Wednesday 8 April 2015

TELMISARTAN PART 3/3

TELMISARTAN PART 3/3


 CONT.........................



PAPER
Journal of Organic Chemistry (2015), 80(3), 1915-1919
J. Org. Chem.201580 (3), pp 1915–1919
DOI: 10.1021/jo5025333
Abstract Image


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.
Displaying image015.png
Displaying image016.png
Displaying image017.png
Displaying image018.png
Displaying image019.png
........................

.

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]+
Displaying image004.png
.............................
.

PATENT
WO 2014027280
http://www.google.com/patents/WO2014027280A1?cl=en

Scheme 1 given below: Formula .
Figure imgf000005_0001
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.201479 (21), pp 10568–10580
DOI: 10.1021/jo501665e
Abstract Image
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=enFigure CN102731407AD00041Figure CN102731407AD00042 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
Figure imgf000004_0001
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
Figure imgf000004_0002
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 (2χl36ml) 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 (2χ50ml) 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 esterCompound 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 PatentFiling datePublication dateApplicantTitle
CN100460396CMar 8, 2007Feb 11, 2009杭州盛美医药科技开发有限公司Intermediate of telmisartan, preparation and use thereof
CN100506799CApr 19, 2007Jul 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
CN100548293CAug 8, 2003Oct 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
CN101550107BApr 2, 2009Jan 12, 2011宁波九胜创新医药科技有限公司Method for preparing telmisartan
CN101743228BJul 3, 2008Jan 29, 2014新梅斯托克尔卡托瓦纳兹德拉韦尔公司Process for preparing telmisartan
CN101891735BNov 25, 2009Jul 18, 2012北京理工大学Biphenyl sulfafurazole compound, synthesis method and application thereof
CN102093297BJan 28, 2011Aug 1, 2012海南美兰史克制药有限公司Telmisartan compound and new preparation method thereof
EP1805146A2 *Oct 18, 2005Jul 11, 2007Dr. Reddy's Laboratories Ltd.Process for preparing telmisartan
EP2123648A1May 20, 2008Nov 25, 2009Chemo Ibérica, S.A.A process for the preparation of Telmisartan.
US7501448Oct 13, 2005Mar 10, 2009Teva 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, 2005Apr 8, 2014Cipla LimitedProcess for the preparation of telmisartan
WO2006044648A1*Oct 13, 2005Apr 27, 2006Teva PharmaProcess for preparing telmisartan
WO2007010558A1*Jul 19, 2006Jan 25, 2007Satyanarayana ChavaA process for the preparation of telmisartan
WO2009123483A1Mar 30, 2009Oct 8, 2009Zaklady Farmaceutyczne Polpharma SaProcess for preparation of telmisartan
WO2012028925A2Aug 29, 2011Mar 8, 2012Ogene Systems (I) Pvt LtdAn improved process for the preparation of telmisartan
CN1412183AOct 15, 2001Apr 23, 2003中国科学院上海药物研究所New preparation method of timixatan
CN1620437AJan 15, 2003May 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
CN1768044AMar 26, 2004May 3, 2006贝林格尔·英格海姆国际有限公司Process for manufacture of telmisartan
WO2005108375A1May 10, 2005Nov 17, 2005Cipla LtdProcess for the preparation of telmisartan
CN1344712AJul 30, 2001Apr 17, 2002中国科学院上海药物研究所Synthesis path of Timisatem
CN1412183AOct 15, 2001Apr 23, 2003中国科学院上海药物研究所New preparation method of timixatan
US2006/0094883Title not available
WO03/059890A1Title not available
WO2005/108375A1Title not available
US7501448Oct 13, 2005Mar 10, 2009Teva 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, 2007Dec 27, 2007Krka Tovarna Zdravil D D NovoPreparation of telmisartan salts
WO2010146187A2Jun 21, 2010Dec 23, 2010Krka, Tovarna Zdravil, D.D., Novo MestoProcess for the preparation of telmisartan
WO2012055941A1Oct 26, 2011May 3, 2012Krka,Tovarna Zdravil, D. D., Novo MestoMultilayer pharmaceutical composition comprising telmisartan and amlodipine
WO2003007876A2Jun 25, 2002Jan 30, 2003Sumner H BursteinN-fatty acid-amino acid conjugates and therapeutic uses
WO2003059327A1Jan 16, 2002Jul 24, 2003Boehringer Ingelheim PharmaBilayer pharmaceutical tablet comprising telmisartan and a diuretic and preparation thereof
WO2004028505A1Sep 18, 2003Apr 8, 2004Boehringer Ingelheim IntSolid pharmaceutical formulations comprising telmisartan
WO2004087676A1Mar 26, 2004Oct 14, 2004Boehringer Ingelheim IntMethod for the production of telmisartan
WO2004096215A1Apr 27, 2004Nov 11, 2004Boehringer Ingelheim IntPharmaceutical formulation of the sodium salt of telmisartan
WO2005108375A1*May 10, 2005Nov 17, 2005Cipla LtdProcess for the preparation of telmisartan
WO2006044754A2Oct 18, 2005Apr 27, 2006Muthulingam ArunagiriProcess for preparing telmisartan
WO2006050509A2Nov 3, 2005May 11, 2006Teva PharmaAmorphous and polymorphic forms of telmisartan sodium
WO2006050921A2Nov 9, 2005May 18, 2006Lek PharmaceuticalsPreparation of telmisartan salts with improved solubility
WO2006063737A1Dec 9, 2005Jun 22, 2006Boehringer Ingelheim IntCombination therapy comprising telmisartan and hydrochlorothiazide
WO2006136916A2Jun 20, 2006Dec 28, 2006Glenmark Pharmaceuticals LtdSubstantially pure micronized particles of telmisartan and pharmaceutical compositions containing same
WO2007010559A2Jul 19, 2006Jan 25, 2007Panacea Biotec LtdNovel pharmaceutical modified release dosage form cyclooxygenase enzyme inhibitor
WO2007060170A2Nov 22, 2006May 31, 2007Boehringer Ingelheim IntBilayer tablet comprising telmisartan and diuretic
WO2007144175A2Jun 14, 2007Dec 21, 2007Lek PharmaceuticalsPharmaceutical composition comprising hydrochlorothiazide and telmisartan
WO2007147889A2Jun 22, 2007Dec 27, 2007Krka Tovarna Zdravil D D NovoPreparation of telmisartan salts
WO2009004064A1Jul 3, 2008Jan 8, 2009Krka Tovarna Zdravil D D NovoProcess for preparing telmisartan
CN1412183AOct 15, 2001Apr 23, 2003中国科学院上海药物研究所New preparation method of timixatan
CN1548421AMay 22, 2003Nov 24, 2004上海医药工业研究院Tilmisartan salt and its prepn
EP0502314A1Jan 31, 1992Sep 9, 1992Dr. Karl Thomae GmbHBenzimidazol, medicaments containing them and process for their preparation
EP1144386A1Jan 7, 2000Oct 17, 2001Boehringer Ingelheim Pharma KGTelmisartan polymorphs, methods for producing same and their use in the preparation of a medicament
EP1719766A2Apr 18, 2006Nov 8, 2006Dipharma S.p.A.A process for the preparation of telmisartan
US20060264491Jun 8, 2006Nov 23, 2006Chemagis Ltd.Telmisartan production process
CN101172968BNov 1, 2006May 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
CN101743228BJul 3, 2008Jan 29, 2014新梅斯托克尔卡托瓦纳兹德拉韦尔公司Process for preparing telmisartan
CN102015690BMar 19, 2009Apr 30, 2014力奇制药公司Catalyzed carbonylation in the synthesis of angiotensin II antagonists
CN102036937BMar 19, 2009Jun 4, 2014力奇制药公司2'-halobiphenyl-4-yl intermediates in the synthesis of angiotensin ii antagonists
WO2014067237A1*Oct 31, 2013May 8, 2014Topharman Shanghai Co., Ltd.Telmisartan preparation method and intermediate thereof
WO2010018441A2*Aug 10, 2009Feb 18, 2010Cadila Pharmaceuticals Ltd.An improved process for the preparation of substantially pure telmisartan
WO2010146187A2*Jun 21, 2010Dec 23, 2010Krka, Tovarna Zdravil, D.D., Novo MestoProcess for the preparation of telmisartan
WO2011077444A1*May 28, 2010Jun 30, 2011Inogent Laboratories Private LimitedA new process for the preparation of pure telmisartan
WO2012028925A2*Aug 29, 2011Mar 8, 2012Ogene Systems (I) Pvt LtdAn improved process for the preparation of telmisartan
CN1768044A *Mar 26, 2004May 3, 2006贝林格尔·英格海姆国际有限公司Process for manufacture of telmisartan
CN102731407A *Jul 4, 2012Oct 17, 2012宁波九胜创新医药科技有限公司Method for preparing telmisartan
EP0627433A1 *Dec 7, 1993Dec 7, 1994Eisai Co., Ltd.Process for producing imidazopyridine derivative and intermediate
EP2123648A1 *May 20, 2008Nov 25, 2009Chemo Ibérica, S.A.A process for the preparation of Telmisartan.
EP2305650A1 *Sep 21, 2009Apr 6, 2011Chemo Ibérica, S.A.Novel process for the preparation of telmisartan
KR20090000113A *Title not available
US20040236113Mar 17, 2004Nov 25, 2004Boehringer Ingelheim International GmbhProcess for manufacture of telmisartan
US20130137878Jan 25, 2013May 30, 2013Boehringer Ingelheim International GmbhProcess for manufacture of telmisartan

TELMISARTAN PART 2/3

TELMISARTAN PART 2/3

Figure imgf000002_0001
4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan)


