New and improved synthesis of telmisartan: An antihypertensive drug

Article abstract of DOI:10.1080/00397910902840850

An improved, cost-effective, and industrially advantageous process suitable for large-scale production of telmisartan 1 has been described. The key steps include Suzuki coupling for the preparation of key intermediate 2-(4'-chloromethyl-biphenyl-2-yl)-4,4

Full text of DOI:10.1080/00397910902840850

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New and Improved
Synthesis of Telmisartan: An
Antihypertensive Drug
A. Sanjeev Kumar a , Samir Ghosh a , G. N. Mehta a ,
R. Soundararajan a , P. S. R. Sarma a & Kale Bhima a
a Chemistry Section, Applied Sciences and
Humanities Department , Sardar Vallabhbhai
National Institute of Technology (SVNIT) , Surat,
India
Published online: 29 Oct 2009.
To cite this article: A. Sanjeev Kumar , Samir Ghosh , G. N. Mehta , R.
Soundararajan , P. S. R. Sarma & Kale Bhima (2009) New and Improved Synthesis of
Telmisartan: An Antihypertensive Drug, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 39:23, 4149-4157,
DOI: 10.1080/00397910902840850
To link to this article: http://dx.doi.org/10.1080/00397910902840850
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Synthetic Communications1, 39: 4149–4157, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902840850
New and Improved Synthesis of Telmisartan:
An Antihypertensive Drug
A. Sanjeev Kumar, Samir Ghosh, G. N. Mehta, R. Soundararajan,
P. S. R. Sarma, and Kale Bhima
Chemistry Section, Applied Sciences and Humanities Department,
Sardar Vallabhbhai National Institute of Technology (SVNIT),
Surat, India
Abstract: An improved, cost-effective, and industrially advantageous process
suitable for large-scale production of telmisartan 1 has been described. The key
steps include Suzuki coupling for the preparation of key intermediate 2-(40-
chloromethyl-biphenyl-2-yl)-4,4-dimethyl-4,5-dihydrooxazole 10 of telmisartan,
N-alkylation, and oxazoline hydrolysis.
Keywords: Antihypertensive drug, oxazoline hydrolysis, Suzuki coupling,
telmisartan
INTRODUCTION
Telmisartan (1) is an angiotensin II receptor antagonist useful in the
treatment of hypertension, heart diseases, heart strokes, and bladder
diseases[1,2] (Fig. 1). Telmisartan (1) is currently available in the market
as an antihypertensive drug[3] under the brand name Micardis.
The first reported synthesis[4] of telmisartan (shown in Scheme 1)
involves condensation of 7-methyl-2-propyl-3H-benzimidazole-5-car-
boxylic acid derivative 2 with diamine derivative N-methylbenzene-
1,2-diamine 3 to give the dibenzimidazole derivative 4. Alkylation of
compound 4 with 40-bromomethyl-biphenyl-2-carboxylic acid tert-butyl
Received January 19, 2009.
Address correspondence to R. Soundararajan, Chemistry Section, Applied
Sciences and Humanities Department, Sardar Vallabhbhai National Institute of
Technology (SVNIT), Surat 395 007, India. E-mail: soundara1959@yahoo.com
4149

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A. S. Kumar et al.
Figure 1. Structural framework of telmisartan (1).
ester 5 furnished an ester derivative of telmisartan, 6. Ester hydrolysis of
6 in trifluoroacetic acid yielded telmisartan (1) in an overall yield of
around 21% with several impurities. This process suffers from disadvan-
tages such as (a) linear synthesis involving multiple steps; (b) poor stabi-
lity of 40-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester[5] 5; (c)
low yield and purity during the preparation of 40-bromomethyl-biphenyl-
2-carboxylic acid tert-butyl ester 5 due to the formation of 20–45% of
dibromo impurity 7 in bromination; (d) the solvents dimethylformamide
(DMF) or dimethyl sulfoxide (DMSO) used in the penultimate stage are
Scheme 1. Reported synthetic scheme of telmisartan. Reagents and conditions:
(a) polyphosphoric acid, 150–155ꢀC, 4–5 h; (b) KOt-Bu, dimethyl acetamide,
75–80ꢀC, 5–6 h; (c) triflouroacetic acid, DMF, 10–15 h.

