Efficient and improved synthesis of Telmisartan
(lit mp 260–262 °C);
LIT...... Reddy, K. S.; Srinivasan, N.; Reddy, C. R.; Kolla, N.; Anjaneyulu, Y.; Venkatraman, S.; Bhattacharya, A.; Mathad, V. T. Org. Process Res. Dev. 2007, 11, 81–85. doi:10.1021/op060200g
IR (KBr, cm-1) 2300–3500 (broad), 1680 (C=O);
HRMS m/z calculated for C33H30N4O2 – 515.6169 [M + 1], found – 515.6192;
1H NMR (400 MHz, CDCl3) (δ ppm): 12.8 (1H, s, -COOH), 8.42 (1H, d, J = 8.0 Hz, ArH), 8.02 (1H, d, J = 8.0 Hz, ArH), 7.50–7.26 (8H, m, ArH), 7.20 (2H, d, J = 8.0 Hz, ArH), 7.05 (1H, s, ArH), 6.96 (1H, s, ArH), 5.42 (2H, s, -CH2), 3.82 (3H, s, -CH3), 2.97 (2H, t, J = 7.6 Hz, -CH2), 2.74 (3H, s, -CH3), 1.92 (2H, m, J = 7.6 Hz, -CH2), 1.04 (3H, t, J = 7.6 Hz, -CH3);
13C NMR (100 MHz, DMSO-d6) (δ ppm): 13.5, 16.7, 20.6, 27.6, 32.7, 47.1, 51.7, 112.0, 112.7, 114.7, 118.6, 125.3, 125.7, 125.8, 127.0, 127.4, 128.6, 129.3, 130.4, 130.6, 131.5, 132.3, 133.1, 133.2, 133.7, 134.5, 140.2, 140.5, 150.2, 157.3, 168.1.
An improved synthesis of Telmisartan: an antihypertensive drug
A. Sanjeev Kumar, Samir Ghosh, R. Soundararajan,* and G. N. Mehta
Chemistry Section, Applied Sciences and Humanities Department, SVNIT, Surat-395 007, India
General Papers ARKIVOC 2009 (x) 247-254
melting point: 260-262
°C (lit---Venkataraman, S.; Mathad, V. T.; Kikkuru, S. R.; Neti, S.; Chinta, R. R.; Apuraba, B.;
Anjaneyulu,Y.; Naveenkumar, K. Org. Process Res. Dev. 2007, 11, 81.
mp 260-262 °C);
IR (KBr, cm-1) 2300-3500 (broad), 1680 (C=O);
1H NMR (400 MHz, CDCl3) (δ ppm): 12.8 (1H, s, -COOH), 8.42 (1H, d, J = 8.0 Hz, ArH), 8.02 (1H, d, J = 8.0 Hz,
ArH), 7.50-7.26 (8H, m, ArH), 7.20 (2H, d, J = 8.0 Hz, ArH), 7.05 (1H, s, ArH), 6.96 (1H, s,
ArH), 5.42 (2H, s, -CH2), 3.82 (3H, s, -CH3), 2.97 (2H, t, J = 7.6 Hz, -CH2), 2.74 (3H, s, -CH3),
1.92 (2H, m, J = 7.6 Hz, -CH2), 1.04 (3H, t, J = 7.6 Hz, -CH3);
13C NMR (400 MHz, DMSO-d6)
(δ ppm): 13.5, 16.7, 20.6, 27.6, 32.7, 47.1, 51.7, 112.0, 112.7, 114.7, 118.6, 125.3, 125.7, 125.8,
127.0, 127.4, 128.6, 129.3, 130.4, 130.6, 131.5, 132.3, 133.1, 133.2, 133.7, 134.5, 140.2, 140.5,
150.2, 157.3, 168.1;
MS (m/z): 515 [M+ + 1];
Anal. Calcd for C33H30N4O2: C, 77.02; H, 5.88; N,
10.89; O, 6.22. Found: C, 77.0; H, 5.82; N, 10.86.
crystals and other data
An Improved, Scalable and Cost Effective One-Pot Synthesis of
Premchand B. Patil1*
, Anand Pandey1
, Devanand B. Shinde2and Bhata R. Chaudhari1*
1Organic Research Laboratory Department of Chemistry, JET’s Z. B. PatilCollege,
Dhule, Maharashtra, India.
