A Novel and efficient synthesis of dronedarone hydrochloride, an antiarrhythmic drug substance

Article abstract of DOI:10.1002/jccs.201190133

A novel and efficient synthesis of dronedarone hydrochloride starting from 2-n-butyl-5-nitrobenzofuran by employing mild and selective reaction conditions is described. The synthetic approach is operationally simple and suitable for industrial application.

Full text of DOI:10.1002/jccs.201190133

Journal of the Chinese Chemical Society, 2011, 58, 841-845
841
Communication
A Novel and Efficient Synthesis of Dronedarone Hydrochloride, an
Antiarrhythmic Drug Substance
Saravanan Mohanarangam,a,c* Bollikonda Satyanarayana,b Chandrashekar R. Elati,a
Bolugoddu Vijayabhaskara and Padi Pratap Reddyb
aResearch and Development, Dr. Reddy’s Laboratories Ltd., Hyderabad 500072, India
bResearch and Development, Macleods Pharmaceuticals Ltd., Andheri(E), Mumbai 400093, India
cDepartment of Chemistry, Institute of Science and Technology, J. N. T. University, Hyderabad 500072, India
Received July 30, 2011; Accepted September 21, 2011; Published Online October 4, 2011
A novel and efficient synthesis of dronedarone hydrochloride starting from 2-n-butyl-5-nitrobenzo-
furan by employing mild and selective reaction conditions is described. The synthetic approach is opera-
tionally simple and suitable for industrial application.
Keywords: Dronedarone; Cardiovascular; Hydrogenation; Benzofuran; Aroylation.
INTRODUCTION
Dronedarone HCl (Fig. 1),1 N-{2-Butyl-3-[4-(3-di-
the literature,3-6 a number of challenges and some disad-
vantages such as tedious reaction conditions, low yields,
use of toxic solvent, use of expensive reagents and column
chromatography purifications in the downstream process
still exist. Therefore, development of novel and efficient
synthetic strategy using inexpensive raw material and re-
agents that provides diverse access to the bioactive com-
pound 1 is an important goal. Herein, we report a new, con-
cise and efficient synthesis of dronedarone hydrochloride
(1) from 2-n-buty-5-nitro benzofuran (2) with readily avail-
able inexpensive raw material and reagents in good to ex-
cellent yields, which can be conveniently applied for indus-
trial scale synthesis.
butylaminopropoxy)benzoyl]benzofuran-5-yl} methane
sulfonamide hydrochloride, has been developed by Sanofi-
Aventis to overcome the use limiting iodine-associated ad-
verse effects of the commonly used antiarrhythmic drug
amiodarone.2 Dronedarone is a multi-channel blocker, in-
hibiting the potassium currents (including IK(Ach), IKur,
IKr, IKs) and has been shown to be effective in the treat-
ment of cardiovascular hospitalization in patients with par-
oxysmal or persistent atrial fibrillation (AF) or atrial flutter
(AFL). This drug is currently being marked under the brand
name of MULTAQ.
In recent years, extensive efforts have been made to-
wards the development of convenient and efficient synthe-
sis of dronedarone hydrochloride (1). The first total synthe-
sis of Dronedarone was reported by J. Gubin and co-work-
ers.1 Although few other synthesis have been reported in
RESULTS AND DISCUSSION
From a retrosynthetic analysis (Scheme I), compound
1 could be constructed from N,N-dibutylamine and N-(2-
Butyl-3-(4-(3-chloropropoxy)benzoyl)benzofuran-5-yl)-
methanesulfonamide (9), which in turn could be accessed
through new route from compound 2 and 3 via aroylation,
demethylation, O-alkylation, catalytic transfer hydrogena-
tion and mesylation.
The new synthesis of the target compound 1 was ac-
complished following the synthetic pathway described in
Scheme II. The incorporation of N,N-dibutylamine group
at the later stage of the synthesis provoked us to develop a
Fig. 1. Dronedarone hydrochloride.
* Corresponding author. E-mail: saravananm@drreddys.com; saravanan_jaishu@yahoo.com

842 J. Chin. Chem. Soc., Vol. 58, No. 7, 2011
Scheme I Retrosynthetic analysis of 1
Mohanarangam et al.
