Improved methods for the synthesis of irbesartan, an antihypertensive active pharmaceutical ingredient

Article abstract of DOI:10.1080/00397910701471279

New methods for the preparation of irbesartan 1 have been described. The dehydration and tetrazole formation in one step from substituted cyclopentane derivative 7 with tributyltin chloride and sodium azide is described. Selective hydrolysis of nitrile 3 with HCl has also been described in the preparation of N-acylaminocyclopentane-2-carboxylic acid 4, which is the key intermediate for the preparation of irbesartan. The impurity profiling of irbesartan has also been discussed. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701471279

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Improved Methods for the Synthesis of
Irbesartan, an Antihypertensive Active
Pharmaceutical Ingredient
Korrapati V. V. Prasada Rao a , Ramesh Dandala a , Vijay K. Handa a , Inti V.
Subramanyeswara Rao a , Ananta Rani a & Andra Naidu b
a Research and Development Department , Aurobindo Pharma Ltd. ,
Hyderabad, Andhra Pradesh, India
b Jawaharlal Nehru Technological University , Hyderabad, India
Published online: 30 Aug 2007.
To cite this article: Korrapati V. V. Prasada Rao , Ramesh Dandala , Vijay K. Handa , Inti V. Subramanyeswara
Rao , Ananta Rani & Andra Naidu (2007) Improved Methods for the Synthesis of Irbesartan, an
Antihypertensive Active Pharmaceutical Ingredient, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 37:17, 2897-2905, DOI: 10.1080/00397910701471279
To link to this article: http://dx.doi.org/10.1080/00397910701471279
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Synthetic Communicationsw, 37: 2897–2905, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701471279
Improved Methods for the Synthesis
of Irbesartan, an Antihypertensive Active
Pharmaceutical Ingredient
Korrapati V. V. Prasada Rao, Ramesh Dandala,
Vijay K. Handa, Inti V. Subramanyeswara Rao,
and Ananta Rani
Research and Development Department, Aurobindo Pharma Ltd.,
Hyderabad, Andhra Pradesh, India
Andra Naidu
Jawaharlal Nehru Technological University, Hyderabad, India
Abstract: New methods for the preparation of irbesartan 1 have been described. The
dehydration and tetrazole formation in one step from substituted cyclopentane deriva-
tive 7 with tributyltin chloride and sodium azide is described. Selective hydrolysis of
nitrile 3 with HCl has also been described in the preparation of N-acylaminocyclopen-
tane-2-carboxylic acid 4, which is the key intermediate for the preparation of irbesar-
tan. The impurity profiling of irbesartan has also been discussed.
Keywords: antihypertensive drug, impurities, irbesartan, synthesis
INTRODUCTION
Irbesartan 1 is chemically known as 2-butyl-3-[[20-(1H-tetrazol-5-yl)[1,10-
biphenyl]-4-yl] methyl]-1,3-diazaspiro[4,4]non-1-en-4-one. It is one of the
most important drugs in this class of tetrazole compounds. Tetrazole
compounds have been used as anticancer[1] and antimicrobial[2] agents.
Received January 19, 2007
Address correspondence to Ramesh Dandala, Research and Development Depart-
ment, Aurobindo Pharma Ltd., 313 Bachupally, Hyderabad 500072, Andhra Pradesh,
India. E-mail: rdandala@aurobindo.com
2897

