Efficient and improved synthesis of Telmisartan

Article abstract of DOI:10.3762/bjoc.6.25

An efficient synthesis of the angiotensin II receptor antagonist Telmisartan (1) is presented involving a cross coupling of 4-formylphenylboronic acid 10 with 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline (11) as the key step (90% yield). The benzimidazole moiety 15 was constructed regioselectively via a reductive amination-condensation sequence, replacing the alkylation of the preformed benzimidazole step in the previously published route. This methodology overcomes many of drawbacks associated with previously reported syntheses.

Full text of DOI:10.3762/bjoc.6.25

Efficient and improved synthesis of Telmisartan
A. Sanjeev Kumar, Samir Ghosh and G. N. Mehta*
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2010, 6, No. 25.
Applied Chemistry Department, Sardar Vallabhbhai National Institute
of Technology, Surat-395 007, India
doi:10.3762/bjoc.6.25
Received: 10 January 2010
Accepted: 25 February 2010
Published: 11 March 2010
Email:
G. N. Mehta* - drgnmehta@rediffmail.com
* Corresponding author
Associate Editor: J. A. Porco Jr.
Keywords:
© 2010 Kumar et al; licensee Beilstein-Institut.
License and terms: see end of document.
antihypertensive drug; oxazoline hydrolysis; Suzuki coupling;
Telmisartan
Abstract
An efficient synthesis of the angiotensin II receptor antagonist Telmisartan (1) is presented involving a cross coupling of 4-formyl-
phenylboronic acid 10 with 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline (11) as the key step (90% yield). The benzimidazole
moiety 15 was constructed regioselectively via a reductive amination-condensation sequence, replacing the alkylation of the
preformed benzimidazole step in the previously published route. This methodology overcomes many of drawbacks associated with
previously reported syntheses.
Introduction
Telmisartan (1) is an angiotensin II receptor antagonist useful in angiotensin II receptor antagonist losartan (Lozaar) as the first
the treatment of hypertension, heart diseases, heart attack, and member of a new class of antihypertensive drugs called sartans,
bladder diseases [1-3]. Telmisartan is currently available in the all of which contain a characteristic ortho functionalized biaryl
market as an antihypertensive drug [4] under the brand name of moiety. Telmisartan (1, Boehringer Ingelheim, Micardis®)
Micardis®.
(Figure 1) is an important member of this class of top-selling
drugs because it has the strongest binding affinity to the AT1
Essential hypertension is a major risk factor in cardiovascular receptor, an excellent bioavailability, and a once-per-day
diseases and is responsible for one-third of global deaths. Most dosage.
antihypertensive drugs interact with the renin-angiotensin
system (RAS), which is the central regulator of blood pressure The first total synthesis of Telmisartan as introduced by Ries et
and electrolyte homeostasis. Renin transforms angiotensinogen al. (Scheme 1) starts with the acylation of 4-amino-3-methyl-
into the decapeptide angiotensin I, which is converted by the benzoic acid methyl ester (2) with butyryl chloride, followed by
angiotensin conversion enzyme (ACE) into the octapeptide nitration, reduction of the nitro group, and subsequent cycliza-
angiotensin II. The latter binds to its angiotensin receptor (AT1) tion of the resulting amine to the benzimidazole derivative 3.
and, thereby, becomes a powerful vasoconstrictor. In the early After saponification, the free carboxyl group is condensed with
1990s, Merck introduced the non-peptidic orally active N-methyl-1,2-phenylenediamine to afford the bis-benzimida-
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Beilstein Journal of Organic Chemistry 2010, 6, No. 25.
butoxide in the penultimate step and the use of methanolic HCl
solution instead of trifluoroacetic acid in the final step [6].
However, the main shortcomings of the synthesis remained,
namely, the unsatisfactory regioselectivity in the alkylation of 8
with 4 and the intricate synthesis of the biaryl intermediate 7. In
the original protocol, the latter was synthesized via an Ullmann
coupling of the aryl iodides 5 and 6 using 5 equiv of copper [7].
