Organic Process Research & Development
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as N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-
benzofuran-5-yl)formamide.
(ppm) relative to TMS as internal standard. 13C and DEPT
spectra were recorded on Varian Mercury plus 200 MHz FT-
NMR using CDCl3 as a solvent; the chemical shifts are
reported in δ (ppm) relative to CDCl3 as internal standard.
FT-IR Spectroscopy. The IR spectra were recorded in the
solid state as KBr powder dispersions using a Spectrum-One
FT-IR spectrometer (PerkinElmer, Boston, MA, USA).
Synthesis of Impurities. Synthesis of Impurity I. Impurity
I is the intermediate of Dronedarone, and it was prepared as per
the synthesis shown in Scheme 1. The presence of this impurity
was confirmed by coinjection with Dronedarone in the HPLC.
Synthesis of Impurity II. To a stirred solution of impurity I
(6.0 g, 0.012 mol) and chloroform (60 mL) was added
triethylamine (10.2 mL, 0.10 mol), and the resulting reaction
mixture was heated to 55 °C. Methanesulfonyl chloride (1.8
mL, 0.03 mol) was added at 55 °C, and the reaction mixture
was stirred for 1.5 h. The reaction mixture was allowed to cool
to 25−35 °C, followed by quenching with saturated aqueous
sodium bicarbonate solution (48 mL). The layers were
separated, followed by concentrating the organic layer to
dryness in vacuo. The residual product thus obtained was
purified through column chromatography using ethyl acetate
and hexanes (1:4, v/v) as eluent to afford impurity II with
98.7% purity and 80% yield.
Synthesis of Impurity III. To a stirred solution of impurity I
(10.0 g, 0.015 mol) and dichloromethane (70 mL) was added
sodium bicarbonate (2.55 mL, 0.03 mol), and the resulting
reaction mixture was heated to 37 °C. Chloromethanesulfonyl
chloride (1.6 mL, 0.03 mol) was added at 37 °C and stirred for
4 h. The reaction mixture was allowed to cool to 25−35 °C and
then quenched with saturated aqueous sodium bicarbonate
solution (60 mL). The layers were separated, and the organic
layer thus obtained was concentrated to dryness in vacuo. To
the resulting residual product was added hexane (100 mL), and
the resulting mixture was stirred at 25 °C for 8−10 h. The
separated product was filtered and dried under vacuum at 35
°C to afford impurity III with 96.0% purity and 82.6% yield.
Synthesis of Impurity IV. Impurity IV is a lower analogue of
Dronedarone, and it was prepared from 2-n-propyl-5-nitro-
benzofuran instead of 2-n-butyl-5-nitrobenzofuran as per the
synthesis shown in Scheme 1.
Synthesis of Impurity V. To a stirred solution of impurity I
(10 g, 0.02 mol) and toluene (50 mL) was added formic acid
(1.4 mL, 0.03 mol), and the reaction mixture was heated to
reflux for 3 h. The reaction mixture was allowed to cool to 25
°C followed by washing with water (50 mL) and then
concentration to dryness to afford impurity V with 95.3% purity
and 91.0% yield.
Synthesis of Impurity VI. To a stirred solution of impurity I
(3.6 g, 0.007 mol) and isopropanol (36 mL) was added 1-
chloro-3-di-n-butylaminopropane (1.7 g, 0.008 mol) and
potassium carbonate (1.0 g, 0.008 mol). The resulting reaction
mixture was heated at 75 °C for 12−14 h and then allowed to
cool to 25 °C. The undissolved material was filtered off,
followed by concentration of the filtrate mother liquors to
dryness in vacuo. The residual product thus obtained was
purified through column chromatography using ethyl acetate
and hexanes (1:4, v/v) as eluent to afford impurity VI with
90.2% purity and 98.5% yield.