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K. V. V. P. Rao et al.
Recently, the substituted tetrazole compounds were found to be very useful
drugs in the treatment of cardiovascular complaints. Irbesartan 1, a tetrazole
derivative, is an antihypertensive drug and highly selective nonpeptide
compound that antagonizes angiotensin II.[3–5] It is a very useful drug in
the treatment of cardiovascular complaints[6] such as hypertension, heart
failure, glaucoma, diabetic retinopathy, renal insufficiency, and certain
central nervous system complaints.
RESULTS AND DISCUSSION
Many synthetic approaches have been reported for the synthesis of irbesar-
tan.[3–10] The most studied method developed by Bernhart et al.[3] starts
with a biaryl intermediate 4-(20-bromomethylphenyl) benzonitrile, which is
condensed with 2-n-butyl-1,3-diazaspiro[4,4]-non-1-ene. The resulting nitrile
was converted to irbesartan by a sequence of reactions. The major drawbacks
of the reported methods are complex reactions, longer reaction times, lower
yields, poor quality, and difficulty in use of sodium hydride. In another
method,[10] 4-(2-aminomethylphenyl)benzonitrile (6) was coupled with N-pen-
tanoylaminocyclopentane-1-carboxylic acid (4) in the presence of dicyclo-
hexylcarbodiimide (DCC). The resulting diamide was cyclized to a spiro
compound, which on treatment with 2 molar equivalents each of tributyltin
chloride and sodium azide affords 1. The major disadvantages of this method
are very poor yield, believed to be a result of incomplete conversion and dimer-
ization of free base of 6, to the extent of 17–22%. Another major drawback of
this route is insolubility of the coupling product in methylene chloride under the
conditions. Therefore, it is crystallized out along with dicyclohexylurea, which
is a by-product in this reaction. Hence, it is difficult to separate the desired
product from the reaction mass. To circumvent difficulties, we have devised a
short and high-yield process for the preparation of 1.
In the present method, compound 3 was prepared from 1-aminocyclopen-
tanecarbonitrile 2, which on selective hydrolysis with hydrochloric acid gives
acid 4 in about 90% yield with more than 99% of high performance liquid
chromatographic (HPLC) purity (Scheme 1). We found that hydrolysis is a
temperature-dependent reaction. Temperature should be maintained at 55–
608C for the preparation of compound 4. At higher temperature, amide
cleavage was observed. Compound 4 is one of the key intermediates in the
preparation of compound 1.
Scheme 1.

Synthesis of Irbesartan
2899
Compound 6 was synthesized from bromomethyl compound (5) as shown
in Scheme 2, which was coupled with acid 4 using dicyclohexylcarbodiimide,
diisopropylethylamine (DIPEA) in the presence of 1-hydroxybenzotriazole
(HOBT) to afford diamide 7. Compound 7 was directly converted into irbesar-
tan in one step. We observed that it was necessary to use compound 6 as its
hydrochloride salt, and the coupling reaction of compound 6 with 4 must be
done in the presence of an organic base, because under these conditions
compound 7 remains in solution in methylene chloride and workup became
very easy for the removal of by-product dicyclohexylurea (DCU) and the
isolation of compound 7. Treatment with tributyltin chloride and sodium
azide in the presence of N,N-dimethylformamide (DMF) affords Irbesartan
1 in 70–75% yield. The irbesartan yield increased by 20% with the present
method as compared to the literature methods,[8] and the purity obtained
was 99.85% by HPLC analysis.
Irbesartan obtained with this method contains three potential impurities in
a range of 0.05% to 0.1% by HPLC analysis. These impurities are identified as
desbutyl irbesartan 8, propyl irbesartan 9, and acid 12. The structures of these
impurities are given in Fig 1. Impurity 9 was formed as a result of butyryl
chloride present as an impurity in valeryl chloride, and other impurities are
generated during the synthesis of irbesartan.
All these impurities are synthesized and characterized by 1H NMR,
13C NMR, mass, and IR analysis. The acid impurity 12 has been synthesized
by the condensation of 4-(20-bromomethylphenyl) benzoic acid (10)[11] with
2-butyl-2,3-diazaspiro[4.4]nonane-1,4-dione[3] (11) in a mixture of toluene
Scheme 2. DDC ¼ dicyclohexylcarbodiimide; HOBT ¼ 1-hydroxybenzotriazole.

2900
K. V. V. P. Rao et al.
Figure 1. Chemical structures of Irbesartan impurities.
and water in the presence of sodium hydroxide and a phase-transfer catalyst
(Scheme 3).
EXPERIMENTAL
Solvents and reagents were obtained from commercial sources and used
without purification. Melting-points were determined on a Polmon melting-
point apparatus. All melting points were uncorrected. The 1H NMR and
13C NMR spectra were recorded on Bruker 300-MHz spectrometer. The
chemical shifts are reported in d Parts per million (ppm) relative to TMS.
The IR spectra were recorded in solid state as KBr dispersion using a
Perkin-Elmer FT-IR spectrometer. The mass spectra were recorded on an
API 2000 Perkin-Elmer PE-SCIEX mass spectrometer.
N-Pentanoylaminocyclopentane-1-carboxylic Acid (4)
Triethylamine (379.18 g, 3.75 mol) was added to a stirred suspension of
1-aminocyclopenta-necarbonitrile hydrochloride (2) (500 g, 3.41 mol) in
methylene chloride (3.5 L) at 0–58C in 15 min. Thereafter valerylchloride
(412 g, 3.58 mol) was added slowly at 0–58C in 40 min and stirred at the
same temperature for 2 h. Water (1000 ml) was added and stirred for
10 min. The organic layer was separated and washed with water (1000 ml).
The organic layer obtained was concentrated under reduced pressure at
below 608C. The residue obtained was added to hydrochloric acid (2130 ml,
Scheme 3.