2Department of Chemical Technology Dr. BabasahebAmbedkarMarathwadaUniversity,
Aurangabad, Maharashtra, India
INTERNATIONAL JOURNAL OF RESEARCH IN PHARMA AND BIOMED SCIENCES
Vol. 4 (1) Jan– Mar 2013
1H NMR (DMSO-d6): δ 0.98-1.03 (t,3H), 1.73-
1.86 (m, 2H), 2.5 - 2.63 (s, 3H), 2.90-2.95 (s,
2H),3.82 (s, 3H), 5.62 (s, 2H), 7.16-7.34 (m,7H),
7.40-7.59 (m,4H), 7.68-7.70 (m, 3H), 12.86 (s,
M/Z: 515.50 [M + H]+
EP 2 149 566 A1
1H NMR (300 MHz, DMSO-d6): δ 7.65-7.70 (m, 3H), 7.40-7.56 (m, 4H), 7.15-7.32 (m, 7H), 5.60 (s, 2H), 3.80 (s, 3H),
2.91 (m, 2H), 2.61 (s, 3H), 1.80 (m, 2H), 0.98 (m, 2H).
13C NMR (75 MHz, DMSO-d6): δ 169.50. 156.19, 154.01, 142.70. 142.35, 140.48, 140.16, 136.60. 135.90. 134.70.
132.29, 130.80. 130.32, 129.08, 128.68, 128.21, 127.28, 126.37, 123.14, 122.06, 121.80. 118.65, 110.37, 109.28, 46.12,
31.74, 28.80. 20.71, 16.43, 13.81
Detection, isolation and characterization of principle synthetic route indicative impurity in telmisartanhttp://www.sciencedirect.com/science/article/pii/S1878535212000688
1H-NMR (CDCl3, 300 MHz), δ (ppm), J (Hz): 3.64 (s, 3H, OCH3), 6.71 (s, 1H, CHBr2, 7.36–7.38, (d, J = 8.42, 2H, Ar-H), 7.40–7.43 (t, J = 8.61, 1H, Ar-H), 7.47–7.52 (t, J = 7.69, 1H, Ar-H), 7.58–7.61 (d, J = 6.04, 1H, Ar-H), 7.65–7.68 (d, J = 8.42, 2H, Ar-H) and 7.92–7.95(d, J = 7.69, 1H, Ar-H).
13C-NMR, δ (ppm): 40.77 (–CHBr2, C-1), 51.92 (–OCH3, C-15), 126.18 (–CH, C-7&3), 127.62 (–CH, C-11), 128.56 (–CH, C-6&4), 130.02 (–CH, C-10), 130.57 (–C, C-9), 130.63 (–CH, C-13), 131.42 (–CH, C-12), 140.66 (–C, C-2), 141.37 (–C, C-5), 142.97 (–C, C-8) and 168.55 (CO, C-14).
Adin, Itai; Iustain, Carmen; Brand, Michael; Salman, Ada; Weisman, Alexander Patent: US2006/276525 A1, 2006 ; Location in patent: Page/Page column 7 ;
KRKA, TOVARNA ZDRAVIL, D.D., NOVO MESTO Patent: WO2009/4064 A1, 2009 ; Location in patent: Page/Page column 44-45 ;
KRKA, TOVARNA ZDRAVIL, D.D., NOVO MESTO Patent: WO2009/4064 A1, 2009 ; Location in patent: Page/Page column 44-45 ;
Chinese Patent CN 1344172 discloses the preparation of telmisartan in two steps: namely condensation and hydrolysis. US 5591762 discloses the preparation of telmisartan from its tertiary butyl ester. Hydrolysis is carried out using trifluoro acetic acid in dimethyl formamide at room temperature and maintained for about 12 hours. The crude product obtained is purified over a silica gel column and finally crystallized from acetone. US 2002/0094997 is a divisional application of US 6358986. US 2002/0094997 discloses polymorphs of telmisartan, particularly polymorphic form B, polymorphous mixtures and their preparation. Accordingly, telmisartan Form A is dissolved in a mixture of solvents consisting of water, formic acid and an organic solvent that is miscible therewith; the solution is heated followed by distillation and telmisartan containing Form A and Form B is precipitated from the mixture by addition of a base. The disclosure further refers to advantages of the polymorphic Form B mixture, for example it is easily filterable and has a low tendency to electrostatic charging. The disclosure still further refers to the fact that Form A, which is obtained according to the basic patent, is difficult to filter, is characterized by a very long drying time and exhibits a strong tendency to electrostatic charging. The two telmisartan polymorphs of Form A and B as characterised by US 2002/0094997 differ considerably in their melting point: Form B melts at 183°C (determined by DSC), Form A at 269°C (determined by DSC). The polymorphs A and B also differ in their IR spectrum. Pure polymorph A has a characteristic band at 815 cm"1 in the IR spectrum. In polymorph B, this oscillation is shifted to 830 cm"1. In all the prior art processes, telmisartan is prepared in two or three steps, which is time consuming, product is lost during intermediate isolation, and as such there is a resulting low yield of the final product. It is also suggested in the prior art that the use of dimethyl formamide and alkali metal