovarna Zdravil, D.D., Novo Mesto	Process for the preparation of telmisartan
WO2011077444A1 *	May 28, 2010	Jun 30, 2011	Inogent Laboratories Private Limited	A new process for the preparation of pure telmisartan
WO2012028925A2 *	Aug 29, 2011	Mar 8, 2012	Ogene Systems (I) Pvt Ltd	An improved process for the preparation of telmisartan
CN1768044A *	Mar 26, 2004	May 3, 2006	贝林格尔·英格海姆国际有限公司	Process for manufacture of telmisartan
CN102731407A *	Jul 4, 2012	Oct 17, 2012	宁波九胜创新医药科技有限公司	Method for preparing telmisartan
EP0627433A1 *	Dec 7, 1993	Dec 7, 1994	Eisai Co., Ltd.	Process for producing imidazopyridine derivative and intermediate
EP2123648A1 *	May 20, 2008	Nov 25, 2009	Chemo Ibérica, S.A.	A process for the preparation of Telmisartan.
EP2305650A1 *	Sep 21, 2009	Apr 6, 2011	Chemo Ibérica, S.A.	Novel process for the preparation of telmisartan

KR20090000113A *				Title not available
US20040236113	Mar 17, 2004	Nov 25, 2004	Boehringer Ingelheim International Gmbh	Process for manufacture of telmisartan
US20130137878	Jan 25, 2013	May 30, 2013	Boehringer Ingelheim International Gmbh	Process for manufacture of telmisartan

TELMISARTAN PART 1/3

TELMISARTAN

Telmisartan
CAS No.:	144701-48-4
Synonyms:	TELMISARTAN;
Formula:	C33H30N4O2
Exact Mass:	514.23700

PART 1........http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-13.html

PART 2........http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html

                   OR  http://newdrugapprovals.org/2015/04/06/telmisartan-part-23/

PART3......   http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-33.html

1H NMR PREDICT

13C NNMR

COSY PREDICT

PAPER

Efficient and improved synthesis of Telmisartan

A. Sanjeev Kumar, Samir Ghosh and G. N. Mehta

Applied Chemistry Department, Sardar Vallabhbhai National Institute of Technology, Surat-395 007, India

Associate Editor: J. A. Porco Jr.

Beilstein J. Org. Chem. 2010, 6, No. 25.

 http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-6-25


(lit mp 260–262 °C);
 LIT......  Reddy, K. S.; Srinivasan, N.; Reddy, C. R.; Kolla, N.; Anjaneyulu, Y.; Venkatraman, S.; Bhattacharya, A.; Mathad, V. T. Org. Process Res. Dev. 2007, 11, 81–85. doi:10.1021/op060200g


 IR (KBr, cm^-1) 2300–3500 (broad), 1680 (C=O); 

HRMS m/z calculated for C₃₃H₃₀N₄O₂ – 515.6169 [M + 1], found – 515.6192; 


 ¹H NMR (400 MHz, CDCl₃) (δ ppm): 12.8 (1H, s, -COOH), 8.42 (1H, d, J = 8.0 Hz, ArH), 8.02 (1H, d, J = 8.0 Hz, ArH), 7.50–7.26 (8H, m, ArH), 7.20 (2H, d, J = 8.0 Hz, ArH), 7.05 (1H, s, ArH), 6.96 (1H, s, ArH), 5.42 (2H, s, -CH₂), 3.82 (3H, s, -CH₃), 2.97 (2H, t, J = 7.6 Hz, -CH₂), 2.74 (3H, s, -CH₃), 1.92 (2H, m, J = 7.6 Hz, -CH₂), 1.04 (3H, t, J = 7.6 Hz, -CH₃); 



 ¹³C NMR (100 MHz, DMSO-d₆) (δ ppm): 13.5, 16.7, 20.6, 27.6, 32.7, 47.1, 51.7, 112.0, 112.7, 114.7, 118.6, 125.3, 125.7, 125.8, 127.0, 127.4, 128.6, 129.3, 130.4, 130.6, 131.5, 132.3, 133.1, 133.2, 133.7, 134.5, 140.2, 140.5, 150.2, 157.3, 168.1.



Second set


An improved synthesis of Telmisartan: an antihypertensive drug 

A. Sanjeev Kumar, Samir Ghosh, R. Soundararajan,* and G. N. Mehta 


Chemistry Section, Applied Sciences and Humanities Department, SVNIT, Surat-395 007, India

General Papers ARKIVOC 2009 (x) 247-254 

http://www.arkat-usa.org/get-file/28995/

melting point: 260-262
°C (lit---Venkataraman, S.; Mathad, V. T.; Kikkuru, S. R.; Neti, S.; Chinta, R. R.; Apuraba, B.;
Anjaneyulu,Y.; Naveenkumar, K. Org. Process Res. Dev. 2007, 11, 81.
 mp 260-262 °C);

IR (KBr, cm-1) 2300-3500 (broad), 1680 (C=O);

1H NMR (400 MHz, CDCl3) (δ ppm): 12.8 (1H, s, -COOH), 8.42 (1H, d, J = 8.0 Hz, ArH), 8.02 (1H, d, J = 8.0 Hz,
ArH), 7.50-7.26 (8H, m, ArH), 7.20 (2H, d, J = 8.0 Hz, ArH), 7.05 (1H, s, ArH), 6.96 (1H, s,
ArH), 5.42 (2H, s, -CH2), 3.82 (3H, s, -CH3), 2.97 (2H, t, J = 7.6 Hz, -CH2), 2.74 (3H, s, -CH3),
1.92 (2H, m, J = 7.6 Hz, -CH2), 1.04 (3H, t, J = 7.6 Hz, -CH3);

13C NMR (400 MHz, DMSO-d6)
(δ ppm): 13.5, 16.7, 20.6, 27.6, 32.7, 47.1, 51.7, 112.0, 112.7, 114.7, 118.6, 125.3, 125.7, 125.8,
127.0, 127.4, 128.6, 129.3, 130.4, 130.6, 131.5, 132.3, 133.1, 133.2, 133.7, 134.5, 140.2, 140.5,
150.2, 157.3, 168.1;

 MS (m/z): 515 [M+ + 1];
Anal. Calcd for C33H30N4O2: C, 77.02; H, 5.88; N,
10.89; O, 6.22. Found: C, 77.0; H, 5.82; N, 10.86.