Modern syntheses of 7 involve cross-couplings of sensitive aryl
magnesium [8], zinc [9], or boron [10,11] compounds with
alkyl 2-halobenzoates. Since the commercialization of
Telmisartan, 7 has become readily available at low cost, so that
most subsequent published procedures start from this com-
pound.
Figure 1: The angiotensin II receptor antagonist Telmisartan.
zole 4, which is then alkylated with the 4′-(bromomethyl)-2- In designing an alternative synthesis of Telmisartan our goal
biphenylcarboxylic acid tert-butyl ester (8) to give, after hydro- was to minimize the use of expensive and hazardous metals,
lysis of the ester group, Telmisartan (1) in 21% overall yield circumvent the bromination step, and increase the overall effi-
and with eight steps as the longest sequence [5].
ciency of the synthesis. This was accomplished by reversing the
order of the major bond disconnections. We realized biaryl syn-
Several improvements to the above reaction sequence have been thesis and reductive amination are the key steps, and have the
reported, e.g., the use of KOH instead of potassium tert- potential to overcome both of these weaknesses.
Scheme 1: First literature synthesis of Telmisartan (a) nPrCOCl, C6H5Cl, 100 °C (b) HNO3/H2SO4, 0 °C (c) Pd/C, 5 bar, H2, MeOH (d) AcOH, 120 °C,
yield: 78% (e) NaOH, MeOH/H2O, 100 °C (f) 2-MeNH-C6H4-NH2, PPA, 150 °C, yield: 64% (g) tBuOK, DMSO, RT (h) TFA, DCM, RT, yield: 42% (i) Cu
(5 equiv), 210 °C, (j) HCl, H2O, 100 °C (k) (COCl)2, DCM, 0 °C, (l) tBuOK, THF, RT, yield: 9% (m) NBS, (PhCOO)2, CCl4, 76 °C.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 25.
Results and Discussion
The reductive amination of the biaryl aldehyde 12 with amine
We identified 4-formylphenylboronic acid (10) and 2-(2- 13 (prepared by the literature procedure [13]) was carried out in
bromophenyl)-4,4-dimethyl-2-oxazoline (11) [12] as the ideal the presence of p-toluenesulfonic acid in toluene and followed
starting materials for the preparation of the key biaryl interme- by hydrogenation in methyl alcohol. The resulting amine 14
diate. Thus, Suzuki coupling of 2-(2-bromophenyl)-4,4- was not isolated but cyclized in situ to the n-propyl benzimida-
dimethyl-2-oxazoline with 4-formylphenylboronic acid in pres- zole 15 in 80% yield in refluxing glacial acetic acid. Finally,
ence of aqueous sodium carbonate and tetrakis(triphenylphos- cleavage of the oxazoline moiety in 15 by acid afforded
phine)palladium(0) in THF solvent gave 2’-(4,4-dimethyl-4,5- Telmisartan (1) (Scheme 3).
dihydro-1,3-oxazol-2-yl)biphenyl-4-carbaldehyde (12) in over
90% yield (Scheme 2).
Conclusion
In conclusion, a concise and selective synthesis of the anti-
hypertensive drug Telmisartan has been developed, featuring a
Suzuki cross-coupling for the construction of the biaryl moiety
and a regiospecific reductive amination-condensation sequence
for the synthesis of the central benzimidazole.
Experimental
All solvents and reagents were purchased from the commercial
suppliers and used without further purification. All non-aqueous
reactions were performed in dry glassware under an atmos-
phere of dry nitrogen. Organic solutions were concentrated
under reduced pressure. Thin layer chromatography was
performed on Merck precoated Silica-gel 60F254 plates. 1H and
Scheme 2: (a) Pd(PPh3)4, aq Na2CO3, THF, 12.0 h, 90%.
Scheme 3: (a) p-TsOH, toluene, 110 °C, 12 h, (b) Pd/C, 7 bar H2, MeOH, 60 °C, 24 h, 100% (c) AcOH, 120 °C, 2 h, 80% (d) Conc. HCl, 100–110 °C,
30 h, 80%.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 25.
