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