Synthesis of Telmisartan
4151
unrecoverable, and the use of potassium tert-butoxide resulted in high
organic volatile impurities (OVI) in telmisartan; (e) deprotection of the
tert-butyl group using trifluoroacetic acid in DMF led to the formation
of several by-products; and (e) sulfated ash (residue on ignition) in active
pharmaceutical ingredients (API) obtained from this process is always
more than 1.0%, which was not acceptable as per International Conference
on Harmonization (ICH) guidelines.
40-Bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester 5, which
has high activity and reacts easily, could not be stored because of poor
stability, resulting from its high activity. Therefore, it had been prepared
immediately before use, and workability was extremely poor. Because of
its high activity, the ester also was liable to cause decomposition or a side
reaction in the reaction, so the obtained product had a low purity and
by-products varied and resulted in difficult purification.
Moreover, N-bromosuccinimide used for bromination in preparation
of 40-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester 5 is unsui-
table for industrial production because this reagent is expensive and bro-
mination is a free radical reaction (and therefore is too rapid to be
controlled). Formation of dibromoimpurity 7 (Scheme 2) varied from
20 to 45% with N-bromosuccinimide. Reaction with 40-Bromomethyl-
biphenyl-2-carboxylic acid tert-butyl ester 5 took much labor to separate
and purify the N-alkylated product and had disadvantages in economic
efficiency and safeness, in addition to its poor working efficiency as an
intermediate. Thus, the ester was not always satisfactory as an intermedi-
ate for industrial production.
Under these circumstances, active 2-(40-chloromethyl-biphenyl-2-yl)-
4,4-dimethyl-4,5-dihydrooxazole[6] 10, which has excellent operatablity,
was prepared by a convergent approach (Scheme 3). The two-step
sequence has greatly improved the synthesis of biaryl oxazoline
10 compared with literature procedure, gave better yield (overall yield
90%), needed less preparation time, and required only one-column
purification.
Scheme 2. Synthesis of 4-bromomethyl biphenyl-2-carboxylic acid t-butyl ester.
Reagents and conditions: (a) N-bromosuccinamide, AIBN, CCl4, 78–80ꢀC, 3–4 h.

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A. S. Kumar et al.
DISCUSSION
In our attempts to prepare telmisartan 1, we have developed an efficient
two-stage process employing Suzuki coupling for the preparation
of 2-(40-chloromethyl-biphenyl-2-yl)-4,4-dimethyl-4,5-dihydrooxazole 10
and later condensation with dibenzimidazole derivative[7,8] 4. Finally,
acid hydrolysis of intermediate 11 provided telmisartan 1 in good yield.
The reported synthesis for the preparation of 10 started from nucleophilic
displacement of methoxy group of 2-(2-methoxy phenyl)-4,4-dimethyl-4,5
dihydrooxazole with excess p-tolylmagnesium bromide reagent in tetra-
hydrofuran (THF) to give 4,4-dimethyl-2-(40methyl biphenyl 2-yl)-4,
4-dihydrooxazole, which on oxidation with potassium permanganate
under basic conditions followed by reduction with lithium aluminium
hydride yielded [20-(4,4-dimethyl-4,5-dihydro oxazol-2-yl)-biphenyl-4-yl]
methanol 9. Finally, on reaction with thionyl chloride, it yielded the
desired intermediate 10 (Scheme 5).
We identified 4-(hydroxymethyl)phenylboronic acid and 2-(2-
bromophenyl)-4,4-dimethyl-2-oxazoline[9] as key starting materials for
the preparation of key intermediate 2-(40-chloromethyl-biphenyl-
2-yl)-4,4-dimethyl-4,5-dihydrooxazole 10. Suzuki coupling was employed
for the preparation of the key intermediate by the reaction of
2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline 8 with 4-(hydroxymethyl)
phenylboronic acid in the presence of aqueous sodium carbonate and
tetrakistriphenyl phospine palladium (0), which produced [20-(4,4-
dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-yl]-methanol 9 in more
than 95% yield. Chlorination of [20-(4,4-dimethyl-4,5-dihydro-oxazol-
2-yl)-biphenyl-4-yl]-methanol 9 with thionyl chloride at low temperature
afforded the key intermediate 2-(40-chloromethyl-biphenyl-2-yl)-4,4-
dimethyl-4,5-dihydrooxazole 10 in more than 99% yield (Scheme 3).
In short, Scheme 4 represents safer, and more economical competitive
synthesis of telmisartan than the earlier reported synthesis. To the best of
Scheme 3. Convergent scheme for 2-(40-chloromethyl-biphenyl-2-yl)-4,4-
dimethyl-4,5-dihydro oxazole 10. Reagents and conditions: (a) 4-(hydroxymethyl)
phenylboronic acid, Pd(Ph3P)4, aq. Na2CO3, THF, 5–6 h; (b) thionyl chloride,
dichloromethane, 0–5ꢀC, 1–2 h.

