An alternative approach to synthesis of 2-n-butyl-5-nitrobenzofuran derivative: A key starting material for dronedarone hydrochloride

Article abstract of DOI:10.1007/s12039-012-0299-0

A practical synthesis of (2-butyl-5-nitrobenzofuran-3-yl)(4-hydroxyphenyl) methanone, a key intermediate in the preparation of anti arrhythmic drug, is described. The commercially available 4-nitrophenol (3) is converted in five steps to 2-butyl-5-nitrobenzofuran (9) which upon Friedel-Crafts acylation with 4-methoxybenzoyl chloride followed by deprotection of methyl group gives (2). Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-012-0299-0

c
J. Chem. Sci. Vol. 124, No. 5, September 2012, pp. 1077–1085. ꢀ Indian Academy of Sciences.
An alternative approach to synthesis of 2-n-butyl-5-nitrobenzofuran
derivative: A key starting material for dronedarone hydrochloride
P RAJA GOPALa,b,∗, E R R CHANDRASHEKARa, M SARAVANANa, B VIJAYA BHASKARa
and P VEERA SOMAIAHb
aResearch and Development, Dr. Reddy’s Laboratories Ltd., Integrated Product Development Organization,
Hyderabad 500 072, India
bDepartment of Chemistry, Osmania University, Hyderabad 500 007, India
e-mail: rajagopal@drreddys.com
MS received 30 September 2011; revised 13 March 2012; accepted 19 April 2012
Abstract. A practical synthesis of (2-butyl-5-nitrobenzofuran-3-yl)(4-hydroxyphenyl)methanone, a key
intermediate in the preparation of anti arrhythmic drug, is described. The commercially available 4-nitrophenol
(3) is converted in five steps to 2-butyl-5-nitrobenzofuran (9) which upon Friedel–Crafts acylation with
4-methoxybenzoyl chloride followed by deprotection of methyl group gives (2).
Keywords. Fries rearrangement; selective α-bromination; cyclisation; Friedel–Crafts acylation.
1. Introduction
methoxyphenyl)-2-oxoethyl)-4-nitrophenyl pentanoate,
cyclisation of 2-(2-(4-methoxyphenyl)-2-oxoethyl)-4-
nitrophenyl pentanoate in the presence of tributylamine
and unmodified molecular seives afforded (2-butyl-
5-nitrobenzofuran-3-yl)(4-methoxyphenyl)methanone (10)
and further deprotection of methyl group with tributyl-
amine hydrochloride at 200◦C furnished 2. Gubin et al.
(scheme 3) described another process in US5223510
patent. In this process, 4-nitrophenol was converted to
3-(bromomethyl)-4-nitrophenol in the presence of para
formaldehyde, 50% aq. HBr and 36N H2SO4. Wittig
reaction of 3-(bromomethyl)-4-nitrophenol with triph-
enylphosphine gave respective ylide and subsequent
reaction with pentanoyl chloride in the presence of TEA
produced 2-butyl-5-nitrobenzofuran (9). Acylation
of 2-butyl-5-nitrobenzofuran with 4-methoxybenzoyl
chloride using Lewis acid SnCl4 afforded (2-butyl-5-
nitrobenzofuran-3-yl)(4-methoxyphenyl)methanone (10)
and demethylation of (2-butyl-5-nitrobenzofuran-3-
yl)(4-methoxyphenyl)methanone with AlCl3 gave 2.
All the above reported synthetic pathways presented
certain draw backs such as usage of commercially not
available reagents, vigorous conditions like depro-
tection at 200◦C, preparation of moisture sensitive
intermediate like ylide and expensive reagents usage
such as SnCl4. As a result of these limitations, an alter-
native approach to 2 was investigated to provide more
rapid and convenient to access to this valuable synthetic
intermediate3–7, using inexpensive and commercially
available raw materials.
This report describes an alternative approach for the syn-
thesis of (2-butyl-5-nitrobenzofuran-3-yl)(4-hydroxy-
phenyl)methanone (2) (figure 1). This key functiona-
lized scaffold is required for the preparation of
dronedarone hydrochloride 1 (figure 1) which is anti
arrhythmic drug. It is used for the treatment of atrial fib-
rillation and atrial flutter in patients whose hearts have
either returned to normal rhythm or who undergo drug
therapy or electric shock treatment to maintain normal
rhythm.