13C NMR spectra were recorded in DMSO-d6 and CDCl3 using then concentrated. Water (150 mL) was added to residue. The
400 MHz, on a Varian Gemini 400 MHz FT NMR spectro- product was extracted twice with ethyl acetate (2 × 50 mL) and
meter. The chemical shifts were reported in δ ppm relative to evaporated under vacuum at 55 °C. The residue was triturated
TMS (tetramethylsilane). The IR spectra were recorded in the with n-hexane (40 mL) to yield a solid which was removed by
solid state as KBr dispersion using Perkin Elmer FT-IR spectro- filtration and dried at 50–55 °C for 3–4 h to afford 15 as a white
photometer. The mass spectra were recorded on Shimadzu crystalline powder (yield 5.7 g, 80% yield); melting point
LCMS-QP 800 LC-MS and AB-4000 Q-trap LC-MS/MS. 191–193 °C; IR (KBr, cm-1) 1630 (C=N); HRMS m/z calcu-
Melting points were obtained by using the open capillary lated for C37H37N5O – 568.7225 [M + 1], found – 568.7222;
method and are uncorrected.
1H NMR (400 MHz, CDCl3) (δ ppm): 7.78 (1H, d, J = 8.0 Hz,
ArH), 7.68 (1H, m, J = 8.0 Hz, ArH), 7.47–7.26 (10H, m, ArH),
2’-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)biphenyl-4- 7.07 (2H, m, J = 8.0 Hz, ArH), 5.45 (2H, s, -CH2), 3.82 (3H, s,
carbaldehyde (12): To a mixture of 4-formylphenylboronic -CH3), 3.58 (2H, s, -CH2), 2.97 (2H, t, J = 7.6 Hz, -CH2), 2.74
acid (10) (5.0 g, 0.032 mol) and 2-(2-bromophenyl)-4,4- (3H, s, -CH3), 1.92 (2H, m , J = 7.6 Hz, -CH2), 1.29 (6H, s, 2 x
dimethyl-2-oxazoline (11) (10.1 g, 0.039 mol) in tetrahydro- -CH3), 1.04 (3H, t, J = 7.6 Hz, -CH3); 13C NMR (100 MHz,
furan (50.0 mL), 2 M aqueous sodium carbonate solution CDCl3) (δ ppm): 13.9, 16.7, 21.6, 27.6, 29.6, 31.6, 46.9, 67.2,
(20.0 mL) was added at room temperature. The resulting 79.0, 108.8, 109.2, 119.3, 122.1, 122.2, 123.5, 123.6, 125.6,
biphasic solution was degassed with nitrogen gas for 20 min. 127.0, 127.2, 128.8, 129.1, 129.7, 129.9, 130.2, 134.4, 134.8,
Tetrakis(triphenylphosphine)palladium(0) (0.25 g) was added 136.4, 140.6, 140.8, 142.6, 142.8, 154.2, 156.2, 163.1.
and heated to reflux (64 °C). The reaction mixture was main-
tained under reflux for 12 h. After completion of the reaction, 4’-[(1,7’-dimethyl-2’-propyl-1H,3’H-2,5’-bibenzimidazol-3’-
the reaction mixture was cooled to 26 °C and saturated yl)methyl]biphenyl -2-carboxylic acid (1): A mixture of 15
ammonium chloride solution (50 mL) and ethyl acetate (50 mL) (4.0 g, 0.007 mol) and concentrated hydrochloric acid (40 mL)
added. The organic layer was separated, washed twice with was heated at reflux (100–110 °C) for about 30 h. The reaction
water (50.0 mL), dried over sodium sulfate and evaporated mass was cooled to 0–5 °C. Sodium hydroxide solution (20%)
under vacuum. The residue was chromatographed on silica gel was added until the pH of the reaction mixture was 9–10 and
eluting with hexane/ethyl acetate 80:20 to give the title com- then stirred at room temperature for a further 2 h. The resulting
pound 12 as an oil (8.0 g, 90%); 1H NMR (400 MHz, DMSO- solid was removed by filtration and washed with water (50 mL).
