New synthesis of analogues of the antihypertensive active pharmaceutical ingredient Irbesartan

Article abstract of DOI:10.1080/00397910600634514

A simple and new synthetic approach to various analogues of Irbesartan is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600634514

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New Synthesis of Analogues of the
Antihypertensive Active Pharmaceutical
Ingredient Irbesartan
B. Satyanarayana a , Y. Sumalatha a , C. Sridhar a , S. Venkatraman a & P.
Pratap Reddy a
a Research and Development Centre , Dr. Reddy's Laboratories Limited ,
Hyderabad, India
Published online: 20 Aug 2006.
To cite this article: B. Satyanarayana , Y. Sumalatha , C. Sridhar , S. Venkatraman & P. Pratap Reddy (2006)
New Synthesis of Analogues of the Antihypertensive Active Pharmaceutical Ingredient Irbesartan, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:14,
2079-2086, DOI: 10.1080/00397910600634514
To link to this article: http://dx.doi.org/10.1080/00397910600634514
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Synthetic Communicationsw, 36: 2079–2086, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600634514
New Synthesis of Analogues of the
Antihypertensive Active Pharmaceutical
Ingredient Irbesartan
B. Satyanarayana, Y. Sumalatha, C. Sridhar, S. Venkatraman,
and P. Pratap Reddy
Research and Development Centre, Dr. Reddy’s Laboratories Limited,
Hyderabad, India
Abstract: A simple and new synthetic approach to various analogues of Irbesartan is
described.
Keywords: Active pharmaceutical ingredient, analogues, angiotensin, antihyperten-
sive drug, Irbesartan
INTRODUCTION
Sartans such as Irbesartan,[1] Valsartan,[2], Candesartan,[3] Olmesartan,[4]
Telmisartan,[5] and Losartan[6] belong to a class of antihypertensive active
pharmaceutical ingredients. They function as specific and competitive angio-
tensin I receptor antagonists, thereby blocking the actions of endogenous
ligand angiotensin II and in turn preventing the increase in blood pressure.
In continuation of our work on the synthesis of Irbesartan,[7] herein we
report a new general approach to the synthesis of various analogues of
Irbesartan.
Received January 12, 2006
DRL Pub. No. IPDO-IPM 00018
Address correspondence to P. Pratap Reddy, Research and Development Centre,
Dr. Reddy’s Laboratories Limited, Bulk Actives Unit IV, IDA, Jeedimetla,
Hyderabad, AP 500 055, India. Tel.: 91 40 23098610; E-mail: reddyppou@yahoo.co.in
2079

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B. Satyanarayana et al.
DISCUSSION
Acylation of 1-amino-cyclohexanecarboxylic acid 1[8] with propionyl chloride
in the presence of water and sodium hydroxide yielded 1-propionylamino-cyclo-
hexane carboxylic acid 2a. Its condensation with 40-aminomethyl-biphenyl-2-
carbonitrile 3[9] in the presence of dicyclohexyl carbodiimide (DCC) and a
catalytic amount of 1-hydroxybenzotriazole (HOBT) in methylene chloride
gave 1-propionylamino-cyclohexanecarboxylic acid (20-cyano-biphenyl-4-
ylmethyl)-amide (4a). Reaction of 4a with tributyltin chloride and sodium
azide in xylene produced the tetrazole derivative 5a. Trifluoro acetic acid–
mediated dehydrative cyclization of 5a in toluene yielded 2-alkyl-3-[20-(1H-
tetrazol-5-yl)-biphenyl-4-ylmethyl]-1,3-diaza-spiro[4.5]dec-1-en-4-one 6a.