There are several synthetic routes appeared in the
literature for the preparation of 2. Cambrex karlskoga
et al.1 (scheme 1) in 2009 reported for the prepa-
ration of 2 using 1-chloro-4-nitrobenzene and ethyl
N-hydroxyacetimidate. Hydrolysis of ethyl N-4-nitro-
phenoxyacetimidate with HCl in acetonitrile gave O-
(4-nitrophenyl)hydroxylamine, condensation and re-
arrangement of O-(4-nitrophenyl)hydroxylamine and
1-(4-hydroxyphenyl)heptane-1,3-dione afforded 2 in
acetic acid via an in situ intermediate of 1-(4-hy-
droxyphenyl)-3-((4-nitrophenoxy)imino)heptan-1-one.
Kretzschmar et al.2 (scheme 2) in 2010 developed an
alternative process commenced from 1-bromo-4-nitro-
benzene and 1-(4-methoxyphenyl)ethanone oxime. 2-
(2-hydroxy-5-nitrophenyl)-1-(4-methoxyphenyl)ethanone
reacted with pentanoyl chloride gave 2-(2-(4-
∗For correspondence
1077

1078
P Raja Gopal et al.
Figure 1. Structure of dronedarone hydrochloride 1 and key starting material 2.
HO
N
OC2H5
Cl
O
OC2H5
O
ONH2
HCl
N
Acetonitrile
O2N
NaOH,DMF
O2N
O
O2N
O
O
C2H5O
Acetic acid,
115oC
Sodium-t-butoxide,
THF
OH
O
OH
O
Acetic acid
O
O2N
OH
N
O
OH
O2N
2
Scheme 1. Synthetic pathway reported by Cambrex Karlskoga et al.
Br
OH
N
1.8N HCl
in AcOH
OH
O
N
O
NO2
Water
O2N
NaH, DMSO O2N
H3CO
OCH3
OCH3
O
K2CO3, Acetone
Cl
N(n-Bu)3,Xylene
unmodified
molecular seives
O
O
N(n-Bu)3.HCl
O
2
O2N
200 oC
O2N
OCH3
O
O
OCH3
Scheme 2. Synthetic pathway reported by Kretzschmar et al.

An efficient synthesis of KSM for dronedarone HCl
1079
Scheme 3. Synthetic pathway reported by Gubin et al.
2. Experimental
for C12H15NO4: C,60.75; H, 6.37; N, 5.90, Found: C,
60.67; H, 6.28; N, 5.88%.
1
The H NMR spectra were recorded in CDCl3 on a
Varian Gemini-2000 at 400 and 500 MHz FT NMR
spectrometer, the chemical shifts were reported in δ
ppm relative to TMS. The FT–IR spectra were recorded
in the solid state as KBr dispersion medium using
Perkin Elimer 1650 FT-IR spectrophotometer. The mass
analysis was performed on HP-5989A LC/MS spec-
trometer. Elemental analysis was performed using a
Perkin-Elmer 2400 II CHN Analyzer. The solvents and
reagents were used without further purification.
2.2 1-(2-hydroxy-5-nitrophenyl)hexan-1-one (5)
To a mixture of 4-nitrophenyl hexanoate (4) (100 g,
0.42 mol) in nitrobenzene (600 mL) was added anhy-
drous AlCl3 (61.8 g, 0.46 mol), then contents were
heated to 140◦C and maintained for 5 h. After comple-
tion of the reaction, slowly poured into chilled aqueous
5% HCl (1000 mL) and stirred for 15 min, extracted the
compound with DCM (200 mL) and washed the organic
layer with water (300 mL). The obtained organic layer
was distilled off at 40◦C under vacuum until DCM
traces evaporates, gave dark brown coloured liquid.
Slowly added above liquid into chilled 15% aqueous
NaOH (900 mL) at room temperature (rt) and stirred
for 1 h at same temperature and precipitated solid was
isolated by filtration and washed with water (200 mL).