Scheme II
novel and efficient synthesis of 1. The first step of our syn-
thesis commenced from commercially available 2-n-butyl-
5-nitrobenzofuran (2), which was reacted with p-methoxy-
benzoyl chloride (3) in the presence of aluminium chloride
in dichloromethane at 25 oC for 4 h in a modification of lit-
erature procedure to furnish the 3-aroyl benzofuran deriva-
tive 4 in 88% yield.1 Subsequent demethylation of 4 was
also conducted in chlorobenzene in the presence of alu-
o
minium chloride at 85 C and gave the corresponding
demethylated derivative 5 in 92% yield. O-alkylation of
phenolic function7 in 5 with 1-bromo-3-chloropropane (6)
o
in the presence of potassium carbonate in DMF at 25 C
Reagents and conditions: (a) DCM, AlCl3, 25 oC, 4 h, 88%; (b)
Chlorobenzene, AlCl3, 85 oC, 4 h, 92%; (c) DMF, K2CO3, 25 oC,
yielded the chloroalkyl ether derivative 7 in 88.8% yield.
The usage of equimolar quantity of 6 led to more than 10%
of dimer impurity 10 (Fig. 2) as a result of competitive side
reaction of resulted product 7 with 5, however the forma-
tion of 10 was controlled to <0.5% using 4 mole equivalent
of 6.
o
20 h, 88.8%; (d) IPA, 10% Pd-C, HCOONH4, 50 C, 30 min,
94.2%; (e) DCM, NaHCO3, 35 oC, 6 h, 81%; (f) DMF,
N,N-dibutylamine, 125 oC, 4 h, EtOAc, 10% HCl in EtOAc, 25
oC, 2 h, 63%.
action conditions (reaction temperature, catalyst load, am-
monium formate quantity, reaction time and choice of sol-
vent) the best result was achieved by catalytic transfer hy-
drogenation of 7 in isopropyl alcohol with 7.5% load of
Pd-C (50% wet) with 6 equivalent of ammonium formate at
50 oC for 30 min to accomplish amine 8 in 94.2% yield with
<0.2% of 11.
The reduction of nitro to amine function using hydro-
gen gas and a metal catalyst is a reaction familiar to all or-
ganic chemists. We have utilized catalytic transfer hydro-
genation methodology8-11 for mild and selective reduction
of nitro function in 7 over the keto function by employing
Pd-C as catalyst and ammonium formate as hydrogen
source. N-formyl derivative 11 (Fig. 2) was observed as an
impurity in this reaction. With systematic screening of re-
In the next step, which involves mono mesylation of

A Novel and Efficient Synthesis of Dronedarone HCl
J. Chin. Chem. Soc., Vol. 58, No. 7, 2011 843
1
out further purification. The H NMR spectra were re-
corded on a Varian Mercury plus 400 MHz FT NMR spec-
trometer, the chemical shifts are reported on d ppm relative
to TMS. The 13C NMR spectra were recorded on a Varian
Mercury plus 200 MHz FT NMR spectrometer, the chemi-
cal shifts are reported on d ppm relative to CDCl3. The IR
spectra were recorded in the solid state as KBr dispersion
using Perkin Elmer FT-IR spectrometer. The mass spectra
were recorded on Shimadzu LCMS-QP8000 and Micro-
mass LCT Premier XE mass spectrometer.
(2-Butyl-5-nitrobenzofuran-3-yl)(4-methoxyphenyl)-
methanone (4)
Fig. 2. Structure of side products 10, 11 & 12.