carbonates as solvent resulted in dimer formation, which also contributed to low yield. The aim of the present invention is, therefore, to provide an improved process for the preparation of telmisartan. In particular, it is an aim of the present invention to prepare telmisartan in a one step process, thereby increasing the yield, decreasing the cost and avoiding filtration and drying problems. Surprisingly, it has been found according to the present invention that telmisartan can be synthesised in one step from intermediates [1H - Benzimidazole - 2- n-propyl-4- methyl-6-(1 '-methyl benzimidazole-2'-yI)] and methyI-4-(bromomethyl) biphenyl-2- carboxylate. According to the present invention, therefore, there is provided a process for the preparation of telmisartan of formula (I), or a pharmaceutically acceptable salt thereof
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PATENT IN 2013MU02627 TELMISARTAN
Improved process for the preparation of telmisartan
Telmisartan chemically known as 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-1'-yl)methyl]-[l,1-biphenyl]-2-carboxylic acid and is known from U.S. patent no. 5,591,762 and is represented by compound of structural formula (I)
Telmisartan is an angiotensin II receptor (typeAT1) antagonist which is suitable for the treatment of high blood pressure and other medical indications as described in EP 502314 Bl. Telmisartan belongs to the group of angiotensin II antagonists, which are being therapeutically used as medicaments for the cardiovascular system, especially to control high blood pressure. A dosage form of Telmisartan was introduced in the market in 1998 by Boehringer Ingelheim under the protected name Micardis This group contains important drugs like Losartan (Cozaar ®), Irbesartan (Avapro®), or Valsartan (Diovan®). However, unlike these substances Telmisartan shows better efficiency even in the last hours of the administration interval.
U.S. patent no. 5,591,762 describes process to prepare Telmisartan which includes,
a) condensation of 2-n-propyl-4-methyl-6-(l'-methylbenzimidazol-2'-yl)benzimidazole compound of the formula (II) with tert-butyl-4'-bromomethyl biphenyl-2-carboxylate compound of the formula(V) in the presence of an acid binding agent (potassium-tert-butoxide) in a solvent or mixture of solvents (dimethyl sulphoxide (DMSO) to obtain t-butyl 4'-[4-methyl-6-(1 -methyl-1 H-benzimidazol-2-yl)-2-n-propyl-1H-benzimidazole-l-yl-methyl]biphenyl-2-carboxylate compound of the formula(VI) (tert. Butyl ester of Telmisartan)
b) hydrolyzing tert. Butyl ester of Telmisartan compound of the formula (VI) with trifluroacetic acid (TFA) in dimethylformamide (DMF) to obtain crude Telmisartan is purified over a silica gel column and crystallized from acetone to obtain Telmisartan compound of the formula (1) 63.9%.
U.S. Patent no. 7,193,089 describes the process to prepare Telmisartan, which includes,
a) reacting 2-n-propyl-4-methyl-6-(l'-methylbenzimidazol-2, -yl)benzimidazoie
compound of the formula (II) with 4'-(bromomethyl)-[l,l'-biphenyl]-2-carbonitrile compound of the formula (III) in presence of solvent or mixture of solvents (dimethylacetamide), optionally in the presence of an acid -binding agent such as potassium tert-butoxide or potassium hydroxide at a temperature range 0°C to 20°C, to obtain 2-cyano-4'-[2"-n-propyl-4,,-methyl-6"-(l'"-methylbenzimidazol-2'"-yl)benzimidazol-1"-ylmethyl ]biphenyl , cyanotelmisartan compound of the formula (IV).
b) hydrolysis of cyanotelmisartan compound of the formula (IV) is carried out in presence solvent selected form water, an organic solvents or mixture thereof (such as ethylene glycol/water) in presence of an acid or a base at temperature between 140°C to 200°C.
c) distilled off the solvent from reaction mixture and residue is diluted with water and in hydrochloride acid to obtained Telmisartan hydrochloride is further dissolved in acetic acid and then NaOH is added drop wise at 80°C to 90°C and Telmisartan free base is filtered off.
