Efficient synthesis of olmesartan medoxomil, an antihypertensive drug

Article abstract of DOI:10.1080/00397910802372558

This document describes a simple and robust process for the synthesis of olmesartan medoxomil. This tailored process allows us to synthesize olmesartan medoxomil on a large scale with 50% overall yield. Also, our process has excellent control of the impurity profile in all the stages. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802372558

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Efficient Synthesis of
Olmesartan Medoxomil, an
Antihypertensive Drug
Karrothu Srihari Babu a , Mallepalli Srinivasa Reddy
a , Amirisetty Ravindranath Tagore a , Gade Srinivas
Reddy a , Sony Sebastian a , Mudunuru Satish Varma
a , Gandu Venkateswarlu b , Apurba Bhattacharya a ,
Padi Pratap Reddy a & Ramasamy Vijaya Anand a
a Center of Excellence , Dr. Reddy's Laboratories
Ltd. , Bachupalli, Qutubullapur, India
b Department of Chemistry , Nizam College ,
Hyderabad, India
Published online: 22 Dec 2008.
To cite this article: Karrothu Srihari Babu , Mallepalli Srinivasa Reddy , Amirisetty
Ravindranath Tagore , Gade Srinivas Reddy , Sony Sebastian , Mudunuru Satish Varma ,
Gandu Venkateswarlu , Apurba Bhattacharya , Padi Pratap Reddy & Ramasamy Vijaya
Anand (2008) Efficient Synthesis of Olmesartan Medoxomil, an Antihypertensive Drug,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:2, 291-298, DOI: 10.1080/00397910802372558
To link to this article: http://dx.doi.org/10.1080/00397910802372558
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Synthetic Communications1, 39: 291–298, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802372558
Efficient Synthesis of Olmesartan Medoxomil,
an Antihypertensive Drug
Karrothu Srihari Babu,1 Mallepalli Srinivasa Reddy,1
Amirisetty Ravindranath Tagore,1 Gade Srinivas Reddy,1
Sony Sebastian,1 Mudunuru Satish Varma,1 Gandu Venkateswarlu,2
Apurba Bhattacharya,1 Padi Pratap Reddy,1
and Ramasamy Vijaya Anand1
1Center of Excellence, Dr. Reddy’s Laboratories Ltd., Bachupalli,
Qutubullapur, India
2Department of Chemistry, Nizam College, Hyderabad, India
Abstract: This document describes a simple and robust process for the synthesis
of olmesartan medoxomil. This tailored process allows us to synthesize olmesar-
tan medoxomil on a large scale with 50% overall yield. Also, our process has
excellent control of the impurity profile in all the stages.
Keywords: Angiotensin receptor antagonist, anti-hypertensive, olmesartan
INTRODUCTION
Hypertension is a serious disease with a momentous impact on health and
life expectancy. Controlling blood pressure and preventing complications
such as coronary heart disease, renal failure, and cerebral vascular disease
are the main objectives for the treatment of hypertension.[1] Olmesartan
medoxomil (1) (Benicar1, Sankyo pharma)[2] is the latest angiotensin
Received April 30, 2008.
DRL-IPD Communication No. IPDO-IPM-00114
Address correspondence to Ramasamy Vijaya Anand, Center of Excellence,
IPDO-Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Bachupalli, Qutu-
bullapur, R. R. Dist. 500072, Andhra Pradesh, India. E-mail: vijayaanandr@
drreddys.com
291

292
K. S. Babu et al.
receptor antagonist approved by the U.S. Food and Drug Administra-
tion for the treatment of hypertension (Fig. 1). The drug works by inhi-
biting the effects of angiotensin II, a potent vasoconstrictor and one of
the key contributors to cardiovascular and renal disease.[3]
Herein, we report an improved, scalable, and cost-effective route to
the synthesis of olmesartan medoximil 1.
RESULTS AND DISCUSSION
We started our approach by condensing 2 with trimethyl orthobutyrate in
CH3CN to get the dicyano imdazole derivative 3 in 96% yield and 98%
high-performance liquid chromatography (HPLC) purity (Scheme 1).[4]
An additional distillation of the reaction mixture in toluene using
Dean–Stark reaction took care of the complete conversion of the inter-
mediate 11 (Fig. 2) to the product 3 by expulsion of methanol. Acidic
hydrolysis of 3 under reflux conditions provided 4, which on thionyl
chloride–mediated esterification in methanol at 40–50 ꢀC afforded the
diester 5 in 98% yield and 99.8 HPLC purity.
The diester 5 was then condensed with biphenyl derivative 6[5] in the
presence of potassium carbonate in refluxing acetone to provide the
N-alkylated imidazole derivative 7 in excellent yield and purity. However,
the major yield improvement in this stage was achieved during the
workup procedure; out of several solvents tried, water was found to be
the best. Product 7 was isolated in 98% yield and 99.9% HPLC purity.
The most decisive step in our scheme (Scheme 1) was the Grignard reac-
tion of the diester 7 because there is a possibility of getting the impurities
12 and 13 (Fig. 2). At this stage, we thought that the presence of bulky
Figure 1. Structural framework of olmesartan medoximil 1.