..................................................

crystals and other data
http://ccp14.chem.ucl.ac.uk/ccp/web-mirrors/pssp/pdf/telmisartan.pdf

http://scholarsresearchlibrary.com/aasr-vol2-iss5/AASR-2010-2-5-135-141.pdf





.............................................

An Improved, Scalable and Cost Effective One-Pot Synthesis of
Telmisartan
Premchand B. Patil1*
, Anand Pandey1
, Devanand B. Shinde2and Bhata R. Chaudhari1*

1Organic Research Laboratory Department of Chemistry, JET’s Z. B. PatilCollege,
Dhule, Maharashtra, India.
2Department of Chemical Technology Dr. BabasahebAmbedkarMarathwadaUniversity,
Aurangabad, Maharashtra, India
INTERNATIONAL JOURNAL OF RESEARCH IN PHARMA AND BIOMED SCIENCES
Vol. 4 (1) Jan– Mar 2013

1H NMR (DMSO-d6): δ 0.98-1.03 (t,3H), 1.73-
1.86 (m, 2H), 2.5 - 2.63 (s, 3H), 2.90-2.95 (s,
2H),3.82 (s, 3H), 5.62 (s, 2H), 7.16-7.34 (m,7H),
7.40-7.59 (m,4H), 7.68-7.70 (m, 3H), 12.86 (s,
1H).
M/Z: 515.50 [M + H]+

http://www.ijrpbsonline.com/files/48-4186.pdf

......................................
PATENT
EP 2 149 566 A1
https://data.epo.org/publication-server/pdf-document?pn=2149566&ki=A1&cc=EP
1H NMR (300 MHz, DMSO-d6): δ 7.65-7.70 (m, 3H), 7.40-7.56 (m, 4H), 7.15-7.32 (m, 7H), 5.60 (s, 2H), 3.80 (s, 3H),
2.91 (m, 2H), 2.61 (s, 3H), 1.80 (m, 2H), 0.98 (m, 2H).
13C NMR (75 MHz, DMSO-d6): δ 169.50. 156.19, 154.01, 142.70. 142.35, 140.48, 140.16, 136.60. 135.90. 134.70.
132.29, 130.80. 130.32, 129.08, 128.68, 128.21, 127.28, 126.37, 123.14, 122.06, 121.80. 118.65, 110.37, 109.28, 46.12,
31.74, 28.80. 20.71, 16.43, 13.81







..............................
PAPER

Detection, isolation and characterization of principle synthetic route indicative impurity in telmisartan

• V. Srinivasan^a, b, , , , 
 
• H. Sivaramakrishnan^b, 
 
• B. Karthikeyan^c

• ^a Analytical Development Laboratory, Piramal Healthcare Ltd., Ennore, Chennai 600 057, India
• ^b Research and Development Laboratory, Piramal Healthcare Ltd., Ennore, Chennai 600 057, India
• ^c Department of Chemistry, Annamalai University, Annamalainagar 608 002, India
• 
  

Arabian Journal of Chemistry

Available online 1 April 2012

http://www.sciencedirect.com/science/article/pii/S1878535212000688

A sample of telmisartan which was synthesized in our laboratory when subjected to HPLC analysis by chromatographic conditions published in the USP monograph offor telmisartan (USP-NF, 2010), an unknownimpurity at 1.59 RRT was observed to a level of 0.09%. As per regulatory guidelines, it is necessary to know the structure of the impurity to develop a synthetic process to remove the impurity and also the knowledge of the structure and the source of the new impurity areis necessary in order to develop a more robust synthetic process. It is therefore, essential to isolate and characterize unidentified impurities present in the drug sample. The structure elucidation of this impurity is object of this work.

The sample was taken for the isolation of unknown impurity by using preparative HPLC and the isolated impurity was characterized by using MS, NMR and IR. To the best of our knowledge, the impurity detected at 1.59 RRT was established for the first time

Figure 5.

Impurity structure with numbering of C atoms.

NMR Spectral data of Impurity-1:

 ¹H-NMR (CDCl₃, 300 MHz), δ (ppm), J (Hz): 3.64 (s, 3H, OCH₃), 6.71 (s, 1H, CHBr₂, 7.36–7.38, (d, J = 8.42, 2H, Ar-H), 7.40–7.43 (t, J = 8.61, 1H, Ar-H), 7.47–7.52 (t, J = 7.69, 1H, Ar-H), 7.58–7.61 (d, J = 6.04, 1H, Ar-H), 7.65–7.68 (d, J = 8.42, 2H, Ar-H) and 7.92–7.95(d, J = 7.69, 1H, Ar-H). 

¹³C-NMR, δ (ppm): 40.77 (–CHBr₂, C-1), 51.92 (–OCH₃, C-15), 126.18 (–CH, C-7&3), 127.62 (–CH, C-11), 128.56 (–CH, C-6&4), 130.02 (–CH, C-10), 130.57 (–C, C-9), 130.63 (–CH, C-13), 131.42 (–CH, C-12), 140.66 (–C, C-2), 141.37 (–C, C-5), 142.97 (–C, C-8) and 168.55 (CO, C-14).

....................


PATENT


17103-26-3;

Adin, Itai; Iustain, Carmen; Brand, Michael; Salman, Ada; Weisman, Alexander Patent: US2006/276525 A1, 2006 ; Location in patent: Page/Page column 7 ;

Telmisartan (Compound I below), 4′-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid, is a non-peptide ATI-subtype angiotensin II receptor antagonist.

Telmisartan is indicated for treatment of hypertension, either alone or in combination with diuretic agents. It is effective in once-daily dosing, so that significant blood-pressure lowering effect is observed even during the last 6 hours of the dosing interval. Telmisartan is marketed in the US as MICARDIS® and MICARDIS-HCT® by Boehringer Ingelheim.

Telmisartan was first described in U.S. Pat. No. 5,591,762 (hereinafter the '762 patent). According to Example 9 of the '762 patent, Telmisartan was crystallized from acetone and the resulting product had a melting point of 261-263° C.