To the wet cake, hexane was added (200 mL) at room
temperature, maintained for 30 min, filtered and washed
with hexane (50 mL). To the crude material 5% aque-
ous HCl (100 mL) and hexane (200 mL) added, heated
to 55–60◦C and maintained for 20 min, separated the
layers, repeated the extraction process with hexane
(3 × 50 mL). The combined hexane layer was washed
with water (50 mL) and distilled under vacuum at 50◦C
which afforded 5. Off white colour solid, yield 45%
(45.0 g). DSC: endothermic peak 64.7◦C; MS: m/z 236
2.1 4-nitrophenyl hexanoate (4)
Hexanoyl chloride (106 g, 0.79 mol) was added drop-
wise to a stirred solution of 4-nitrophenol (3) (100 g,
0.72 mol), TEA (150 mL, 1.08 mol) in DCM (500 mL)
at 0–5◦C under nitrogen atmosphere maintained for
1 h. After completion of the reaction, water was added
(500 mL), DCM (500 mL) and stirred for 15 min.
Layers were separated and organic layer was washed
with 5% aqueous HCl (400 mL) and water (100 mL).
The obtained DCM layer was washed with 5%
aqueous NaHCO3 (400 mL) followed by 5% aque-
ous NaCl (100 mL). Separated organic layer was
distilled at below 40◦C under vacuum afforded 4.
Viscous oil, yield 95% (161.5 g). MS: m/z 296,
(M++ CH3COOH); FT-IR (cm−1): 1765 (O-C=O ester
1
stretching), 1096 (aromatic–O-C stretching); H NMR (M+-H); FT-IR (KBr) cm−1: 1644 (−C=O keto stretch-
1
(400 MHz, CDCl3): δ 8.24–8.28 (d, 2H), 7.23–7.29 (d, ing); H NMR (500 MHz, CDCl3): δ 13.02 (s, 1H),
2H), 2.58–2.61 (t, J = 8.5 Hz, 2H), 1.73–1.78 (m, 2H), 8.74 (d, J = 2.5 Hz, 1H), 8.33–8.36 (dd, J = 9.5,
3.0 Hz, 1H), 7.08–7.1 (d, J = 9.5 Hz, 1H), 3.07–3.1
(t, J = 7.0 Hz, 2H), 1.77–1.8 (m, 2H), 1.39–1.42
(m, 4H), 0.93–0.96 (t, J = 7.0 Hz, 3H); 13C NMR
1.32–1.41 (m, 4H), 0.91–0.95 (t, J = 6.8 Hz, 3H);
13C NMR (400 MHz, CDCl3): δ 171.1, 155.4, 145.0,
124.9, 122.3, 34.0, 31.0, 24.2, 22.1, 13.7; Anal. calcd.

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P Raja Gopal et al.
(400 MHz, CDCl3): δ 206.3, 167.2, 139.4, 130.7, 126.4, (s, 3H), 2.20–2.26 (m, 1H), 1.99–2.18 (m, 1H), 1.38–
119.5, 118.1, 38.2, 31.1, 23.6, 22.3, 13.8; Anal. calcd. 1.47 (m, 4H), 0.92–0.96 (t, J = 7.6 Hz, 3H); 13C NMR
for C12H15NO4: C, 60.75; H, 6.37; N, 5.90, Found: C,
60.73; H, 6.42; N, 5.88%.
(400 MHz, CDCl3): δ 193.8, 161.9, 141.4, 128.8, 127.2,
126.5, 111.9, 56.7, 52.8, 32.7, 29.4, 22.1, 13.7; Anal.
calcd. for C13H16BrNO4: C, 47.29; H, 4.88; N, 4.24,
Found: C, 47.31; H, 4.71; N, 4.10%.