Synthesis of Olmesartan Medoxomil
293
Scheme 1. Synthetic scheme of olmesartan medoxomil 1. Reagents and
conditions: (i) CH3CN, reflux, PhMe; (ii) 6N aq. HCI; (iii) methanol=SOCI2;
(iv) 6 K2CO3, acetone; (v) CH3MgCI, toluene; (vi) NaOH=H2O=acetone;
(vii) Na2CO3=DMF; and (viii) acetic acid=acetone.
biphenyl tetrazole moiety in 7 would help in getting the right regio-
selectivity during the Grignard reaction.
As we expected, the Grignard reaction of 7 with 3 equivalents of
MeMgCl in anhydrous toluene proceeded smoothly, and the required ter-
tiary hydroxyl derivative 8 was obtained in 95% yield and 95% HPLC

294
K. S. Babu et al.
Figure 2. Olmesartan impurities.
Figure 3. Effect of temperature on Grignard reaction. ., 5-Acetyl impurity and
^, 4-acetyl impurity.
purity. Although we observed the formation of impurities 12 and 13 in
small quantities, we could able to optimize the reaction conditions to
minimize the impurity level to less than 2%. Reaction temperature played
a major role in controlling the regioisomeric impurities. At higher tem-
perature (more than 40 ꢀC), the formation of 12 was more (up to
7.5%), and 13 was formed in trace amounts (0.6%). At lower temperature
(less than 20 ꢀC), 13 was observed at a higher level (5.8%) and 12 was
detected in trace quantities (0.2%). Based on the experiments, the opti-
mum temperature of this reaction was found to be 20–40 ꢀC. The effect
of temperature on Grignard reaction is represented in Fig. 3. Saponifica-
tion of teritiary hydroxyl ester 8 with aqueous NaOH afforded the
sodium salt 9, which on alkylation with 4-chloromethyl-5-methyl-1,3-
dioxolen-2-one provided 10 in 80% yield. Deprotection of trityl group
in 10 with acetic acid in acetone provided olmesartan medoximil 1 in
80% yield and 99.7% HPLC purity after crystallization (Scheme 1).
CONCLUSION
An efficient method for the synthesis of olmesartan medoxomil was
achieved and realized on a plant scale.

Synthesis of Olmesartan Medoxomil
295
EXPERIMENTAL
General Methods and Materials
1H NMR spectra were recorded in CDCl3 and dimethyl sulfoxide
(DMSO-d6), using a Varian Gemini 200-MHz FT NMR spectrometer;
the chemical shifts are reported in d ppm relative to tetramethyl silane
(TMS). FT-IR spectra were recorded on a Perkin-Elmer 1650 FT-IR
spectrophotometer. The mass spectra (70 eV) were recorded on HP-
5989A liquid chromatography-mass spectra (LC-MS) spectrometer. The
melting points were determined using the capillary method on a Polmon
(model MP-96) melting-point apparatus and are uncorrected. The sol-
vents and reagents were used without further purification.
2-Propylimidazole-4,5-dicarbonitrile (3)[2a]
A mixture of diaminomaleonitrile 2 (100.0 kg, 926 mol) and trimethyl ortho
butyrate (165.0 kg, 114.8 mol) in CH3CN (300.0 L) was refluxed for 5 h.
After the solvent was removed in vacuo, the residue was diluted with toluene
(300.0 L) and refluxed in a Dean–Stark reaction setup for 7–8 h. After cool-
ing to 60 ꢀC, cyclohexane (200.0 L) was added, and the mixture was stirred at
room temperature for 30–60 min. The precipitated product 3 was collected
by filtration and washed with cyclohexane (50.0L). Yield 145.0 kg (98%);
mp 142–144 ꢀC (literature mp 141–144 ꢀC).[2a] Purity by HPLC: 99.0%.
2-Propylimidazole-4,5-dicarboxylic Acid (4)[2a]
A solution of 3 (100.0 kg, 625 mol) in 6N aq. HCl (1000.0 L) was refluxed
for 4 h. After cooling to room temperature, water (1000.0 L) was added,
and the precipitated solid was filtered and charged in to a beaker contain-
ing water (1000.0 L). The pH of the solution was maintained between 9
and 10 using 10% sodium hydroxide solution (100.0 L), and it was sub-
jected to carbon treatment. Then the pH of the solution was adjusted
between 1 and 2 using aqueous hydrochloric acid (12.0 L) and stirred
for 1 h. The precipitated product 4 was collected by filtration. Yield
117.5 kg (95%); mp 262–264 ꢀC (literature mp 261–263 ꢀC).[2a] FT-IR
(KBr) 3454, 1744 cmꢁ1, Purity by HPLC: 99.8%.
Dimethyl 2-Propylimidazole-4,5-dicarboxylate (5)
Thionyl chloride (92.0 L, 2500 mol) was added slowly to a solution of 4
(100.0 kg, 505 mol) in methanol (300 L) at 40–45 ꢀC for about 1 h and