U.S. Pat. No. 6,358,986 (hereinafter the '986 patent) describes two crystalline forms of Telmisartan denoted as forms A and B. It is stated in the '986 patent that the crystals of Telmisartan polymorph A, which is obtainable according to the prior art, have the shape of long needles. As a result of this crystalline shape, the use of Telmisartan polymorph A in large-scale manufacture, purification, isolation and drying of the material is severely limited.

As alleged in the '986 patent, the process for preparing crystalline Telmisartan form A comprises mixing the material with ethanol, adding activated charcoal and aqueous ammonia and mixing for one hour, then filtering to another stirring apparatus and washing with ethanol. The next step is heating to 70-80° C., adding glacial acetic acid and stirring for further 1.5-2 hours at the same temperature, cooling to 0-10° C., stirring for further 2 hours, isolating the product by centrifugation, washing with ethanol then with water and drying at 70-90° C. According to the detailed description given in the '986 patent, in addition to the disadvantageously prolonged drying process of the Telmisartan form A, very hard particles are obtained. The grinding process of these particles produces a dry powder, which has strong tendency to electrostatic charging and which is virtually impossible to pour and manipulate for pharmaceutical preparations. On the other hand, Telmisartan form B is free from the above mentioned limitations. However, the inventors of the '986 patent could not obtain pure, dry form B because upon drying, some of form B transformed into form A. According to the teachings of the '986 patent, mixtures of Telmisartan form A and form B ranging from 90:10 to 60:40 are suitable for industrial scaling-up, and even a content of 10% of form B is sufficient to ensure that the product will have the positive qualities required for large-scale production.

Therefore, as a consequence of the alleged unsuitability of Telmisartan form A for pharmaceutical use, only a mixture of crystalline Telmisartan form A and form B is claimed in the '986 patent, wherein Telmisartan form A is characterized by having an endothermic maximum at 269±2° C., and Telmisartan form B is characterized by having an endothermic maximum at 183±2° C.

Apparently Telmisartan form A is similar to the original form characterized by its melting point in the '762 patent. The differences between the DSC value and the measured melting point may be attributed to the different methodologies used—the DSC maxima can be slightly different than the visually observed melting point.

Differences in physical properties of crystalline materials (such as flowability) may be caused by different production processes for obtaining these crystalline materials.

Hence, the prior art teaches a lengthy, complicated and industrially disadvantageous process for obtaining crystalline Telmisartan form A.

A mixed solvated-hydrated modification form of Telmisartan, designated as form C, is mentioned in an article by Dinnebier et al., J. Pharm. Sci. 89(11), 2000. Telmisartan form C consists of ⅓ mole equivalent of formic acid and ⅔ mole equivalent of water, which is produced by crystallization from mixtures containing formic acid and water. According to the above mentioned publication, drying of form C leads to pure form B (mentioned above). The article mentions detailed crystallographic data of this form as well as of forms A and B.

The re-crystallization of Telmisartan from N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA) is mentioned in examples 1-3 of the '986 patent. However, since the product is further processed it is believed by the inventors of the present invention that the Telmisartan which is obtained according to the '986 patent, has some defects. Therefore, there is a need in the art for a new process for preparing highly pure Telmisartan form A, which is free-flowing and which does not tend to gain electrostatic charge.

The need to further reprocess the re-crystallized Telmisartan, as taught in the examples of the '986 patent, shows that the product was not highly-pure and/or that it contained residual solvents, because the solvents used therein have high boiling point. By precipitating Telmisartan from an aqueous solution containing acetic acid, as detailed herein, highly pure Telmisartan form A is obtained in high yield e.g., 93%. The obtained Telmisartan form A has low content of residual solvents and is characterized by having a different crystal shape than needles, namely a bulky shape.

HPLC Analysis:

Column: Inertsil ODS-3, 5μ, 250×4.6 mm (GL Sciences Cat. No.: 5020-01732). Mobile phase: 70% methanol and 30% water containing 10 ml triethylamine per 1.0 liter, pH adjusted to 3.0 using phosphoric acid.

Flow rate: 1 ml/min; UV detection: 226 nm; Oven temperature: 35° C.

Reference Example 1

In a 1000 ml three-necked round bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, 4-[(1,4′-dimethyl-2′-propyl[2,6′-bi-1H-benzimidazol]-1′-yl)methyl]-[1,1′-biphenyl]-2-carboxylic acid methyl ester (50 g, 0.095 mole) was charged, and methanol (300 ml) was added followed by addition of water (26 ml) and 47% NaOH solution (27 ml). The mixture was refluxed for 2 hours. Part of the solvent was evaporated and water (500 ml) was added in portions at 85° C. to afford a solution. The insoluble matter was removed by filtration and the mixture was neutralized with a solution of acetic acid (31.7 ml) in water (75 ml). The thus obtained crude Telmisartan cake was collected by filtration and washed with water to obtain 150 g of wet Telmisartan, which was dried under vacuum to obtain 48 g of the crude product in 98.6% yield, having a purity of 97%.

Example 1

In a 500 ml three necked round bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, Telmisartan (15 g) was dissolved in DMSO (290 ml). The solution was heated to 65° C. using an oil bath, and left to cool down to 25° C. After few days the resulting crystals were filtered off, washed with fresh water and dried at 100° C. under vacuum to obtain 11.55 g of Telmisartan form A in 77% yield, having a purity of 99.5% (according to HPLC).

Depending on the drying strength, different batches of dried material contained residual DMSO level in the range of 500-1000 ppm and had LOD values in the range of 0.2-0.3%, as measured by means of TGA.

The obtained solid material contained lumps, which could be easily ground by means of conventional mill. The obtained ground material has improved flowability, namely it is a free flowing crystalline powder that does not tend to gain electrostatic charge upon grinding. It has a bulk density of about 0.3 g/ml.

Particle size distribution was found to be: D(v,0.1)=1.60μ; D(v,0.2)=2.25μ; D(v,0.5)=4.98μ; D(v,0.8)=11.46μ; D(v,0.9)=16.78μ; D(v,0.95)=22.21μ; D(v,0.98)=29.03μ; D(v,1.0)=52.87μ.