To verify the generality of this synthetic sequence, it was extended to three
other acid chlorides, and in all the cases corresponding tetrazolyl diaza-spiro
compounds were obtained as the final products in good yields. All these
compounds are fully characterized based on their IR, 1H NMR, and mass
spectral data and also by elemental analysis. IR spectra of compounds 4a–d
were characterized by the presence of CN and two carbonyl absorptions at
ꢀ2225 cm21, 1720 and 1655 cm21 respectively. Compounds 5a–d showed NH
absorptions at ꢀ3363, 3330, 3060 and carbonyl at ꢀ1730 cm21. The final
compounds 6a–d exhibited C55O and NH absorptions at ꢀ1730 cm21 and
ꢀ3420 cm21 respectively. 1H NMR spectra of 6a–d are characterized by signals
due to benzylic protons in the region 4.5–4.8 d and aromatic protons at 7.0–8.0 d.
In conclusion, we have disclosed a simple, general, and new synthetic
route for the preparation of the new analogues of Irbesartan.

Analogues of Irbesartan
EXPERIMENTAL
2081
1H NMR spectra were measured on a Gemini 200-MHz FTNMR spectrometer,
and the chemical shifts were reported as d values in ppm relative to TMS as an
internalstandard.TheIRspectrawererecordedinthesolidstateasKBrdispersion
using Perkin Elmer FT-IR spectrophotometer. Mass spectra were recorded on
Shimadzu LCMS-QP 8000, LC-MS, and AB-4000 Q-trap LC-MS/MS.
General Procedure for the Preparation of 1-Acylamino-
cyclohexanecarboxylic Acid (2a–d)
1-Amino-cyclohexanecarboxylic acid (1, 50.0 g, 0.349 mol) was added to a
solution of sodium hydroxide (55.9 g, 1.398 mol) in water (200 mL) at 0–
108C and stirred for 10–15 min. The appropriate acyl chloride (0.699 mol)
in toluene (100 mL) was added slowly over 90 min at 0–108C. After com-
pletion of the reaction, water (250 mL) was added to the reaction mass and
stirred for 15–30 min. The organic and aqueous layers were separated, and
the aqueous layer was washed with toluene (50 mL). The aqueous layer pH
was adjusted to 2.0–2.5 using HCl and stirred for 15–30 min. The solid
was filtered and washed with water (50 mL). To the wet compound, cyclo-
hexane (150 mL) was added and stirred for 45 min. The solid was filtered,
washed with cyclohexane (50 mL), and dried to yield 2a–d.
Data
1-Propionylamino-cyclohexanecarboxylic acid (2a)
Yield: 80%; IR (cm21): 3363.3 (N-H), 1735.7 (C55O), 1715.6 (C55O);
1H NMR (CDCl3): 1.1–1.3 (t, 3H, CH3), 1.3–2.2 (m, 10H, CH2), 2.2–2.4
(q, 2H, CH2); mass: 200 (Mþ); anal. calcd. for C10H17NO3 (199.12): C,
60.28; H, 8.60; N, 7.03; found: C, 60.15; H, 8.64; N, 7.01.
1-Butyrylamino-cyclohexanecarboxylic acid (2b)
Yield: 76%; IR (cm21): 3338.7 (N-H), 1736.7 (C55O), 1709.6 (C55O);
1H NMR (CDCl3): 0.8–1.1 (t, 3H, CH3), 1.3–2.0 (m, 12H, CH2), 2.2–2.4
(t, 2H, CH2); mass: 214 (Mþ); anal. calcd. for C11H19NO3 (213.14): C,
61.95; H, 8.98; N, 6.57; found: C, 61.99; H, 8.92; N, 6.49.
1-Pentanoylamino-cyclohexanecarboxylic acid (2c)
Yield: 74%; IR (cm21): 3365.7 (N-H), 1734.7 (C55O), 1714.2 (C55O); 1H
NMR (CDCl3): 0.8–1.0 (t, 3H, CH3), 1.2–1.5 (sext, 2H, CH2), 1.5–2.2 (m, 12H,
CH2), 2.2–2.4 (t, 2H, CH2); mass: 228 (Mþ); anal. calcd. for C12H21NO3
(227.15): C, 63.41; H, 9.31; N, 6.16; found: C, 63.37; H, 9.35; N, 6.21.

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B. Satyanarayana et al.