To a solution of 2 (25 g, 0.114 mol) in dichloro-
methane (200 mL), was added aluminium chloride (19 g,
0.143 mol), p-methoxybenzoyl chloride (16.7 g, 0.125
mol) and reaction was maintained at 25 oC for 4 h. The re-
action mixture was quenched with water (100 mL) and lay-
ers were allowed to separate. The organic layer was washed
with water twice (50 mL each time) and concentrated under
reduced pressure to afford residue. Isopropyl alcohol (75
mL) was added to the residue and aged at 0 oC for 2 h. The
separated solid was filtered, washed with isopropyl alcohol
(25 mL) and dried at 70 oC to afford the title compound 4
(35.5 g, 88% yield, purity by HPLC 99.2%) as pale brown
solid. IR (KBr, cm-1) 1640 (C=O), 1525 & 1342 (NO2); 1H
NMR (400 MHz, CDCl3) d 8.3 (d, J = 2.0 Hz, 1H), 8.2 (dd,
J = 2.4, 8.8 Hz, 1H), 7.8 (dd, J = 2.0, 6.8 Hz, 2H), 7.5 (d, J =
8.8 Hz, 1H), 7.0 (dd, J = 2.0, 6.8 Hz, 2H), 3.9 (s, 3H), 2.9 (t,
J = 7.6 Hz, 2H), 1.7 (m, 2H), 1.3 (m, 2H), 0.91 (t, J = 7.2
Hz, 3H); MS (EI): m/z 354.1 (M+H)+.
8, it is observed that, the base used for the reaction plays
critical role in controlling obvious competitive dimesylated
product 12 (Fig. 2). We explored the mesylation reaction in
DCM as solvent using different organic and inorganic
bases. The usage of organic bases (TEA, DIPEA, Imida-
zole and DIPA) produced >20% 12, whereas exclusively
mono mesylated product was resulted using inorganic
bases. After conducting reactions with different inorganic
bases (NaHCO3, Na2CO3 and K2CO3), usage of sodium bi-
carbonate proved to be best. A combination of 1.5 equiva-
lent of sodium bicarbonate and 1.3 equivalent of methane
sulfonly chloride in DCM at 35 oC for 6 h provided the de-
sired mono mesyl derivative 9 in 81% yield with <0.30% of
dimesylate impurity 12. Finally in the last step, condensa-
tion of 9 with N,N-dibutylamine was screened with differ-
ent solvents such as isopropyl alcohol, acetonitrile, toluene
and DMF and different bases such as TEA, DBU, NaOH
and Na2CO3. Among the set of solvents and bases screened,
condensation of 9 with 3 equivalent of N,N-dibutylamine in
one volume of DMF at 125 oC for 4 h produced fruitful re-
sults, and yielded the drug substance dronedarone hydro-
chloride (1) as white crystalline powder in 63% yield, after
the usual downstream workup.
(2-Butyl-5-nitrobenzofuran-3-yl)(4-hydroxyphenyl)-
methanone (5)
To a solution of 4 (30 g, 0.084 mol) in chlorobenzene
(180 mL), was added aluminium chloride (28.3 g, 0.212
mol) and heated at 85 oC for 4 h. The reaction mixture was
o
allowed to cool to 60 C, quenched with water (120 mL)
o
then further cooled to 35 C. Dichloromethane (150 mL)
CONCLUSION
was added and aged for about 30 min then the layers were
allowed to separate. The organic layer was washed with
water (150 mL) and concentrated under reduced pressure
to a residue. Chlorobenzene (60 mL) was added to the resi-
due and aged at 0 oC for 2 h. The separated solid was fil-
tered, washed with chlorobenzene (15 mL) and dried at 65
oC to afford 5 (26.5 g, 92% yield, purity by HPLC 98.6%)
as pale brown solid. IR (KBr, cm-1) 3352 (OH), 1640
(C=O), 1525 & 1342 (NO2); 1H NMR (400 MHz, CDCl3) d
8.3 (d, J = 2.4 Hz, 1H), 8.2 (dd, J = 2.0, 8.8 Hz, 1H), 7.8
In conclusion, a new and highly efficient synthetic
approach to dronedarone hydrochloride (1) has been devel-
oped using commercially available raw materials and re-
agents. This approach provides an industrial viable proce-
dure for the synthesis of 1.
EXPERIMENTAL SECTION
General methods
All solvents and reagents were used as received with-

844 J. Chin. Chem. Soc., Vol. 58, No. 7, 2011
Mohanarangam et al.
(dd, J = 2.0, 6.8 Hz, 2H), 7.5 (d, J = 9.2 Hz, 1H), 6.9 (dd, J =
2.0, 6.8 Hz, 2H), 2.9 (t, J = 7.6 Hz, 2H), 1.7 (m, 2H), 1.3 (m,
2H), 0.90 (t, J = 7.2 Hz, 3H); MS (EI): m/z 339.1 (M+H)+.
