A modification to the synthesis of Telmisartan: An antihypertensive drug

Article abstract of DOI:10.3184/030823410X12656400473065

A highly efficient approach to the synthesis of Telmisartan is described. Directed ortho-metalation of 4,4-dimethyl-2-phenyl-4,5-dihydrooxazole provided the key organozinc intermediate for a palladium catalysed biaryl coupling with 3′-(4-bromobenzyl)-1,7′-dimethyl-2′-propyl-1 H,3′ H-2,5′-bibenzo[d]imidazole which was obtained from alkylation of 1,7′-dimethyl-2′-propyl-1 H,3′H-2,5′-bibenzo[d] imidazole. This methodology overcomes many of the drawbacks associated with previously reported syntheses.

Full text of DOI:10.3184/030823410X12656400473065

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 95
FEBRUARY, 95–97
A modification to the synthesis of Telmisartan: an antihypertensive drug
A. Sanjeev Kumar, Samir Ghosh and G. N. Mehta*
Applied Chemistry Department, S. V. National Institute ofTechnology, Surat-395 007, India
A highly efficient approach to the synthesis of Telmisartan is described. Directed ortho-metalation of 4,4-dimethyl-2-
phenyl-4,5-dihydrooxazole provided the key organozinc intermediate for a palladium catalysed biaryl coupling
with 3’-(4-bromobenzyl)-1,7’-dimethyl-2’-propyl-1H,3’H-2,5’-bibenzo[d]imidazole which was obtained from alkylation
of 1,7’-dimethyl-2’-propyl-1H,3’H-2,5’-bibenzo[d]imidazole. This methodology overcomes many of the drawbacks
associated with previously reported syntheses.
Keywords: Telmisartan, antihypertensive drug, Negishi coupling and oxazoline hydrolysis
Telmisartan 1 is an angiotensin II receptor antagonist which is
useful in the treatment of hypertension, heart disease and
strokes, and bladder diseases.1–3 Telmisartan is available in the
market as an antihypertensive drug4 under the brand name of
Micardis.
In designing an alternative synthesis of Telmisartan our goal
was to minimise the use of expensive and hazardous metals,
circumvent the bromination step, and increase the overall effi-
ciency of the synthesis. This was accomplished by reversing
the order of the major bond disconnections. Alkylation of
the dibenzimidazole 4 with commercially available 4-
bromobenzyl bromide obviated the free-radical bromination;
this offered a suitable substrate for metal-catalysed biaryl
coupling via Negishi coupling and finally acid hydrolysis of
intermediate 12 provided Telmisartan 1 in good yield.
Most current methods for preparation of biaryls require
either the regiospecific introduction of the desired halogen as a
precursor to the organometallic reagent or the isolation of the
prerequisite organometallic after directed metalation prior to
cross coupling. While these methods have had some success,
especially the Suzuki boronic acid cross coupling as developed
by Snieckus, we felt that a methodology which eliminated
the isolation and purification steps would have some useful
advantages. Our approach involved the directed metalation of
an appropriate carboxy protecting group followed by trans-
metalation with zinc chloride then a transition metal catalysed
cross coupling with aryl bromides.
The reported synthesis5,6 ofTelmisartan in Scheme 1 involves
the condensation of the 7-methyl-2-propyl-3H-benzimidazole-
5-carboxylic acid derivative 2 with N-methyl- benzene-1,2-
diamine 3 to give the dibenzimidazole derivative 4. Alkylation
of compound 1,7p-dimethyl-2p-propyl-1H,3pH-2,5p-bibenzo[d]
imidazole5–7 4 with 4p-bromomethyl-biphenyl-2-carboxylic
acid tert-butyl ester 5 furnished ester derivative of Telmisartan
6. Hydrolysis of the ester 6 in trifluoroacetic acid yielded
Telmisartan 1 in an overall yield of around 21% containing
several impurities. This process suffers from disadvantages
such as (a) linear multi-step synthesis (b) poor stability of
4p-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester8
5 (c) low yield and purity obtained during the preparation of
4p-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester
5 arising from the formation of 20–45% of dibromo impurity
8 in a bromination step.