1-Hexanoylamino-cyclohexanecarboxylic acid (2d)
Yield: 78%; IR (cm21): 3340.5 (N-H), 1731.6 (C55O), 1708.9 (C55O);
1H NMR (CDCl3): 0.8–1.0 (t, 3H, CH3), 1.2–2.2 (m, 16H, CH2), 2.2–2.4
(t, 2H, CH2); mass: 242 (Mþ); anal. calcd. for C13H23NO3 (241.17): C,
64.70; H, 9.61; N, 5.80; found: C, 64.65; H, 9.64; N, 5.89.
General Procedure for the Preparation of 1-Acylamino-
cyclohexanecarboxylic Acid (20-Cyano-biphenyl-4-ylmethyl)-amide
(4a–d)
Compound 2 (0.312 mol) and HOBT (6.5 g, 0.048 mol) were added to a
solution of 3 (0.240 mol) in methylene chloride (750 mL) and stirred at rt
for 10–15 min. To this mixture, DCC (49.5 g, 0.240 mol) in methylene
chloride (150 mL) was added slowly. After completion of the reaction, it
was filtered and washed with methylene chloride (100 mL). The organic
layer was washed with saturated sodium bicarbonate solution (250 mL) and
water (150 mL) and concentrated. Cyclohexane (250 mL) was added to the
residue and stirred for 45 minutes at rt. The isolated compound was filtered,
washed with cyclohexane (125 mL), and dried to yield 4a–d.
Data
1-Propionylamino-cyclohexanecarboxylic acid (20-cyano-biphenyl-4-
ylmethyl)-amide (4a)
Yield: 88%; IR (cm21): 3327.8 (N-H), 3308.3 (N-H), 2224.4 (CN), 1719.5
1
(C55O), 1652.4 (C55O); H NMR (CDCl3): 1.1–1.2 (t, 3H, CH3), 1.3–1.5
(m, 6H, CH2), 1.6–1.8 (m, 2H, CH2), 1.8–2.0 (m, 2H, CH2), 2.2–2.3 (t, 2H,
CH2), 4.4–4.6 (s, 2H, Ar-CH2), 7.3–7.6 (m, 6H, Ar-H), 7.6–7.7 (m, 1H, Ar-
H), 7.7–7.9 (d, 1H, Ar-H); mass: 390 (Mþ); anal. calcd. for C24H27N3O2
(389.21): C, 74.01; H, 6.99; N, 10.79; found: C, 73.90; H, 6.85; N, 10.84.
1-Butyrylamino-cyclohexanecarboxylic
ylmethyl)-amide (4b)
acid
(20-cyano-biphenyl-4-
Yield: 82%; IR (cm21): 3332.2 (N-H), 3310.3 (N-H), 2223.7 (CN), 1720.4
1
(C55O), 1655.8 (C55O); H NMR (CDCl3): 0.8–1.0 (t, 3H, CH3), 1.2–1.5
(m, 8H, CH2), 1.6–1.8 (sext, 2H, CH2), 1.8–2.0 (t, 2H, CH2), 2.1–2.3 (t, 2H,
CH2), 4.5–4.7 (s, 2H, Ar-CH2), 7.4–7.6 (m, 6H, Ar-H), 7.6–7.7 (t, 1H, Ar-
H), 7.7–7.8 (d, 1H, Ar-H); mass: 404 (Mþ); anal. calcd. for C25H29N3O2
(403.23): C, 74.41; H, 7.24; N, 10.41; found: C, 74.45; H, 7.20; N, 10.35.
1-Pentanoylamino-cyclohexanecarboxylic acid (20-cyano-biphenyl-4-
ylmethyl)-amide (4c)
Yield: 85%; IR (cm21): 3337.4 (N-H), 3306.5 (N-H), 2222.0 (CN),
1
1721.0 (C55O), 1650.2 (C55O); H NMR (CDCl3): 0.9–1.0 (t, 3H, CH3),
1.2–1.5 (m, 6H, CH2), 1.6–2.0 (m, 8H, CH2), 2.1–2.3 (t, 2H, CH2),

Analogues of Irbesartan
2083
4.4–4.6 (s, 2H, Ar-CH2), 7.3–7.5 (m, 6H, Ar-H), 7.6–7.7 (t, 1H, Ar-H),
7.7–7.9 (d, 1H, Ar-H); mass: 418 (Mþ); anal. calcd. for C26H31N3O2
(417.24): C, 74.79; H, 7.48; N, 10.06; found: C, 74.72; H, 7.37; N, 9.56.
