Organic Process Research & Development
Communication
Table 5. PMI, e-factor, and atom economy of the developed process without recovery
process
overall yield
theoretical PMI
actual PMI
aq PMI
solvent PMI
e-factor
atom economy
present process
65.56
33.82
4.15
4.15
4.66
52.16
72.87
39.31
422
77.25
504.7
56
U.S. Pat. 5,223,510
11.22
39.33
HPLC Method for Calculating the Chemical Purity and
Assay of the Compounds. Related substances and assay of
dronedarone hydrochloride were estimated by a gradient
HPLC analysis method developed at Megafine using an
Ascentis Express C18 column (4.6 cm × 10 cm i.d., particle
size 2.7 μm) column; mobile phase A comprising a mixture of
buffer (5 mM ammonium dihydrogen orthophosphate) and
methanol in the ratio of 80:20 v/v; mobile phase B comprising
a mixture of acetonitrile/methanol/water in the ratio 45:45:10
Preparation of Dronedarone Hydrochloride (1). Raney
nickel (0.56 kg) was added to a solution of 9 (4.491 kg, 8.8
mol) in 2-methyl tetrahydrofuran (27.0 L). The reaction
mixture was maintained at 60−65 °C for 3−5 h under 5 kg/m2
pressure of hydrogen in the autoclave. After completion of the
reaction, the catalyst was filtered off through a Celite bed, and
the bed was washed with 2-methyl tetrahydrofuran (4.50 L).
The filtrate obtained was taken ahead as such for the acylation
reaction. [HPLC purity of compound 10 in filtrate: 99.12%.]
Pyridine (1.04 kg, 13.22 mol) and a solution of methanesulfo-
nylchloride (1.311 kg, 11.44 mol) in 2-methyl tetrahydrofuran
(2.25 L) were added to the filtrate at 0−5 °C. The reaction
mass was maintained at 0−5 °C for 3−5 h. After completion of
the reaction, the reaction mass was washed with a 10% aqueous
solution of hydrochloric acid (22.5 L × 2 times) followed by
washing with water (22.5 L). The organic layer was distilled off
azeotropically to remove water content (around 10%) using
Dean−Stark apparatus (approximately 3.20 L of water
removed) at 70−80 °C till less than 1.0% of moisture was
achieved in the organic layer. The mixture was cooled to 0−5
°C for 2 h, and precipitated dronedarone hydrochloride (1)
was filtered and washed with 2-methyl tetrahydrofuran (4.50
L). HPLC Purity: 99.68%; Wet dronedarone hydrochloride
was dissolved in isopropyl alcohol (30.0 L) at 60−65 °C until
the clear solution was obtained. The resulted clear solution was
cooled at 0−5 °C, and the slurry was stirred for 90−120 min at
0−5 °C. The obtained solid was filtered, washed with chilled
isopropyl alcohol (2.0 L), and dried under vacuum (700 mm/
Hg) for 4−5 h at 50−55 °C to get pure dronedarone
hydrochloride (1) as an off-white solid. Yield: 3.87 kg (73.9%);
Melting point: 140−142 °C (Lit.2 141−143 °C) MS: m/z:
557.2 (M+ + 1). 1H NMR (DMSO): δ 7.39 (d, 1 H), 7.31 (dd,
1 H), 7.18 (d, 1 H), 2.9 (t, 2 H), 2.38 (m, 2 H), 1.36 (m, 6 H),
0.88 (t, 3 H), 7.9 (s, 1 H), 7.75 (dt, 2 H), 6.9 (dt, 2H), 2.8 (s,
3H), 4.19 (t, 2H), 3.24 (t, 2H), 1.69−1.81 (m, 6H), 3.03 (m,
4H), 0.948 (t, 6H). 13C NMR (CDCl3): δ 165.9, 119.9, 131.7,
151.35, 116.5, 115.5, 133.13, 111.34, 23.51, 29.9, 22.18, 13.56,
189.8, 127.6, 131.5, 114.13, 161.82, 38.39, 64.80, 27.73, 50.06,
52.15, 24.84, 19.93, 13.56. Elemental analysis: C, 62.62; H,
7.71; N, 4.76; S, 5.55. Purity by HPLC: 99.79%. Residual
solvent by GC HS (ppm): Toluene: not detected; 2-methyl
tetrahydrofuran: 4; isopropyl alcohol: 2741, dichloromethane:
not detected, pyridine: not detected. Nickel content in API:
0.34 ppm (by induced coupled-plasma optical emission
spectroscopy [ICP-OES] as per USP, chapter ⟨233⟩: Elemental
impurities - procedures).
