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

 CONT.........................

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.

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

.

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]+

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

.

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.

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

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

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

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.

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


  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:

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

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

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

IN 262831/EP 1912975

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

JP 2014201585

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

 IN 2013KO00463/WO 2014174397

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

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).


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


  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%.

 .........................

  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%



   .........................


  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

 .......................

  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.


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


  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)

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

  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
CN100548293C	Aug 8, 2003	Oct 14, 2009	贝塞斯达药物股份有限公司	Novel PPAR ligands that do not cause fluid retention, edema or congestive heart failure
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