1-Hexanoylamino-cyclohexanecarboxylic acid (20-cyano-biphenyl-4-yl
methyl)-amide (4d)
Yield: 82%; IR (cm21): 3338.7 (N-H), 3302.6 (N-H), 2222.8 (CN), 1720.5
1
(C55O), 1655.8 (C55O); H NMR (CDCl3): 0.8–0.9 (t, 3H, CH3), 1.1–1.3
(m, 2H, CH2), 1.4–2.1 (m, 14H, CH2), 2.1–2.3 (t, 2H, CH2), 4.3–4.4 (s, 2H,
Ar-CH2), 7.3–7.7 (m, 5H, Ar-H), 7.7–7.8 (t, 1H, Ar-H), 7.9–8.1 (d, 1H, Ar-
H), 8.0–8.1 (d, 1H, Ar-H); mass: 432 (Mþ); anal. calcd. for C27H33N3O2
(431.26): C, 75.14; H, 7.71; N, 9.74; found: C, 75.18; H, 7.65; N, 9.67.
Preparation of 1-acylamino-cyclohexanecarboxylic acid [20-(1H-tetrazol-
5-yl)-biphenyl-4-yl methyl]-amide (5a–d)
A mixture of 4 (0.128mol), o-xylene (50 mL), tributyltin chloride (124.9g,
0.384 mol), and sodium azide (24.96g, 0.384 mol) was refluxed until reaction
completion. To the reaction mass at 25–358C, acetone (400mL) and water
(500 mL) were added and stirred. The pH of the reaction mass was adjusted
to 4.0–4.5 using acetic acid, and cyclohexane (500mL) was added to this
and stirred for solid isolation. The isolated solid was filtered, washed with cyclo-
hexane (150mL), and dried to a constant weight to yield 5a–d.
1-Propionylamino-cyclohexanecarboxylic acid [20-(1H-tetrazol-5-yl)-
biphenyl-4-ylmethyl]-amide (5a)
Yield: 84%; IR (cm21): 3363.6 (N-H), 3304.0 (N-H), 3059.9 (N-H),
1
1670.9 (C55O), 1630.4 (C55O); H NMR (CDCl3): 0.9–1.0 (t, 3H, CH3),
1.3–1.8 (m, 10H, CH2), 2.1–2.3 (q, 2H, CH2), 4.2–4.3 (s, 2H, Ar- CH2),
7.0–7.1 (d, 1H, Ar-H), 7.2–7.4 (d, 1H, Ar-H), 7.4–7.7 (m, 5H, Ar-H),
7.9–8.0 (t, 1H, Ar-H); mass: 433 (Mþ); anal. calcd. for C24H28N6O2
(432.23): C, 66.65; H, 6.53; N, 19.43; found: C, 66.70; H, 6.51; N, 19.39.
1-Butyrylamino-cyclohexanecarboxylic
biphenyl-4-ylmethyl]-amide (5b)
acid
[20-(1H-tetrazol-5-yl)-
Yield: 86%; IR (cm21): 3364.4 (N-H), 3302.3 (N-H), 3061.6 (N-H),
1
1672.0 (C55O), 1626.6 (C55O); H NMR (CDCl3): 0.9–1.0 (t, 3H, CH3),
1.4–1.9 (m, 12H, CH2), 2.2–2.3 (t, 2H, CH2), 4.3–4.5 (s, 2H, Ar-CH2),
7.0–7.3 (m, 6H, Ar-H), 7.5–7.6 (m, 1H, Ar-H), 7.6–7.7 (m, 1H, Ar-H);
mass: 447 (Mþ); anal. calcd. for C25H30N6O2 (446.24): C, 67.24; H, 6.77;
N, 18.82; found: C, 67.20; H, 6.76; N, 18.79.