2.3 1-(2-methoxy-5-nitrophenyl)hexan-1-one (6)
To a stirred mixture of 1-(2-hydroxy-5-nitrophenyl)
hexan-1-one (5) (20 g, 0.084 mol), DBU (31.5 mL,
0.21 mol) in acetone (100 mL) was added methyl iodide
2.5 2-Bromo-1-(2-hydroxy-5-nitrophenyl)hexan-
1-one (8)
(4 × 2.6 mL, 0.16 mol) in four portions with time To a stirred solution of 2-bromo-1-(2-methoxy-5-
intervals of 30 min and maintained at room tempera- nitrophenyl)hexan-1-one (7) (15 g, 0.045 mol) in DCM
ture for 2 h. After completion of reaction, distilled off (90 mL) was added slowly AlCl3 (18.1 g, 0.14 mol) at
acetone under vacuum at below 50◦C to obtain crude 15–20◦C then raised to room temperature and main-
material. To the crude, the water was added (100 mL), tained for 1 h. After completion of the reaction poured
DCM (100 mL) and stirred for 15–20 min, then sepa- the reaction mass in to chilled 5% aqueous HCl
rated two layers and extracted aqueous layer with DCM (150 mL) and stirred for 15 min. Separated DCM layer
(50 mL). Combined organic layer was washed with 5% was washed with water (75 mL) followed by 5% aque-
aqueous HCl (50 mL), followed by water (50 mL) and ous NaHCO3 (75 mL) and finally water (75 mL). Distil-
finally distilled off below 40◦C which gave 6. Off white lation of DCM layer under vacuum at 30◦C gave 8. Off
colour solid, yield 83% (17.6 g). DSC: endothermic white colour solid, yield 86% (12.3 g). DSC: endother-
peak 47.5◦C; MS: m/z 252.2 (M++H); FT-IR (KBr) mic peak 73.3◦C; MS: m/z 314 (M+-H), 316 (M+2-H);
cm−1: 1683 (−C=O keto stretching), 1011 (aromatic– FT-IR (KBr) cm−1: 3409 (Aromatic-O-H stretching),
1
O-CH3 ether stretching); 1H NMR (400 MHz, CDCl3): 1648 (−C=O keto stretching); H NMR (400 MHz,
δ 8.51–8.52 (d, J = 2.8 Hz, 1H), 8.31–8.34 (dd, J = CDCl3): δ 12.51 (s, 1H), 8.76–8.77 (d, J = 4.0 Hz,
9.2 Hz, 2.8 Hz, 1H), 7.07–7.09 (d, J = 9.2 Hz, 1H), 1H), 8.36–8.39 (dd, J = 9.6 Hz, J = 3.2 Hz, 1H),
4.03 (s, 3H), 2.93–2.97 (t, J = 7.2 Hz, 2H), 1.65–1.73 7.13–7.15 (d, J = 9.2 Hz, 1H), 5.17–5.20 (t, J =
(m, 2H), 1.31–1.35 (m, 4H), 0.89–0.92 (t, J = 7.2 Hz, 8.0 Hz, 1H), 2.12–2.27 (m, 2H), 1.40–1.59 (m, 4H),
3H); 13C NMR (400 MHz, CDCl3): δ 200.6, 162.4, 0.99–1.03 (t, J = 7.6 Hz, 3H); 13C NMR (400 MHz,
141.3, 128.9, 128.2, 126.0, 111.7, 56.4, 43.5, 31.3, 23.7, CDCl3): δ 198.3, 167.9, 139.5, 131.3, 126.3, 119.9,
22.4, 13.8; Anal. calcd. for C13H17NO4: C, 62.14; H, 115.9, 45.6, 32.4, 29.6, 22.1, 13.7; Anal. calcd. for
6.82; N, 5.57, Found: C, 62.20; H, 6.76; N, 5.44%.
C12H14BrNO4: C, 45.59; H, 4.46; N, 4.43, Found: C,
45.51; H, 4.55; N, 4.36%.
