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Monday, 6 April 2015

TELMISARTAN PART 1/3



[1860-5397-6-25-1]











TELMISARTAN

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

1H NMR PREDICT










13C NNMR






COSY PREDICT


PAPER

Efficient and improved synthesis of Telmisartan

A. Sanjeev KumarSamir Ghosh and G. N. MehtaEmail of corresponding author

Applied Chemistry Department, Sardar Vallabhbhai National Institute of Technology, Surat-395 007, India
Associate Editor: J. A. Porco Jr.
Beilstein J. Org. Chem. 2010, 6, No. 25.
 http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-6-25


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


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

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


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



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



Second set


An improved synthesis of Telmisartan: an antihypertensive drug 

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


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

General Papers ARKIVOC 2009 (x) 247-254 

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

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

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

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

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


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

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

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





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

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

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

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

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







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

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

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

Available online 1 April 2012
http://www.sciencedirect.com/science/article/pii/S1878535212000688

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

















Full-size image (5 K)
Figure 5.
Impurity structure with numbering of C atoms.


NMR Spectral data of Impurity-1:

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

13C-NMRδ (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 (Cdouble bond; length as m-dashO, C-14).

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


PATENT


17103-26-3;

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

Telmisartan (Compound I below), 4′-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid, is a non-peptide ATI-subtype angiotensin II receptor antagonist.
Figure US20060276525A1-20061207-C00001
Telmisartan is indicated for treatment of hypertension, either alone or in combination with diuretic agents. It is effective in once-daily dosing, so that significant blood-pressure lowering effect is observed even during the last 6 hours of the dosing interval. Telmisartan is marketed in the US as MICARDIS® and MICARDIS-HCT® by Boehringer Ingelheim.
Telmisartan was first described in U.S. Pat. No. 5,591,762 (hereinafter the '762 patent). According to Example 9 of the '762 patent, Telmisartan was crystallized from acetone and the resulting product had a melting point of 261-263° C.
U.S. Pat. No. 6,358,986 (hereinafter the '986 patent) describes two crystalline forms of Telmisartan denoted as forms A and B. It is stated in the '986 patent that the crystals of Telmisartan polymorph A, which is obtainable according to the prior art, have the shape of long needles. As a result of this crystalline shape, the use of Telmisartan polymorph A in large-scale manufacture, purification, isolation and drying of the material is severely limited.
As alleged in the '986 patent, the process for preparing crystalline Telmisartan form A comprises mixing the material with ethanol, adding activated charcoal and aqueous ammonia and mixing for one hour, then filtering to another stirring apparatus and washing with ethanol. The next step is heating to 70-80° C., adding glacial acetic acid and stirring for further 1.5-2 hours at the same temperature, cooling to 0-10° C., stirring for further 2 hours, isolating the product by centrifugation, washing with ethanol then with water and drying at 70-90° C. According to the detailed description given in the '986 patent, in addition to the disadvantageously prolonged drying process of the Telmisartan form A, very hard particles are obtained. The grinding process of these particles produces a dry powder, which has strong tendency to electrostatic charging and which is virtually impossible to pour and manipulate for pharmaceutical preparations. On the other hand, Telmisartan form B is free from the above mentioned limitations. However, the inventors of the '986 patent could not obtain pure, dry form B because upon drying, some of form B transformed into form A. According to the teachings of the '986 patent, mixtures of Telmisartan form A and form B ranging from 90:10 to 60:40 are suitable for industrial scaling-up, and even a content of 10% of form B is sufficient to ensure that the product will have the positive qualities required for large-scale production.
Therefore, as a consequence of the alleged unsuitability of Telmisartan form A for pharmaceutical use, only a mixture of crystalline Telmisartan form A and form B is claimed in the '986 patent, wherein Telmisartan form A is characterized by having an endothermic maximum at 269±2° C., and Telmisartan form B is characterized by having an endothermic maximum at 183±2° C.
Apparently Telmisartan form A is similar to the original form characterized by its melting point in the '762 patent. The differences between the DSC value and the measured melting point may be attributed to the different methodologies used—the DSC maxima can be slightly different than the visually observed melting point.
Differences in physical properties of crystalline materials (such as flowability) may be caused by different production processes for obtaining these crystalline materials.
Hence, the prior art teaches a lengthy, complicated and industrially disadvantageous process for obtaining crystalline Telmisartan form A.
A mixed solvated-hydrated modification form of Telmisartan, designated as form C, is mentioned in an article by Dinnebier et al., J. Pharm. Sci. 89(11), 2000. Telmisartan form C consists of ⅓ mole equivalent of formic acid and ⅔ mole equivalent of water, which is produced by crystallization from mixtures containing formic acid and water. According to the above mentioned publication, drying of form C leads to pure form B (mentioned above). The article mentions detailed crystallographic data of this form as well as of forms A and B.
The re-crystallization of Telmisartan from N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA) is mentioned in examples 1-3 of the '986 patent. However, since the product is further processed it is believed by the inventors of the present invention that the Telmisartan which is obtained according to the '986 patent, has some defects. Therefore, there is a need in the art for a new process for preparing highly pure Telmisartan form A, which is free-flowing and which does not tend to gain electrostatic charge.