The intermediate 4p-bromomethyl-biphenyl-2-carboxylic
acid tert-butyl ester 5, could not be stored because of its poor
stability and shorter shelf life. Therefore, it was used immedi-
ately after its preparation. Because of its high reactivity, the
ester also has the disadvantage of being liable to decomposi-
tion or a side reaction in the reaction, thereby resulting in low
purity.
N-Bromosuccinimide which is used for the preparation of
4p-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester 5
is unsuitable for industrial production because of its cost and
reactivity. It is also difficult to control the reaction and avoid
the formation of undesired 4p-dibromomethyl-biphenyl-2-
carboxylic acid tert-butyl ester 8 as a dibromo impurity
(Scheme 2).
We chose the oxazoline moiety as a carboxy synthon because
of its excellent ortho-metalating properties, its stability to
many common reaction conditions, its use as a versatile syn-
thetic intermediate, and the ease of recovering the parent acid
under mild conditions. Aryl oxazolines were prepared by stan-
dard methods.9 We chose to explore Negishi cross couplings10,
11 because of the great tolerance of zinc-based organometallics
to a wide range of sensitive functionalities.12,13
Results and discussion
In the synthesis of Telmisartan 1, the first stage of this synthe-
sis was the construction of the benzylated imidazole 10
(Scheme 3). The 1,7p-dimethyl-2p-propyl-1H,3pH-2,5p-bibenzo
[d]imidazole 4 was benzylated with 4-bromobenzyl bromide 9
in dimethylacetamide at 25–30 °C with potassium carbonate
as the base to provide 3p-(4-bromobenzyl)-1,7p-dimethyl-
2p-propyl-1H,3pH-2,5p-bibenzo[d]imidazole 10 as a white
crystalline solid.
The 4,4-dimethyl-2-phenyl-4,5-dihydrooxazole 11 was
metalated with 2.5M n-BuLi at 0 °C for 60 mins and
transmetalated with ZnCl in THF as the solvent. The 3p-(4-
bromobenzyl)-1,7p-dimet2hyl-2p-propyl-1H,3pH-2,5p-bibenzo
[d]imidazole 10 was then added together with tetrakis(triphen
ylphosphine)palladium(0) and the mixture was stirred for
24 hours at 55 °C to afford the 2-(4p-((1,7p-dimethyl-2p-propyl-
1H,3pH-2,5p-bibenzo[d]imidazol-3p-yl)-methyl)biphenyl-2-
yl)-4,4-dimethyl-4,5-dihydrooxazole 12 in 55% yield. Finally
oxazoline intermediate was readily cleaved by acid hydrolysis
to afford Telmisartan 1.
Fig. 1
In summary, an extremely efficient approach to the biphenyl
oxazoline structure of the Telmisartan has been developed by
employing a combination of the directed ortho metalation and
* Correspondent. E-mail: drgnmehta@rediffmail.com

96 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 1 Reagents and conditions: (a) polyphosphoric acid, 150–155 °C, 4.0 h, 80%; (b) KOt–Bu, dimethyl acetamide, 75–80 °C,
3.0 h, 70%; (c) trifluoroacetic acid, DMF, 4.0 h, 70%
Scheme 2 Reagents and conditions: (a) N-bromosuccinimide, AIBN, CCl4, reflux, 5.0 h, 50–75%.