2.4 2-bromo-1-(2-methoxy-5-nitrophenyl)hexan-
1-one (7)
2.6 2-butyl-5-nitrobenzofuran (9)
To a stirred clear solution of 2-bromo-1-(2-hydroxy-5-
nitrophenyl)hexan-1-one (8) (15 g, 0.047 mol) in DCM
(75 mL) was added TEA (13.2 mL, 0.094 mol) at room
temperature and maintained for 2 h. After completion
of reaction slowly water was added (50 mL), stirred for
15 min then layers were separated and washed organic
layer with 5% aqueous HCl (50 mL), water (50 mL)
and upon distillation of DCM under vacuum at 30◦C
afforded syrup material. Dissolved syrup compound
in methanol (75 mL) and added a solution of NaBH4
(2.4 g, 0.071 mol) in methanol (10 mL) over a period of
10–15 min at 0–5◦C. The mixture was stirred at same
temperature for 30 min then raised to room tempera-
ture and maintained for 1 h. After completion of reac-
tion added 15% aqueous HCl (50 mL) and heated to
90–95◦C, maintained the reaction at same temperature
To a stirred solution of 1-(2-methoxy-5-nitrophenyl)hexan-
1-one (6) (20 g, 0.079 mol) in dichloromethane (20 mL)
was added bromine (4.1 mL, 0.079 mol) at room tem-
perature over a period of 10 min and maintained
for 1 h. After completion of reaction added more
dichloromethane (20 mL) and decolourized the unre-
acted bromine by washing with 10% aqueous sodium
thiosulphate (20 mL). Evaporation of resultant organic
layer afforded intermediate 7. Off white colour solid,
yield 93% (24.4 g). DSC: endothermic peak 60.1◦C;
MS: m/z 330.2 (M++H), 332.2 (M+2+H); FT-IR (KBr)
cm−1: 1670 (−C=O keto stretching), 1012 (aromatic–
O−CH3 ether stretching); 1H NMR (400 MHz, CDCl3):
δ 8.57–8.58 (d, J = 2.8 Hz, 1H), 8.35–8.38 (dd, J =
8.8 Hz, J = 2.4 Hz, 1H), 7.08–7.10 (d, J = 9.2 Hz,
1H), 5.25–5.28 (dd, J = 8.4 Hz, J = 6.4 Hz, 1H), 4.05

An efficient synthesis of KSM for dronedarone HCl
1081
for 5 h, after completion of reaction, the contents were 2.8 (2-butyl-5-nitrobenzofuran-3-yl)(4-
cooled to room temperature, added toluene (90 mL) hydroxyphenyl)methanone (2)
and stirred for 15 min. Separated aqueous and organic
To a stirred solution of AlCl3 (20.3 g, 0.15 mol))
in chlorobenzene (140 mL) was added drop-wise
a solution (2-butyl-5-nitrobenzofuran-3yl)(4-methoxy-
phenyl)methanone (10) (20 g, 0.056 mol) in chloroben-
zene (40 mL) over a period of 10 min at room tempe-
rature, contents were heated to 75–80◦C and maintained
for 5 h. After completion of reaction poured the reac-
tion mass into chilled 5% HCl (200 mL), DCM (80 mL)
and stirred for 15 min. Separated aqueous layer was
extracted with DCM (40 mL), combined organic layer
was washed water (2 × 60 mL), finally distillation of
organic layer at 75–80◦C afforded the title compound 2
in crude form. Pure compound was isolated by dissolv-
ing the crude material 2 in chlorobenzene (40 mL) and
heated to 75–80◦C and maintained for 15 min, cooled
to 0–5◦C for 1 h and filtered. White colour solid, yield
85% (16.3 g). DSC: endothermic peak 131.2◦C MS:
m/z 338 (M+-H); FT-IR (KBr) cm−1: 3216 (aromatic–
O–H stretching), 1599 (–C=O keto stretching), 1166
layer, extracted aqueous layer with toluene (45 mL).
Combined organic layer was washed with water (2 ×
25 mL), evaporation of resultant organic layer under
vacuum afforded 9. Viscous oil, yield 73% (7.6 g).
MS: m/z 218 (M+-H); FT-IR cm−1: 1064 (aromatic–
1
O–CH ether stretching); H NMR (400 MHz, CDCl3):
δ 8.36–8.37 (d, J = 2.4 Hz, 1H), 8.10–8.13 (dd, J =
8.8 Hz, J = 2.0 Hz, 1H), 7.42–7.44 (d, J = 8.8 Hz,
1H), 6.49–6.50 (d, J = 8.0 Hz, 1H), 2.77–2.81 (t, J =
7.6 Hz, 2H), 1.70–1.78 (m, 2H), 1.40–1.47 (m, 2H),
0.94–0.98 (t, J = 7.2 Hz, 3H); 13C NMR (400 MHz,
CDCl3): δ 163.3, 157.4, 143.7, 129.3, 118.9, 116.4,
110.7, 102.4,29.3, 28.0, 22.1, 13.6; Anal. calcd. for
C12H13NO3: C, 65.74; H, 5.98; N, 6.39, Found: C,
65.59; H, 5.75; N, 6.45%.