XRPD pattern of the resulting material is shown in FIG. 4 and it resembles the pattern of form A.

........................
PATENT

http://www.google.im/patents/WO2009004064A1?cl=en

144702-27-2

KRKA, TOVARNA ZDRAVIL, D.D., NOVO MESTO Patent: WO2009/4064 A1, 2009 ; Location in patent: Page/Page column 44-45 ;

Telmisartan with its chemically name 4'-[(2-n-propyl-4-methyl-6-(l -methylbenzimidazol- 2-yl)-benzimidazol-l-yl)-methyl]-bipheny]-2-carboxylic acid and formula 1

is a non-peptide antagonist of subtype 1 of the angiotensin II receptor (ATj -antagonist) used for the treatment of hypertension. It can be used alone or in combination with another pharmaceutically active compound, e.g. hydrochlorothiazide.

Telmisartan is disclosed in EP O 502 314 as well as in J. Med. Chem., 36(25), 4040-4051 ( 1993 j. Its polymorphs are known from EP 1 144 386 and J. Pharm. Sci. 89 ( I i ;. J4ό.v 1479 (2000).

EP 0 502 314 A and J. Med. Chem., 36(25), 4040-4051 (1993), disclose a method for the preparation of ielmisartan using its tert-butyl substituted intermediate (Scheme j ). The final product of this method is difficult to be filtered, washed and isolated. These properties are an obstacle to an effective large-scale production.

Scheme 1

The synthesis of telmisartan from a compound with the chemical name 4'-[(2-n-propy!-4- methyl-6-(l-methylbenzimidazo]-2-yl)-benzimidazol-l -yl)-methyl]-biphenyl-2-nitrile (further named as telmisartan nitriie) and represented by formula 3

is disclosed in EP 0 502 314A, WO 2004/087676, CN 1412183 and US 2006/264491.

In WO 2004/087676 and CN 1412183 telmisartan is prepared by hydrolyzing the compound of formula 3 (Scheme 2): Scheme 2

The disclosed method can be used in the large-scale production of telmisartan and allows for a relatively easy purification thereof.

US 2006/0264491 discloses reacting 4'((l,4^"-dimethyl-2'-propyl(2,6'-bi-lH- benzimidazol)-r-yl)-methyl)-( l ,r-biphenyl)-2-carboxamide via hydrolysis into telmisartan, isolating crude telmisartan and optionally purifying the crude telmisartan via crystallization.

Amorphous telmisartan is disclosed in US 2006/1 11417 and WO 2006/050921, while crystalline forms of telmisartan are disclosed in WO 00/43370, IN 2005MU00164 and US 2006/0276525.

Various salts of telmisartan are known, for example from CN 1548421, WO 03/037876, WO 2006/044754, WO 2006/050509, WO 2006/050921, EP 1 719 766, WO 2006/136916, WO 2007/01055k and WO 20C7/ 14788^<>

In addition to the above-discussed preparation processes of telmisartan, there still is a need for a yet further improved synthetic route lo telmisartan. Therefore, the object of the present invention is to provide new methods for the production of telmisartan intermediates substituted on position 2 of the biphenyl group of (4'-[(2-n- proρyl-4-methy]-6-( l-methylbenzimidazol-2-yl)-benzimidazol-l-yI)-methyl]-biphenyl) which methods are suitable for use on an industrial scale and which are economical, i.e. both cost and time effective and allow for the production of intermediates that can be converted into telmisartan and/or salts thereof with high quality and high yield.

Another object of the present invention is to provide novel intermediates of telmisartan and derivatives thereof that enable new, cost and time effective synthetic routes to such compounds.

Summary of the invention

In one aspect, the present invention provides processes for the preparation of the key intermediate of the synthesis of telmisartan, namely a telmisartan intermediate substituted on position 2 of the biphenyl group of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazoi- 2-yl)-benzimidazol-l-yl)-methyl]-biphenyl.

In another aspect, the present invention provides novel intermediates useful for the synthesis of telmisartan intermediates substituted on position 2 of the biphenyl group of 4^"- [(2-n-propyl-4-methy^]~6-(l -methylbenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]- biphenyl optionally in isolated and/or purified form and their use as intermediates in the preparation of telmisartan and/or its salts.

In another aspect, the present invention provides telmisartan intermediates substituted on position 2 of the biphenyl group of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2- yl)-benzimidazol-l-yl)-methyl]-biphenyl prepared by the processes according to the oresenr invention having a purity of greater than 989r preferablv greater than 99<7r , wherein the amount of each individual impurity is less than 0.15%.

http://www.google.im/patents/WO2009004064A1?cl=en

144702-27-2

KRKA, TOVARNA ZDRAVIL, D.D., NOVO MESTO Patent: WO2009/4064 A1, 2009 ; Location in patent: Page/Page column 44-45 ;

Example 16 Preparation of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazoI-2-yl)-benzimidazoI- l-yI)-methyl]-biphenyl-2-carboxylic acid (compound 1)

A mixture of 2.5 g of compound 3 (5 mmol), 1.0 2 sodium hydroxide (25 mmol). 0.18 g water (10 mmol) and 30 ml etbyleneglycol was refluxed for 8 h. After the reaction was completed, the reaction mixture was cooled to room temperature and HoO (250 ml ) was added. After the pH value of this solution was adjusted to 4 with HOAc ( J 2 ml), the product precipitated and was extracted three times with CHoCIo. The combined organic layers were washed with brine, dried over NaSθ₄ and filtered and the filtrate was concentrated to give 2.55 g of crude compound 1 (yield: 98%).

Example 17 Preparation of 4'-[(2-n-propyl-4-methyl-6-(l-methylben2imidazol-2-yI)-benzimidazoI- l~yI)-methyI]-biphenyl-2-carboxyIic acid (compound 1):

A mixture of 15 g of compound 3 (30 mmol), 6.0 g potassium hydroxide (91 mmol}. 1.6 g water and 54 ml propylene glycol was refiuxed for 19 h. After the reaction was completed, the reaction mixture was cooled to room temperature and H?O (120 ml) was added. After the pH value of this solution was adjusted to 4.9 with 6M HCl (17 ml), the product was extracted three times with CH₂CIi. The combined organic layers were washed with water, dried over NaSO₄ and filtered and the filtrate was concentrated. To the residue acetone was added. The suspension was filtered to give 12.55 g of crude compound 1.