PART3......
GENERAL DESCRIPTION
Telmisartan is currently available as oral tablets in 20, 40, and 80 mg strengths for use in the treatment of hypertension. It is also marketed as Micardis® HCT which is a fixed dose combination with Hydrochlorothiazide (HCTZ) in 40/12.5, 80/12.5, 80/25 mg/mg strengths, and Twynsta® its fixed dose combination with Amlodipine in 40/5, 80/5, 40/10, 80/10 mg/mg strengths.
In 2009, Boehringer Ingelheim (Boehringer) gained approval to extend the market authorised indication of the Telmisartan 80 mg strength to include reducing the risk of myocardial infarction, stroke or death from cardiovascular disorders.  
The Telmisartan molecule was discovered and developed by Boehringer, and was launched in Europe and the US in 1998. Boehringer has co-marketing agreements with Bayer Schering Pharma and GlaxoSmithKline in certain countries.
Displaying image001.png
Telmisartan (1) is an angiotensin II receptor antagonist useful in the treatment of hypertension, heart diseases, heart strokes, and bladder diseases.1 Telmisartan (1) is currently available in the market as an antihypertensive drug2 under the brand name of MICARDIS. The first reported synthetic method3 for this molecule consists of 8 steps (Scheme 1) involving condensation of 4-amino-3-methyl benzoic acid methyl ester (2) with butyryl chloride (3) in chlorobenzene to yield 4. Nitration of 4 followed by reduction of the resulting 5-substituted nitro compound 5 over Pd-C in methanol yielded amine 6. Cyclisation of 6 in acetic acid reflux affords the monobenzimidazole derivative 7, which upon further hydrolysis yielded an acid intermediate 8 by a saponification process. Condensation of compound 8 with diamine derivative 9 in polyphosphoric acid yielded the dibenzimidazole compound 10, which was further alkylated with 4′-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (11)4 to afford product 12. Finally, hydrolysis of ester12 in trifluoracetic acid yielded telmisartan (1) in an overall yield of around 21% with several impurities. This process suffers from disadvantages such as (a) a multistep synthesis for compound 8 (3 steps from compound 5); (b) the solvents dimethyl formamide (DMF) or dimethylsulfoxide (DMSO) used in the penultimate stage are unrecoverable, while the use of potassium tert-butoxide resulted in high organic volatile impurities (OVI) in telmisartan; (c) deprotection of the tert-butyl group using trifluoroacetic acid in DMF lead to the formation of several byproducts; (d) residue on ignition (ROI) in API obtained from this process is always >1.0% (ICH limit <0.1%), and there is no specified process mentioned in the literature to control the ash content. This is mainly due to very poor solubility of the telmisartan in most of the solvents including water; and (e) the overall yield (21%) of this process is discouraging, which makes the process less viable for commercial production.
(1) (a) Battershill, A. J.; Scott, L. J. Drugs 2006, 66 (1), 51-83. (b) Norbert, H.; Berthold, N.; Uwe, R.; Jacobus, C. A.; Van, M.; Wolfgang, W.; Michael, E. U.S. Patent 5,591,762, 1997. (c) Ruth, R. W.; William, J. C.; John, D. I.; Michael, R. C.; Kristine, P.; Ronald, D. S.; Pieter, B. M. W. M. T. J. Med. Chem. 1996, 39 (3), 625-656.
(2) http://www.rxlist.com/cgi/generic2/telmisartan.htm.
(3) (a) Uwe, J. R.; Gerhard, B. N.; Kai, M. H.; Helmut, W.; Michael, E.; Jacobus, C. A.; Van, M.; Wolfgang, W.; Norbert, H. H. J. Med. Chem. 1993, 36, 4040-4051. (b) Merlo
(4) Carini, D. J.; Dunicia, J. V. Eu. Patent 2,53,310, 1988. (5) Venkataraman, S.; Mathad, V. T.; Kikkuru, S. R.; Neti, S.; Chinta, R. R.; Arunagiri, M.; Routhu, L. K PCT WO 06/044754A2, 2006.
(6) The intermediate 9 is prepared via monomethylation of o-nitroaniline (15) using dimethylsulfate followed by hydrogenation over Pd-C catalyst in methanol with 75% of overall yield. Of the several methylating agents such as CH3I, DMS, HCOOH, and H2CO explored
(7) Structures of these impurities were tentatively proposed based on MS-MS data and a probable reaction mechanism and then synthesized as shown in Scheme 3. These impurities were characterized by NMR, mass, and IR techniques and further confirmed to be present in the sample by HPLC coinjection and spiking methods (0.1%). (8) Shen, J.; Li, J.; Yan, T.; Li, H.; Ji, R. CN 1,344,712, 2002.
(9) Several brominating agents such as molecular bromine, N-bromosuccinimide (NBS), and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) resulted in 13 along with the dibromo impurity 26. The formation of the dibromo impurity 26 is varying from 20-45% by HPLC. The content of 26 is nearly 45% in the case of NBS bromination, whereas the same is in the range of 15%- 20% in the case of DBDMH. Hence, DMDBH has been utilized as the brominating agent in the process. However impurity 26 did not participated in the next step and was easily washed out to a nondetected level during the isolation of 14 in the condensation step.
(10) Robert, E. D.; Peter, S.; Herbert, N.; Kenneth, S.; William, I. F. D. J. Pharm. Sci. 2000, 89 (11), 1465-1479.
Whilst patent protection for Telmisartan molecule, DE4103492A, has expired in Canada, it is still in force in the US until January 2014, receiving the longer term based on 17 years from the issue date for patents filed prior to June 8 1995. The equivalent European patent, EP0502314 (‘314), has been extended by SPC in France, Germany, Spain and the UK until December 2013 (see Figure 3).
Boehringer, seeking to protect its Telmisartan franchise, has also filed SPC applications for its Telmisartan-HCTZ and Telmisartan-Amlodipine products, for the basic patent ‘314, in France, Germany, Spain and the UK, potentially extending protection until January 2017 (see Figure 3). GenericsWeb’s proprietary SPC analyser has identified the basic patent as a ‘C3’ category, suggesting the claims of the basic patent do not protect the combinations and therefore the SPC may be invalid. The response by the national IPOs in respect to the invalidity of SPCs for the Telmisartan combinations has varied. The French SPC application (FR02C0028) for Telmisartan-HCTZ was initially rejected by the Institut National de la Propriété Industrielle (INPI) in December 2010, finding the claims of the basic patent did not protect a medicine comprising Telmisartan in association with HCTZ. The Paris Court of Appeal upheld INPI’s decision in June 2012, denying Boehringer’s request for appeal. Similarly, on June 2012, the Juzgado de lo Mercantil de Pamplona (the Court) held the Spanish SPC (C20020018) for Telmisartan-HCTZ invalid following a revocation suit filed by Cinfa and Actavis against Boehringer in April 2010. The Court’s decision relied on the ECJ’s findings in the ‘Medeva’ decision relating to SPCs for combination products, which concluded that to satisfy article 3(a) of SPC regulation 469/2009 the wording of the claims of the basic patent had to specify all active ingredients. Therefore, the Court found the SPC to be invalid on the grounds of article 15.1(a) in regard to 3(a), finding ‘314 did not specify a composition of Telmisartan in association with HCTZ. In February 2013, revocation proceedings were filed in the Bundespatentgericht for the German SPC (DE10299029) for Telmisartan-HCTZ. This raises the question of whether the SPC will prevent a generic Telmisartan-HCTZ product in Germany until conclusion of the revocation proceedings or will generic companies launch their products ‘at risk’ upon expiry of the SPC for Telmisartan, therefore assuming invalidity based on the ‘Medeva’ decision and similar findings by other PTOs and Courts in the matter.
The French (FR11C0008), German (DE122011000013) and Spanish (C201100010) SPCs for the Telmisartan-Amlodipine combination have been withdrawn. However, the UKIPO has granted the SPCs for both combination products (see Figure 3). No litigation proceedings have been detected in the UK. This may be due to amendments, under section 27 of the Patents Act 1977, of the specification for the UK designation of ‘314, in 2004 and 2011. The amendments were in the form of amended claim pages which included a pharmaceutical composition comprising HCTZ or a calcium channel blocker. Patents in the family with priority GB9722026A protect authorised indicated uses of the 80 mg dosage form of Telmisartan for reducing cardiac tissue damage associated with myocardial infarction and prevention or treatment of stroke, so are considered to be a constraint only for those indicated uses.
The family with the priority DE19901921A protects the crystalline form used in the commercially available product but are not considered to be a constraint to generic competition because the protected technology is likely to be circumvented. Families AU2002242676A, DE10301371A and EP04026234A protect Telmisartan combination products (see Figure 2). AU2002242676A and EP04026234A claim bilayer tablets comprising Telmisartan and HCTZ or Amlodipine, respectively. They are not considered to be a constraint to generic competition because the protected technologies are likely to be circumvented by generic reformulation. However, patents in the family DE19901921A expiring in July 2024, claiming composition of Telmisartan and several other drugs, including Amlodipine, are considered to be a constraint to generic competition for the Telmisartan-Amlodipine product. The family was deemed key due to its Canadian member 2534006 being listed on Health Canada’s patent register. Equivalent patents in the US have not been granted yet, but claims listed in the image wrapper in USPTO appear to limit the claims to a currently unauthorised use of Telmisartan and Amlodipine, therefore may not be a constraint for generic entry in the US.