d6) (δ ppm): 10.0 (1H, s, -CHO), 7.91 (2H, d, J = 8.4 Hz, ArH), The wet cake was dissolved in a mixture of water (60 mL) and
7.73 (1H, d, J = 8.4 Hz, ArH), 7.48 (2H, d, J = 7.8 Hz, ArH), acetonitrile (20 mL) and then heated to 60–65 °C. The pH of the
7.44–7.34 (2H, m, ArH), 7.30 (1H, m, J = 7.4 Hz, ArH), 3.80 resulting clear solution was adjusted to 5.0–5.5 with 5% acetic
(2H, s, -CH2), 1.12 (6H, s, 2 × -CH3); 13C NMR (100 MHz, acid, and stirring continued for 2 h. The precipitated solid was
DMSO-d6) (δ ppm); 28.0, 68.0, 78.9, 128.0, 128.5, 129.5, filtered and washed with water (50 mL). After drying at
129.6, 130.4, 130.5, 131.2, 135.3, 140.2, 147.0, 161.8, 193.2.; 70–75 °C for 4–5 h under a vacuum Telmisartan (1) was
MS (m/z): 280 [M+ + 1].
obtained as a white crystalline powder (yield 2.9 g, 80%);
melting point: 260–262 °C (lit [6] mp 260–262 °C); IR (KBr,
3'-{[2'-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)biphenyl-4- cm-1) 2300–3500 (broad), 1680 (C=O); HRMS m/z calculated
yl]methyl}-1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-bibenzimi- for C33H30N4O2 – 515.6169 [M + 1], found – 515.6192;
dazole (15): A mixture of 13 (4.0 g, 0.01 mol), 12 (3.5 g, 1H NMR (400 MHz, CDCl3) (δ ppm): 12.8 (1H, s, -COOH),
0.01 mol), and p-TsOH (0.21 g, 0.001 mol) was suspended in 8.42 (1H, d, J = 8.0 Hz, ArH), 8.02 (1H, d, J = 8.0 Hz, ArH),
toluene (40 mL) under nitrogen, and the mixture refluxed for 7.50–7.26 (8H, m, ArH), 7.20 (2H, d, J = 8.0 Hz, ArH), 7.05
16 h and then concentrated. The residue was diluted with meth- (1H, s, ArH), 6.96 (1H, s, ArH), 5.42 (2H, s, -CH2), 3.82 (3H, s,
anol (40 mL) and transferred to a stainless steel autoclave. -CH3), 2.97 (2H, t, J = 7.6 Hz, -CH2), 2.74 (3H, s, -CH3), 1.92
Palladium on charcoal (10%, 1.0 g) was added and the reaction (2H, m, J = 7.6 Hz, -CH2), 1.04 (3H, t, J = 7.6 Hz, -CH3); 13C
mixture stirred under H2 pressure (7 bar) for 24 h at 60 °C. NMR (100 MHz, DMSO-d6) (δ ppm): 13.5, 16.7, 20.6, 27.6,
After cooling to room temperature and filtration, the filter cake 32.7, 47.1, 51.7, 112.0, 112.7, 114.7, 118.6, 125.3, 125.7, 125.8,
was rinsed with ethyl acetate (3 × 50 mL). The filtrate was 127.0, 127.4, 128.6, 129.3, 130.4, 130.6, 131.5, 132.3, 133.1,
washed with water, and the aqueous layer basified to pH 10 133.2, 133.7, 134.5, 140.2, 140.5, 150.2, 157.3, 168.1.
with aqueous ammonia and extracted with ethyl acetate (2 ×
50 mL). The combined organic layers were dried over MgSO4 Acknowledgements
and concentrated. The crude amine 14 was diluted with glacial We are grateful to SVNIT, Surat and IICT, Hyderabad for
acetic acid (40 mL), the resulting solution refluxed for 2 h and supporting this work.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 25.
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