Organic Process Research & Development
Article
Preparation of 3-[4-(3-Chloro propoxy)benzoyl] 2-n-
Butyl Benzofuran-5-yl-1H-isoindole-1,3 (2H) Dione (14).
Eaton’s reagent was prepared by adding P2O5 (2.78 kg 19.58
mol) portionwise to methane sulfonic acid (10.6 L) under
nitrogen atmosphere and stirred for 30 min at 25 to 35 °C. To
this intermediate, 13 (1.76 kg 8.22 mol) was added and allowed
to stir for 15 min, then phthalimido derivative 12 (2.5 kg, 7.83
mol) was charged and stirred for 1 h at 35 °C. After complete
consumption of the starting material, the reaction was
quenched by pouring reaction mass into a mixture of water
(25.0 L) and DCM (5.0 L) below 15 °C and layers were
separated. The organic layer was washed twice with 5% sodium
bicarbonate solution (10.0 L), followed by a water wash (10.0
L). DCM was distilled off, the residue was slurred with
methanol (20.0 L), and the solids were filtered, washed with
methanol (5.0 L), and dried at below 45 °C to furnish chloro
compound 14 (3.07 kg, 76%).
Preparation of Dronedarone Hydrochloride (2).
Dioxalate salt 16 (3.0 kg, 4.55 mol) was added portionwise
into the stirred mixture of water (9.0 L), DCM (9.0 L), and
sodium bicarbonate (1.7 kg, 20.24 mol). The suspension was
stirred for 30 min. Inorganic solids were filtered and layers were
separated. The organic layer containing precursor free amine
was washed with water (2 × 6.0 L). DCM was distilled out. To
this crude residue, toluene (9.0 L) was added, followed by
triethyl amine (690 g, 6.83 mol), and cooled to −5 °C.
Methane sulfonyl chloride (548 g, 4.78 mol) was added
dropwise at −5 to 5 °C and stirred for 30 min. Reaction mass
was quenched by adding 5.0% aqueous sodium bicarbonate
solution (9.0 L) and layers were separated and washed with
water (6.0 L). Toluene was distilled out and the residue was
stirred with a mixture of DCM (9.0 L), concentrated
hydrochloric acid (1 L) ,and water (9.0 L) for 30 min. After
layer separation, the organic layer was washed with water (2 ×
6.0 L). DCM was distilled out and to the residue mixture of
ethyl acetate and isopropyl alcohol (30.0 L, 9:1) was added and
stirred at 25 °C for 4 h. The reaction mixture was cooled to 5
°C and stirred for 2 h. The precipitated solids were filtered to
afford dronedarone hydrochloride crude (2.0 kg, 75%).
Recrystallisation of crude dronedarone hydrochloride from
acetone results in pure dronedarone hydrochloride with purity
more than 99.5% by HPLC and any individual impurity less
than 0.10% (1.62 kg, 60%).
1
Mp: 109 °C; m/z: 516.1 (M + H)+; H NMR (400 MHz,
CDCl3): δ 0.90 (t, J = 7.4 Hz, 3H), 1.32−1.41 (m, 2H), 1.73−
1.80 (m, 2H), 2.24−2.29 (m, 2H), 2.95 (t, J = 7.5 Hz, 2H),
3.75 (t, J = 6.3 Hz, 2H), 4.20 (t, J = 5.8 Hz, 2H), 6.97 (d, J =
8.8 Hz, 2H), 7.29 (dd, J = 8.7 Hz, 2.1 Hz, 1H), 7.38 (d, J = 2.1
Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.76−7.78 (m, 2H), 7.85 (d,
J = 8.8 Hz, 2H), 7.86−7.94 (m, 2H). 13C NMR(100 MHz,
CDCl3):13.55, 22.16, 27.70, 29.93, 31.88, 41.15, 64.38, 111.40,
114.15, 116.75, 120.11, 123.15, 123.47, 126.98, 127.66, 131.49,
131.57, 134.15, 152.65, 162.47, 165.90, 167.22, 189.46. Anal.
Calcd for C30H26ClNO5: C, 69.83; H, 5.08; N, 2.71. Found: C,
70.08; H, 5.09; N, 2.72.