(4-(3-Chloropropoxy)phenyl)(2-butyl-5-nitrobenzo-
furan-3-yl)methanone (7)
(ESI): (M+H)+ m/z calcd for C22H24ClNO3: 386.1523,
found: 386.1528.
N-(2-Butyl-3-(4-(3-chloropropoxy)benzoyl)benzofuran-
5-yl)methanesulfonamide (9)
To a solution of 8 (12 g, 0.031 mol) in dichloro-
methane (84 mL), was added sodium bicarbonate (4.2 g,
0.05 mol) and heated to 35 oC. Methane sulfonyl chloride
(2.5 mL, 0.032 mol) was added at 35 oC and aged at 35 oC
for 6 h. The reaction mixture was allowed to cool to 25 oC,
and quenched with water (72 mL). The mixture was aged
for about 30 min and then the layers were allowed to sepa-
rate. The organic layer was washed with saturated sodium
bicarbonate solution (72 mL) then with water (72 mL) and
concentrated under reduced pressure to a residue. To this
To a solution of 5 (20 g, 0.058 mol) in DMF (50 mL),
was added 6 (37.1 g, 0.23 mol) and potassium carbonate (8
g, 0.058 mol). The resulted solution was stirred at 25 oC for
20 h. Water (140 mL) and dichloromethane (150 mL) were
added and the mixture was aged for about 15 min and then
the layers were allowed to separate. The organic layer was
washed twice with water (100 mL each time), then with 2%
aqueous NaOH solution (100 mL) and water (100 mL). The
resulted organic layer was concentrated under reduced
pressure at 95 oC to afford 7 (21.8 g, 88.8% yield, purity by
HPLC 98.5%) as pale brown solid. IR (KBr, cm-1) 1631
(C=O), 1525 & 1348 (NO2); 1H NMR (400 MHz, CDCl3) d
8.3 (d, J = 2.0 Hz, 1H), 8.2 (dd, J = 2.4, 9.2 Hz, 1H), 7.8
(dd, J = 2.4, 7.2 Hz, 2H), 7.6 (d, J = 8.8 Hz, 1H), 6.9 (dd, J =
2.0, 6.8 Hz, 2H), 4.2 (t, J = 6.0 Hz, 2H), 3.8 (t, J = 6.4 Hz,
2H), 2.9 (t, J = 7.2 Hz, 2H), 2.3 (m, 2H), 1.8 (m, 2H), 1.3
(m, 2H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (200 MHz,
CDCl3) d 188.9, 167.1, 163.0, 156.2, 144.5, 131.6, 131.1,
127.8, 120.1, 117.6, 117.2, 114.4, 111.3, 64.6, 41.2, 32.0,
29.8, 27.9, 22.3, 13.6; MS (EI): m/z 416.1 (M+H)+; HRMS
(ESI): (M+H)+ m/z calcd for C22H22ClNO5: 416.1265,
found: 416.1267.
o
residue, n-hexane (100 mL) was added and aged at 25 C
for overnight to afford the title compound 9 (11.7 g, 81.0%
yield, purity by HPLC 96.8%) as cream colour solid. IR
(KBr, cm-1) 1625 (C=O), 3191 (sulfonamide NH); 1H NMR
(400 MHz, CDCl3) d 7.8 (dd, J = 2.0, 7.2 Hz, 2H), 7.4 (dd, J
= 0.8, 8.4 Hz, 1H), 7.25 (m, 2H), 6.9 (dd, J = 2.4, 7.4 Hz,
2H), 6.7 (br, s 1H), 4.2 (t, J = 6.0 Hz, 2H), 3.7 (t, J = 6.0 Hz,
2H), 2.9 (s, 3H), 2.8 (t, J = 7.6 Hz, 2H), 2.3 (m, 2H), 1.7 (m,
2H), 1.3 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR (200
MHz, CDCl3) d 190.1, 165.9, 162.8, 151.8, 132.3, 131.8,
131.6, 128.2, 120.0, 116.7, 115.5, 114.4, 111.8, 64.7, 41.2,
39.2, 32.1, 30.0, 28.0, 22.3, 13.6; MS (EI): m/z 464.1 (M+
H)+; HRMS (ESI): (M+H)+ m/z calcd for C23H26ClNO5S:
464.1298, found: 464.1307.