2.7 (2-Butyl-5-nitrobenzofuran-3yl)(4-
methoxyphenyl)methanone (10)
1
(aromatic–O–CH ether stretching); H NMR (CDCl3):
To a stirred solution of AlCl3 (19.7 g, 0.14 mol) in DCM
(250 mL) was added drop-wise 4-methoxybenzoyl
chloride (21.3 g, 0.12 mol) over a period of 20 min at
0–5◦C and maintained for 30 min. To the above con-
tents, 2-butyl-5-nitrobenzofuran (9) (25 g, 0.11 mol)
was added drop-wise over a period of 15 min, raised to
room temperature and maintained for 4 h. After comple-
tion of reaction, poured the reaction mass in to chilled
5% HCl (250 mL) and stirred for 15 min. Separated
DCM layer was washed with 5% aqueous NaHCO3
(125 mL) followed by water (125 mL) and finally dis-
tillation of organic layer afforded crude 10. Dissolved
the crude 10 material in i-PrOH (75 mL), cooled to
0–5◦C and maintained for 1 h, collected the solid by
filtration and washed with chilled i-PrOH (12.5 mL)
δ 8.34 (d, J = 2.0 Hz, 1H), 8.20–8.23 (dd, J = 8.8 Hz,
J = 2.0 Hz, 1H), 7.77–7.80 (m, 2H), 7.55–7.58 (d,
J = 9.2 Hz, 1H), 6.93–6.97 (m, 2H), 6.43 (s, 1H),
2.90–2.94 (t, J = 7.6 Hz, 2H), 1.72–1.80 (m, J =
7.6 Hz, 2H), 1.30–1.40 (m, J = 7.2 Hz, 2H), 0.87–0.91
(t, J = 7.2 Hz, 3H). 13C NMR (400 MHz, CDCl3): δ
190.3, 167.6, 161.6, 156.3, 144.5, 132.1, 130.3, 127.7,
120.2, 117.5, 117.1, 115.8, 111.4 29.7, 27.9, 22.2, 13.5;
Anal. calcd. for C19H17NO5: C, 67.25; H, 5.05; N, 4.13,
Found: C, 67.17; H, 5.11; N, 4.20%.
3. Results and discussion
which gave pure 10. Off white colour solid, yield Our synthesis (scheme 4) of 2 commenced from
82% (33.0 g). DSC: endothermic peak 95.4◦C MS: commercially available 4-nitrophenol (3), which was
m/z 354.1 (M++H); FT-IR (KBr) cm−1: 1640 (−C=O reacted with hexanoyl chloride8–11 in the presence of
keto stretching), 1165 (aromatic–O–CH ether stretch- TEA to furnish 4-nitrophenyl hexanoate (4) in residue
ing),1023 (aromatic–O–CH3 ether stretching); 1H NMR form with 90–95% yield. However, the obtained 4
(400 MHz, CDCl3): δ 8.34 (d, J = 2.4 Hz, 1H), 8.20– was substantiated by IR spectrum, a strong absorption
8.23 (dd, J = 8.8 Hz, J = 2.4 Hz,1H), 7.81–7.85 (m, band observed in functional group region at 1765 cm−1
2H), 7.55–7.57 (d, J = 8.8 Hz, 1H), 6.97–7.01 (m, 2H), attributed to ester stretching. Further, Fries rearrange-
3.91 (s, 3H), 2.90–2.94 (t, J = 7.2 Hz, 2H), 1.72–1.80 ment12–15 of 4 in nitrobenzene solvent at 140◦C afforded
1
(m, J = 7.2 Hz, 2H), 1.30–1.40 (m, J = 7.2 Hz, 2H), 1-(2-hydroxy-5-nitrophenyl)hexan-1-one (5). The H
0.87–0.91 (t, J = 7.2 Hz, 2H); 13C NMR (400 MHz, NMR spectrum of 5 depicted three non-equivalent sets
CDCl3): δ 188.9, 167.0, 163.9, 156.2, 144.5, 131.5, of proton signals at δ 8.74, 8.33, 7.08 corresponding to
130.8, 127.8, 120.1, 117.5, 117.1, 113.9, 111.2, 55.4, aromatic region, which proved that the rearrangement
29.8, 27.8, 22.2, 13.5; Anal. calcd. for C20H19NO5: C, could have occurred in 4, the para position which is
67.98; H, 5.42; N, 3.96, Found: C, 67.78; H, 5.58; N, substituted by nitro group. Hence, coming acyl cation
3.90%.