Synthesis of Irbesartan
2901
30% w/w) slowly in 45 min at 25–558C, and the temperature during the
addition rose to 50–608C. Thereafter, the reaction contents were stirred at
55–608C for 2 h and poured into a mixture of water (13.2 L) and ethyl
acetate (1500 ml) at 25–358C. The solid obtained was filtered and washed
with water (10 L) followed by ethyl acetate (2 L). The wet material was
dried at 50–558C to afford N-pentanoylaminocyclopentane-1-carboxylic
acid 4 as an off-white crystalline powder (654 g, 90%).
Mp: 178–1798C; IR (KBr, cm21): 3330 (NH), 1704, 1621 (CO); 1H NMR
(DMSO, d ppm): 0.83–0.88 (t, 3H, CH3), 1.24–1.26 (quintet, 2H, CH2),
1.42–1.45 (sextet, 2H, CH2), 1.59 (m, 4H, cyclopentyl), 1.84–2.07 (m, 4H,
cyclopentyl), 2.50–2.51 (t, 2H, CH2), 8.02 (s, 1H, NH), 12.01 (brs, 1H,
OH); mass: 212.1(M2). Anal. calcd. for C11H19NO3: C, 61.97; H, 8.92; N,
6.57. Found: C, 61.85; H, 8.90; 6.54.
4-(20-Aminomethylphenyl)benzonitrile Hydrochloride (6)
Sodium azide (126 g, 1.938 mol) was added to a stirred solution of 4-(20-bro-
momethylphenyl)benzonitrile (5[11] (500 g, 1.838 mol) in DMF (1500) at 25–
308C. After 10 min of the addition, the temperature rose to 35–408C. The
reaction mass was stirred at 30–408C for 30 min. DM water (10 L) was
added, followed by ethyl acetate (5 L), and stirred for 15 min. The organic
layer was separated and washed with saturated sodium chloride solution
(2 ꢀ 5 L) and dried over sodium sulfate (1 kg). Triphenylphosphine (810 g,
3.09 mol) was added to the ethyl acetate solution and stirred for 2 h at 25–
358C. DM water (181 g, 10.05 mol) was added in one lot and stirred for
24 h at 25–308C. The reaction mass was diluted with ethyl acetate (5 L)
and cooled to 0–58C. Hydrochloric acid (210 g, 35% w/w) was added in
30–45 min at the same temperature, while this addition solid precipitated
out. The resulting slurry was stirred at 0–58C for 1 h. The solid was
filtered, and washed with precooled ethyl acetate (2 L). The wet solid was
dried at 50–558C under reduced pressure to afford the title compound as a
white crystalline powder (385 g, 92%).
Mp 239–2408C; IR (KBr, cm21): 3338 (NH), 1702, 1627 (CO); 1H NMR
(DMSO, d ppm): 4.08–4.12 (d, 2H, CH2), 7.58–7.98 (m, 8H, bi-phenyl), 8.73
(brs, 3H, NH2 HCl); 13C NMR: 42.6, 111.0, 119.4, 129.3, 129.7, 130.2,
.
131.0, 134.5, 134.8, 135.6, 138.7, 144.8. Mass: 209.1(Mþ); Anal. calcd. for
C14H13N2Cl: C, 68.71; H, 5.31; N, 11.45. Found: C, 68.47; H, 5.30; 11.39.
4-(a-Pentanoylamino)cyclopetamidomethyl]-20-cyanobiphenyl (7)
Compound 3 (300 g, 1.408 mol) was added to a stirred suspension of
compound (6) (288.5 g, 1.099 mol) in methylene chloride (6 L) at 258C. To
the resulting suspension, dicyclohexylcarbodiimide (300.9 g, 1.461 mol),
1-hydroxybenzotriazole (35.75 g, 0.265 mol), and diisopropylethylamine

