ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
209
instrument. The HPLC analysis data was reported in area per cent, not adjusted to
weight, using an Agilent 1100 instrument.
Ethyl (S)-4-{4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine} butyrate 4
The potassium carbonate was crushed by a grinder to obtain a fine powder, as noted in
Table 1. In a 30 L reactor, acetone (9.5 L) was placed, and 2 (1.90 kg, 6.27 mol), 3
(1.35 kg, 6.92 mol) and potassium carbonate (1.04 kg, 7.53 mol) were added with stirring.
The mixture was heated to reflux and stirred. When TLC indicated the reaction was
complete (10 hr), the mixture was cooled to 30 ꢀC and vacuum filtered. The filter cake
was washed with acetone. The mother liquor was concentrated under reduced pressure
1
to obtain intermediate 4, 2.62 kg, 99.9%, light yellow viscous liquid. H-NMR DMSO-
d6, 500 MHz)d 1.17 (t, 3H, J ¼ 7.1Hz), 1.5 (br, 2H), 1.67 (m, 2H), 1.82 (m, 2H), 2.02
(m, 2H), 2.26 (m, 4H), 2.64 (br, 2H), 3.49 (br, 1H), 4.04 (dd, 2H, J ¼ 7.1Hz, 7.1Hz),
5.66 (s, 1H), 7.25 (t, 1H, J ¼ 5.6Hz), 7.36 (d, 2H, J ¼ 8.4Hz), 7.42 (d, 2H, J ¼ 8.4Hz),
7.55 (d, 1H, J ¼ 7.9Hz), 7.79 (t, 1H, J ¼ 7.7Hz), 8.48 (d, 1H, J ¼ 4.3Hz); 13C-NMR
(DMSO-d6, 300 MHz) d 172.68, 161.49, 148.66, 140.89, 136.87, 136.83, 128.52
(2 ꢁ C), 128.04 (2 ꢁ C), 122.42, 120.22, 79.83, 72.92, 59.50, 56.67, 50.44 (2 ꢁ C), 31.45,
31.09 (2 ꢁ C), 21.89, 13.98. MS (M þ H): Calcd for C23H29ClN2O3, m/z 417.1.
Found, m/z 416.19.
Synthesis of (S)-4-{4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine} butyric acid
5 and preparation of crude bepotastine besilate 1
To a 30 L reactor was added ethanol (13 L), 4 (2.60 kg, 6.24 mol), sodium hydroxide
(0.50 kg 12.48 mol) and water (2.6 L). The mixture was stirred at 25 ꢀC for 1h. Then
benzene sulfonic acid (1.97 kg, 12.48 mol) in ethanol (2.6 L) was added and stirred for
45 min. The mixture was concentrated at 50 ꢀC under reduced pressure until no further
liquid could be removed. Acetonitrile (2.6 L) was added and the mixture was then con-
centrated at 55 ꢀC under reduced pressure until no further liquid could be removed.
Acetonitrile (13 L) was added and the mixture was stirred for 2 hours. The mixture was
vacuum filtered and the filter cake was washed with acetonitrile (7.8 L). Benzene sul-
fonic acid (0.89 kg, 5.62 mol) was added to the mother liquor, which was heated to
80 ꢀC and stirred for 0.5 h. The mixture was filtered and the filter cake was discarded.
The mother liquor was cooled and crystallized, then centrifuged and washed with aceto-
nitrile. The resulting solid was dried in vacuum at 45 ꢀC to obtain crude 1, 2.37 kg,
1
69.5%, white powder with a purity of 99.9%. H-NMR DMSO-d6, 500 MHz, cf. refer-
ence 10)d 1.86 (m, 6H), 2.31 (t, 2H), 3.07 (br, 3H), 3.27 (br, 3H), 3.68 (br, 1H), 5.70
(d, 1H), 7.32 (m, 4H), 7.40 (m, 4H), 7.64 (m, 3H), 7.82 (t, 1H, J ¼ 7.6 Hz), 8.48 (d, 1H,
J ¼ 4.4 Hz), 12.00 (br, 2H); 13C-NMR(DMSO-d6, 300 MHz)d 173.29, 161.42, 149.36,
148.22, 140.91, 137.65, 132.61, 129.28 (2 ꢁ C), 129.20 (2 ꢁ C), 128.74 (2 ꢁ C), 128.26,
125.95 (2 ꢁ C), 123.21, 120.98, 80.69, 70.68, 55.36, 49.01 (2 ꢁ C), 31.04, 28.25 (2 ꢁ C),
19.61. MS (M þ H): Calcd for C21H25ClN2O3ꢂC6H6O3S, m/z 389.2. Found, m/
z 388.16 þ 158.00.