Structure Elucidation of Impurity VI. The ESI-MS
spectrum of the impurity VI exhibited a protonated molecule
peak at m/z 648.7 (M + H)+ in positive ion mode, indicating
the molecular mass of this impurity to be 647.7, which is 91
amu more than that of impurity I. In the IR spectrum of this
impurity, only one weak absorption peak appeared at 3423
cm−1 instead of two weak absorption peaks in impurity I. This
suggested that the aromatic amine group could be mono-
alkylated with 1-chloro-3-di-n-butylaminopropane. Also, its
molecular weight is matched well with the protonated
molecular mass observed in the ESI mass spectrum, and this
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was further substantiated by the H NMR, 13C NMR, and
DEPT spectra. Based on the synthetic methodology and the
above spectral data, the molecular formula of impurity VI could
be deduced as C41H65N3O3 and the corresponding structure
was characterized as (2-butyl-5-((3-(dibutylamino)propyl)-
amino)benzofuran-3-yl)(4-(3-(dibutylamino)propoxy)phenyl)-
methanone.
EXPERIMENTAL SECTION
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Materials and Reagents. The investigated sample,
Dronedarone hydrochloride, was synthesized at DRL research
and development centre, IPDO, Dr. Reddy’s Laboratories Ltd.,
A.P., India. HPLC grade acetonitrile, potassium dihydrogen
phosphate, tetrabutylammonium hydrogen sulfate, and tri-
fluoroacetic acid used in the analysis were purchased from
Merck, Mumbai, India. Water used for preparing the mobile
phase was purified using a Millipore milli-Q plus (Milford, MA,
USA) purification system. NMR solvent CDCl3 was purchased
from Cambridge Isotope Laboratories Inc., MA, USA. Formic
acid, methanesulfonyl chloride, chloromethanesulfonyl chlor-
ide, and triethylamine used for the synthesis of impurities were
purchased from Sigma-Aldrich, Hyderabad, India.
High Performance Liquid Chromatography (HPLC).
An in-house HPLC method was developed for the analysis of
Dronedarone and its potential impurities (Agilent series 1100
with empower software, G1312A binary pump, G1314A
variable wavelength detector, Waldbronn, Germany), where a
column Inertsil C8-3 (150 mm × 4.6 mm, 3 μm) with a mobile
phase consisting of A: 1.36 g of KH2PO4 and 3.39 g of TBAHS
in 1000 mL of MQ water, B: acetonitrile and water (9:1, v/v),
with a timed gradient program of T/%B: 0/35, 5/35, 15/40,
30/45, 35/50, 40/80, 45/90, 52/90, 54/35, 60/35 with a flow
rate of 0.8 mL/min and UV detection at 288 nm was used. This
HPLC method was able to detect all the impurities.
Liquid Chromatography−Mass Spectrometry (LC-
MS). An in-house LC-MS method was developed for the
analysis of Dronedarone and its potential impurities, where a
column Inertsil C8-3 (150 mm × 4.6 mm, 3.5 μm) with a
mobile phase consisting of A: 1.0 mL TFA in 1000 mL water,
B: 1.0 mL TFA in acetonitrile and water (9:1, v/v), with a
timed gradient program of T/%B: 0/35, 5/35, 15/40, 30/45,
35/50, 40/80, 45/90, 52/90, 54/35, 60/35 with a flow rate of
0.8 mL/min and UV detection at 288 nm was used. This LC-
MS method was able to detect all the impurities.
Mass Spectrometry. The mass spectra were recorded on
Schimadzu LCMS-QP8000 and Micromass LCT Premier XE
mass spectrometers.
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CONCLUSION
The process-related impurities (impurities I−VI) in the
Dronedarone hydrochloride bulk drug were identified,
NMR Spectroscopy. The H NMR spectra were recorded
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on a Varian Mercury plus 400 MHz FT-NMR spectrometer
using CDCl3 as a solvent; the chemical shifts are reported in δ
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dx.doi.org/10.1021/op400190b | Org. Process Res. Dev. 2014, 18, 157−162