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


HPLC Analysis:
Column: Inertsil ODS-3, 5μ, 250×4.6 mm (GL Sciences Cat. No.: 5020-01732). Mobile phase: 70% methanol and 30% water containing 10 ml triethylamine per 1.0 liter, pH adjusted to 3.0 using phosphoric acid.
Flow rate: 1 ml/min; UV detection: 226 nm; Oven temperature: 35° C.
Reference Example 1
In a 1000 ml three-necked round bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, 4-[(1,4′-dimethyl-2′-propyl[2,6′-bi-1H-benzimidazol]-1′-yl)methyl]-[1,1′-biphenyl]-2-carboxylic acid methyl ester (50 g, 0.095 mole) was charged, and methanol (300 ml) was added followed by addition of water (26 ml) and 47% NaOH solution (27 ml). The mixture was refluxed for 2 hours. Part of the solvent was evaporated and water (500 ml) was added in portions at 85° C. to afford a solution. The insoluble matter was removed by filtration and the mixture was neutralized with a solution of acetic acid (31.7 ml) in water (75 ml). The thus obtained crude Telmisartan cake was collected by filtration and washed with water to obtain 150 g of wet Telmisartan, which was dried under vacuum to obtain 48 g of the crude product in 98.6% yield, having a purity of 97%.
Example 1
In a 500 ml three necked round bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, Telmisartan (15 g) was dissolved in DMSO (290 ml). The solution was heated to 65° C. using an oil bath, and left to cool down to 25° C. After few days the resulting crystals were filtered off, washed with fresh water and dried at 100° C. under vacuum to obtain 11.55 g of Telmisartan form A in 77% yield, having a purity of 99.5% (according to HPLC).
Depending on the drying strength, different batches of dried material contained residual DMSO level in the range of 500-1000 ppm and had LOD values in the range of 0.2-0.3%, as measured by means of TGA.
The obtained solid material contained lumps, which could be easily ground by means of conventional mill. The obtained ground material has improved flowability, namely it is a free flowing crystalline powder that does not tend to gain electrostatic charge upon grinding. It has a bulk density of about 0.3 g/ml.
Particle size distribution was found to be: D(v,0.1)=1.60μ; D(v,0.2)=2.25μ; D(v,0.5)=4.98μ; D(v,0.8)=11.46μ; D(v,0.9)=16.78μ; D(v,0.95)=22.21μ; D(v,0.98)=29.03μ; D(v,1.0)=52.87μ.
XRPD pattern of the resulting material is shown in FIG. 4 and it resembles the pattern of form A.