Amongst the US approvals, Watson is the only company to have obtained tentative market approvals for all dosage strengths for the Telmisartan tablets and the fixed dose combination of Telmisartan and HCTZ. Lupin has gained a tentative approval for the Telmisartan and Amlodipine fixed dose combination. No generics are currently on the market in the UK due to unexpired patent protection, however several companies including Egis, Sandoz and Glenmark have obtained market authorisation for Telmisartan tablets in all dosage strengths. Actavis and Teva have obtained market authorisations via the centralised procedure. Dr Reddy’s Lab and Krka hold generic authorisations for both Telmisartan and Telmisartan-HCTZ fixed dose combination tablets. These generic approvals are suggestive of the competition Micardis® will face across Europe upon molecule patent expiry. Currently no generic Telmisartan-Amlodipine approvals have been identified in Europe. This is due to data exclusivity previsions in Europe, preventing the filing of generic market authorisation until October 2018, and a further 2 year market exclusivity period could prevent the launch of a generic equivalent until October 2020. In Canada, Mylan was one of the generic competitors to launch Telmisartan and Telmisartan-HCTZ following molecule patent expiry. This is likely to be mirrored in other territories upon expiry of the molecule patent.
Figure 4: Marketing Authorisations for products containing Telmisartan in Key Countries
In summary, patent protection remains a significant barrier to generic entry for the Telmisartan products in most major markets due to the molecule patent being in force. Boehringer’s lifecycle management attempts to maintain a monopoly for their blockbuster drug, including combination products and extensions of indications. Patent protection for its products, apart from the molecule patent, include a ‘use’ patent and combination patents which may pose a barrier to generic competition and may see Boehringer retain some of their market share. SPCs for the Telmisartan-HCTZ combination have been the subject of litigation in France and Spain, resulting in their invalidation, a revocation proceeding is on-going in Germany. Data exclusivity provisions in Europe will prevent the launch of a generic Telmisartan-Amlodipine fixed dose combination. In Canada, generic competition for Telmisartan and Telmisartan-HCTZ entered the market shortly after the expiry of the molecule patent. This is likely to be mirrored in other territories with generic companies already holding market authorisations for both products.
............................................
PATENT
WO 2010018441
Telmisartan is chemically named as 4'-[(1,4'-Dimethyl-2I-propyl[2l6'-bi-1H- benzimidazol]-1'-yl)methyl][1 ,1'-biphenyl]-2-carboxylic acid; or 4'-[[4-methyl-6-(1-methyl-2- benzimidazolyO^-propyl-i-benzimidazolyllmethyll^-biphenylcarboxylic acid.
Figure imgf000002_0001
The key raw material used to prepare Telmisartan is Bltyl, chemically named as 1,7'- dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole, also known by other names, i.e 2-Propyl-4- methyl-6-(1 -methylbenzimidazol-2-yl)benzimidazole; 4-Methyl-6-(1 -methyl benzimidazol-2- yl)-2-propylbenzimidazole, and the structure shown as below:
Figure imgf000002_0002
BIM WO2006136916 describes substantially pure micronized particles of Telmisartan or a pharmaceutically acceptable salt, ester or derivative. The "substantially pure" is further defined as "Telmisartan or pharmaceutically acceptable salt, ester or derivative thereof having a purity of greater than or equal to about 98%, preferably a purity of greater than or equal to about 99% and more preferably a purity of greater than or equal to about 99.5%.° The substantially pure Telmisartan or a pharmaceutically acceptable salt, ester or derivative has an effective average particle size of less than about 300 microns.
A Journal of www.IP.com (2005), 5(7B), 4 - describes a process for purification of 4'-(2-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-ylmethyl)biphenyl-2- carboxylic acid (Telmisartan). The pure compound was isolated by filtration under reduced pressure.
US20060276525 claims Telmisartan form A having HPLC purity > 99.5 %. It further provides a process for preparing Telmisartan form A by crystallization from a polar organic solvent selected from the group consisting of dimethyl sulfoxide, DMF, N.N-dimethyl acetamide, N-methyl 2-pyrrolidone, water and mixtures thereof. The process provides Telmisartan with a limit of DMSO at a level of < 1000 ppm. The process uses high boiling solvent in the last step for getting required purity, and which is also an extra purification step, which limits its commercial application.
US5591762 ( column-37,38 ) described the general process for the preparation of compound of formula-V
Figure imgf000003_0001
wherein bromine in structure IV is leaving group. There are several other leaving groups such as chlorine, iodine, a substituted sulphonyloxy group, e.g. a methane sulphonyloxy, phenylsulphonyloxy or p-toluenesulphonyloxy group are reported.
US5591762 describes preparation of Telmisartan from Telmisartan tert. butyl ester using trifluoroacetic acid in DMF as a solvent in 63.9 % yield. (Example-9) The resulting product had a melting point of 261-2630C.
Figure imgf000003_0002
The process for the preparation of tert. Butyl ester of Telmisartan is not commercially viable and deprotection involving the use of trifluoro acetic acid is not eco-friendly.
US 6385986 describes polymorphs of 4'-[2-n-propyl-4-methyl-6-(1-methylbenzimid- azol-2-yl) benzimidazol-1-ylmethyl] biphenyl-2-carboxylic acid (Telmisartan) i.e. polymorphic form B, mixtures of the polymorphs. The processes for preparing Telmisartan containing form B and the use for preparing a pharmaceutical composition. US '986 further describes that Telmisartan obtained process of as described in EP502314B1 to give a solid in the form of long needles which is difficult to filter, wash and isolate. It is further characterized that it requires a long time for drying due to the presence of solvent which forms large and hard fragments during the drying process. The fragments on grinding produce a dry powder which exhibits strong tendency to electrostatic charging and is virtually impossible to pour. The polymorphic form B of Telmisartan shows virtually no tendency to electrostatic charging and easy for suction filtration, centrifuge, washing, drying and is free-flowing even without being ground up.
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.
Hence, the prior art teaches a lengthy, complicated and industrially disadvantageous process for obtaining crystalline Telmisartan form A. 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. JMC-1993, vol-36, No25 pg-4040-4051 describes preparation of Telmisartan tert. butyl ester using BIM and 2-(4'bromomethyl phenyl) tert. butyl benzoate using pot. Tert butoxide as a base in DMSO as solvent.
Figure imgf000004_0001
Formula 6
The preparative details for compound of formula-VII on page-4049, coloumn-3, compound 33, paragraph-4; line1-4 reads as follows.
Potassium tert-butoxide was added to the solution of BIM in DMSO at room temperature followed by the addition of the compound of formula Vl. Upon stirring for 14 hrs, the mixture was poured into water and extracted with ethyl acetate, the combined extract was dried on MgSO4 and evaporated. Residue was purified by silica gel column chromatography to give compound of formula-VII. The above mentioned process uses chromatographic purification, which is generally cumbersome and time consuming process and also requires solvents in high volume.
US20060094883 describes a process for the preparing Telmisartan, wherein Telmisartan alkyl ester - a
Figure imgf000005_0001
compound of formula-ll is prepared , comprising the steps of :
(a) combining i.y-dimethyl^'-propyl-IH.S'H-p.S1 ] bibenzimidazole (referred to as BIM) of formula III,
Figure imgf000005_0002
Formula 3 with 4'-bromomethyl-biphenyl-2-carboxylic acid alkyl ester (referred to as BMBP alkyl ester) of formula IV1
Figure imgf000005_0003
Formula 4 an inorganic base and a low boiling point organic solvent, to obtain a mixture;
(b) heating the mixture obtained in step (a) to a temperature of about 55°C. to about 1200C;
(c) maintaining the mixture obtained in step (b) for about 1 hour to about 8 hours, to obtain Telmisartan alkyl ester of formula II; and
Figure imgf000006_0001
(d) recovering Telmisartan alkyl ester of formula II, wherein, R is a straight or branched chain C1-C4 alkyl.
WO2005108375 describes process for the preparation of Telmisartan, characterized in that 1H-Benzimidazole-2-n-propyl-4-methyl-6-(1 '-methyl benzimidazole- 2'yl) of formula (II) and methyl-4- (bromo methyl)biphenyl 2-carboxylate of formula (III) are subjected to
Figure imgf000006_0002
WO 2007/010558 describes a method for the preparation of Telmisartan involving
Telmisartan dihydrochloride which comprises, i) condensing 4-Methyl-2-n-propyl-IH- benzimidazole-6-carboxylic acid with N-Methyl- O-phenylene diamine dihydrochloride to yields 4-methyl-6 (1 -methyl benzimidazol-2- yl)-2-n-propyl IH- benzimidazole, ii) treating 4- methyl-6-(l -methyl benzimidazol-2-yl)-2-n-propyl-IH-benzimidazole with
4*- (bromomethyl)-2-biphenyl-2-carboxylate in presence of a base in an organic solvent and isolating the ester as acid addition salt, iii) converting ester acid addition salt to Telmisartan dihydrochloride and iv) converting Telmisartan dihydrochloride to Telmisartan. CN1344712 describes method comprising reaction of 4-methyl-6-(1-methyl-2(1H)- benzimidazolyl)-1H-benzimidazole with 4'-bromomethyl-biphenyl-2-carboxylic acid alkyl ester [wherein alkyl is methyl or ethyl] in solvent i.e. DMF, DMSO, THF, dioxane, chloroform, dichloroethane, etc. in the presence of base [such as Na alcoholate, triethylamine, tributylamine, tripropylamine, KOH, NaOH, CsOH, Ba(OH)2 etc.] as acid capturer at 20- 1000C for 8-10 hrs, and then hydrolyzing with acid (such as H2SO4, HCI, HBr, HOAc, etc) at room temp, to reflux temp, or with base in Ci-5 alc.-water at 20-1600C for 1-10 hour. WO 2006/125592 describes a new process for the preparation of saltans 2-butyl-3- [[2"-[1 -(triphenylmethyl)-i H- tetrazol-5-yl][1 , 1 '-biphenyl]-4-yl]methyl]-1 ,3-diazaspiro[4.4] non- 1-en-4-one is disclosed, which proceeds via novel intermediate, 4-[(2-butyl-4-oxo-1 ,3- diazaspiro[4.4]non-1-en-3-yl)methyl]phenylboronic acid (Formula (H)) or its analogs. Compound (II) reacts with 5-(2-bromophenyl)-1-(triphenylmethyl)-1H-tetrazole (III) in the presence of catalyst, using conditions of Suzuki reaction, to give trityl irbesartan (I), whereas analogs to compound (II) may give candesartan, valsartan, Telmisartan, losartan and olmesartan.