1-Pentanoylamino-cyclohexanecarboxylic acid [20-(1H-tetrazol-5-yl)-
biphenyl-4-ylmethyl]-amide (5c)
Yield: 80%; IR (cm21): 3311.4 (N-H), 3337.6 (N-H), 3063.0 (N-H),
1
1677.5 (C55O), 1629.3 (C55O); H NMR (CDCl3): 0.8–0.9 (t, 3H, CH3),

2084
B. Satyanarayana et al.
1.2–1.9 (m, 14H, CH2), 2.1–2.3 (t, 2H, CH2), 4.3–4.4 (s, 2H, Ar-CH2),
7.0–7.1 (d, 1H, Ar-H), 7.1–7.2 (d, 1H, Ar-H), 7.4–7.6 (m, 5H, Ar-H),
7.7–7.8 (d, 1H, Ar-H); mass: 461 (Mþ); anal. calcd. for C26H32N6O2
(460.26): C, 67.80; H, 7.00; N, 18.25; found: C, 67.75; H, 6.99; N, 18.30.
1-Hexanoylamino-cyclohexanecarboxylic acid [20-(1H-tetrazol-5-yl)-
biphenyl-4-ylmethyl]-amide (5d)
Yield: 83%; IR (cm21): 3352.6 (N-H), 3305.4 (N-H), 3059.4 (N-H),
1
1673.5 (C55O), 1626.1 (C55O); H NMR (CDCl3): 0.8–1.0 (t, 3H, CH3),
1.2–2.1 (m, 16H, CH2), 2.2–2.3 (t, 2H, CH2), 4.3–4.4 (s, 2H, Ar-CH2),
7.0–7.1 (d, 1H, Ar-H), 7.2–7.3 (d, 1H, Ar-H), 7.5–7.8 (m, 6H, Ar-H);
mass: 475 (Mþ); anal. calcd. for C27H34N6O2 (474.27): C, 68.33; H, 7.22;
N, 17.71; found: C, 68.28; H, 7.20; N, 17.77.
General Procedure for the Preparation of 2-Alkyl-3-[20-(1H-
tetrazol-5-yl)-biphenyl-4-ylmethyl]-1,3-diaza-spiro[4.5]dec-1-en-4-
one (6a–d)
A mixture of 5 (0.115 mol), toluene (500 mL) and trifluoroacetic acid (39.5 g,
0.347 mol) was refluxed azeotropically until reaction completion. The reaction
mass was cooled to rt. The isolated solid was filtered and washed with toluene
(50 mL). Water (250 mL) was added to the wet compound, and pH was
adjusted to 4–5 using caustic lye. The isolated solid was filtered, washed
with water (50 mL), and dried to a constant weight at 60–708C. Recrystalliza-
tion using isopropyl alcohol yielded 6a–d.
Data
2-Ethyl-3-[20-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1,3-diaza-
spiro[4.5]dec-1-en-4-one (6a)
Yield: 74%; IR (cm21): 3419.4 (N-H), 1731.6 (C55O); 1H NMR (CDCl3):
1.0–1.2 (t, 3H, CH3), 1.3–1.8 (m, 10H, CH2), 2.3–2.4 (q, 2H, CH2), 4.6–4.7
(s, 2H, Ar-CH2), 7.0–7.2 (m, 4H, Ar-H), 7.4–7.5 (d, 1H, Ar-H), 7.5–7.7
(m, 2H, Ar-H), 7.9–8.0 (d, 1H, Ar-H); mass: 415 (Mþ); 13C NMR (CDCl3):
186.44, 164.50, 156.00, 141.57, 139.36, 135.99, 131.51, 131.01, 130.86,
129.95, 128.27, 126.96, 123.49, 78.36, 77.71, 69.97, 48.57, 43.28, 33.42,
25.30, 24.99, 22.59, 21.40, 10.11; anal. calcd. for C24H26N6O (414.22): C,
69.54; H, 6.32; N, 20.27; found: C, 69.70; H, 6.34; N, 20.29.