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

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

144702-27-2

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


Telmisartan with its chemically name 4'-[(2-n-propyl-4-methyl-6-(l -methylbenzimidazol- 2-yl)-benzimidazol-l-yl)-methyl]-bipheny]-2-carboxylic acid and formula 1
Figure imgf000002_0001
is a non-peptide antagonist of subtype 1 of the angiotensin II receptor (ATj -antagonist) used for the treatment of hypertension. It can be used alone or in combination with another pharmaceutically active compound, e.g. hydrochlorothiazide.
Telmisartan is disclosed in EP O 502 314 as well as in J. Med. Chem., 36(25), 4040-4051 ( 1993 j. Its polymorphs are known from EP 1 144 386 and J. Pharm. Sci. 89 ( I i ;. J4ό.v 1479 (2000).
EP 0 502 314 A and J. Med. Chem., 36(25), 4040-4051 (1993), disclose a method for the preparation of ielmisartan using its tert-butyl substituted intermediate (Scheme j ). The final product of this method is difficult to be filtered, washed and isolated. These properties are an obstacle to an effective large-scale production.
Scheme 1
Figure imgf000003_0001
The synthesis of telmisartan from a compound with the chemical name 4'-[(2-n-propy!-4- methyl-6-(l-methylbenzimidazo]-2-yl)-benzimidazol-l -yl)-methyl]-biphenyl-2-nitrile (further named as telmisartan nitriie) and represented by formula 3
Figure imgf000003_0002
is disclosed in EP 0 502 314A, WO 2004/087676, CN 1412183 and US 2006/264491.
In WO 2004/087676 and CN 1412183 telmisartan is prepared by hydrolyzing the compound of formula 3 (Scheme 2): Scheme 2
Figure imgf000004_0001
The disclosed method can be used in the large-scale production of telmisartan and allows for a relatively easy purification thereof.
US 2006/0264491 discloses reacting 4'((l,4"-dimethyl-2'-propyl(2,6'-bi-lH- benzimidazol)-r-yl)-methyl)-( l ,r-biphenyl)-2-carboxamide via hydrolysis into telmisartan, isolating crude telmisartan and optionally purifying the crude telmisartan via crystallization.
Amorphous telmisartan is disclosed in US 2006/1 11417 and WO 2006/050921, while crystalline forms of telmisartan are disclosed in WO 00/43370, IN 2005MU00164 and US 2006/0276525.
Various salts of telmisartan are known, for example from CN 1548421, WO 03/037876, WO 2006/044754, WO 2006/050509, WO 2006/050921, EP 1 719 766, WO 2006/136916, WO 2007/01055k and WO 20C7/ 14788<>
In addition to the above-discussed preparation processes of telmisartan, there still is a need for a yet further improved synthetic route lo telmisartan. Therefore, the object of the present invention is to provide new methods for the production of telmisartan intermediates substituted on position 2 of the biphenyl group of (4'-[(2-n- proρyl-4-methy]-6-( l-methylbenzimidazol-2-yl)-benzimidazol-l-yI)-methyl]-biphenyl) which methods are suitable for use on an industrial scale and which are economical, i.e. both cost and time effective and allow for the production of intermediates that can be converted into telmisartan and/or salts thereof with high quality and high yield.
Another object of the present invention is to provide novel intermediates of telmisartan and derivatives thereof that enable new, cost and time effective synthetic routes to such compounds.
Summary of the invention
In one aspect, the present invention provides processes for the preparation of the key intermediate of the synthesis of telmisartan, namely a telmisartan intermediate substituted on position 2 of the biphenyl group of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazoi- 2-yl)-benzimidazol-l-yl)-methyl]-biphenyl.
In another aspect, the present invention provides novel intermediates useful for the synthesis of telmisartan intermediates substituted on position 2 of the biphenyl group of 4"- [(2-n-propyl-4-methy]~6-(l -methylbenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]- biphenyl optionally in isolated and/or purified form and their use as intermediates in the preparation of telmisartan and/or its salts.
In another aspect, the present invention provides telmisartan intermediates substituted on position 2 of the biphenyl group of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2- yl)-benzimidazol-l-yl)-methyl]-biphenyl prepared by the processes according to the oresenr invention having a purity of greater than 989r preferablv greater than 99<7r , wherein the amount of each individual impurity is less than 0.15%.