WO 2006/050509 describes the amorphous form of Telmisartan sodium and the preparation thereof. Also provided are the Telmisartan sodium polymorph crystal Forms 0 to
XIII and XV to XX and preparations thereof. Also provided are pharmaceutical composition of amorphous and polymorphic forms of Telmisartan sodium or mixtures thereof, and methods of treatment of a mammal in need thereof.
WO 2006/044754 describes a process for preparing Telmisartan and intermediates formed in the process.
WO 2004/087676 describes a novel method for the production of Telmisartan by reacting 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl)-benzimidazol with a compound of general formula (IV)1 in which Z is a leaving group, wherein the compound 2-cyano-4'-[2"- n-propyl-4"-methyl-6"-(1 '"-methylbenzimidazol-2l"-yl)benzimidazol-1 "-ylmethyl]biphenyl is obtained, and subsequently conducting hydrolysis of the nitrile to acid function.
WO2000/043370 describes polymorphs of 4'-[2-n-propyl-4-methyl-6(1 -methyl benzimidazol -2-yl) benzimidazol -1-ylmethyl] biphenyl-2-carboxylic acid (INN: Telmisartan), and in particular the polymorphous form B of formula (I), characterized by an endothermic peak at 183 ± 2°C during thermal analysis by differential scanning calorimetry. The invention also relates to mixtures of said polymorphs, methods for producing Telmisartan containing form B and to the use thereof in the preparation of a medicament.
Example-5 : Preparation of 4'-[[2-n-propyl-4methyl-6-(1-methylbenzimidazol-2-yl)- benzimidazol-1-yl]-methyl] biphenyl carboxylic acid [Telmisartan]
90 gm of ethyl-4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol- 1-yl]-methyl] biphenyl carboxylate was stirred with 810 ml aq. HCI [32-35 % wt/ vol] at 95±2°C for about 8-10 hours. The reaction mixture was cooled to 25-300C. 180 ml of Dichloromethane and 1350 ml of water were added, pH of the reaction mixture was adjusted to -9.0 to 10.0 using 20 % aq. NaOH. The reaction mixture was stirred at 30-350C for about 30 minutes and the layer was allowed to separate. 1800 ml of MDC was added to aqueous phase at 25-300C. pH of the solution was adjusted to ~3 to 3.5 with acetic acid. The mixture was stirred for about 20 minutes and the layer was allow to separate. The aqueous layer was extracted with 900 ml DCM and organic layer was separated and washed with 2 X 900 ml water. The organic phase was dried over anhy. Sodium sulfate and charcoalized followed by distillation to remove about 80-85 % of DCM at 40-420C. The reaction mixture was slowly cooled to 80C and stirred at 8-120C for about 1Hr. 2700 ml of acetone (100C was slowly added and temperature is maintained at 8-12°C.The reaction mixture was stirred for 2 hours with slow RPM. The mixture was filtered at 8-120C and washed with 2x180 ml of acetone. The product was obtained through suction drying for 30-45 minutes, and under vacuum at 85-900C. 70.0 gm of Telmisartan is obtained having purity of 99.84%.
..............................
PATENT
WO2009006860A2
Telmisartan (I) is produced in accordance with the original patent of Boehringer Ingelheim (US 5 591 762) from telmisartan tert-butyl ester (II). The hydrolysis is carried out using of trifluoroacetic acid in the toxic solvent N,N-dimethylformamide.
Figure imgf000003_0001
According to another patent applied by the same company (US 2004 236113) the manufacture was problematic and this is why this procedure was replaced with hydrolysis of the corresponding nitrile (III). However, during the hydrolysis, which is carried out with potassium hydroxide in ethylene glycol, a high temperature (160 0C) is used, which causes browning of the product, which must be subsequently purified by means of activated carbon. Also, the energy demands of several-ton production would be considerably high.
Figure imgf000003_0002
In a newer application of Cipla (WO 2005/10837) the last two synthetic steps (iii+iv) are combined and telmisartan is isolated after alkaline hydrolysis by acidifying of the reaction mixture in water or extraction with dichloromethane and precipitation with acetone. Both the ways of isolation are unsuitable for industrial production. In the case of telmisartan of crystalline form A its isolation from water or aqueous solutions of organic solvents is very difficult since a hardly filterable product is formed. Extraction of the product with dichloromethane and precipitation with acetone brings a well-filterable product, but the use of dichloromethane is virtually impossible from the point of view of environment protection.
Figure imgf000004_0001
Another method has been described by Dr. Reddy (WO 2006/044754), which starts from telmisartan methylester hydrochloride, which is hydrolyzed to produce the potassium salt of termisartan, which is further acidified in aqueous acetonitrile; after isolation it crystallizes from a dichloromethane/methanol mixture and finally from methanol alone, and wherein a pressure apparatus is used for the dissolution in methanol at a temperature above its boiling point (80 °C). The result of this complex procedure, which manifests the already above mentioned shortcomings, is a low yield of the product.
The method of Teva (WO 2006/044648) is in many aspects similar to the above mentioned procedure of Cipla, wherein the last two steps of the synthesis are also combined. The method comprises phase separations, which lead to low yields (69 % - 80 %) besides increased tediousness. Matrix starts from telmisartan tert-butyl ester (II), which is first converted to telmisartan dihydrochloride, which in turn, by action of aqueous ammonia in methanol, provides telmisartan with a low total yield of 73%.
Example 1
4'-[[4-methyl-6-(l-methyl-lH"-benzimidazol-2-yl)-2-proρyl-lH-benzimidazol- lyl]methyl]biphenyl-2-carboxylic acid (telmisartan)
Telmisartan methylester (VI) (40 g) was refluxed in methanol (440 ml) with potassium hydroxide (14.9 g) for 24 hours. To the boiling solution, methanol (240 ml) and then acetic acid (45.5 g) were added. While boiling, the mixture was stirred for another 1 hour, after cooling to 4°C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 35.18 g (90 %) of the product were obtained.
Analytic assessment: HPLC purity: 99.90 %,
Content of residual solvents: methanol (below the detection limit) acetic acid (360 ppm) Titration content: 100.9 % Sulfate ash content: 0.04 % DSC: form A
Example 2
4'-[[4-Methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-lH-benzimidazol- lyl]methyl]biphenyl-2-carboxylic acid (telmisartan)
Telmisartan methylester (VI) (20 g) was refluxed in methanol (300 ml) with potassium hydroxide (7 g ) for 24 h. After addition of formic acid (17 g) and after cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 18.7 g (96 %) of the product were obtained.
Example 3
4'-[[4-methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-l/J-benzimidazol- lyl]methyl]biρhenyl-2-carboxylic acid (telmisartan)
Telmisartan methylester (VT) (20 kg) was refluxed in methanol (400 1) with potassium hydroxide (7 kg) for 24 h. After addition of acetic acid (20 kg) and cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 1). After drying at the laboratory temperature (24 h) 18.5 kg (95 %) of the product were obtained. Example 4
4'-[[4-methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-lH'-benzimidazol- lyl]methyl]biphenyl-2-carboxylic acid (telmisartan)
Telmisartan methylester (40 g) was refluxed in methanol (240 ml) with potassium hydroxide (14.9 g) for 24 h. To the boiling solution methanol (240 ml) and then acetic acid (45.5 g) were added. After cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 36 g (92%) of the product were obtained.
................................
PAPER
Displaying image002.png
Org. Process Res. Dev.200711 (1), pp 81–85
DOI: 10.1021/op060200g
Abstract Image
Telmisartan (1), a substituted dibenzimidazole derivative, is an antihypertensive drug, essentially used to control blood pressure. An improved, cost-effective, and impurity-free process for telmisartan (1) suitable for large-scale production is described here by addressing various process development issues. The overall yield obtained from this newly developed process is around 50% (over five steps) compared to the literature reported process (21%, over eight steps).
4′-[(1,4′-Dimethyl-2′-propyl-[2,6′-bi-1H-benzimidazol]- 1′-yl)methyl]-[1,1′-biphenyl]-2-carboxylic Acid (1).
Telmisartan (1) as a white crystalline powder. Yield 7 g (77%); purity by HPLC 99.9%; mp 260- 262 °C; Pd content not detected; Heavy metals <10 ppm; MS m/z 515 (M+ + H);
1 H NMR (CDCl3) δ 12.8 (s, 1H), 7.05-7.5 (m, 14H), 5.60 (s, 2H), 3.82 (s, 3H), 2.97 (t, J ) 7.5, 2H), 2.63 (s, 3H), 1.88 (q, J ) 7.3, 2H), 1.04 (t, J ) 7.3, 3H);
13C NMR (DMSO-d6) δ 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, 133.7, 134.5, 140.2, 140.5, 150.2, 157.3, 168.1.
Anal. Calcd for C33H30N4O2: C, 77.02; H, 5.88; N, 10.89; O, 6.22. Found: C, 77.0; H, 5.82; N, 10.89; O, 6.20.
......................
PATENT
EP1719766A2
he present invention provides a process for the preparation of a compound of formula (I) or a salt thereof
Figure imgb0002
comprising the reaction of a compound of formula (II) or a salt thereof
Figure imgb0003
with a synthon of formula (III) or a salt thereof
Figure imgb0004
prepared by reaction of a compound of formula (IV)
Figure imgb0006
with a compound of formula (V)
Figure imgb0007
  • Telmisartan, 4'-[(1,7' -dimethyl-2' -propyl[2,5' -bis-l H-benzimidazol]-3'-yl)methyl][1,1'-biphenyl]-2-carboxylic acid is a known ACE inhibitor useful in therapy as antihypertensive agent. Its preparation is disclosed inEP 502314 and comprises the alkylation of 4-methyl-6-(1-methyl-benzimidazol-2-yl)-2-propylbenzimidazole (A) with t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate (B)
