ALTERNATIVE SYNTHESIS OF BILASTINE
1401
Methyl 2-(4-(2-(4-(1-(2-Ethoxyethyl)-1H-benzo[d]imidazol-2-
yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate (17)
A solution of 16 (0.92 g, 3.38 mmol) in DMF (5 mL) was treated with 13
(1.22 g, 4.06 mmol) and DIPEA (1.31 g, 10.1 mmol). The reaction was heated at
80 ꢀC for 16 h. The reaction mixture was diluted with brine and extracted with
EtOAc. The organic layer was dried over Na2SO4 and evaporated. The residue
was purified by flash chromatography (Redisep silica gel, 19:1 CH2Cl2=MeOH) to
afford 17 (1.01 g, 62% yield) as a brown oil: 1H NMR (300 MHz, CDCl3) d
7.78–7.72 (m, 1H), 7.34–7.30 (m, 1H), 7.29–7.17 (m, 6H), 4.36 (t, J ¼ 5.4 Hz, 2H),
3.73 (t, J ¼ 5.4 Hz, 2H), 3.65 (s, 3H), 3.43 (q, J ¼ 6.9 Hz, 2H), 3.16 (d, J ¼ 5.1 Hz,
2H), 3.0–2.97 (m, 1H), 2.84–2.79 (m, 2H), 2.66–2.61 (m, 2H), 2.25–2.10 (m, 4H),
2.04 (bs, 2H), 1.57 (s, 6H), 1.13 (t, J ¼ 6.9 Hz, 3H). HRMS (EI): m=z calcd. for
C29H39N3O3: 447.2991. Found: 447.2978.
2-(4-(2-(4-(1-(2-Ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-
yl)ethyl)phenyl)-2-methylpropanoic acid (1): Bilastine
A solution of 17 (170 mg, 0.36 mmol) in 10 mL MeOH=THF=H2O (1:2:2) was
treated with LiOH (15 mg, 0.63 mmol) and heated at 70 ꢀC for 16 h. The reaction
mixture was acidified with 1 M HCl and extracted with EtOAc. The organic layer
was dried over Na2SO4 and evaporated. The residue was purified by flash chroma-
tography (Redisep silica gel, 9:1 CH2Cl2=MeOH) to afford 1 (106 mg, 64% yield)
as a yellow solid: 1H NMR (300 MHz, CD3OD) d 7.63–7.49 (m, 2H), 7.39 (d,
J ¼ 8.1 Hz, 2H) 7.30–7.21 (m, 2H), 7.18 (d, J ¼ 8.1 Hz, 2H), 4.50 (t, J ¼ 4.8 Hz,
2H), 3.77 (t, J ¼ 4.8 Hz, 2H), 3.58 (d, J ¼ 12.3 Hz, 2H), 3.43 (q, J ¼ 6.9 Hz, 3H),
3.12–3.07 (m, 2H), 2.97–2.82 (m, 4H), 2.28–2.17 (m, 4H), 1.51 (s, 6H), 1.08 (t,
J ¼ 6.9 Hz, 3H).
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