1
Mp: 143 °C; m/z: 557.3 (M + H)+; H NMR (400 MHz,
CDCl3): δ 0.90 (t, J = 7.4 Hz, 3H), 0.98 (t, J = 7.3 Hz, 6H),
1.34−1.45 (m, 6H), 1.72−1.84 (m, 6H), 2.38−2.45 (m, 2H),
2.91 (s, 3H), 2.96 (t, J = 7.7 Hz, 2H), 3.03−3.07 (m, 4H),
3.22−3.27 (m, 2H), 4.24 (t, J = 5.4 Hz, 2H), 6.93 (d, J = 8.8
Hz, 2H), 7.18 (d, J = 2.1 Hz, 1H), 7.31 (dd, J = 2.1 Hz, 8.8 Hz,
1H), 7.42 (d, J = 8.8 Hz, 1H), 7.66 (s, 1H) 7.78 (d, J = 8.8 Hz,
2H), 11.93 (s, 1H); 13C NMR(100 MHz, CDCl3): 13.23,
13.35, 19.70, 21.95, 23.32, 24.75, 27.57, 29.67, 38.15, 49.84,
52.08, 64.72, 111.12, 113.99, 115.18, 116.38, 119.75, 127.42,
131.30, 131.50, 133.06, 151.14, 161.77, 165.55, 189.79. Anal.
Calcd for C31H45ClNO5S: C, 62.77; H, 7.56; N, 4.72; S, 5.40.
Found: C, 62.83; H, 7.46; N, 4.91; S, 5.60.
Preparation of 5-Amino-3-[4-(3-di-n-butyl amino
propoxy)benzoyl] 2-n-Butyl Benzofuran Dioxalate (16).
Chloro compound 14 (3.0 kg, 5.81 mol), potassium iodide
(0.97 kg, 5.84 mol), tetra n-butyl ammonium bromide (150 g,
0.46 mol), di-n-butyl amine (1.5 kg, 11.63 mol), and dimethyl
formamide (4.5 L) were heated to 85 °C for 14 h. The reaction
mixture was cooled to 25 °C, and water (18.0 L) and DCM
(6.0 L) were added. Layers were separated, and the organic
layer was sequentially washed with 2.0 N hydrochloric acid (6.0
L) and water (2 × 15.0 L) followed by saturated sodium
bicarbonate solution (7.5 L). DCM was distilled completely to
afford amine 15 as oil. Isopropyl alcohol (12.0 L) followed by
methylamine 40% aqueous solution (3.0 L) was added and the
mixture was heated for 1 h at 75 °C. The reaction mixture was
concentrated under vacuum. The residue was diluted with
isopropyl alcohol (15.0 L) and oxalic acid dihydrate (1.47 kg,
11.63 mol) was added and stirred at 65 °C for 30 min. The
reaction mixture was cooled to 5 °C and stirred for 1 h. The
precipitated solids were filtered and washed with isopropyl
alcohol (3.0 L) followed by acetone (3.0 L) and dried at 50 °C
to furnish dioxalate salt 16 (3.15 kg, 82%).
ASSOCIATED CONTENT
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S
* Supporting Information
1H and 13C NMR spectra. This material is available free of
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
1
Mp: 170 °C; m/z: 479.3 (M + H)+; H NMR (400 MHz,
DMSO-d6): δ 0.79 (t, J = 7.4 Hz, 3H), 0.91 (t, J = 7.4 Hz, 6H),
1.19−1.24 (m, 2H), 1.28−1.37 (m, 4H), 1.57−1.65 (m, 6H),
2.12−2.18 (m, 2H), 2.72 (t, J = 7.5 Hz, 2H), 3.04−3.09 (m,
4H), 3.20−3.24 (m, 2H), 4.17 (t, J = 5.9 Hz, 2H), 6.53 (d, J =
2.0 Hz, 1H), 6.59 (dd, J = 8.7 Hz, 2.2 Hz, 1H), 7.08 (d, J = 8.8
ACKNOWLEDGMENTS
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We thank Dr. Mukund K. Gurjar, Mr. Samit Mehta, our
management and ARD group of Emcure Pharmaceuticals Ltd.
for their generous support and constant encouragement.
Hz, 2H), 7.27 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H); 13
C
REFERENCES
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NMR(100 MHz, DMSO_d6): 13.63, 13.73, 19.64, 21.85,
23.16, 25.17, 27.44, 29.75, 49.07, 52.05, 65.39, 107.01, 111.55,
114.73, 116.46, 127.61, 131.59, 131.65, 141.06, 148.03, 162.35,
163.68, 164.22, 190.10. Anal. Calcd for C34H46N2O11: C, 61.99;
H, 7.04; N, 4.25. Found: C, 61.91; H, 7.15; N, 4.41.
(1) Patel, P. B.; Patel, K. C.; Mehta, H. R. Int. Res. J. Pharm. 2011, 2
(3), 59−65.
(2) Patel, P. D.; Bhuriya, R.; Patel, D. D.; Arora, B. L.; Singh, P. P.;
Arora, R. R. Vasc. Health Risk Manage. 2009, 5, 635−642.
(3) Dobromir, D.; Stanley, N. Lancet 2010, 375, 1212−1223.
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dx.doi.org/10.1021/op300017v | Org. Process Res. Dev. 2012, 16, 677−681