    Figure imgb0001
  • However, compound (B) is not commercially available and its synthesis requires a number of steps, among them the protection of the carboxylic function which is finally removed by hydrolysis. There is therefore the need for an alternative synthesis for the industrial preparation of telmisartan, which makes use of commercially available or easy to prepare intermediates and which, if possible, avoids the additional steps of protection and deprotection of the carboxylic function.
Example 4. 4'-[[4-Methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl]methyl]-2-biphenylcarboxylic acid (telmisartan)
  • (4'-Methyl-2'-propyl-1H-benzimidazol-6'-yl)-1-methyl benzimidazole (3.0 g, 9.8 mmol), 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl methanesulfonate (3.12 g, 10 mmol), tetrahydrofuran (15 ml) and potassium carbonate (1.38 g, 10 mmol) are loaded into a round-bottom flask equipped with magnetic stirrer, condenser and under nitrogen atmosphere. The mixture is stirred at room temperature for 8 hours, then 10% hydrochloric acid is added to pH=2.
  • THF is evaporated off, which causes precipitation of boronic acid. After recrystallization from ethyl acetate, 4.2 g of product are obtained.
  • The boronic acid (3.5 g, 8.0 mmol), ethyl 2-bromoacetate (1.83 g, 8.0 mmol), sodium hydroxide (1.28 g, 32 mmol), water (5 ml), tetrahydrofuran (20 ml), triphenylphosphine (315 mg, 1.2 mmol) and palladium acetate (90 mg, 0.4 mmol) are loaded into a round-bottom flask equipped with magnetic stirrer and condenser. All the residual air is removed with nitrogen and then the mixture is heated at 60°C for 18 hours, thereafter is cooled, added with water (30 ml) and tetrahydrofuran is evaporated off. Ethyl acetate is added (30 ml) and the mixture is acidified with acetic acid to pH=5. The product is filtered and washed with water, to obtain 2.8 g of crude telmisartan, which is purified by dissolution in concentrated ammonia (2 ml), addition of acetone and reprecipitation with acetic acid.
........................
PATENT
Figure imgb0005
  • Telmisartan and its physiologically acceptable salts have valuable pharmacological properties. Telmisartan is an angiotensin-II-antagonist, which may be used to treat hypertension and cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina). Furthermore, Telmisartan may be used to prevent the progression of cardiac insufficiency after myocardial infarct, to treat diabetic neuropathy, glaucoma, gastrointestinal diseases and bladder diseases. Telmisartan is also suitable for treating pulmonary diseases, e. g. lung oedema and chronic bronchitis, for preventing arterial restenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy. In view of the effects of angiotensin on the release of acetyl-choline and dopamine in the brain, Telmisartan is also suitable for alleviating central nervous system disorders, e. g. depression, Alzheimer's disease, Parkinson syndrome, bulimia and disorders of cognitive function.
  • Telmisartan is a compound of formula (I)
    Figure imgb0001
    chemically known as 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-2,5',-bibenzo[d]imidazol-3'-yl)methyl)biphenyl-2-carboxylic acid, which is disclosed in EP 502314 B1 and marketed under the trade name Micardis®.
  • Several methods have been used to prepare Telmisartan.
  • The process described inEP 502314 B1 comprises the alkylation of 4-methyl-6-(1-methyl-benzimidazol-2-yl)-2-propylbenzimidazole (III)
    Figure imgb0002
    with t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate and subsequently hydrolysis to Telmisartan. t-Butyl 4'-(bromomethyl)biphenyl-2-carboxylate is not commercially available and its synthesis requires a number of steps, among them the protection of the carboxylic function which is finally removed by hydrolysis.
  • The patent application WO 2006044648 relates to a method for the production of Telmisartan by reacting 4-methyl-6-(1-methyl-benzimidazol-2-yl)-2-propylbenzimidazole (III) with 4'-(bromomethyl)biphenyl-2-carboxylic acid alkyl ester and subsequently hydrolysis.
  • The patent application WO 2004087676 relates to a method for the production of Telmisartan by reacting 4-methyl-6-(1-methyl-benzimidazol-2-yl)-2-propylbenzimidazole (III) with 4-bromomethyl-2'-cyanobiphenyl and subsequently hydrolysis of the nitrile to the acid function.
  • The patent application EP 1719766 relates to a method for the production of Telmisartan, by coupling with a Suzuki reaction the N-4-bromobenzyl derivative of the compound of formula (III) with 2-carboxylphenyl boronic acid. As described in EP 1878735 , 2-carboxyphenyl boronic acid requires a very laborious process to separate it, since it is extremely soluble in water, making the process unattractive for an industrial application. Thus, the active substance prepared by the process known up till now can only be obtained in a satisfactory quality after running through a number of process steps, wherein additional steps of protection and deprotection of the carboxylic function or additional steps to obtain the carboxylic function are often present.
Example 2 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-bibenzo[d]imidazol-3'-yl)methyl)biphenyl-2-carboxylic acid (I)
  • Figure imgb0011
  • A 2L four-necked glass reactor, fitted with mechanical stirrer, thermometer, dropping funnel, under nitrogen atmosphere, was charged with sodium hydride (60% in mineral oil) (12.5 g, 312 mmol) and toluene (450 mL). The suspension was stirred and trimethylsilanol (31 g, 343 mmol) was added dropwise. After stirring for 15 minutes, methyl 4'-((1,7'-dimethyl-2'-propyl-1H, 3'H-2,5'-bibenzo[d]imidazol-3'-yl)methyl)biphenyl-2-carboxylate (V) (145 g, 274 mmol) was added, the mixture was stirred for 5 hours at about 100°C and monitored by quantitative TLC (elution with 5% MeOH in EtOAc) until complete conversion. The mixture was then cooled at room temperature, water (130 mL) was added, and the mixture was brought at 50°C. The phases were separated and the aqueous phase was stripped under vacuum to remove residual toluene.
    350 g of an aqueous solution were obtained and used as such in the next step.
  • A 1L four-necked glass reactor, fitted with mechanical stirrer, thermometer, dropping funnel, under nitrogen atmosphere, was charged with the aqueous solution in MeOH (600 mL). The mixture was heated under stirring at 40°C until dissolution and charcoal (7 g) was added. The suspension was stirred at 40°C for 30 minutes, filtered through a pad of Celite and the resulting solid was washed with a mixture of MeOH/water 4/1 (100 mL). The filtrate and the washings were combined, the resulting solution was heated to reflux temperature and acetic acid (17.7 g, 295 mmol) was added dropwise over 1 hour. The suspension was then cooled, filtered and the solid was washed with a mixture MeOH/water 4/1 (3 x 50 mL). The collected solid was then dried at 55°C under reduced pressure affording the title compound (130 g) as a white solid.
...........................
PATENT
WO2014067237A1
Telmisartan is a novel non-peptide angiotensin Π (ΑΤ Π) receptor antagonist, for the clinical treatment of hypertension, its chemical name is 4 '- [(1,4'-dimethyl - 2'-propyl [2,6'- two -1Η- benzoimidazol] -Γ--yl) methyl] biphenyl] -2-carboxylic acid, knot
Figure imgf000002_0001
Telmisartan
Telmisartan synthetic route has mainly 3-methyl-4-amino-benzoic acid methyl ester as the starting material by N- acylation, nitration, reduction, cyclization, ester hydrolysis and condensation reaction intermediates 2-n-propyl-4-methyl - 6 - (1 - methyl-benzimidazol-2-yl) benzimidazole-α), Ϊ with 4'-bromomethyl-biphenyl-2-carboxylate (V) via nucleophilic substitution, hydrolysis reaction to give the final product two Bu telmisartan (reaction formula 1) (J Med Chem, 1993, 36: 4040-4051).
Reaction Scheme 1
Figure imgf000002_0002
After has been reported by 4'-bromomethyl-biphenyl-2-carboxylic acid methyl ester (or ethyl ester) (VI) or 4'-bromomethyl-biphenyl-2-carbonitrile (VII) Preparation of telmisartan (CN01126367 .9, CN01131915.1).
Figure imgf000003_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000009_0002
Example 16: Preparation of telmisartan
The title compound of Example 15 (III, R = CN) (24.8g, 0.05mol) was added propylene glycol (100ml) and water (100ml) (or other previously described embodiments will be an aqueous mixed solvent :), potassium hydroxide (or e.g. prior to said other inorganic bases) (0.2mol), was refluxed for 10 hours. After no starting material by TLC was cooled to room temperature, concentrated under reduced pressure to a small volume, was added dropwise hydrochloric acid adjusted to pH 5 to 6, the precipitated solid was filtered, washed with water to obtain telmisartan.
Telmisartan Preparation: 17 Examples
The title compound I (30.4g, 0.10moi>, embodiments of Example 14 4'-chloro-methyl-biphenyl-2-carbonitrile (0.12mol), sodium ethoxide (or other organic bases as previously described) (0.3mol) and DMF (or other solvent as previously described) (200ml) mixed, 65 ° C for about 5 hours. TLC detected no starting material, was added ethylene glycol (100ml and water (50ml) (or other aqueous solvent), and heated to 160 ° C. TLC detected no starting material, concentrated hydrochloric acid under ice cooling to adjust pH to 5-6, to precipitate a solid, the resulting solid was filtered, washed with water to give crude telmisartan, by recrystallization in telmisartan.
Examples 18 to 24: Preparation of telmisartan reference method of Example 8, the title compound of Example 6 to the compound of formula I (10g, leq) and implemented as a reactant, with NaH as a base, the reaction temperature under different conditions the reaction, the reaction solution was subjected to phase detection by conventional post-treatment to give telmisartan (crude), yield was calculated, and the purity of the liquid phase detection telmisartan. The test results are shown in Table 2.
Table 2 compares the reaction conditions
Figure imgf000019_0001
 ..........................
PATENT
WO2011077444A1