Synthesis of Telmisartan
4153
Scheme 4. Modified synthetic scheme of telmisartan. Reagents and conditions:
(a) polyphosphoric acid, 150–155ꢀC, 4–5 h; (b) NaH, THF, dimethyl acetamide,
75–80ꢀC, 5–6 h; (c) concentrated hydrochloric acid, 100–110ꢀC, 20–32 h.
our knowledge, this protocol is more economically advantageous than the
earlier reported synthesis because of high yields and fewer stages.
EXPERIMENTAL
Materials and Instruments
All solvents and reagents were purchased from the suppliers and used
without further purification. All nonaqueous reactions were performed
Scheme 5. Reported synthetic scheme for the preparation of 2-(40-Chloromethyl-
biphenyl-2-yl)-4,4-dimethyl-4, 5-dihydrooxazole (10). Reagents and conditions:
(a) p-Tolylmagnesium bromide=THF=25–35ꢀC=12–13 h. (b) KMnO4=pyridine=
100–105ꢀC=5–6 h. (c) Lithium aluminium hydride=THF=25–35ꢀC= 2–3 h. (d)
Thionyl chloride=DCM=0–5ꢀC=1–2 h.

4154
A. S. Kumar et al.
in dry glassware under an atmosphere of dry nitrogen. Organic solutions
were concentrated under reduced pressure. Thin-layer chromatography
1
(TLC) was performed on Merck precoated silica-gel 60F254 plates. H
and 13C NMR spectra were recorded in dimethyl sulfoxide (DMSO-d6)
and CDCl3 using a Varian Gemini 400-MHz Fourier transform (FT)
NMR spectrometer. The chemical shifts were reported in d parts per million
(ppm) relative to tetramethylsilane (TMS). The infrared (IR) spectra were
recorded in the solid state as KBr dispersion using a Perkin-Elmer FT-IR
spectrophotometer. The mass spectra (MS) were recorded on a Shimadzu
LCMS-QP 800 LC-MS and AB-4000 Q-trap LC-MS=MS. Melting points
were obtained using the open capillary method and are uncorrected.
[20-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-yl]-methanol (9)
To a mixture of 4-(hydroxymethyl) phenylboronic acid (5.0 g, 0.032 mol)
and 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline 8 (10.1 g, 0.039 mol) in
tetrahydrafuran (THF, 50.0 mL), 2 M aqueous sodium carbonate solu-
tion (20.0 mL) was added at room temperature. The resulting biphase
solution was degassed with nitrogen gas for 20 min. Tetrakistriphenyl
phosphine palladium(0) (0.25 g) was added and heated to reflux (64ꢀC).
The reaction mixture was maintained under reflux for 12 h. After comple-
tion of the reaction, the reaction mixture was cooled to 26ꢀC, and 50 mL
of saturated ammonium chloride solution and 50 mL of ethyl acetate
were added. The separated organic layer was washed twice with
water (50.0 mL). The organic layer was dried over sodium sulfate and
evaporated under vacuum. The residue was chromatographed on silica
gel eluting with hexane=ethyl acetate (50:50) to give the title compound
as a white solid (8.8 g, 95%); melting point: 97–98ꢀC; IR (cmꢁ1) 3330
1
=
(OH), 1640 (C N); H NMR (CDCl3) (d ppm): 7.74 (dd, J ¼ 8.0, 1H),
7.48 (ddd, J ¼ 8.0, 1H), 7.26–7.42 (6H, m), 4.75 (2H, s), 3.82 (2H, s),
1.8 (1H, broad-s), 1.30 (6H, s); 13C NMR (CDCl3) (d ppm) 28.6, 64.3,
68.1, 78.9, 127.1, 126.9, 127.7, 128.5, 129.4, 129.4, 130.2, 137.2, 140.2,
141.2, 164.9. MS (m=z): 282 [Mþ þ 1]. Anal. calcd. for C18H19NO2: C,
76.84; H, 6.81; N, 4.98; O, 11.37. Found: C, 76.86; H, 6.82; N, 4.99.
2-(40-Chloromethyl-biphenyl-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (10)
Thionyl chloride was added (2.0 g, 0.017 mol) dropwise to a solution of [20-(4,
4-dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-yl]-methanol 9 (4.0g, 0.014
mol) in methylene chloride (40.0 mL) at 0–5ꢀC, and the temperature
was maintained for 2 h. The reaction mixture was poured into an aqueous
solution of 20% of sodium hydrogen carbonate solution (40.0 mL). The