Example 18

Crystallization of 4'-[(2-n-propyl-4-methyl-6-(l -methylbenzimidazoI-2-y])- benzimidazol-l-yl)-methyl]-biphenyl-2~carboxylic acid (compound 1):

A mixture of 3 g of telmisartan and 20 ml of N,N-dimethylforrnamide was heated to a temperature of about 100 ⁰C until telmisartan was dissolved. Then the solution was filtered and cooled to room temperature. The solution was stirred at this temperature for 3h and then 2h at 0 ⁰C. The product was filtered, washed with DMF and dried under reduced pressure at 70-90 ⁰C to give 2.7 g of telmisartan (HPLC purity: 99.5%).

Example 19

Crystallization of 4'-[(2-n-propyI-4-methyl-6-(l-methyIbenzimidazol-2-yl)- benzimidazo!-l-yI)-methyIl-biphenyf-2-carboxylic acid (compound 1):

A mixture of 21.4 g of telmisartan, 107 ml of ethanol and 1.3 g of charcoal was stirred at room temperature for 15 min. Then 4.7 ml of 25% NH-, was added and the mixture was stirred for another 1.5h. The mixture was then filtered and the filtrate was heated to 80 ⁰C. At this temperature. 4.76 ml of acetic acid was slowly added and the mixture was cooled to room temperature. The mixture was stirred at this temperature for Ih, then the product was filtered, washed with water and ethanol and dried under reduced pressure at 70-90 ⁰C to give 19.7 g of telmisartan (HPLC purity: 99.6%)

.............................

PATENT

CIPLA LIMITED; TURNER, Craig, Robert Patent: WO2005/108375 A1, 2005 ; Location in patent: Page/Page column 2-4,7,9-10 ;

Chinese Patent CN 1344172 discloses the preparation of telmisartan in two steps: namely condensation and hydrolysⁱs. US 5591762 discloses the preparation of telmisartan from its tertiary butyl ester. Hydrolysis is carried out using trifluoro acetic acid in dimethyl formamide at room temperature and maintained for about 12 hours. The crude product obtained is purified over a silica gel column and finally crystallized from acetone. US 2002/0094997 is a divisional application of US 6358986. US 2002/0094997 discloses polymorphs of telmisartan, particularly polymorphic form B, polymorphous mixtures and their preparation. Accordingly, telmisartan Form A is dissolved in a mixture of solvents consisting of water, formic acid and an organic solvent that is miscible therewith; the solution is heated followed by distillation and telmisartan containing Form A and Form B is precipitated from the mixture by addition of a base. The disclosure further refers to advantages of the polymorphic Form B mixture, for example it is easily filterable and has a low tendency to electrostatic charging. The disclosure still further refers to the fact that Form A, which is obtained according to the basic patent, is difficult to filter, is characterized by a very long drying time and exhibits a strong tendency to electrostatic charging. The two telmisartan polymorphs of Form A and B as characterised by US 2002/0094997 differ considerably in their melting point: Form B melts at 183°C (determined by DSC), Form A at 269°C (determined by DSC). The polymorphs A and B also differ in their IR spectrum. Pure polymorph A has a characteristic band at 815 cm^"1 in the IR spectrum. In polymorph B, this oscillation is shifted to 830 cm^"1. In all the prior art processes, telmisartan is prepared in two or three steps, which is time consuming, product is lost during intermediate isolation, and as such there is a resulting low yield of the final product. It is also suggested in the prior art that the use of dimethyl formamide and alkali metal carbonates as solvent resulted in dimer formation, which also contributed to low yield. The aim of the present invention is, therefore, to provide an improved process for the preparation of telmisartan. In particular, it is an aim of the present invention to prepare telmisartan in a one step process, thereby increasing the yield, decreasing the cost and avoiding filtration and drying problems. Surprisingly, it has been found according to the present invention that telmisartan can be synthesised in one step from intermediates [1H - Benzimidazole - 2- n-propyl-4- methyl-6-(1 '-methyl benzimidazole-2'-yI)] and methyI-4-(bromomethyl) biphenyl-2- carboxylate. According to the present invention, therefore, there is provided a process for the preparation of telmisartan of formula (I), or a pharmaceutically acceptable salt thereof

(I) characterised in that lH-Benzimidazole-2-n-propyl-4-methyl-6-(l '-methyl benzimidazole- 2'yl) of formula (II), and methyl-4-(bromomethyl) biphenyl-2-carboxylate of formula (III), are subjected to condensation and hydrolysis in a single step (in other words, a "one pot" synthesis)

(II) (in)

A process for the preparation of telmisartan of formula (I), or a pharmaceutically acceptable salt thereof

(I)

characterised in that lH-Benzimidazole-2-n-propyl-4-methyl-6-(l'-methyl benzimidazole- 2'yl) of foraiula (II) and methyl-4-(bromomethyl) biphenyl-2-carboxylate of formula (III) are subjected to condensation and hydrolysis in a single step

(II) (ffl)

Example I

Preparation of f4'-r2-n-propyl-4-methyl-6-(1-methyl benzimidazol-2-yl) benzimidazol — 1-yl methyl! biphenyl-2-carboxylic acid] 50 gm of [1 H — Benzimidazole-2-n-propyl-4-methyl-6-(1 'methyl benzimidazole-2'- yl)] was added to 200 ml dimethyl sulfoxide and 50 gm of potassium hydroxide. To this was added 60 gm of methyl-4-(bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30°C, then heated to 40-50°C and maintained for 2 hours. About 500 ml water was added to the reaction mixture at room temperature and acidified to pH 4 with acetic acid. The reaction mixture was filtered and washed with purified water, dried under reduced pressure at 50-60°C to give 80 gm (88 %) of the title product.