has to attack at ortho position of hydroxyl group. In

1082
P Raja Gopal et al.
OH
O
O
OH
b
a
O2N
O2N
O2N
O
c
5
4
3
CH3
O
CH3
O
OH
Br
d
e
Br
O2N
O2N
O2N
O
O
7
O
6
8
f
O
O
O
g
h
2
O2N
O2N
OCH3
9
10
Scheme 4. Proposed synthetic scheme for the preparation of 2.
order to optimize the temperature in this stage, reac- desired α-brominated compound was isolated using
tion was carried out at lower temperature (<140◦C), no 1.0 equiv of bromine with 80–85% yield and unde-
product formation was observed in TLC. Removal of sired dibromo compound 6a was observed using 2.0
nitrobenzene was bottle neck in this step during the iso- equiv of bromine solution (scheme 5). This reaction
lation of 5 and due to cumbersome workup procedure, was favourable in diethyl ether, methyl t-butylether,
the yield in this step was in range of 45–50%.
dichloromethane solvents at room temperature. Mass
spectrum of 7 substantiated the bromo abundance in
1:1 ratio, single proton signal in deshielding zone of
1H NMR at δ 5.25 corresponding to bromo attached
proton.
3.1 Reagents and condition
(a) Hexanoyl chloride, TEA, DCM, 0–5◦C, 1 h; (b)
AlCl3, nitrobenzene, 140◦C, 5 h; (c) CH3I, DBU, ace-
tone, 25–30◦C, 2 h; (d) Br2, DCM, 25–30◦C, 1 h; (e)
AlCl3, DCM, 25–30◦C, 1 h; (f) TEA, DCM, 25–30◦C,
then NaBH4, 25–30◦C, 30 min, 15% HCl, 90–95◦C,
4–6 h; (g) 4-methoxybenzoyl chloride, AlCl3, DCM,
25–30◦C, 4–5 h; (h) AlCl3, chlorobenzene, 75–80◦C,
4–5 h.
At earlier stages, we have targeted for the synthesis of
8 from compound 5, enthusiastic results were not found
using various brominating reagents such as Br2,, NBS,
NH4Br/(NH4)2S2O8 23,24 at different conditions.
1H NMR of the obtained compound 5a depicted the
absence of proton at ortho position to hydroxy group
(scheme 6). The keto group of 5 involving in resonance
and exhibiting hydroxy character (scheme 7).
Methylation of resultant 5 with methyl iodide16–19
afforded 1-(2-methoxy-5-nitrophenyl)hexan-1-one (6),
during the feasibility study incompletion of reaction
was noticed using 2.0 equiv of methyl iodide in a single
lot and for further completion of reaction added excess
amount of reagent, even if we used excess equiv in a
single lot, starting material still remains and at the end
of the final process included the lot-wise addition of
methyl iodide with 2.0 equiv. The isolated compound 6
exhibited upward signal in DEPT spectrum at δ 56.4,
singlet in 1H NMR at δ 4.03 attributed to O−CH3. Com-
pound 6 was treated with bromine20–22 gave 2-bromo-1-
(2-methoxy-5-nitrophenyl)hexan-1-one (7), exclusively
Compound 7 was further subjected to deprotec-
tion with AlCl3 to give 2-bromo-1-(2-hydroxy-5-
25
nitrophenyl)hexan-1-one (8), confirmed the compound
1
by H NMR and observed that the absence of O−CH3
protons at δ 4.03. Cyclization26,27 of 8 (scheme 8) in the
presence of TEA gave an 2-butyl-5-nitrobenzofuran-
3(2H)-one (8a), further reduction with sodium borohy-
dride28 afforded an in situ intermediate of 2-butyl-5-
nitro-2,3-dihydrobenzofuran-3-ol (8b) and dehydration
of in situ substrate by 15% aqueous HCl28 furnished
2-butyl-5-nitrobenzofuran (9) with 70–75% of yield.