Synthesis of Telmisartan
4155
organic layer was separated and washed twice with water (50.0 mL). The
organic layer was reduced under pressure to give the title compoundꢁ110
as a white solid (4.2 g, 99% yield): melting point: 73–75ꢀC; IR (cm
)
1
=
1620 (C N); H NMR (CDCl3) (d ppm) 7.73 (ddd, J ¼ 7.6, 1H), 7.62 (td,
J ¼ 7.6, 1H), 7.35–7.43 (6H, m), 4.64 (2H, s), 3.82 (2H, s), 1.29 (6H, s);
13C NMR (CDCl3) (d ppm); 28.6, 46.3, 68.1, 78.9, 127.1, 127.7, 128.5,
129.4, 130.2, 137.2, 140.2, 164.9. MS (m=z): 300 [Mþ þ 1]. Anal. calcd.
for C18H18ClNO: C, 72.11; H, 6.05; Cl, 11.83; N, 4.67; O, 5.34. Found:
C, 72.21; H, 6.10; N, 4.68.
30-[20-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-
4-ylmethyl]-1,70-dimethyl-20-propyl-1h,30h-[2,50] bibenzoimidazolyl (11)
A solution of 1,40-dimethyl-20-propyl-1H,30H-2,5-dibenzimidazole 4 (3.0 g,
0.0098mol) and THF (30 mL) was added dropwise to the mixture of 60%
sodium hydride (0.59 g, 0.0148mol) in THF (30 mL) under an inert atmo-
sphere. The reaction mixture was stirred for 30min at room temperature.
2-(40-Chloromethyl-biphenyl-2-yl)-4,4-dimethyl-4,5-dihydrooxazole 10 (3.5 g,
0.0118 mol) dissolved in THF (30 mL), and dimethylacetamide (10 mL)
was added to the reaction mixture. The reaction mixture was heated to
reflux, maintained for 8 h, and cooled to 25–35ꢀC; the reaction mixture
was poured into a solution of saturated aqueous ammonium chloride
(50 mL). The product was extracted twice with ethyl acetate (50 mL)
and evaporated under vacuum at 55ꢀC. The obtained residue was tritu-
rated with n-hexane (36 mL) to get the solid material, which was and
filtered and dried at 50–55ꢀC for 3–4 h to obtain 11 as a white crystalline
powder (yield 4.75 g, 85% yield): melting point 191–193ꢀC; IR (cmꢁ1) 1630
1
=
(C N); H NMR (CDCl3) (d ppm): 7.05–7.8 (14H, m), 5.45 (2H, s), 3.82
(3H, s), 3.58 (2H, s), 2.97 (t, J ¼ 7.6, 2H), 2.56 (3H, s), 1.92 (q, J ¼ 7.2, 2H),
1.29 (6H, s), 1.04 (t, J ¼ 7.2, 3H); 13C NMR (CDCl3) (d ppm): 13.9, 16.7,
21.6, 27.6, 29.6, 31.6, 46.9, 67.2, 79.0, 108.8, 109.2, 119.3, 122.1, 122.29,
123.5, 123.67, 125.6, 127.0, 128.8, 129.1, 129.7, 129.9, 130.2, 134.4,
134.8, 136.4, 140.6, 140.8, 142.6, 154.2, 156.2, 163.1. MS (m=z): 568
[Mþ þ 1]. Anal. calcd. for C37H37N5O: C, 78.28; H, 6.57; N, 12.34; O,
2.82. Found: C, 78.26; H, 6.51; N, 12.30.
40-(1,70-Dimethyl-20-propyl-1h-[2,50]bibenzoimidazolyl-30-
ylmethyl)-biphenyl-2-carboxylic Acid (1)
A mixture of 11 (4.0 g, 0.007 mol) and concentrated hydrochloric acid
(40.0 mL) was heated to reflux (100–105ꢀC) for about 30 h. The reaction

4156
A. S. Kumar et al.
mass was cooled to 0–5ꢀC. Sodium hydroxide solution (20%) was added
until the reaction mixture pH reached 9–10, and it was stirred at room
temperature for 2 h. The obtained solid was filtered and washed with
water (50.0 mL). The wet cake was dissolved in a mixture of water
(60.0 mL) and acetonitrile (20.0 mL) and then heated to 60–65ꢀC. The
pH of the resulting clear solution was adjusted to 5.0–5.5 using 5% acetic
acid, and stirring continued for 2 h. The precipitated solid was filtered,
washed with water (50 mL), and dried at 70–75ꢀC for 4–5 h under a
vacuum to obtain telmisartan 1 as a white crystalline powder (yield
ꢁ1
3.0 g 85%): mp 260–262ꢀC; IR (cm ) 2300–3500 (broad), 1680 (C O);
=
1H NMR (CDCl3) (d ppm): 12.8 (1H, s), 7.0–8.4 (14H, m), 5.40 (2H,
s), 3.80 (3H, s), 3.15 (t, J ¼ 8.4, 2H), 2.71 (3H, s), 2.0 (q, J ¼ 7.6, 2H),
1.15 (t, J ¼ 7.6, 3H); 13C NMR (DMSO-d6) (d 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, 133.7,
134.5, 140.2, 140.5, 150.2, 157.3, 168.1; MS (m=z): 515 [Mþ þ 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.
ACKNOWLEDGMENTS
We are grateful to SVNIT, Surat, and Indian Institute of Chemical
Technology, Hyderabad, for supporting this work.
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