Example 2

Preparation of r4'-[2-n-propyl-4-methyl— 6-(1 -methyl benzimidazol-2-vObenzimidazol — 1- yl methvπbiphenyl-2-carboxylic acid] 50 gin of [1H — Benzimidazole-2-n-propyl-4-methyl-6-(1'- methyl benzimidazole- 2'-yI)] was added to 200 ml dimethyl sulphoxide and 50 gm of potassium hydroxide. To this was added 60 gm of methyl-4- (bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30°C. The contents were heated to 40-50°C and maintained for 2 hours. About 500 ml water was added to the reaction mixture at room temperature and acidified with acetic acid to pH 3.8, extracted twice with 250 ml of dichloromethane and the combined extracts were concentrated and isolated by filtration after addition of 300 ml acetone, dried under reduced pressure at 50-60°C to give 75 gm (80 %) of the title product

Example 3

Preparation of \4' - F2-n-propyl — 4-methyl-6-(1 -methyl benzimidazol-2-yl) benzimidazol — 1-yl methyll biphenyl-2-carboxylic acid] 50 gm of [1 H — Benzimidazole-2-n - propyl-4-methyl-6-(1 '-methyl benzimidazole-2'- yl)] was added to 200 ml dimethyl sulfoxide and 50 gm of sodium hydroxide. To this was added 60 gm of methyl-4- (bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30°C and then heated to 40-50 and maintained for 2 hours. About 500 ml water was added to the reaction mixture and acidified with acetic acid to pH 4.2, extract4ed twice with 250 ml of dichloromethane and the combined extracts were concentrated and isolated by filtration after addition of 300 ml acetone, dried under reduced pressure at 50-60°C to give 75.0 gm (80%) of the title compound.

Example 4

Purification of 14' - r2-n-propyl-4-methyl-6-(1 -methyl benzimidazol-2-vh benzimidazol-1-yl methyll biphenyl-2-carboxylic acid] 50gm of [4' - [2-n-propyl-4-methyl-6-(1 -methyl benzimidazol-2-yl) benzimidazol-1-yl methyl] biphenyl-2-carboxylic acid] (obtained according to any of Examples 1, 2 or 3) was added to 500ml of methanol. To this was slowly added 50ml of methanolic ammonia (10-15%) at 25-30°C. The contents were stirred for 30 minutes at 25-30°C. About 3gm charcoal was added and stirred at 25-30°C for 30 minutes. The reaction mixture was filtered over hyflo, bed washed with methanol. The clear filtrate pH was adjusted to 3.5-4.0 using acetic acid. The contents were stirred at 20-30°C for 1 hour. Pure telmisartan was isolated by filtration, dried under reduced pressure at 50-60°C to yield 45gm (90%) of the title product with HPLC purity of about 99.3%.

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Kumar, A. Sanjeev; Ghosh, Samir; Mehta Journal of Chemical Research, 2010 , # 2 p. 95 - 97

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KRKA, tovarna zdravil, d.d., Novo mesto; ZUPANCIC, Silvo; SEDMAK, Gregor Patent: WO2010/146187 A2, 2010 ; Location in patent: Page/Page column 37-38 ;

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Chemo Iberica, S.A. Patent: EP2149566 A1, 2010 ; Location in patent: Page/Page column 12 ;
will be

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WO2014/27280 A1, ;will be

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keep watching this is being updated 

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 PATENT IN 2013MU02627 TELMISARTAN

Improved process for the preparation of telmisartan

By: Sathe, Dhananjay G.; Das, Arijit; Patel, Bhavesh; Chincholikar, Vikas

Assignee: Unichem Laboratories Limited, India

The present invention describes an improved process for the synthesis of 4-​[(1,​4-​dimethyl-​2-​propyl-​[2,​6-​bi-​1H-​benzimidazol]​-​1-​yl)​ methyl]​-​[1,​1-​biphenyl]​-​2-​carboxylic acid, that is Telmisartan (I)​.  This process comprises hydrolyzing compd. II [R = CN or aminocarbonyl] in acid at temp. range 60-​130°C, preferably 80-​130°C, more preferably between 100-​130°C, in presence of alkali metal nitrite at temp. range 20-​50°C, more preferably 45-​50°C, to obtain compd. I, and optionally isolating and hydrolyzing compd. II [R = aminocarbonyl] while hydrolyzing compd. II [R = CN] into compd. I at temp. range 20-​50°C, more preferably 45-​50°C.
NOTE

4'-[(l,4-dimethyl-2-propyl [2,6'-bi-lH-benzimidazol]-1'-yl)methyl]-[l,l'-biphenyl]-2-carboxylic acid, IS  Telmisartan  COMPD 1

Telmisartan chemically known as 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-1'-yl)methyl]-[l,1-biphenyl]-2-carboxylic acid and is known from U.S. patent no. 5,591,762 and is represented by compound of structural formula (I)

Telmisartan is an angiotensin II receptor (typeAT1) antagonist which is suitable for the treatment of high blood pressure and other medical indications as described in EP 502314 Bl. Telmisartan belongs to the group of angiotensin II antagonists, which are being therapeutically used as medicaments for the cardiovascular system, especially to control high blood pressure. A dosage form of Telmisartan was introduced in the market in 1998 by Boehringer Ingelheim under the protected name Micardis This group contains important drugs like Losartan (Cozaar ®), Irbesartan (Avapro®), or Valsartan (Diovan®). However, unlike these substances Telmisartan shows better efficiency even in the last hours of the administration interval.

U.S. patent no. 5,591,762 describes process to prepare Telmisartan which includes,
a) condensation of 2-n-propyl-4-methyl-6-(l'-methylbenzimidazol-2'-yl)benzimidazole compound of the formula (II) with tert-butyl-4'-bromomethyl biphenyl-2-carboxylate compound of the formula(V) in the presence of an acid binding agent (potassium-tert-butoxide) in a solvent or mixture of solvents (dimethyl sulphoxide (DMSO) to obtain t-butyl 4'-[4-methyl-6-(1 -methyl-1 H-benzimidazol-2-yl)-2-n-propyl-1H-benzimidazole-l-yl-methyl]biphenyl-2-carboxylate compound of the formula(VI) (tert. Butyl ester of Telmisartan)
b) hydrolyzing tert. Butyl ester of Telmisartan compound of the formula (VI) with trifluroacetic acid (TFA) in dimethylformamide (DMF) to obtain crude Telmisartan is purified over a silica gel column and crystallized from acetone to obtain Telmisartan compound of the formula (1) 63.9%.