1 Telmisartan .....................................2 Impurity B
Table 1 : Preparation of Telmisartan and 2 with reported synthetic schemes

process for the preparation of telmisartan, comprising: condensation of -n-propyl-4-methyl-6-(l'-methylbenzimidazol-2'-yl)benzimidazole (I)

with a compound of general formula II)

wherein Z denotes a leaving group such as a halogen atom, for example, a chlorine, bromine, or iodine atom to obtain the compound 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-( 1 "'-methylbenzimidazol-2"'-yl)benzimidazol- 1 "-ylmethyl]biphenyl (III), and subsequent

hydrolysis of nitrile in the presence of excess base and solvent followed by acid/base purification to obtain pure telmisartan.
Scheme-I

EXAMPLES:
Experiment-1: Preparation of 2-cyano-4-[2-n-propyl-4-methyI-6-(l- methylbenzimidazol-2-yl) bnzimidazol-l-ylmethyl] biphenyl.
Add 2-n-propyl-4-methyl-6-(l '-methylbenzimidazol-2'-yl) benzimidazole 100 g in 1000ml of acetone and of potassium hydroxide 22.0 g with stirring at 20-25°C. Then of 4-bromomethyl-2'-cyanobiphenyl 92g is added at 20-25°C. Monitor the reaction on thin layer chromatography, after compilation reaction, the crystals are suction filtered, washed with chilled acetone, water, and then dried in a air drying cupboard at 80° C. Yield: 135.0 g (82.82% of theory); melting point: 196° C.-197° C; HPLC: 99.30%. N-3 isomer: 0.08%.
Experiment-2: Preparation of 2-cyano-4-[2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl) benzimidazol-l-ylmethyl] biphenyl.
Add 2-n-propyl-4-methyl-6-( -methylbenzimidazol-2'-yl) benzimidazole 100 g in 1000ml of acetone and of potassium hydroxide 22.0 g with stirring at 20-25°C. Then of 4-bromomethyl-2'-cyanobiphenyl 92g is added at 20-25 °C. Monitor the reaction on thin layer chromatography, after the reaction is completed, cooled to 0 to 5.0° C. and stirred for another hour at this temperature. The material is filtered, washed with chilled acetone, then wash with water, and then dried in a air drying cupboard at 80° C. Yield: 141.50 g (87.73% of theory); melting point: 196° C.-197° C; HPLC: 99.50%. N-3 isomer: 0.16%
Experiment-3: Preparation of Telmisartan.
Add potassium hydroxide 80g in 500ml of ethylene glycol then add 2-cyano-4'- [2-n-propyl-4-methyl-6-( 1 -methyl benzimidazol-2-yl) benzimidazol- 1 -ylmethyl] biphenyl lOOgm at room temperature. Stir the reaction mixture and raise temperature to 150- 155° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 30 to 35°C then diluted with 800 ml methanol then telmisartan precipitates by adding of acetic acid at 25 to 30°C and further diluted with water. Then stirred for further 90min at 25 to 30°C. After the crystals have been suction filtered. The wet material dissolve in 500ml methanol with 12gm potassium hydroxide then after treatment of charcoal crystallize the telmisartan to adjusting of pH 6.0 to 6.4 by acetic acid then dilute with 400ml water. Filtered and then dried in a vacuum tray drier at 85°C. Yield: 90g (87.37% of theory); HPLC: 99.91%.
Experiment-4: Preparation of Telmisartan.
Add potassium hydroxide lOOg in 500ml of ethylene glycol then add 2-cyano- 4'-[2-n-propyl-4-methyl-6-(l -methyl benzimidazol-2-yl) benzimidazol- 1 -ylmethyl] biphenyl 1 OOgm at room temperature. Stir the reaction mixture and raise temperature to 150-155° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 30 to 35°C then diluted with 800ml methanol then telmisartan crystallize by adding of acetic acid at 25 to 30°C then dilute with 300ml water. Stir for further 90min at 25 to 30°C. Filter and then dried in a vacuum drying cupboard at 85°C. Yield: 101 g (1.03% of theory); HPLC: 99.90%.
Experiment-5: Preparation of pure Telmisartan.
Crude telmisartan 101 g (from example 4) & activated carbon lOg is added in methanol 100ml , dichloromethane 500ml at 25 to 30°C. Stir the reaction mixture then the brown solution is filtered through hyflow bed, Completely distilled out filtrate below 50°C then add 800ml water at that temperature and stir for lhr. The telmisartan is hot filtered and washed with water. The telmisartan is dried at 80° C. in a vacuum drying cupboard. Yield: 90 g (87.37% of theory); HPLC: >99.95%.
Experiment-6: Preparation of Telmisartan.
2-cyano-4'- [2-n-propyl-4-methyl-6-( 1 -methyl benzimidazol-2-yl) benzimidazol- 1 - ylmethyl] biphenyl lOOgm is added in 500ml of ethylene glycol with lOOg of potassium hydroxide powder at 20-25°C. Stir and raise temperature to 160° C. to 165° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 70 to 75°C then diluted with methanol and water then telmisartan crystallize by adding of acetic acid to adjust the pH 5.5 to 6.0 at 25 to 30°C. Stir for further 60min at 25 to 30°C. After the crystals have been suction filtered. The wet material dissolve in methanol with potassium hydroxide 12gm then after treatment of charcoal crystallize the telmisartan by adding of acetic acid by adjusting of pH 6.0 to 6.4 then stir for further 60min. The material is filtered and dried in a vacuum drying cupboard at 85°C. Yield: 86.56g (84.03% of theory); HPLC: >99.96%.
Experiment-7: Preparation of Telmisartan.
of 2-n-propyl-4-methyl-6-(r-methylbenzimidazol-2'-yl) benzimidazole 100 g is add in 1000 ml of acetone, and of potassium hydroxide 22 gm with stirring at 20-25° C and then 90.0 g of 4-bromomethyl-2'-cyanobiphenyl is added at 20-25°C. The temperature of the reaction mixture is maintained at 20 to 25° C. Stir for a further 6.0 to 8.0 hours at 20 to 25° C. Monitor the reaction on thin layer chromatography, after compilation reaction distil out acetone. Add ethylene glycol 500ml and potassium hydroxide lOOgm to residue Stir the reaction mixture and raise temperature to 150° C. to 155° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 30 to 35°C. Reaction mass diluted with methanol and stir for 30min then telmisartan precipitated by adding of acetic acid to adjust the pH 6.0 to 6.5 at 25 to 30°C. Then dilute with water and filter, wash with of methanol. Wet telmisartan is dissolved in methanolic potassium hydroxide, filtered to remove un dissolved material. Acetic acid is added to adjust the pH 6.0 to 6.4 , water added for complete precipitation of material. Finally telmisartan is suction filter and wash with water at 40 to 45 °C. The telmisartan is dried at 80° C. in a vacuum drying cupboard. Yield: 130g
HPLC: 99.4%.
1H NMR (DMSO-d6) δ 1.0 (t,3H), 1.9 (q, 2H), 2.95 (t, 2H), 2.4 (s, 3H), 3.95 (s, 3H), 5.8 (s, 2H), 7.28 (s,lH),7.80 (s,lH), 7.75 (d, 2H), 7.25 (t, 2H), 7.10 (d, 2H), 7.30 (d, 2H), 7.40 (d, 1H), 7.40 (t, 1H), 7.30 (t, 1H), 7.45 (d, 1H). 12.9 (s, 1H).
m/z 514.7 [ M + H]+.
 .....................
PATENT
US 6358986
Figure US06358986-20020319-C00002
EXAMPLE
3185 kg of recrystallised telmisartan (recrystallised from dimethylformamide or dimethylacetamide), 5.6 kg of activated charcoal, 185 l of water, 190.4 kg of formic acid (99-100%) and 185 l of methylethylketone are placed in a 1200 l stirring apparatus. The mixture is stirred for about 1 h at 60-70° C. and then filtered into another 1200 l stirring apparatus and washed with a mixture of 74 l of methylethylketone and 8.3 kg of formic acid (99-100%). About 278 l of solvent are distilled off at 80-100° C. whilst simultaneously 278 l of water are added. The mixture is then cooled to 20-30° C. and precipitated by the metered addition of 281.5 kg of 25% ammonia solution. The product precipitated is centrifuged, washed with water and dried at 120-125° C. Yield: 178 kg of telmisartan (96.2% of theory)
Comparison Example
150 kg of telmisartan (recrystallised from dimethylformamide or dimethylacetamide), 7.5 kg of activated charcoal, 750 l of ethanol and 30 kg of 25% aqueous ammonia solution are placed in a 1200 l stirring apparatus. The mixture is stirred for about 1 h and then filtered into another 1200 l stirring apparatus and washed with 150 l of ethanol. The mixture is heated to 70-80° C., 35 kg of glacial acetic acid are added and the mixture is stirred for a further 1.5-2 h at 75-80° C. The mixture is then cooled to 0-10° C. and stirred for a further 2 h. The product precipitated is centrifuged, washed with 300 l of ethanol and with 300 l of water and dried at 70-90° C. Yield: 135 kg of telmisartan (90% of theory) pure form AIn the preparation process according to the invention, as a result of the partial conversion of the polymorphic form B into the polymorphic form A during the drying process, telmisartan occurs as a pure substance in a mixture of two polymorphic forms. However, this does not affect the properties of the pharmaceutical composition, as in the course of the manufacture of telmisartan tablets, for example, the mixture of the polymorphic forms A and B is dissolved in 0.1 N NaOH solution and converted by spray drying into a homogeneous and totally amorphous granulate which is then subjected to the other tablet making steps. For more detailed information on the use of the products according to the invention for preparing a pharmaceutical composition, cf. EP 502314 B1, the contents of which are hereby referred to.