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

144702-27-2

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



Example 16 Preparation of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazoI-2-yl)-benzimidazoI- l-yI)-methyl]-biphenyl-2-carboxylic acid (compound 1)
A mixture of 2.5 g of compound 3 (5 mmol), 1.0 2 sodium hydroxide (25 mmol). 0.18 g water (10 mmol) and 30 ml etbyleneglycol was refluxed for 8 h. After the reaction was completed, the reaction mixture was cooled to room temperature and HoO (250 ml ) was added. After the pH value of this solution was adjusted to 4 with HOAc ( J 2 ml), the product precipitated and was extracted three times with CHoCIo. The combined organic layers were washed with brine, dried over NaSθ4 and filtered and the filtrate was concentrated to give 2.55 g of crude compound 1 (yield: 98%).
Example 17 Preparation of 4'-[(2-n-propyl-4-methyl-6-(l-methylben2imidazol-2-yI)-benzimidazoI- l~yI)-methyI]-biphenyl-2-carboxyIic acid (compound 1):
A mixture of 15 g of compound 3 (30 mmol), 6.0 g potassium hydroxide (91 mmol}. 1.6 g water and 54 ml propylene glycol was refiuxed for 19 h. After the reaction was completed, the reaction mixture was cooled to room temperature and H?O (120 ml) was added. After the pH value of this solution was adjusted to 4.9 with 6M HCl (17 ml), the product was extracted three times with CH2CIi. The combined organic layers were washed with water, dried over NaSO4 and filtered and the filtrate was concentrated. To the residue acetone was added. The suspension was filtered to give 12.55 g of crude compound 1.
Example 18
Crystallization of 4'-[(2-n-propyl-4-methyl-6-(l -methylbenzimidazoI-2-y])- benzimidazol-l-yl)-methyl]-biphenyl-2~carboxylic acid (compound 1):
A mixture of 3 g of telmisartan and 20 ml of N,N-dimethylforrnamide was heated to a temperature of about 100 0C until telmisartan was dissolved. Then the solution was filtered and cooled to room temperature. The solution was stirred at this temperature for 3h and then 2h at 0 0C. The product was filtered, washed with DMF and dried under reduced pressure at 70-90 0C to give 2.7 g of telmisartan (HPLC purity: 99.5%).
Example 19
Crystallization of 4'-[(2-n-propyI-4-methyl-6-(l-methyIbenzimidazol-2-yl)- benzimidazo!-l-yI)-methyIl-biphenyf-2-carboxylic acid (compound 1):

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


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

PATENT


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

Chinese Patent CN 1344172 discloses the preparation of telmisartan in two steps: namely condensation and hydrolysis. US 5591762 discloses the preparation of telmisartan from its tertiary butyl ester. Hydrolysis is carried out using trifluoro acetic acid in dimethyl formamide at room temperature and maintained for about 12 hours. The crude product obtained is purified over a silica gel column and finally crystallized from acetone. US 2002/0094997 is a divisional application of US 6358986. US 2002/0094997 discloses polymorphs of telmisartan, particularly polymorphic form B, polymorphous mixtures and their preparation. Accordingly, telmisartan Form A is dissolved in a mixture of solvents consisting of water, formic acid and an organic solvent that is miscible therewith; the solution is heated followed by distillation and telmisartan containing Form A and Form B is precipitated from the mixture by addition of a base. The disclosure further refers to advantages of the polymorphic Form B mixture, for example it is easily filterable and has a low tendency to electrostatic charging. The disclosure still further refers to the fact that Form A, which is obtained according to the basic patent, is difficult to filter, is characterized by a very long drying time and exhibits a strong tendency to electrostatic charging. The two telmisartan polymorphs of Form A and B as characterised by US 2002/0094997 differ considerably in their melting point: Form B melts at 183°C (determined by DSC), Form A at 269°C (determined by DSC). The polymorphs A and B also differ in their IR spectrum. Pure polymorph A has a characteristic band at 815 cm"1 in the IR spectrum. In polymorph B, this oscillation is shifted to 830 cm"1. In all the prior art processes, telmisartan is prepared in two or three steps, which is time consuming, product is lost during intermediate isolation, and as such there is a resulting low yield of the final product. It is also suggested in the prior art that the use of dimethyl formamide and alkali metal carbonates as solvent resulted in dimer formation, which also contributed to low yield. The aim of the present invention is, therefore, to provide an improved process for the preparation of telmisartan. In particular, it is an aim of the present invention to prepare telmisartan in a one step process, thereby increasing the yield, decreasing the cost and avoiding filtration and drying problems. Surprisingly, it has been found according to the present invention that telmisartan can be synthesised in one step from intermediates [1H - Benzimidazole - 2- n-propyl-4- methyl-6-(1 '-methyl benzimidazole-2'-yI)] and methyI-4-(bromomethyl) biphenyl-2- carboxylate. According to the present invention, therefore, there is provided a process for the preparation of telmisartan of formula (I), or a pharmaceutically acceptable salt thereof
Figure imgf000004_0001
(I) characterised in that lH-Benzimidazole-2-n-propyl-4-methyl-6-(l '-methyl benzimidazole- 2'yl) of formula (II), and methyl-4-(bromomethyl) biphenyl-2-carboxylate of formula (III), are subjected to condensation and hydrolysis in a single step (in other words, a "one pot" synthesis)
Figure imgf000004_0002
(II) (in)