2902
K. V. V. P. Rao et al.
(160 g, 1.231 mol) were added at 25–308C. Thereafter, the reaction mass was
heated to reflux at 38–418C and stirred for 7 h. The reaction mass was cooled
to 258C. The salts were filtered and washed with methylene chloride (600 ml).
The filtrate was washed with water (2 ꢀ 1500 ml). The organic layer was con-
centrated to 2100 ml at temperatures less than 458C. The slurry obtained was
cooled to 0–58C and stirred for 1 h. The solid was filtered, washed with
precooled methtylene chloride (600 ml), and dried to afford 4-(a-pentanoyla-
mino)cyclopetamidomethyl]-20-cyanobiphenyl 7 as a white amorphous
powder (525.80 g, 93%).
Mp 135–1378C; IR (KBr, cm21): 3313 (NH), 3256, 2221 (CN), 1650,
1598 (CO); 1H NMR (DMSO, d ppm): 0.82–0.87 (t, 3H, CH3), 1.24–
1.1.27 (quintet, 2H, CH2), 1.45–1.50 (sextet, 2H, CH2), 1.63 (m, 4H,
cyclopentyl), 1.88–2.08 (m, 4H, cyclopentyl), 2.11–2.16 (t, 2H, CH2),
4.34–4.35 (d, 2H, CH2), 7.32–7.95 (m, 9H, biphenyl þ NH), 8.07–8.10
(t, 1H, NH); 13C NMR: 14.6, 22.7, 24.8, 28.1, 36.0, 37.1, 42.9, 67.0, 111.0,
119.5, 127.9, 128.9, 129.3, 130.9, 134.4, 134.7, 136.8, 141.7, 145.3, 173.3,
174.7; mass: 402.2 (M2). Anal. calcd. for C25H29N3O2: C, 74.44; H, 7.20;
N, 10.42. Found: C, 74.50; H, 7.22; 10.44.
2-Butyl-3-[[20-(1H-tetrazol-5-yl)[[1,10-biphenyl]-4-yl]methyl-1,3-
diazaspiro[4,4]non-1-en-4-one, Irbesartan (1)
Sodium azide (60.50 g, 0.93 mol) was added to tributyltin chloride (302.60 g,
0.93 mol) under nitrogen atmosphere and stirred for 30 min at 20–258C. DMF
(45.28 g, 0.62 mol) was added to the stirred suspension, and stirring continued
for 30 min. Thereafter, o-xylene (250 ml) was added followed by 4-(a-penta-
noylamino)cyclopetamidomethyl]-20-cyanobiphenyl (7) (250 g, 0.62 mol).
The reaction mixture was heated to 150–1558C, and stirring continued at
the same temperature for 20 h. Thereafter, temperature was brought down
to 20–258C. Methylene chloride (1500 ml), o-xylene (500 ml), and water
(500 ml) were added followed by hydrochloric acid (64.75 g, 35% w/w,
0.62 mol). The reaction mass was stirred for 2 h at 20–258C. The resulting
slurry was stirred for 1 h at 20–258C. The solid was filtered and washed
with 500 ml of 1:3 v/v mixture of o-xylene and methylene chloride. The
wet material was dried at 75–808C under reduced pressure to afford (1), irbe-
sartan, as an off-white powder. The crude product (250 g) was suspended in
absolute alcohol (5 L) and heated to reflux for 30 min to get a hazy
solution. The resulting solution was cooled to 508C, and carbon (12.5 g)
and hyflo (25 g) were added, heated to reflux for 15 min cooled to 608C,
and filtered through hyflo. The residue was washed with 500 ml of hot
absolute alcohol. The filtrate was concentrated to distill the alcohol
(2800 ml). The resulting suspension was cooled to 5–108C and stirred for
60 min to complete the crystallization. The solid was filtered and washed
with precooled absolute alcohol (250 ml, 5–108C). The wet material was