U.S. patent application no. 2006/0264491 describes process for preparation of Telmisartan. which includes, hydrolysis of 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-1'-yl)methyl]-[l,1'-biphenyl]-2-carboxamide compound of the formula (V) in presence of potassium hydroxide in propylene glycol at temperature at about 150°C.
EP2277866 Al discloses a process for preparing Telmisartan from 2-cyano-4;-[2"-n-propyl-4"-methyl-6"-(1"-methylbenzimidazol-2"'-yl) benzimidazol-l"-yl methyl] biphenyl compound of the formula (IV) using 60% NaOH in n-butanol in presence of phase transfer catalyst i.e. tetra butyl ammonium hydrogen sulphate at 115-120°C for 22h.
EP2443094B1/WO2010/146187A2 describes a process for the synthesis of Telmisartan from cyano Telmisartan and carboxamido telmisartan using 1:1 sulphuric acid at 125°C for 30 h and 28 h respectively.
The existing process requires very high temperature for 30 h or 28 h which limits its large scale application and invites safety risks too. In addition to this, formation of different kind of impurities takes place at 125°C.
Chinese patent application CN 1412183A describes the process for preparation of Telmisartan which includes reacting compound of the formula (II) with compound of the formula (111) in presence of organic base or inorganic base and reaction solvent to afford compound of the formula (IV). It also describes different hydrolysis conditions for compound of the formula (IV) such as,
a. a 1:2 volume ration of concentrated acetic acid: concentrated hydrochloric
acid refluxed for 24 hours at about 100°C
b. a 2:1 volume ration of ethanol: 2 M NaOH refluxed for 24 hours at about
c. a 1: 1.5 volume ration of sodium ethanolate in glycol: water refluxed for 24
hours and finally obtained Telmisartan is crystallization with N, N-
Chinese patent application CN102070534A discloses a process for preparation of 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1"-methylbenzimidazol-2'"-yl) benzimidazol-1"-ylmethyl ]biphenyl compound of the formula (IV) which includes reacting compound of the formula (II) with compound of the formula (III) under the effect of phase transfer catalyst and inorganic base in the presence of low boiling organic solvents at temperature rang in between 0°C-10oC.
WO 2007/147889 discloses the process for preparation of Telmisartan by hydrolyzing compound of the formula (IV) by addition of water and conc. HC1 heated at reflux temperature for 136 hours and then cooled reaction mixture at room temperature and add 1M NaOH to adjust pH to about 5 to 7. The product is filtered, wash and dried to obtain Telmisartan.
The disclosed process in WO '889 is time intensive besides corrosive and hazardous reaction condition.
U.S. patent no. 5,591,762 teaches the hydrolysis of cyanotelmisartan compound of the formula (IV) using trifluroacetic acid in dimethyl formamide and is not eco-friendly. It involves long time for hydrolysis. Separation of Telmisartan using silica gel column chromatography results into lower yields. Further the preparation of tert. Butyl ester of Telmisartan is relatively expensive method.
U.S. Patent no. 7,193,089 is silent about the purity of the free Telmisartan. The solvents used such as dimethyl acetamide and ethylene glycol have a boiling point greater than about 140°C. These solvents are difficult to remove from the reaction using various evaporation techniques known in the art. These reaction conditions are hazardous and far from being environmental friendly. The process is carried out at very high temperature. Removal of residual solvents from reaction mixture, using various evaporation techniques is tedious and difficult.
U.S. patent application no. 2006/0264491 describes a process in which, an expensive solvent is used. Reactions are carried out at very high temperatures which itself is very difficult to maintain at plant scale manufacturing. These process conditions discourage use of this process.