v/v/v; gradient elution: time (min)/A (v/v): B (v/v); T0.01
65:35, T7.0/45:55, T17.0/45:55, T24.0/30:70, T28.0/30:70, T29.0
/
/
65:35, T35.0/65:35; flow rate 1.2 mL/min; column temperature
35 °C; wavelength 220 nm. The observed retention time of
dronedarone under these chromatographic conditions is about
11.9 min
Preparation of 2-n-Butyl 3-(4-hydroxybenzoyl)-5-
nitrobenzofuran (7). Anisoyl chloride (5, 1.626 kg, 9.53
mol) was added to a solution of 2-n-butyl 5-nitrobenzofuran (4
1.5 kg, 6.84 mol) and anhydrous aluminium chloride (0.456 kg,
3.41 mol) in DCM (6.0 L). The mixture was stirred for 22 h at
25−30 °C. The reaction mixture was chilled and poured slowly
into chilled water (15.0 L) maintaining the temperature below
15 °C and extracted with DCM (1.5 L). The obtained DCM
layer was washed with water (3.0 L), followed by a 5% solution
of NaHCO3 (3.0 L) and subjected for deprotection reaction
[HPLC purity of compound 6 in DCM layer: 95.0%].
Anhydrous aluminium chloride (3.39 kg, 25.45 mol) was
added lot-wise to a DCM layer at 25−30 °C; the reaction
mixture was heated and maintained at reflux temperature for 40
h. The reaction mixture was cooled to 25−30 °C and poured
into ice-chilled water (30.0 L), maintaining the temperature
below 15 °C. The DCM layer was separated, washed with water
(15.0 L), and concentrated to give residue which was further
crystallized using n-heptane (12.0 L) to obtain 7 as a light-
brown solid. Yield: 2.02 kg (87.6%). Melting point: 120−122
°C (Lit.2 121 °C). MS m/z: 338.0 (M+ + 1). 1H NMR
(CDCl3): δ 7.55 (d, 1 H), 8.22 (dd, 1 H), 8.31 (d, 1 H), 2.91
(t, 2 H), 1.75 (m, 2 H), 1.35 (m, 2H), 0.888 (t, 3 H), 7.77 (dd,
2H), 6.93 (dd, 2H). Purity by HPLC: 98.56.
P r e p a r a t i o n o f 2 - n - B u t y l 3 [ 4 - ( 3 - D i - n -
butylaminopropoxy)benzoyl]-5-nitrobenzofuran (9). Po-
tassium carbonate (1.22 kg, 8.8 mol) was added to a solution of
7 (3.0 kg, 8.8 mols) in toluene (21.0 L). The mixture was
stirred for 30 min at 25−30 °C and heated to 105−110 °C
followed by addition of 1-chloro 3-di-n-butylamino propane (8,
1.9 kg, 9.23 mol) at reflux temperature. The reaction mixture
was maintained at reflux temperature for 7−9 h until
completion of the reaction. The reaction mixture was cooled
to 25−30 °C, inorganic solid was filtered and washed with
toluene (3.0 L). Filtrate was collected and concentrated under
reduced pressure to obtain 9 as transferable syrup. Yield: 4.49
AUTHOR INFORMATION
■
Corresponding Author
*Telephone: +91 2557 250121 or +91 9822581611. Fax: +91
1
kg (99.5%). MS m/z: 508.6 (M+ + 1). H NMR (CDCl3): δ
7.91 (d, 1 H), 8.24 (m, 2 H), 2.82 (t, 2 H), 1.66 (q, 2 H), 1.22
(m, 6 H), 0.79 (t, 9H), 7.8 (d, 2 H), 7.09 (d, 2H), 4.12 (t, 2H),
1.82 (m, 2H), 2.49 (m, 2H), 2.32 (t, 4H), 1.32 (m, 4H), 1.22
(m, 4H), 0.79 (t, 6H). Purity by HPLC: 99.50%.
Notes
†Megafine Publication Number MF/014/2013.
The authors declare no competing financial interest.
E
dx.doi.org/10.1021/op400008e | Org. Process Res. Dev. XXXX, XXX, XXX−XXX