 ................................
PATENT
WO2009006860A2
Telmisartan (I) is produced in accordance with the original patent of Boehringer Ingelheim (US 5 591 762) from telmisartan tert-butyl ester (II). The hydrolysis is carried out using of trifluoroacetic acid in the toxic solvent N,N-dimethylformamide.
Figure imgf000003_0001
According to another patent applied by the same company (US 2004 236113) the manufacture was problematic and this is why this procedure was replaced with hydrolysis of the corresponding nitrile (III). However, during the hydrolysis, which is carried out with potassium hydroxide in ethylene glycol, a high temperature (160 0C) is used, which causes browning of the product, which must be subsequently purified by means of activated carbon. Also, the energy demands of several-ton production would be considerably high.
Figure imgf000003_0002
In a newer application of Cipla (WO 2005/10837) the last two synthetic steps (iii+iv) are combined and telmisartan is isolated after alkaline hydrolysis by acidifying of the reaction mixture in water or extraction with dichloromethane and precipitation with acetone. Both the ways of isolation are unsuitable for industrial production. In the case of telmisartan of crystalline form A its isolation from water or aqueous solutions of organic solvents is very difficult since a hardly filterable product is formed. Extraction of the product with dichloromethane and precipitation with acetone brings a well-filterable product, but the use of dichloromethane is virtually impossible from the point of view of environment protection.
Figure imgf000004_0001
Another method has been described by Dr. Reddy (WO 2006/044754), which starts from telmisartan methylester hydrochloride, which is hydrolyzed to produce the potassium salt of termisartan, which is further acidified in aqueous acetonitrile; after isolation it crystallizes from a dichloromethane/methanol mixture and finally from methanol alone, and wherein a pressure apparatus is used for the dissolution in methanol at a temperature above its boiling point (80 °C). The result of this complex procedure, which manifests the already above mentioned shortcomings, is a low yield of the product.
The method of Teva (WO 2006/044648) is in many aspects similar to the above mentioned procedure of Cipla, wherein the last two steps of the synthesis are also combined. The method comprises phase separations, which lead to low yields (69 % - 80 %) besides increased tediousness. Matrix starts from telmisartan tert-butyl ester (II), which is first converted to telmisartan dihydrochloride, which in turn, by action of aqueous ammonia in methanol, provides telmisartan with a low total yield of 73%.
WO2009006860A2
Example 3
4'-[[4-methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-l/J-benzimidazol- lyl]methyl]biρhenyl-2-carboxylic acid (telmisartan)
Telmisartan methylester (VT) (20 kg) was refluxed in methanol (400 1) with potassium hydroxide (7 kg) for 24 h. After addition of acetic acid (20 kg) and cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 1). After drying at the laboratory temperature (24 h) 18.5 kg (95 %) of the product were obtained.
Example 4
4'-[[4-methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-lH'-benzimidazol- lyl]methyl]biphenyl-2-carboxylic acid (telmisartan)
Telmisartan methylester (40 g) was refluxed in methanol (240 ml) with potassium hydroxide (14.9 g) for 24 h. To the boiling solution methanol (240 ml) and then acetic acid (45.5 g) were added. After cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 36 g (92%) of the product were obtained.
.....................................
PATENT
WO2010004385
Telmisartan was first disclosed in US 5,591,762. US 5,591,762 also discloses a process for the preparation of Telmisartan by reacting l,4'-dimethyl-2'-propyl[2,6'-bi-lH- benzimidazole (II) with 4'-(bromomethyl)[l,r-biphenyl]-2-carboxylic acid 1,1- dimethylethyl ester (III) in a solvent optionally in the presence of an acid binding agent to produce the intermediate 4'-[(l,4'-dimethyl-2'-propyl[2,6l-bi-lH-benzimidazol]-l- yl)methyl]-[l,l'-biphenyl]-2-carboxylic acid 1,1-dimethylethyl ester (IV), which is further hydrolysed to produce crude Telmisartan. The crude product obtained is purified over a silica gel column and finally crystallized from acetone. The process is shown in Scheme 1 :
Figure imgf000003_0001
Hydrolysis
Figure imgf000003_0002
(I)
The disadvantage with the above process is the use of column chromatography in the purification of Telmisartan. Employing column chromatography technique is tedious and laborious and also involves use of large quantities of solvents, and hence is not suitable for industrial scale operations.
US 6,358,986 describes two crystalline forms of Telmisartan donated as Form A, Form B. In US 6,358,986, the process for preparing crystalline Telmisartan Form A comprises mixing the Telmisartan with ethanol, adding activated charcoal and aqueous ammonia and mixing for one hour, then filtering to another stirring apparatus and washing with ethanol. Resulting solution is heated 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 US '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 US '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 US '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.
US 2006/0276525 Al describes a process for the preparation of crystalline solid of Telmisartan Form A by dissolving Telmisartan in a polar solvent such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), ΛζiV-dimethylacetamide (DMA)5 iV-methyl-2-pyrrolidone (ΝMP) and cooling the solution for sufficient time to produce Telmisartan Form A crystals, which are filtered and dried.
EXAMPLE-8
PREPARATION OF 4'-[[4-METHYL-O-(I-METHYL-Z-BENZIMIDAZOLYL) ^- PROPYL-1-BENZIMIDAZOLYL] METHYL]-Z-BIPHENYLCARBOXYLIC
ACID [TELMISARTAN]
Powdered sodium hydroxide (6.83 g) was added in N,N~dimethylformamide (175 ml) at 4°C followed by 4-methyl-6-(l-methyl-2-benzimidazolyl)-2 -propyl- 1- benzimidazole monohydrate (50 g) and stirred for 5 min. Thereafter, methyl-2-[4'- (bromomethylphenyl)]benzoate (54.76 g) was added at 0°C and stirred to the reaction mass till completion of the reaction. Methylene chloride (250 ml) was added, followed by water (500 ml) at 20C and stirred for 10 min. The aqueous layer was separated and extracted with methylene chloride (50 ml). The combined organic extract was washed with water (250 ml) to obtain 380 ml of the organic solution containing Telmisartan methyl ester. 320 ml of this organic layer was concentrated at ambient pressure to collect 210 ml of the distillate. Methanol (120 ml) was added to the concentrated mass and distilled to collect 96 ml of the distillate. The concentrated mass was diluted with 160 ml of methanol at 5O0C. Thereafter, aqueous sodium hydroxide solution (17.4 g of NaOH in 40 ml of water) was added at 5O0C and heated to reflux at 69-7O0C and stirred at reflux temperature till completion of hydrolysis reaction. Thereafter, the reaction mass was concentrated under reduced pressure at 60-650C till no more solvent distils. Water (600 ml) and methylene chloride (200 ml) was added to this solution. pH was adjusted to 4 with hydrochloric acid (22 ml, 35% w/w) at 27-28°C. The aqueous layer was separated and extracted with methylene chloride (40 ml). The combined organic layer was washed with water (80 ml) to obtain 280 ml of the organic solution. This is divided in to four parts and taken for isolation of Telmisartan as given below.
Part-1 The organic layer (70 ml) as obtained above was diluted with N,N-dimethylformamide (500 ml) at 27°C and seeded with Telmisartan form-A. The solution was left on standing without stirring for 30 min. The resulting suspension was stirred at 27-28°C for 30 min at this temperature. Solid was filtered, washed with precooled N5N- dimethylformamide (15 ml, -5°C) followed by precooled ethanol (10 ml, -2°C) and dried at 85-900C under reduced pressure to afford 10.1 g of Telmisartan.
Part-2
The organic layer (70 ml) as obtained above was diluted with N,N-dimethylformamide (50 ml) at 27°C and seeded with Telmisartan form-A. The solution was left on standing without stirring for 30 min. The resulting suspension was concentrated under reduced pressure at 65-700C to collect 30 ml of the distillate. Thereafter, the concentrated mass was cooled to -5°C and stirred for 30 min at this temperature. Product was filtered, washed with precooled N,N-dimethylformamide (15 ml, -3°C) followed by precooled ethanol (10 ml, -2°C) and dried at 85-900C under reduced pressure to afford 11.4 g of Telmisartan.
Part-3
The organic layer (70 ml) as obtained above was diluted with N,N-dimethylformamide (60 ml) at 27°C and seeded with Telmisartan form-A. The solution was left on standing without stirring for 30 min. The resulting suspension was concentrated under reduced pressure at 65-70°C to collect 50 ml of the distillate. Thereafter, stirred at 30°C for 15 min, cooled to -5°C and stirred for 30 min at this temperature. Product was filtered, washed with precooled N,N-dimethylformamide (15 ml, -5°C) followed by precooled ethanol (10 ml, -20C) and dried at 85-900C under reduced pressure to afford 11.7 g of Telmisartan.