A process for the preparation of telmisartan of formula (I), or a pharmaceutically acceptable salt thereof
Figure imgf000010_0001
(I)
characterised in that lH-Benzimidazole-2-n-propyl-4-methyl-6-(l'-methyl benzimidazole- 2'yl) of foraiula (II) and methyl-4-(bromomethyl) biphenyl-2-carboxylate of formula (III) are subjected to condensation and hydrolysis in a single step
Figure imgf000010_0002
(II) (ffl)





Example I
Preparation of f4'-r2-n-propyl-4-methyl-6-(1-methyl benzimidazol-2-yl) benzimidazol — 1-yl methyl! biphenyl-2-carboxylic acid] 50 gm of [1 H — Benzimidazole-2-n-propyl-4-methyl-6-(1 'methyl benzimidazole-2'- yl)] was added to 200 ml dimethyl sulfoxide and 50 gm of potassium hydroxide. To this was added 60 gm of methyl-4-(bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30°C, then heated to 40-50°C and maintained for 2 hours. About 500 ml water was added to the reaction mixture at room temperature and acidified to pH 4 with acetic acid. The reaction mixture was filtered and washed with purified water, dried under reduced pressure at 50-60°C to give 80 gm (88 %) of the title product.
Example 2
Preparation of r4'-[2-n-propyl-4-methyl— 6-(1 -methyl benzimidazol-2-vObenzimidazol — 1- yl methvπbiphenyl-2-carboxylic acid] 50 gin of [1H — Benzimidazole-2-n-propyl-4-methyl-6-(1'- methyl benzimidazole- 2'-yI)] was added to 200 ml dimethyl sulphoxide and 50 gm of potassium hydroxide. To this was added 60 gm of methyl-4- (bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30°C. The contents were heated to 40-50°C and maintained for 2 hours. About 500 ml water was added to the reaction mixture at room temperature and acidified with acetic acid to pH 3.8, extracted twice with 250 ml of dichloromethane and the combined extracts were concentrated and isolated by filtration after addition of 300 ml acetone, dried under reduced pressure at 50-60°C to give 75 gm (80 %) of the title product
Example 3
Preparation of \4' - F2-n-propyl — 4-methyl-6-(1 -methyl benzimidazol-2-yl) benzimidazol — 1-yl methyll biphenyl-2-carboxylic acid] 50 gm of [1 H — Benzimidazole-2-n - propyl-4-methyl-6-(1 '-methyl benzimidazole-2'- yl)] was added to 200 ml dimethyl sulfoxide and 50 gm of sodium hydroxide. To this was added 60 gm of methyl-4- (bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30°C and then heated to 40-50 and maintained for 2 hours. About 500 ml water was added to the reaction mixture and acidified with acetic acid to pH 4.2, extract4ed twice with 250 ml of dichloromethane and the combined extracts were concentrated and isolated by filtration after addition of 300 ml acetone, dried under reduced pressure at 50-60°C to give 75.0 gm (80%) of the title compound.
Example 4
Purification of 14' - r2-n-propyl-4-methyl-6-(1 -methyl benzimidazol-2-vh benzimidazol-1-yl methyll biphenyl-2-carboxylic acid] 50gm of [4' - [2-n-propyl-4-methyl-6-(1 -methyl benzimidazol-2-yl) benzimidazol-1-yl methyl] biphenyl-2-carboxylic acid] (obtained according to any of Examples 1, 2 or 3) was added to 500ml of methanol. To this was slowly added 50ml of methanolic ammonia (10-15%) at 25-30°C. The contents were stirred for 30 minutes at 25-30°C. About 3gm charcoal was added and stirred at 25-30°C for 30 minutes. The reaction mixture was filtered over hyflo, bed washed with methanol. The clear filtrate pH was adjusted to 3.5-4.0 using acetic acid. The contents were stirred at 20-30°C for 1 hour. Pure telmisartan was isolated by filtration, dried under reduced pressure at 50-60°C to yield 45gm (90%) of the title product with HPLC purity of about 99.3%.
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Kumar, A. Sanjeev; Ghosh, Samir; Mehta Journal of Chemical Research, 2010 , # 2 p. 95 - 97
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KRKA, tovarna zdravil, d.d., Novo mesto; ZUPANCIC, Silvo; SEDMAK, Gregor Patent: WO2010/146187 A2, 2010 ; Location in patent: Page/Page column 37-38 ;