Synthesis of Irbesartan
2903
dried at 50–608C to obtain 2-butyl-3-[[20-(1H-tetrazol-5-yl)[[1,10-biphenyl]-
4-yl]methyl-1,3-diazaspiro[4,4]non-1-en-4-one, irbesartan (1), as a white
amorphous powder (160 g, 71%).
Mp 181–1828C; IR (KBr, cm21): NH 3447, CO 1733, 1H NMR (DMSO,
d ppm): 0.7–0.9 (t, 3H, CH3), 1.20–1.40 (sextet, 2H, CH2), 1.45–1.60
(quintet, 2H, CH2) 1.60–2.00 (m, 8H, cyclopentyl), 2.2–2.4 (t, 2H, CH2),
3–3.6 (br, 1H, NH), 4.60–4.80 (s, 2H, Ar-CH2), 7.32–7.95 (m, 8H,
biphenyl); 13C NMR: 14.5, 22.4, 26.3, 27.4, 28.3, 37.7, 43.1, 76.7, 124.3,
127.1, 128.7, 130.1, 131.4, 131.9, 137.2, 139.2, 141.9, 155.9, 162.0, 186.5;
mass: 429 (Mþ). Anal. calcd. for C25H28N6O: 70.07, 6.59, 19.61. Found:
70.35, 6.61, 19.61.
3-[[20-(1H-Tetrazol-5-yl)[[1,10-biphenyl]-4-yl]methyl-1,3-diazaspiro
[4,4]non-1-en-4-one, Desbutyl Irbesartan (8)
Formic acid (85.6 g, 1.86 mol) was added to acetic anhydride (158.14 g,
1.55 mol) under stirring at 20–458C over 30–40 min. The reaction mixture
was stirred for 90 min at 40–458C and cooled to 15–208C. 1-Amino-1-cyano-
cyclopentane carboxylic acid[9] (20 g, 0.155 mol) was added in one lot at 15–
258C, and the reaction mixture was stirred for 90 min. Thereafter, the resulting
slurry was cooled to 0–58C and stirred for 2 h at the same temperature. The
solid was filtered and washed with ethyl acetate (100 ml). The wet solid
was dried at 40–458C under reduced pressure to afford the corresponding
formyl derivative (14 g). This formyl compound (9.63 g, 0.0613 mol) was
added to a stirred suspension of 4–(20-aminomethylphenyl) benzonitrile (6)
(15 g, 0.0613 mol) in methylene chloride (300) at 258C. To the resulting sus-
pension, dicyclohexylcarbodiimide (13.90 g, 0.067 mol), and 1-hydroxyben-
zotriazole (1.65 g, 0.012 mol) were added, followed by diisopropylethylamine
(8.77 g, 0.067 mol) at 25–308C. Thereafter, the reaction mass was heated to
reflux at 38–418C and stirred for 4 h. The reaction mass was cooled to 258C.
The salts were filtered and washed with methylene chloride (38 ml). The
filtrate was washed with water (2 ꢀ 38 ml). The organic layer was concentrated
to distill 160 ml of methylene chloride at atmospheric pressure. The slurry
obtained was cooled to 0–58C and stirred for 1 h. The solid was filtered,
washed with precooled methtylene chloride (38 ml, 28C), and dried. The
dried compound (16.5 g) was added to a stirred suspension of tributyltin
chloride (23.20 g, 0.071 mol), sodium azide (4.65 g, 0.071 mol), DMF
(3.47 g, 0.047 mol), and o-xylene (16.5 ml). The reaction mixture was heated
to 150–1558C and stirred for 5 h at the same temperature. The reaction mass
was cooled to 258C, and methylene chloride (100 ml), o-xylene (35 ml), and
water (35 ml) were added. Thereafter, hydrochloric acid (5 g, 35% w/w,
0.048 mol) was added over 15 min and stirred for 15 h. The slurry obtained
was diluted with xylene (50 ml) and stirred for 30 min. The solid was
filtered, washed with xylene, and dried to afford the crude compound as a