Part-4
The organic layer (70 ml) as obtained above was diluted with N,N-dimethylformamide (40 ml) at 27°C arid seeded with Telmisartan form-A. The solution was left on standing without stirring for 30 min. The resulting suspension was concentrated under reduced pressure at 65-700C to collect 45 ml of the distillate. Thereafter, stirred at 300C for 15 min, cooled to -5°C and stirred for 30 min at this temperature. Product was filtered, washed with precooled N,N-dimethylformamide (15 ml, -5°C) followed by precooled ethanol (10 ml, -20C) and dried at 85-900C under reduced pressure to afford 12.3 g of Telmisartan.
.......................................
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; LIU, LI-YAN: "Study on the optimization synthesis of telmisartan" XP002548425 retrieved from STN Database accession no. 2007:587025 & HUAXUE GONGCHENGSHI , 21(3), 60-61 CODEN: HGUOAP; ISSN: 1002-1124, 2007,
WO2006044754A2 *18 Oct 200527 Apr 2006Muthulingam ArunagiriProcess for preparing telmisartan
WO2009006860A2 *8 Jul 200815 Jan 2009Zentiva AsA method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan)
EP0502314A1 *31 Jan 19929 Sep 1992Dr. Karl Thomae GmbHBenzimidazol, medicaments containing them and process for their preparation
US20060211866 *21 Mar 200621 Sep 2006Glenmark Pharmaceuticals LimitedProcess for the preparation of angiotensin receptor blockers and intermediates thereof
US673743230 Oct 200218 May 2004Boehringer Ingelheim Pharma KgCrystalline form of telmisartan sodium
US719308917 Mar 200420 Mar 2007Boehringer Ingelheim International GmbhProcess for manufacture of telmisartan
US750144813 Oct 200510 Mar 2009Teva 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
US751114530 Jul 200431 Mar 2009Genelabs Technologies, Inc.Bicyclic heteroaryl derivatives
US794378118 Oct 200517 May 2011Dr. Reddy's Laboratories LimitedProcess for preparing telmisartan
US8541593 *20 Jun 200824 Sep 2013Amgen Inc.Process for making substituted 2-amino-thiazolones
US869199910 May 20058 Apr 2014Cipla LimitedProcess for the preparation of telmisartan
US20100222402 *8 Jul 20082 Sep 2010Jan StachMethod of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan)
US20100280255 *20 Jun 20084 Nov 2010Amgen Inc.Process for making substituted 2-amino-thiazolones
US20120196896 *17 Sep 20102 Aug 2012Georgetown UniversityTreatment for Oxidative Stress and/or Hypertension
EP2420231A24 Oct 200722 Feb 2012Boehringer Ingelheim Vetmedica GmbHAngiotensin II receptor antagonist for the prevention or treatment of cardiovascular disease in cats
EP2420232A24 Oct 200722 Feb 2012Boehringer Ingelheim Vetmedica GmbHAngiotensin II receptor antagonist for the prevention or treatment of cardiovascular diseases in cats
EP2420233A24 Oct 200722 Feb 2012Boehringer Ingelheim Vetmedica GmbHAngiotensin II receptor antagonist for the prevention or treatment of systemic diseases in cats
WO2005108375A1 *10 May 200517 Nov 2005Cipla LtdProcess for the preparation of telmisartan
WO2009006860A2 *8 Jul 200815 Jan 2009Zentiva AsA method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan)
WO2010075347A222 Dec 20091 Jul 2010Takeda Pharmaceutical Company LimitedMethods of treating hypertension with at least one angiotensin ii receptor blocker and chlorthalidone
EP0502314B131 Jan 199220 May 1998Dr. Karl Thomae GmbHBenzimidazol derivatives, medicaments containing them and process for their preparation
WO2010018441A2 *10 Aug 200918 Feb 2010Cadila Pharmaceuticals Ltd.An improved process for the preparation of substantially pure telmisartan
WO2010146187A2 *21 Jun 201023 Dec 2010Krka, Tovarna Zdravil, D.D., Novo MestoProcess for the preparation of telmisartan
WO2011077444A1 *28 May 201030 Jun 2011Inogent Laboratories Private LimitedA new process for the preparation of pure telmisartan
WO2012028925A2 *29 Aug 20118 Mar 2012Ogene Systems (I) Pvt LtdAn improved process for the preparation of telmisartan
CN1768044A *26 Mar 20043 May 2006贝林格尔·英格海姆国际有限公司Process for manufacture of telmisartan
CN102731407A *4 Jul 201217 Oct 2012宁波九胜创新医药科技有限公司Method for preparing telmisartan
EP0627433A1 *7 Dec 19937 Dec 1994Eisai Co., Ltd.Process for producing imidazopyridine derivative and intermediate
EP2123648A1 *20 May 200825 Nov 2009Chemo Ibérica, S.A.A process for the preparation of Telmisartan.
EP2305650A1 *21 Sep 20096 Apr 2011Chemo Ibérica, S.A.Novel process for the preparation of telmisartan
EP0502314B131 Jan 199220 May 1998Dr. Karl Thomae GmbHBenzimidazol derivatives, medicaments containing them and process for their preparation
EP1719766A218 Apr 20068 Nov 2006Dipharma S.p.A.A process for the preparation of telmisartan
EP1878735A128 Jun 200716 Jan 2008Dipharma Francis S.r.l.Process for the preparation of boronic acids and derivatives thereof
WO2004087676A126 Mar 200414 Oct 2004Boehringer Ingelheim IntMethod for the production of telmisartan
WO2006044648A113 Oct 200527 Apr 2006Teva PharmaProcess for preparing telmisartan
WO2006136916A2 *20 Jun 200628 Dec 2006Glenmark Pharmaceuticals LtdSubstantially pure micronized particles of telmisartan and pharmaceutical compositions containing same
EP1878735A1 *28 Jun 200716 Jan 2008Dipharma Francis S.r.l.Process for the preparation of boronic acids and derivatives thereof
EP2103609A1 *20 Mar 200823 Sep 2009Lek Pharmaceuticals D.D.Catalyzed carbonylation in the synthesis of angiotensin ii antagonists
EP2123648A120 May 200825 Nov 2009Chemo Ibérica, S.A.A process for the preparation of Telmisartan.
EP2149566A115 Jul 20083 Feb 2010Chemo Ibérica, S.A.A process for the preparation of telmisartan
EP2305650A121 Sep 20096 Apr 2011Chemo Ibérica, S.A.Novel process for the preparation of telmisartan
CN102015690B19 Mar 200930 Apr 2014力奇制药公司Catalyzed carbonylation in the synthesis of angiotensin II antagonists
US841028519 Mar 20092 Apr 2013Lek Pharmaceuticals D.D.2′-halobiphenyl-4-yl intermediates in the synthesis of angiotensin II antagonists
US844569319 Mar 200921 May 2013Lek Pharmaceuticals D.D.Catalyzed carbonylation in the synthesis of angiotensin II antagonists
WO2009115585A1 *19 Mar 200924 Sep 2009Lek Pharmaceuticals D.D.Catalyzed carbonylation in the synthesis of angiotensin ii antagonists
WO2009123483A130 Mar 20098 Oct 2009Zaklady Farmaceutyczne Polpharma SaProcess for preparation of telmisartan
WO2010018441A2 *10 Aug 200918 Feb 2010Cadila Pharmaceuticals Ltd.An improved process for the preparation of substantially pure telmisartan
WO2010146187A221 Jun 201023 Dec 2010Krka, Tovarna Zdravil, D.D., Novo MestoProcess for the preparation of telmisartan
EP0502314A1 *31 Jan 19929 Sep 1992Dr. Karl Thomae GmbHBenzimidazol, medicaments containing them and process for their preparation
DE4142366A1 *20 Dec 199124 Jun 1993Thomae Gmbh Dr KNew phenylalkyl derivs. - are angiotensin II antagonists used to treat hypertension, coronary insufficiency, angina, cns disorders etc.
US20040162327 *12 Feb 200419 Aug 2004Boehringer Ingelheim Pharma KgTreatment of hypertension and cardiac insufficiency, ischaemic peripheral circulatory disorders, diabetic neuropathy, glaucoma, gastrointestinal diseases and bladder diseases
WO2004087676A1 *26 Mar 200414 Oct 2004Boehringer Ingelheim IntMethod for the production of telmisartan
WO2005108375A110 May 200517 Nov 2005Cipla LtdProcess for the preparation of telmisartan
WO2006044648A1 *13 Oct 200527 Apr 2006Teva PharmaProcess for preparing telmisartan
WO2006044754A2 *18 Oct 200527 Apr 2006Muthulingam ArunagiriProcess for preparing telmisartan
US6358986 *10 Jan 200019 Mar 2002Boehringer Ingelheim Pharma KgPolymorphs of telmisartan
US2004023611317 Mar 200425 Nov 2004Boehringer Ingelheim International GmbhProcess for manufacture of telmisartan
WO2010004385A1 *15 Jun 200914 Jan 2010Aurobindo Pharma LimitedProcess for the preparation of pure 4'-[4-methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl]methyl]-2-biphenylcarboxylic acid
WO2010018441A2 *10 Aug 200918 Feb 2010Cadila Pharmaceuticals Ltd.An improved process for the preparation of substantially pure telmisartan
WO2012055941A126 Oct 20113 May 2012Krka,Tovarna Zdravil, D. D., Novo MestoMultilayer pharmaceutical composition comprising telmisartan and amlodipine
WO2005108375A1 *10 May 200517 Nov 2005Cipla LtdProcess for the preparation of telmisartan
WO2006044754A2 *18 Oct 200527 Apr 2006Muthulingam ArunagiriProcess for preparing telmisartan
WO2009006860A2 *8 Jul 200815 Jan 2009Zentiva AsA method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan)
EP1719766A2 *18 Apr 20068 Nov 2006Dipharma S.p.A.A process for the preparation of telmisartan
US20060211866 *21 Mar 200621 Sep 2006Glenmark Pharmaceuticals LimitedProcess for the preparation of angiotensin receptor blockers and intermediates thereof
US20060276525 *17 May 20067 Dec 2006Itai AdinProcesses of preparing highly pure telmisartan form A, suitable for pharmaceutical compositions