U.S. Patent no. 7,193,089 describes the process to prepare Telmisartan, which includes,
a) reacting 2-n-propyl-4-methyl-6-(l'-methylbenzimidazol-2, -yl)benzimidazoie
compound of the formula (II) with 4'-(bromomethyl)-[l,l'-biphenyl]-2-carbonitrile compound of the formula (III) in presence of solvent or mixture of solvents (dimethylacetamide), optionally in the presence of an acid -binding agent such as potassium tert-butoxide or potassium hydroxide at a temperature range 0°C to 20°C, to obtain 2-cyano-4'-[2"-n-propyl-4,,-methyl-6"-(l'"-methylbenzimidazol-2'"-yl)benzimidazol-1"-ylmethyl ]biphenyl , cyanotelmisartan compound of the formula (IV).
b) hydrolysis of cyanotelmisartan compound of the formula (IV) is carried out in presence solvent selected form water, an organic solvents or mixture thereof (such as ethylene glycol/water) in presence of an acid or a base at temperature between 140°C to 200°C.
c) distilled off the solvent from reaction mixture and residue is diluted with water and in hydrochloride acid to obtained Telmisartan hydrochloride is further dissolved in acetic acid and then NaOH is added drop wise at 80°C to 90°C and Telmisartan free base is filtered off.

U.S. patent application no. 2006/0264491 describes process for preparation of Telmisartan. which includes, hydrolysis of 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-1'-yl)methyl]-[l,1'-biphenyl]-2-carboxamide compound of the formula (V) in presence of potassium hydroxide in propylene glycol at temperature at about 150°C.

EP2277866 Al discloses a process for preparing Telmisartan from 2-cyano-4;-[2"-n-propyl-4"-methyl-6"-(1"-methylbenzimidazol-2"'-yl) benzimidazol-l"-yl methyl] biphenyl compound of the formula (IV) using 60% NaOH in n-butanol in presence of phase transfer catalyst i.e. tetra butyl ammonium hydrogen sulphate at 115-120°C for 22h.

EP2443094B1/WO2010/146187A2 describes a process for the synthesis of Telmisartan from cyano Telmisartan and carboxamido telmisartan using 1:1 sulphuric acid at 125°C for 30 h and 28 h respectively.

The existing process requires very high temperature for 30 h or 28 h which limits its large scale application and invites safety risks too. In addition to this, formation of different kind of impurities takes place at 125°C.

Chinese patent application CN 1412183A describes the process for preparation of Telmisartan which includes reacting compound of the formula (II) with compound of the formula (111) in presence of organic base or inorganic base and reaction solvent to afford compound of the formula (IV). It also describes different hydrolysis conditions for compound of the formula (IV) such as,
a. a 1:2 volume ration of concentrated acetic acid: concentrated hydrochloric
acid refluxed for 24 hours at about 100°C
b. a 2:1 volume ration of ethanol: 2 M NaOH refluxed for 24 hours at about
100°C
c. a 1: 1.5 volume ration of sodium ethanolate in glycol: water refluxed for 24
hours and finally obtained Telmisartan is crystallization with N, N-
dimethylformamide (DMF).

Chinese patent application CN102070534A discloses a process for preparation of 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1"-methylbenzimidazol-2'"-yl) benzimidazol-1"-ylmethyl ]biphenyl compound of the formula (IV) which includes reacting compound of the formula (II) with compound of the formula (III) under the effect of phase transfer catalyst and inorganic base in the presence of low boiling organic solvents at temperature rang in between 0°C-10oC.

WO 2007/147889 discloses the process for preparation of Telmisartan by hydrolyzing compound of the formula (IV) by addition of water and conc. HC1 heated at reflux  temperature for 136 hours and then cooled reaction mixture at room temperature and add 1M NaOH to adjust pH to about 5 to 7. The product is filtered, wash and dried to obtain Telmisartan.
The disclosed process in WO '889 is time intensive besides corrosive and hazardous reaction condition.

U.S. patent no. 5,591,762 teaches the hydrolysis of cyanotelmisartan compound of the formula (IV) using trifluroacetic acid in dimethyl formamide and is not eco-friendly. It involves long time for hydrolysis. Separation of Telmisartan using silica gel column chromatography results into lower yields. Further the preparation of tert. Butyl ester of Telmisartan is relatively expensive method.

U.S. Patent no. 7,193,089 is silent about the purity of the free Telmisartan. The solvents used such as dimethyl acetamide and ethylene glycol have a boiling point greater than about 140°C. These solvents are difficult to remove from the reaction using various evaporation techniques known in the art. These reaction conditions are hazardous and far from being environmental friendly. The process is carried out at very high temperature. Removal of residual solvents from reaction mixture, using various evaporation techniques is tedious and difficult.

U.S. patent application no. 2006/0264491 describes a process in which, an expensive solvent is used. Reactions are carried out at very high temperatures which itself is very difficult to maintain at plant scale manufacturing. These process conditions discourage use of this process.

Process disclosed by EP2277866A1 requires high temperature and longer time to complete the reaction which invites safety risks. Use of lower temperatures substantially impacts on yield. Moreover the isolation procedure from n-butanol to get crude telmisartan is very tedious.

Process disclosed by WO 2010/146187A2 requires very high temperature for longer durations. It limits its application for large scale production. It also invites safety risks. The process leads to formation of different kind of impurities at 125°C. Carrying out reaction at elevated temperatures is not easy and not advisable. Use of lower temperatures substantially impacts yield.

Chinese patent application CN1412183A describes conditions that required long time for hydrolysis and results in lower yields. Moreover ethylene glycol and DMF are high boiling solvent so it will be very difficult to recover and reuse.

CN102070534A teaches a reaction which is carried out at a temperature range of 0-10°C, a range which is difficult and energy intensive. Industry will welcome a reaction which is carried out at ambient temperatures and yet having shorter durations. Besides this inconvenient temperature range the reaction necessitates low boiling solvents and thereby restricts selection range of solvents.