1
The obtained 9 was confirmed using H NMR, single
proton signal at δ 6.49 attributed to third position

An efficient synthesis of KSM for dronedarone HCl
1083
Scheme 5. Formation of dibromo compound using 2.0 equiv of bromine.
Scheme 6. Formation of aromatic brominated compound from 5 using
brominating reagents (i) Br2 or NH4Br/(NH4)2S2O8 or NBS.
Scheme 7. Resonance structure of 5.
Scheme 8. Intermediates during the conversion of 8 to 9.
Table 1. Optimization of AlCl3 mole ratio from 9 to 10 and per-
formed at 25–30◦C.
Entry Mole ratio Solvent Puritya (area%) 9 (area%) Yieldb (%)
1
2
3
4
5
6
2.0
1.6
1.5
1.3
1.2
4.0
DCM
DCM
DCM
DCM
DCM
DCM
94.03
94.8
95.6
97.3
97.0
68.3c
0.2
71.3
75.1
80.3
82.8
78.3
–
0.13
0.08
0.03
–
21.9
a,bAfter i-PrOH purification, cReaction performed at reflux temperature,
HPLC purity was calculated before i-PrOH purification

1084
P Raja Gopal et al.
Table 2. Screening of reagent, solvent and mole ratio of AlCl3 for 10 to 2.
Entry
Reagent
Mole ratio
Solvent
Temp (◦C)
Purityb (area %)
10 (area %)
Yieldc (%)
1
2
3a
4
5
6
7
8
9
Aq. HCl
Aq. HBr
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
3.0
3.0
2.5
2.7
1.5
2.0
2.5
2.7
4.0
Acetonitrile
MIBK
DCM
Toluene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
75–80
110–115
42
105–110
75–80
75–80
75–80
75–80
75–80
–
–
–
–
66.8
78.4
99.2
99.5
98.3
–
–
–
–
–
–
35
53
68
83
85
73
–
26.2
9.5
0.3
0.15
0.03
aCompound was not isolated and monitored the reaction by TLC.
b,cAfter chlorobenzene purification
aromatic –CH of benzofuran moiety and it indicated incompletion of reaction noticed during demethyla-
that 8 was cyclised.
tion using dichloromethane solvent for both stages, by
Existing literature28 for preparation of 10 was employing excess amount of AlCl3 also did not give
involved Friedel–Crafts acylation of 9 with 4- a good results. Purification of crude 2 in minimum
methoxybenzoyl chloride in the presence of SnCl4 amount of chlorobenzene afforded 2 with 99.0% HPLC
which is one of the expensive reagents and replaced purity.
the reagent by AlCl3 with significant yield and purity.
IR spectrum of 10 depicted a strong absorption band
4. Conclusion
at 1640 cm−1 corresponding to keto stretching, absence
of δ 6.49 signal in 1H NMR indicating that acyl cation
In conclusion, we have developed an alternative process
attacked at third position of benzofuran moiety. To
with inexpensive and commercially available raw mate-
improve the yield, reaction was screened with differ-
rials for the preparation of 2-butyl-5-nitrobenzofuran-3-
ent mole ratio of AlCl3. Though the reaction completed
yl)(4-hydroxyphenyl)methanone, a key intermediate of
using 1.6 and 2.0 equiv of AlCl3, the yield of the pro-
dronedarone hydrochloride.
duct was moderate due to the formation of impurities,
where as the reaction did not go for completion using
1.2 equiv. Finally, usage of 1.3 equiv of AlCl3 led to
Acknowledgements
true conversion of reaction to afford crude 10, which
was recrystallized in i-PrOH and gave 97% HPLC pure
10 with 82% yield (table 1).
The authors wish to thank the management of Dr. Reddy’s
Laboratories Ltd., Hyderabad for supporting this work.
28
Finally, demethylation of 10 with AlCl3 afforded
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