2904
K. V. V. P. Rao et al.
pale yellow powder (10 g), which was crystallized from ethanol to afford the
title compound as white amorphous powder.
1
Mp: 190–1918C; IR (KBr, cm21): 3436 (NH), 1734 (CO), H NMR
(DMSO, d ppm): 1.65–1.86 (m, 8H, cyclopentyl), 4.65 (s, 2H, CH2), 7.08–
7.19 (m, 4H, phenylic), 7.54–7.71 (m, 4H, phenylic), 8.0 (s, 1H, CH), 16.37
(brs, 1H, NH); 13C NMR: 26.2, 37.4, 44.1, 77.7, 124.3, 127.8, 128.7, 130.1,
131.5, 132, 137, 139.4, 141.9, 153.3, 155.9, 185.5; mass: 371.1 (M2). Anal.
calcd. for C21H20 N6O: 67.73, 5.41, 22.57. Found: 67.85, 5.42, 22.60.
2-Propyl-3-[[20-(1H-tetrazol-5-yl)[[1,10 -biphenyl]-4-yl]methyl-1,3-
diazaspiro[4,4]non-1-en-4-one, Propyl Irbesartan (9)
This compound was prepared per the methods described for the preparation of
irbesartan by changing valeryl chloride by butyryl chloride in the preparation
of compound 3.
1
Mp: 110–1128C; IR (KBr, cm21): 3338 (NH), 1702 (CO), H NMR
(DMSO, d ppm): 0.83–0.89 (t, 3H, CH3), 1.55–1.60 (quintet, 2H, CH2),
1.85–2.02 (m, 8H, cyclopentyl), 2.72–2.77 (t, 2H, CH2), 3.20–3.80 (br,
1H, NH), 7.10–7.20 (m, 4H, biphenyl), 7.50–7.70 (m, 4H, biphenyl); 13C
NMR: 14.0, 19.0, 26.1, 29.8, 37.6, 44.2, 72.7, 124.4, 127.7, 128.8, 130.2,
131.4, 131.5, 131.9, 134.9, 139.9, 141.8, 155.9, 172.5, 180.4; Mass: 413.2
(M2). Anal. calcd. for C24H26N6O: C, 69.56; H, 6.28; N, 20.28. Found: C,
69.63; H, 6.29; N, 20.30.
1[20-Carboxybiphenyl-4-yl-methyl]-2-n-butyl-4-spirocyclopentane-
2-imidazoline-5-one (12)
Sodium hydroxide (5.28 g, 0.132 mol) was dissolved in water (20 ml) at 20–
258C and cooled to 158C. 2-Butyl-2,3-diazaspiro[4.4]nonane-1,4-dione[3] 11
(12 g, 0.055 mol), toluene (165 ml), and 75% w/w tetrabutylammoniumhydr-
oxide solution (1 ml) were added to the sodium hydroxide solution followed
by 2-(4-bromomethylphenyl) benzoic acid, 10[11] (10 g, 0.0343 mol). The
reaction mixture was warmed to 32–348C and stirred for 24 h at the same
temperature. Thereafter, the reaction mixture was diluted with toluene
(165 ml) and water (50 ml). The organic layer was separated, and the
aqueous layer was washed with ethyl acetate (60 ml). The aqueous layer
was cooled to 5–108C, and the pH was adjusted to 4 with 1:1 HCl solution.
The sticky material obtained was washed with water (3 ꢀ 50 ml) at 50–
558C, dissolved in isopropyl alcohol (150 ml), and cooled to 2–58C. The
solid crystallized out was filtered washed with precooled IPA (15 ml).
The wet material was dried at 50–558C under reduced pressure to afford
the title compound as a white crystalline powder (4.5 g, 24%).

Synthesis of Irbesartan
2905
Mp 149–1508C; IR (KBr, cm21): NH 3451; CO 1734; 1H NMR (DMSO, d
ppm): 0.79–0.81 (t, 3H, CH3), 1.26–1.29 (m, 2H, CH2), 1.50 (brs, 2H, CH2)
1.68–1.86 (m, 10H, cyclopentyl and CH2), 2.35 (brs, 2H, CH2), 4.73 (s, 2H,
Ar-CH2), 7.17–7.74 (m, 8H, Ar), 12.77 (brs, 1H, COOH); 13C NMR: 14.5,
22.4, 26.3, 27.5, 28.4, 37.7, 43.2, 76.7, 127.0, 128.4, 129.6, 130.0, 131.3,
131.8, 133.0, 136.8, 140.9, 141.4, 162.0, 170.4, 186.5; mass: 405.3 (Mþ).
Anal. calcd. for C25H28N2O3 C, 74.23; H, 6.98; N, 6.93. Found: C, 74.43; H,
6.99; N, 6.94
ACKNOWLEDGMENT
The authors thank the management of Aurobindo Pharma ltd., Research and
Development Department, for supporting this work. The authors also thank
the Analytical Research Department for its valuable contribution to this work.
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