(4-(3-Chloropropoxy)phenyl)(5-amino-2-butylbenzo-
furan-3-yl)methanone (8)
N-{2-Butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]
benzofuran-5-yl}methanesulfonamide, hydrochloride
(1)
To a solution of 7 (19 g, 0.045 mol) in isopropyl alco-
hol (114 mL), was added 10% Pd-C (50% wet, 1.42 g, 7.5%
based on 7) and ammonium formate (17.3 g, 0.274 mol).
To a solution of 9 (5 g, 0.011 mol) in DMF (5 mL),
was added N,N-dibutylamine (4.2 g, 0.032 mol) and heated
at 125 oC for 4 h. The reaction mixture was allowed to cool
o
The reaction mixture was heated at 50 C for 30 min and
o
cooled to 25 C. Pd-C was filtered off from the reaction
o
mixture and the resulted filtrate was concentrated under re-
duced pressure to afford the title compound 8 (16.6 g,
94.2% yield, purity by HPLC 95.7%) as pale brown resi-
due. IR (KBr, cm-1) 1636 (C=O), 3367 & 3352 (NH2); 1H
NMR (400 MHz, CDCl3) d 7.8 (dd, J = 2.0, 6.8 Hz, 2H), 7.2
(d, J = 1.2 Hz, 1H), 6.9 (dd, J = 2.0, 8.4 Hz, 2H), 6.7 (m,
2H), 4.2 (t, J = 6.0 Hz, 2H), 3.7 (t, J = 6.0 Hz, 2H), 2.8 (t, J
= 7.6 Hz, 2H), 2.2 (m, 2H), 1.7 (m, 2H), 1.3 (m, 2H), 0.80
(t, J = 7.2 Hz, 3H); 13C NMR (200 MHz, CDCl3) d 190.6,
165.2, 162.4, 148.4, 141.4, 132.1, 131.9, 131.6, 127.9,
116.5, 114.1, 113.5, 111.2, 106.9, 64.5, 41.3, 32.1, 30.1,
27.9, 22.3, 13.7; MS (EI): m/z 386.1 (M+H)+; HRMS
to 25 C then water (25 mL) and toluene (25 mL) were
added. The layers were separated and organic layer was
washed twice with water (25 mL each time) and concen-
trated under reduced pressure to a residue. To this residue,
ethyl acetate (2´ 25 mL) was added and concentrated under
reduced pressure below 70 oC. The resulted residual prod-
uct was dissolved in ethyl acetate (50 mL) and treated with
10% HCl in ethyl acetate (6 mL) and aged at 25 oC for 2 h.
The separated solid was filtered, washed with ethyl acetate
(10 mL) and dried at 70 oC to afford the title compound 1
(5.3 g, 63% yield, purity by HPLC 99.4%) as white crystal-
line solid. IR (KBr, cm-1) 1637 (C=O), 3067 (sulfonamide

A Novel and Efficient Synthesis of Dronedarone HCl
J. Chin. Chem. Soc., Vol. 58, No. 7, 2011 845
NH); 1H NMR (400 MHz, CDCl3) d 8.0 (br, s, 1H), 7.77 (d,
J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 2.0,
8.5 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 8.5 Hz,
2H), 4.21 (t, J = 5.5 Hz, 2H), 3.26 (t, J = 8.0 Hz, 2H), 3.05
(m, 4H), 2.94 (t, J = 8.0 Hz, 2H), 2.90 (s, 3H), 2.41 (m, 2H),
1.77 (m, 8H), 1.40 (m, 6H), 0.97 (t, J = 7.5 Hz, 6H), 0.90 (t,
J = 7.5 Hz, 3H); 13C NMR (200 MHz, CDCl3) d 190.0,
166.4, 161.7, 151.5, 132.9, 132.0, 131.6, 127.7, 119.8,
116.6, 115.6, 114.3, 111.5, 64.8, 52.2, 50.2, 38.7, 30.0,
27.8, 24.9, 23.7, 22.3, 20.1, 13.7, 13.5; MS (EI): m/z 557.4
(M+H)+; Anal. Calc. for C31H45ClN2O5S: C, 62.76; H,
7.65; N, 4.72. Found: C, 62.81; H, 7.62; N, 4.74.
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