Therefore the processes taught by prior patents and prior art disclosures have several drawback's namely expensive nature, not suitable for scale up at plant level, energy intensive, difficult, giving lower yields, forcing use of corrosive acids, longer duration of corrosive reaction and less user friendly.
Therefore industry strongly needs a process that is simpler, financially cheaper and energy economic process, an environment friendly process that does not use hygroscopic and pyrophoric chemicals. Industry needs a process to produce Telmisartan that can be carried out at lower temperatures yet giving good yields, a process that has improved carbon efficiency and is free from hazards and draw backs of prior art.




EXAMPLE -8:
Preparation of 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-bcnzimidazol)-r-yI)methyl]-
ll,l'-biphenyll-2-carboxyIic acid

100 gm of 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1"-methylbenzimidazol-2'"-yl) benz-imidazol-1'-ylmethyl] biphenyl and 550 mL 80% sulfuric acid, were heated to 80°C-85° C. The reaction mixture stirred for 8-10 h at this temperature. Water (500 mL) was added at the same temperature and the reaction mixture was stirred for 15-20 h and reaction was completed at 120-130 C. 
The reaction was then cooled to 20-25 C. pH of mixture was adjusted tol2 by adding 40% NaOH solution. After that 500 ml of n-Butanol were added and separated out layers. The oily residue thus obtain after distillation was dissolved in 500 mL of water to get clear solution. The aqueous layer was washed with

distillation of methylene dichloride was added in 300 mL of acetone. Suck dry the wet cake.
Wet cake was directly charged in a reaction assembly containing 900 mL 30% sulfuric acid solution. NaN02 solution (48.75 gm, 0.7 moles in 200 ml water) was added drop wise and the temperature of the reaction mass was kept at 25-50 C. 
The reaction was then heated to 45°C-50°C and maintained for 2-5 h and then cooled to 20-25° C. pH of mixture was adjusted to 12 by adding 40% NaOH solution. After that 500 ml of n-Butanol were added and separated out layers. 
The oily residue thus obtain after distillation was dissolved in 700 mL of methanol and 15 mL of ammonia followed by charcolization. pH of the filtrate was adjusted to 4-5 using acetic acid. Solid obtained was filtered and washed with methanol (100 mL) and dried at 60-65 °C. The solid was then treated with water (500 mL) at 40-45 °C for 3h to remove inorganic matters and then dried at 60-65 °C for 10 h. 
The solid thus obtain was treated with methanol (1000 mL) at 60-65 °C for 8-10 h and then filtered to get pure Telmisartan. The product obtained was then dried at 60-65 °C to get 73 gm (yield 75.9 %) of compound (I) having purity > 99.7 % by HPLC
........................................................................



Reddy, Kikkuru Srirami; Srinivasan, Neti; Reddy, Chinta Raveendra; Kolla, Naveenkumar; Anjaneyulu, Yerremilli; Venkatraman, Sundaram; Bhattacharya, Apurba; Mathad, Vijayavitthal T. Organic Process Research and Development, 2007 , vol. 11, # 1 p. 81 - 85

LEK PHARMACEUTICALS D.D. Patent: WO2006/103068 A1, 2006 ; Location in patent: Page/Page column 11; 18 ; WO 2006/103068 A1

Boehringer Ingelheim International GmbH Patent: US2004/236113 A1, 2004 ; Location in patent: Page 6 ;

Chemo Iberica, S.A. Patent: EP2123648 A1, 2009 ; Location in patent: Page/Page column 13 ;

Venugopal; Ramanatham; Devanna; Sanjeev Kumar; Ghosh, Samir; Soundararajan; Kale, Bhima; Mehta Asian Journal of Chemistry, 2010 , vol. 22, # 4 p. 2767 - 2773

Cited Patent	Filing date	Publication date	Applicant	Title
WO2000027397A1 *	6 Nov 1998	18 May 2000	Boehringer Ingelheim Int	Antihypertensive medicaments containing lacidipine and telmisartan
WO2004087676A1 *	26 Mar 2004	14 Oct 2004	Boehringer Ingelheim Int	Method for the production of telmisartan
EP0502314A1 *	31 Jan 1992	9 Sep 1992	Dr. Karl Thomae GmbH	Benzimidazol, medicaments containing them and process for their preparation
US6358986 *	10 Jan 2000	19 Mar 2002	Boehringer Ingelheim Pharma Kg	Polymorphs of telmisartan
US20020094997 *	16 Nov 2001	18 Jul 2002	Heinrich Schneider	Polymorphs of telmisartan

* Cited by examiner

Citing Patent	Filing date	Publication date	Applicant	Title
WO2006136916A2 *	20 Jun 2006	28 Dec 2006	Glenmark Pharmaceuticals Ltd	Substantially pure micronized particles of telmisartan and pharmaceutical compositions containing same
WO2009006860A2	8 Jul 2008	15 Jan 2009	Zentiva As	A method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan)
WO2009123483A1	30 Mar 2009	8 Oct 2009	Zaklady Farmaceutyczne Polpharma Sa	Process for preparation of telmisartan
WO2010018441A2 *	10 Aug 2009	18 Feb 2010	Cadila Pharmaceuticals Ltd.	An improved process for the preparation of substantially pure telmisartan
WO2010053233A1 *	6 Mar 2009	14 May 2010	Chong Kun Dang Pharmaceutical Corp.	The new telmisartan zinc salt and the preparation thereof
WO2010146187A2 *	21 Jun 2010	23 Dec 2010	Krka, Tovarna Zdravil, D.D., Novo Mesto	Process for the preparation of telmisartan
WO2011102645A2 *	17 Feb 2011	25 Aug 2011	Dong Wha Pharm. Co., Ltd.	An improved process for preparing telmisartan
WO2012055941A1	26 Oct 2011	3 May 2012	Krka,Tovarna Zdravil, D. D., Novo Mesto	Multilayer pharmaceutical composition comprising telmisartan and amlodipine
CN101172968B	1 Nov 2006	12 May 2010	浙江天宇药业有限公司	2-propyl-4 methyl-6-(tolimidazole-2group) benzoglioxaline salt and method for producing the same
EP2123648A1	20 May 2008	25 Nov 2009	Chemo Ibérica, S.A.	A process for the preparation of Telmisartan.