2-Propyl-3-[20-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1,3-diaza-
spiro[4.5]dec-1-en-4-one (6b)
Yield: 72%; IR (cm21): 3424.1 (N-H), 1731.4 (C55O); 1H NMR (CDCl3):
0.9–1.0 (t, 3H, CH3), 1.3–1.8 (m, 12H, CH2), 2.2–2.3 (t, 2H, CH2), 4.5–4.7
(s, 2H, Ar-CH2), 7.0–7.1 (s, 1H, Ar-H), 7.1–7.2 (s, 1H, Ar-H), 7.4–7.6

Analogues of Irbesartan
2085
(m, 5H, Ar-H), 7.8–7.9 (d, 1H, Ar-H); mass: 429 (Mþ); 13C NMR (CDCl3):
186.07, 162.39, 155.58, 140.85, 138.85, 135.47, 130.91, 130.52, 130.47,
129.47, 127.80, 126.37, 123.18, 77.63, 76.36, 69.59, 48.46, 33.01, 30.44,
30.11, 26.67, 20.99, 19.16, 19.10, 13.22; anal. calcd. for C25H28N6O
(428.23): C, 70.07; H, 6.59; N, 19.61; found: C, 70.15; H, 6.58; N, 19.64.
2-Butyl-3-[20-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1,3-diaza-
spiro[4.5]dec-1-en-4-one (6c)
Yield: 70%; IR (cm21): 3331.2 (N-H), 1727.9 (C55O); 1H NMR (CDCl3):
0.8–0.9 (t, 3H, CH3), 1.2–1.8 (m, 14H, CH2), 2.1–2.3 (t, 2H, CH2), 4.6–4.7
(s, 2H, Ar-CH2), 7.0–7.2 (m, 4H, Ar-H), 7.4–7.5 (d, 1H, Ar-H), 7.5–7.6
(t, 1H, Ar-H), 7.6–7.7 (t, 1H, Ar-H) 7.9–8.0 (d, 1H, Ar-H); mass: 443
(Mþ); 13C NMR (CDCl3): 185.43, 163.34, 161.18, 156.47, 156.14, 140.88,
139.21, 135.47, 130.91, 130.72, 130.56, 129.61, 127.93, 126.39, 123.74,
109.31, 77.63, 69.59, 42.83, 32.98, 28.33, 28.02, 24.74, 22.09, 21.04, 13.48;
anal. calcd. for C26H30N6O (442.25): C, 70.56; H, 6.83; N, 18.99; found: C,
70.58; H, 6.80; N, 19.05.
2-Pentyl-3-[20-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1,3-diaza-
spiro[4.5]dec-1-en-4-one (6d)
Yield: 74%; IR (cm21): 3437.6 (N-H); 1732.7 (C55O); 1H NMR (CDCl3):
0.8–0.9 (t, 3H, CH3), 1.2–1.8 (m, 16H, CH2), 2.1–2.3 (t, 2H, CH2), 4.6–4.7
(s, 2H, Ar-CH2), 7.0–7.2 (m, 4H, Ar-H), 7.4–7.5 (d, 1H, Ar-H), 7.5–7.6
(t, 1H, Ar-H), 7.6–7.7 (t, 1H, Ar-H), 7.9–8.0 (d, 1H, Ar-H); mass: 457
(Mþ); 13C NMR (CDCl3): 185.05, 163.57, 156.16, 140.82, 139.12, 135.25,
130.74, 130.56, 130.47, 129.47, 127.74, 126.29, 123.69, 77.63, 77.00,
79.36, 69.36, 42.73, 32.84, 30.94, 28.41, 25.58, 24.87, 24.62, 21.87, 20.91,
13.60; anal. calcd. for C27H32N6O (456.26): C, 71.03; H, 7.06; N, 18.41;
found: C, 71.12; H, 7.01; N, 18.38.
ACKNOWLEDGMENT
The authors thank the management of Dr. Reddy’s Laboratories Ltd., Bulk
Actives Unit 1V, for supporting this work.
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