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

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WO2014/27280 A1, ;will be
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keep watching this is being updated 

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 PATENT IN 2013MU02627 TELMISARTAN

Improved process for the preparation of telmisartan

By: Sathe, Dhananjay G.; Das, Arijit; Patel, Bhavesh; Chincholikar, Vikas
Assignee: Unichem Laboratories Limited, India
The present invention describes an improved process for the synthesis of 4-​[(1,​4-​dimethyl-​2-​propyl-​[2,​6-​bi-​1H-​benzimidazol]​-​1-​yl)​ methyl]​-​[1,​1-​biphenyl]​-​2-​carboxylic acid, that is Telmisartan (I)​.  This process comprises hydrolyzing compd. II [R = CN or aminocarbonyl] in acid at temp. range 60-​130°C, preferably 80-​130°C, more preferably between 100-​130°C, in presence of alkali metal nitrite at temp. range 20-​50°C, more preferably 45-​50°C, to obtain compd. I, and optionally isolating and hydrolyzing compd. II [R = aminocarbonyl] while hydrolyzing compd. II [R = CN] into compd. I at temp. range 20-​50°C, more preferably 45-​50°C.
NOTE
4'-[(l,4-dimethyl-2-propyl [2,6'-bi-lH-benzimidazol]-1'-yl)methyl]-[l,l'-biphenyl]-2-carboxylic acid, IS  Telmisartan  COMPD 1

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

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

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

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


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

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

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


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


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


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


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


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


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


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


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

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


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


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


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




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


100 gm of 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1"-methylbenzimidazol-2'"-yl) benz-imidazol-1'-ylmethyl] biphenyl and 550 mL 80% sulfuric acid, were heated to 80°C-85° C. The reaction mixture stirred for 8-10 h at this temperature. Water (500 mL) was added at the same temperature and the reaction mixture was stirred for 15-20 h and reaction was completed at 120-130 C. 

The reaction was then cooled to 20-25 C. pH of mixture was adjusted tol2 by adding 40% NaOH solution. After that 500 ml of n-Butanol were added and separated out layers. The oily residue thus obtain after distillation was dissolved in 500 mL of water to get clear solution. The aqueous layer was washed with

distillation of methylene dichloride was added in 300 mL of acetone. Suck dry the wet cake.
Wet cake was directly charged in a reaction assembly containing 900 mL 30% sulfuric acid solution.
NaN02 solution (48.75 gm, 0.7 moles in 200 ml water) was added drop wise and the temperature of the reaction mass was kept at 25-50 C. 

The reaction was then heated to 45°C-50°C and maintained for 2-5 h and then cooled to 20-25° C. pH of mixture was adjusted to 12 by adding 40% NaOH solution. After that 500 ml of n-Butanol were added and separated out layers. 
The oily residue thus obtain after distillation was dissolved in 700 mL of methanol and 15 mL of ammonia followed by charcolization. pH of the filtrate was adjusted to 4-5 using acetic acid. Solid obtained was filtered and washed with methanol (100 mL) and dried at 60-65 °C. The solid was then treated with water (500 mL) at 40-45 °C for 3h to remove inorganic matters and then dried at 60-65 °C for 10 h. 
The solid thus obtain was treated with methanol (1000 mL) at 60-65 °C for 8-10 h and then filtered to get pure Telmisartan. The product obtained was then dried at 60-65 °C to get 73 gm (yield 75.9 %) of compound (I) having purity > 99.7 % by HPLC
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Reddy, Kikkuru Srirami; Srinivasan, Neti; Reddy, Chinta Raveendra; Kolla, Naveenkumar; Anjaneyulu, Yerremilli; Venkatraman, Sundaram; Bhattacharya, Apurba; Mathad, Vijayavitthal T. Organic Process Research and Development, 2007 , vol. 11, # 1 p. 81 - 85

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

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

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

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



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