solvent was evaporated under vacuum at 55 °C. The residue was tritu-
rated with n-hexane (100 mL) to give a solid which was filtered and
dried at 50–55 °C for 3–4 h to obtain 10 as a white crystalline powder
(yield 12.5 g, 80% yield); HRMS m/z Calcd for C26H25N4Br 474.4075
[M + 1]. Found: 474.4091; 1H NMR (400 MHz, CDCl3) (δ ppm): 7.72
(1H, s, ArH), 7.64–7.62 (2H, dd, J = 8.0 Hz, ArH), 7.47 (1H, s, ArH),
7.42–7.40 (2H, d, J = 8.0 Hz, ArH), 7.28–7.22 (2H, m, ArH), 6.94–
6.92 (2H, d, J = 8.0 Hz, ArH), 5.52 (2H, s, –CH2), 3.8 (3H, s, –CH3),
2.85 (2H, t, J = 8.0 Hz, –CH2), 2.74 (3H, s, –CH3), 1.86 (2H, m,
J = 7.6 Hz, –CH ), 1.01(3H, t, J = 7.6 Hz, –CH3);13CNMR(400 MHz,
CDCl3) (δ ppm2): 14.2, 17.7, 21.6, 30.2, 31.2, 47.2, 109.2, 113.3,
119.7, 121.1, 123.2, 123.5, 125.6, 127.0, 128.2, 129.1, 131.2, 135.4,
135.8, 138.9, 142.6, 144.5, 153.9, 154.5.
2-(4p-((1,7p-Dimethyl-2p-propyl-1H,3pH-2,5p-bibenzo[d]imidazol-3p-
yl)-methyl)biphe-nyl-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (12): To
a stirred solution of 4,4-dimethyl-2-phenyl-4,5-dihydrooxazole 11,
(3 g, 0.017 mol) in THF (30 mL) at 0 °C was added 2.5M n-BuLi
in hexanes (12 mL, 0.02 mol). The mixture was stirred at 0 °C for
60 mins, then 1.0M ZnCl in ether (41 mL, 0.03 mol) was added. The
reaction mixture was wa2rmed to the ambient temperature over 1 h,
then tetrakis(triphenylphosphine)palladium (0) (0.2 g) and 3p-(4-
bromobenzyl)-1,7p-dimethyl-2p-propyl-1H,3pH-2,5p-bibenzo[d]
imidazole 10 (8.1g, 0.017 mol) were added. The mixture was stirred at
55 °C for 24 h, poured into saturated ammonium chloride (200 mL),
and extracted with ethyl acetate (2 × 50 mL). The organic extracts
were combined, washed with water (2 × 50 mL), brine (1 × 50 mL),
dried over MgSO4 and concentrated under vacuum to give residue.
The obtained residue was triturated with n-hexane (50 mL) to give the
solid which was filtered and dried at 50–55 °C for 3–4 h to obtain
Negishi coupling methodologies. Application of this technol-
ogy to the synthesis of telmisartan provided a high-yielding
procedure that rivaled previous approaches.
Experimental
All solvents and reagents were purchased from the commercial sup-
pliers and used without further purification. All non-aqueous reactions
were performed in dry glassware under an atmosphere of dry nitrogen.
Organic solutions were concentrated under reduced pressure. TLC
1
was performed on Merck precoated Silica-gel 60F254 plates. H and
13C NMR spectra were recorded in DMSO-d and CDCl3 using
400 MHz, on a Varian Gemini 400 MHz FT NM6R spectrometer. The
chemical shifts were reported in δ ppm relative to TMS. The IR spec-
tra were recorded in the solid state as KBr dispersion using Perkin
Elmer FT-IR spectrophotometer. The mass spectra were recorded on
Shimadzu LCMS-QP 800 LC-MS and AB-4000 Q-trap LC-MS/MS.
Melting points were obtained by using the open capillary method and
are uncorrected.
3p-(4-Bromobenzyl)-1,7p-dimethyl-2p-propyl-1H,3pH-2,5p-bibenzo
[d]imidazole (10): 1,7p-Dimethyl-2p-propyl-1H,3pH-2,5p-bibenzo[d]
imidazole 4, (10 g, 0.03 mol) and 4-bromobenzyl bromide 9 (8.3 g,
0.03 mol) were dissolved in dimethylacetamide (50 mL). At 25–35 °C
under a nitrogen atmosphere powdered potassium carbonate (4.54 g,
0.03 mol) was added portionwise over 10 mins maintaining the tem-
perature at 25–35 °C. The resulting slurry was stirred at 25–35 °C
for 8 h. The slurry was filtered and the cake was washed with dimethyl
acetamide (15 mL). The filtrate was poured into water (200 mL).