296
K. S. Babu et al.
stirred for 8–10 h. It was cooled to 0–5 ꢀC and then poured slowly to
chilled water (300.0 L). It was neutralized by the addition of 700 L of
10% sodium hydroxide solution. The precipitated product 5 was filtered,
washed with water (200.0 L), and dried at 60–70 ꢀC. Yield 109.5 g (96%);
1
mp 152–155 ꢀC; FT IR (KBr) 3443, 1734 cmꢁ1; H NMR (200 MHz,
DMSO-d6) d 0.90 (t, J ¼ 7.5 Hz, 3H), 1.60–1.79 (m, 2H), 2.60 (t,
J ¼ 7.4 Hz, 2H), 3.78 (s, 3H), 3.8 (s, 3H), 13.10 (bs, 1H). Purity by HPLC:
99.8%; Mþ þ 1 ¼ 227.1.
Dimethyl-2-propyl-1-[4-(2-trityltetrazol-5-yl)phenyl]-phenyl Methyl
Imadazole-4,5-carboxylate (7)
Dimethyl-2-propylimidazole-4,5-dicarboxylate
5 (31.5 kg, 139.3 mol)
was dissolved in acetone (160.0 L). N,N-Dimethyl acetamide (32.0 L)
was added to this solution followed by 6 (81.5 kg, 146 mol) and potas-
sium carbonate (38.5kg, 278 mol). The reaction mixture was heated
to reflux for 4–5 h. Acetone was distilled off partially (50–60% of
initial volume), and the reaction mixture was cooled to room tempera-
ture. Water (315.0 L) was then added, and the stirring continued for
another hour. The precipitated solid was filtered and washed with
water (160 L) and dried at 70–80 ꢀC for 8–10 h to get the title com-
pound 7. Yield 97.0 kg (99%); Mp 162–164 ꢀC; FT IR (KBr)
1740 cmꢁ1
;
1H NMR (200 MHz, CDCl3) d 0.88 (t, J ¼ 7.6 Hz, 3H),
1.59–1.80 (m, 2H), 2.55 (t, J ¼ 7.6 Hz, 2H), 3.70 (s, 3H), 3.93 (s,
3H), 5.30 (s, 2H), 6.70–7.95 (m, 23H). Purity by HPLC: 98.0%;
Mþ þ 1 ¼ 703.6 (m=e).
Methyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-(2-trityltetrazol-
5-yl)phenyl]-phenyl Methyl Imadazole-5-carboxylate (8)
To a solution of 7 (55.0 kg, 78.3 mol) in toluene (165.0 L), a solution of
methyl magnesium chloride in tetrahydrofuran (25.5%, 69.0 L, 234 mol)
was added at room temperature. After completion (1 h), the reaction
mass was quenched with 10% acetic acid (50 L) and extracted with
toluene (55.0 L). Solvent was distilled off under reduced pressure to
obtain the title compound 8 as a residue. Yield 55.0 kg (99%); FT IR
(KBr) 3421 cmꢁ1
;
1H NMR (200 MHz, CDCl3) d 0.88 (t, J ¼ 7.6 Hz,
3H), 1.59–1.80 (m, 2H), 1.71 (s, 6H,), 2.40–2.59 (m, 2H), 3.62 (s, 3H),
5.30 (s, 2H), 6.68–7.90 (m, 23H). Purity by HPLC: 95.0%; Mþ þ 1 ¼ 703.6
(m=e).

