SYNTHESIS OF CARVEDILOL IMPURITIES
91
=
C C), 1253 (C-N stretching), 1124, 1053 (C-O stretching), 743, 715 (Ar-H aromatic
1
bending); HNMR (CDCl3, 300 MHz, d ppm): 8.3 (d, 1H), 7.5 (t, 1H), 7.4 (t, 1H),
7.35 (d, 1H), 7.2 (t, 1H), 6.8–7 (m, 4H), 6.7 (d, 1H), 4.4 (t, 2H), 4.3 (t, 2H), 4.25
(t, 2H), 4.17 (t, 2H), 3.81 (s, 3H), 3.05 (m, 1H), 3.0 (t, 2H), 2.85 (m, 1H); 13CNMR
(CDCl3, 300 MHz, d ppm): 149, 148.1, 142.3, 140.1, 26.5, 124.8, 122.9, 122.1, 121.6,
20.8, 119.4, 111.8, 14.2, 114.0, 108.5, 102.4, 77.3, 68.9, 55.8, 52.5, 51.9, 48.7, 48.4
mass (MþþH) 630.6.
Benzyl-[2-(2-methoxy-phenoxy)ethyl]amine (13)
Triethylamine (6.05 g, 0.06 mol) was added to a solution of benzyl bromide
(4.09 g, 0.024 mol) in toluene (15 mL) and cooled to 0 ꢃC. A solution of compound 9
(5 g, 0.03 mol) in toluene (10 mL) was added slowly at the same temperature and
allowed to reach 25 ꢃC. The reaction mixture was maintained at room temperature
for 8 h. Water (25 mL) was added to the reaction mass and stirred for 15 min. The
layers were separated, and the organic layer was washed with water (15 mL) and dried
over sodium sulfate. The solvent was distilled off completely under reduced pressure
to obtain benzyl-[2-(2-methoxy-phenoxy)-ethyl]-amine 13 as residue. Yield: 3.2 g.
(2RS)1-[Benzyl[2(2-methoxyphenoxy)ethylamino]-3-(9H-carbazol-
4-yloxy)propan-2-ol (Imp-IV)
Compound 8 (1.5, 0.006 mol) was added to a solution of compound 13 (3.2 g,
0.012 mol) in monoglyme (3 mL), and the contents were heated to 75 ꢃC. The reac-
tion mixture was maintained at 75 ꢃC for 6 h. The solvent was distilled off completely
under reduced pressure below 65 ꢃC to obtain the residue, which was solidified by
triturating with ethyl acetate (10 mL). The compound was filtered and washed with
ethyl acetate to afford (2RS)-1-[benzyl [2(2-methoxyphenoxy)ethyl]amino]-3-
(9H-carbazol-4-yloxy)propan-2-ol (Imp-IV) as an off-white solid. Yield: 2.63 g,
85%;IR (KBr, cmꢂ1): 3404 (O-H stretching), 2836, 2873 (C-H aliphatic), 1589,
=
1506 (aromatic C C), 1254 (C-N stretching), 1123, 1102, 1026 (C-O stretching),
1
741, 726 (Ar-H Aromatic bending); HNMR (CDCl3, 300 MHz, d ppm): 8.21 (d,
J ¼ 7.8 Hz, 1H), 8.09 (s, br, 1H exchanged with D2O), 7.4–7.3 (m, 3H), 7.3–7.2 (m,
3H), 6.89–6.87 (m, 1H), 6.86–6.84 (m, 1H), 6.82 (d, J ¼ 2.4, 1H), 6.59 (d, J ¼ 7.8 Hz,
1H), 4.3–4.2 (m, 1H), 4.1 (t, 5.4 Hz, 2H), 4.1 (s, 2H), 3.92 (d, J ¼ 13.5 Hz, 2H), 3.80
(s, 3H),3.74 (d, J ¼ 10.5 Hz, 2H), 3.15 (t, J ¼ 6 Hz, 2H); 13CNMR (CDCl3, 300 MHz,
d ppm): 155.2, 149.5, 148.2, 140.9, 138.7, 128.9, 128.4, 127.2, 126.6, 124.8, 122.9,
122.5, 120.7, 119.6, 113.2, 112.6, 111.6, 109.9, 103.6, 101.1, 70.2, 67.2, 67.1, 59.7,
57.9, 55.7, 53.2; mass (Mþ þH) 497.3.
1-(2-Bromo-ethoxy)-2-methoxy-benzene 15
Potassium carbonate (83.5 g, 0.6 mol) was added to a solution of 2-methoxy
phenol (25 g, 0.2 mol) in acetone (125 mL) and stirred at room temperature for
15 min. 1,2-Dibromoethane (189.2 g, 1.0 mol) was added, and the contents were
heated to 55 ꢃC and maintained at the same temperature for 10 h. The solvent was
distilled off completely under reduced pressure. The residue was partitioned between