The product was extracted twice with ethyl acetate (50 mL) and the

JOURNAL OF CHEMICAL RESEARCH 2010 97
Scheme 3 Reagents and conditions: (a) K2CO , dimethyl acetamide, 8 h, 80% (b) n-BuLi, ZnCl2, Pd(PPh3)4, THF, 24 h, 55%;
(c) concentr3ated hydrochloric acid, reflux, 30 h, 85%.
12 as a white crystalline powder (yield 5.4 g, 55% yield); m.p. 191–
193 °C (lit7 m.p 191–193 °C) ; HRMS m/z Calcd for C37H37N5O
568.7225 [M + 1]. Found: 568.7222; 1H NMR (400 MHz, CDCl3) (δ
ppm): 7.78 (1H, d, J = 8.0 Hz, ArH), 7.68 (1H, s, ArH), 7.64 (1H, s,
ArH), 7.62–7.60 (2H, d, J = 8.0 Hz, ArH), 7.59 (1H, d, J = 8.0 Hz,
ArH), 7.47–7.17 (6H, m, ArH), 7.07 (2H, d, J = 8.0 Hz, ArH), 5.45
(2H, s, –CH ), 3.82 (3H, s, –CH ), 3.58 (2H, s, –CH ), 2.97 (2H, t,
J = 7.6 Hz, –2CH ), 2.74 (3H, s, –C3H ), 1.92 (2H, m, J =27.6 Hz, –CH2),
1.29 (6H, s, 2×2 –CH ), 1.04 (3H,3 t, J = 7.6 Hz, –CH3); 13C NMR
(400 MHz, CDCl ) (δ3ppm): 13.9, 16.7, 21.6, 27.6, 29.6, 31.6, 46.9,
67.2, 79.0, 108.83, 109.2, 119.3, 122.1, 122.2, 123.5, 123.6, 125.6,
127.0, 127.2, 128.8, 129.1, 129.7, 129.9, 130.2, 134.4, 134.8, 136.4,
140.6, 140.8, 142.6, 142.8, 154.2, 156.2, 163.1.
(2H, m, J = 7.6 Hz, –CH2), 1.04 (3H, t, J = 7.6 Hz, –CH3); 13C NMR
(400 MHz, DMSO-d ) (δ ppm): 13.5, 16.7, 20.6, 27.6, 32.7, 47.1,
51.7, 112.0, 112.7, 1614.7, 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.
We are grateful to SVNIT, Surat and IICT, Hyderabad for
supporting this work.
Received 13 December 2009; accepted 1 February 2010
Paper 090911 doi: 10.3184/030823410X12656400473065
Published online: 1 March 2010
4p-[(1,7p-Dimethyl-2p-propyl-1H,3pH-2,5p-bibenzimidazol-3p-yl)
methyl]biphenyl-2-carboxylic acid (1): A mixture of 12 (4.0 g,
0.007 mol) and concentrated hydrochloric acid (40 mL) was heated to
reflux (100–105 °C) for about 30 h. The reaction mass was cooled to
0–5 °C. 20% Sodium hydroxide solution was added until the reaction
mixture pH attained to 9–10 and further stirred at room temperature
for 2 h. The required solid was filtered and washed with water
(50 mL). The wet cake was dissolved in a mixture of water (60 mL)
and acetonitrile (20 mL) and then heated to 60–65 °C. The pH of the
resulting clear solution was adjusted to 5.0–5.5 using 5% acetic acid,
and stirring was continued for 2 h. The precipitated solid was filtered
and washed with water (50 mL). Dried at 70–75 °C for 4–5 h under a
vacuum to obtain Telmisartan 1 as a white crystalline powder (yield
3.0 g, 85%); m.p. 260–262 °C (lit6 mp 260–262 °C); IR (KBr, cm−1)
2300–3500 (broad), 1680 (C=O); HRMS m/z Calcd 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), 7.52–7.28 (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, –CH ), 3.82
(3H, s, –CH3), 2.97 (2H, t, J = 7.6 Hz, –CH2), 2.74 (3H, s, –CH23), 1.92
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