Synthesis of Olmesartan Medoxomil
297
4-(1-Hydroxy-1-methylethyl)-2-propyl-1-[4-(2-trityltetrazol-5-yl)phenyl]-
phenyl Methyl Imadazole-5-carboxylic Acid Sodium Salt (9)
To a solution of 8 (55.0 kg, 78.3 mol) in 385.0 L of acetone, a solution of
sodium hydroxide (3.10 kg, 78 mol) in water (275.0L) was added, and the
reaction mixture was stirred at 25–30 ꢀC for 4–5 h. After completion of
the reaction, it was diluted with 25% aqueous sodium chloride solution
and extracted with ethyl acetate (300.0 L). Solvent was distilled off under
reduced pressure, and the crude product was codistilled with toluene
(165.0 L) and finally stirred with heptane (165.0 L) for 2–3 h. Removal
of the solvent gave the crude product 9, which was dried under vacuum.
This product was directly used in the next step. Crude yield 55.0 kg (99%).
Purity by HPLC: 90%; FT-IR (KBr) 3404 cmꢁ1
.
(5-Methy2-oxo-1,3-dioxolen-4-yl)-methyl-4-(1-hydroxy-1-methylethyl)-
2-propyl-1-[4-(2-trityltetrazol-5-yl)phenyl]-phenyl Methyl Imadazole-
5-carboxylate (10)[2a]
To a solution of 9 (55.0 kg, 77.46 mol) in of N,N-dimethyl acetamide
(162.0 L), sodium carbonate (12.6 kg, 118 mol) and 4-chloromethyl-5-
methyl-1,3-dioxolen-2-one (14.7 kg, 100 mol) were added, and the mix-
ture was heated to 45–50 ꢀC for 4–5 h. Aqueous sodium chloride solution
(10%, 540.0 L) and toluene (270.0 L) were added to the reaction mixture,
and the pH was adjusted to 7–8 with 10% aqueous hydrochloric acid. The
aqueous layer was separated and extracted with toluene (108.0 L). The
combined organic layers were washed with 10% sodium chloride solution
(2 ꢂ 108.0 L). The solvent was evaporated under reduced pressure, and
the residue was recrystallized from acetonitrile to get the title compound
10. Yield 49.6 kg (80%); Mp 103–104 ꢀC (literature mp 102–104 ꢀC ).[2a]
1
FT-IR (KBr) 3404, 1819 cmꢁ1; H NMR (200 MHz, CDCl3) d 0.85 (t,
J ¼ 7.2 Hz, 3H), 1.41–1.60 (m, 2H), 1.56 (s, 6H), 2.0 (s, 3H), 2.30–2.60
(m, 2H), 5.02 (s, 2H), 5.22 (s, 1H), 5.31 (s, 2H), 6.75 (d, J ¼ 8.2 Hz,
2H), 6.82 (d, J ¼ 8.2 Hz, 4H), 6.98 (d, J ¼ 8.2 Hz, 2H), 7.23–7.82 (m,
15H). Purity by HPLC: 99%; Mþ þ 1 ¼ 801.6 (m=e).
Olmesartan Medoximil (1)[2a]
A solution of 10 (25.0 kg, 31.25 mol) in 40% aqueous acetic acid (750.0 L,
60 mol) was heated at 55–60 ꢀC for 2–3 h. It was cooled to room tempera-
ture and diluted with water (375.0 L). The precipitated solids were filtered

298
K. S. Babu et al.
off, and the filtrate was extracted with CH2Cl2 (625.0 L). The organic
layer was washed with a mixture of 5% aqueous sodium bicarbonate solu-
tion (150.0 L) and 5% sodium chloride solution (780.0 L). Removal of the
solvent followed by recrystallization in acetone gave the pure product 1
as a white solid. Yield 14.0 kg (80%); mp 180–182 ꢀC (literature Mp
180–182 ꢀC).[2a] FT-IR (KBr) 1832, 1740, 1707 cmꢁ1
;
1H NMR
(200 MHz, DMSO-d6) d 0.87 (t, J ¼ 7.2 Hz, 3H), 1.41–1.60 (m, 2H),
1.45 (s, 6H), 2.05 (s, 3H), 2.41–2.78 (m, 2H), 5.02 (s, 2H), 5.20 (s, 1H),
5.40 (s, 2H), 6.85 (d, J ¼ 8.0 Hz, 2H), 7.04 (d, J ¼ 8.0 Hz, 2H), 7.52–
7.78 (m, 4H), 15.8 (bs, 1H). Purity by HPLC: 99.9%; Mþ þ 1 ¼ 559.3
(m=e).
ACKNOWLEDGMENT
We greatly appreciate the supportive environment encouraged at
Dr. Reddy’s Laboratories Ltd. We are thankful to Intellectual Property
Management, NMR group of Dr. Reddy’s Research Foundation, and
the analytical group of Integrated Product Development Organization
for their generous support.
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