Process disclosed by EP2277866A1 requires high temperature and longer time to complete the reaction which invites safety risks. Use of lower temperatures substantially impacts on yield. Moreover the isolation procedure from n-butanol to get crude telmisartan is very tedious.
Process disclosed by WO 2010/146187A2 requires very high temperature for longer durations. It limits its application for large scale production. It also invites safety risks. The process leads to formation of different kind of impurities at 125°C. Carrying out reaction at elevated temperatures is not easy and not advisable. Use of lower temperatures substantially impacts yield.
Chinese patent application CN1412183A describes conditions that required long time for hydrolysis and results in lower yields. Moreover ethylene glycol and DMF are high boiling solvent so it will be very difficult to recover and reuse.
CN102070534A teaches a reaction which is carried out at a temperature range of 0-10°C, a range which is difficult and energy intensive. Industry will welcome a reaction which is carried out at ambient temperatures and yet having shorter durations. Besides this inconvenient temperature range the reaction necessitates low boiling solvents and thereby restricts selection range of solvents.
Therefore the processes taught by prior patents and prior art disclosures have several drawback's namely expensive nature, not suitable for scale up at plant level, energy intensive, difficult, giving lower yields, forcing use of corrosive acids, longer duration of corrosive reaction and less user friendly.
Therefore industry strongly needs a process that is simpler, financially cheaper and energy economic process, an environment friendly process that does not use hygroscopic and pyrophoric chemicals. Industry needs a process to produce Telmisartan that can be carried out at lower temperatures yet giving good yields, a process that has improved carbon efficiency and is free from hazards and draw backs of prior art.
Preparation of 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-bcnzimidazol)-r-yI)methyl]-
100 gm of 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1"-methylbenzimidazol-2'"-yl) benz-imidazol-1'-ylmethyl] biphenyl and 550 mL 80% sulfuric acid, were heated to 80°C-85° C. The reaction mixture stirred for 8-10 h at this temperature. Water (500 mL) was added at the same temperature and the reaction mixture was stirred for 15-20 h and reaction was completed at 120-130 C.
The reaction was then cooled to 20-25 C. pH of mixture was adjusted tol2 by adding 40% NaOH solution. After that 500 ml of n-Butanol were added and separated out layers. The oily residue thus obtain after distillation was dissolved in 500 mL of water to get clear solution. The aqueous layer was washed with
distillation of methylene dichloride was added in 300 mL of acetone. Suck dry the wet cake.
Wet cake was directly charged in a reaction assembly containing 900 mL 30% sulfuric acid solution. NaN02 solution (48.75 gm, 0.7 moles in 200 ml water) was added drop wise and the temperature of the reaction mass was kept at 25-50 C.
The reaction was then heated to 45°C-50°C and maintained for 2-5 h and then cooled to 20-25° C. pH of mixture was adjusted to 12 by adding 40% NaOH solution. After that 500 ml of n-Butanol were added and separated out layers.
The oily residue thus obtain after distillation was dissolved in 700 mL of methanol and 15 mL of ammonia followed by charcolization. pH of the filtrate was adjusted to 4-5 using acetic acid. Solid obtained was filtered and washed with methanol (100 mL) and dried at 60-65 °C. The solid was then treated with water (500 mL) at 40-45 °C for 3h to remove inorganic matters and then dried at 60-65 °C for 10 h.
The solid thus obtain was treated with methanol (1000 mL) at 60-65 °C for 8-10 h and then filtered to get pure Telmisartan. The product obtained was then dried at 60-65 °C to get 73 gm (yield 75.9 %) of compound (I) having purity > 99.7 % by HPLC
Reddy, Kikkuru Srirami; Srinivasan, Neti; Reddy, Chinta Raveendra; Kolla, Naveenkumar; Anjaneyulu, Yerremilli; Venkatraman, Sundaram; Bhattacharya, Apurba; Mathad, Vijayavitthal T. Organic Process Research and Development, 2007 , vol. 11, # 1 p. 81 - 85
Chemo Iberica, S.A. Patent: EP2123648 A1, 2009 ; Location in patent: Page/Page column 13 ;
Venugopal; Ramanatham; Devanna; Sanjeev Kumar; Ghosh, Samir; Soundararajan; Kale, Bhima; Mehta Asian Journal of Chemistry, 2010 , vol. 22, # 4 p. 2767 - 2773
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