Organic Process Research & Development
Article
Scheme 8. Way of Hydroxyl Substitution
the mixture is poured into 0.5 M HCl (4 L). After stirring for an
additional 1 h to room temperature, the organic layer was
separated, dried, and evaporated in vacuo to obtain a colorless
oily liquid (91.6 g per 52 min in the flow device, yield 92.3%).
4-(2-(6-Hydroxyhexylidene) Hydrazinyl) Benzonitrile
(13). To a stirred solution of 4-cyanophenyl hydrazine
hydrochloride (2.42 kg, 14.27 mol) in EtOH (15 L)/water
(12 L) at 25 °C was added a solution of 10 (2.0 kg, 17.22 mol) in
EtOH (4 L). The pH was adjusted to 3.5 with 3 M NaOH. After
stirring at the same temperature for 2 h, the reaction mixture was
adjusted to pH 10 with 3 M NaOH and concentrated in vacuo to
remove most of EtOH. The residual two-phase mixture was
extracted with ethyl acetate, dried, and evaporated to obtain an
orange oil. The crude product is recrystallized from n-heptane
(3.29 kg, yield 99.1%). HPLC: 98.93%.13
4-(2-(6-Chlorohexylidene) Hydrazinyl) Benzonitrile
(14). Thionyl chloride (1.23 kg, 10.34 mol) and triethylamine
(1.312 kg, 12.97 mol) were added to the solution of 13 (2 kg,
8.65 mol) in dichloromethane (15 L). The reaction was carried
out at room temperature for 12 h. The reaction solution was
poured into water (20 L), the organic layers were separated, the
aqueous layer was extracted with dichloromethane, dried, and
evaporated to obtain a yellow oily liquid (2.0 kg, yield 93.2%),
which was carried on directly to the next step without any
purification. HPLC: 98.77%.
Figure 1. Selection of chlorinated reagents.
3-(4-Chlorobutyl)-1H-indole-5-carbonitrile (15). 85%
phosphoric acid (6.46 kg, 56 mol) was charged to 14 (2 kg,
8.0 mol) in toluene (16 L), and the reaction mixture was heated
to 100 °C for 1.5 h. After cooling to room temperature, the
organic layer was separated, extracted with ethyl acetate, dried,
and the solvent was evaporated to obtain a yellow oily liquid,
which was recrystallized from ethanol to obtain a light yellow
solid 15 (1.53 kg, yield 82.0%). HPLC: 99.2%.
Figure 2. Investigation of indole synthesis reaction conditions.
Table 3. Scale-Up Synthesis of Vilazodone
Vilazodone Hydrochloride. A mixture of 15 (2 kg, 8.6
mol), 16 (2.1 kg, 8.6 mol), K2CO3 (2.38 kg, 17.2 mol), TEA
(1.74 kg, 17.2 mol), and acetonitrile (30 L) was heated to 82 °C
for 16 h and cooled. The solvent was evaporated, water (30 L)
was added, extracted with ethyl acetate, dried, and the solvent
was evaporated to obtain a light-yellow oily liquid (3.42 kg, yield
90.0%), which was dissolved in isopropanol (20 L), and HCl-
saturated ethyl acetate solution is added until precipitation is
complete (pH = 2−3). The obtained crystals were recrystallized
with methanol−ethanol (v/v = 1:1) and dried to obtain
colorless crystals of vilazodone hydrochloride (3.3 kg, yield
entry
scale/kg
yield/%
purity/%
1
2
3
2
2
3
56.2
55.9
56.4
99.93
99.93
99.87
NMR spectrometer using TMS as the internal standard. Product
purities were determined by high-performance liquid chroma-
tography (HPLC) conducted on an Agilent 1100 system using a
reverse-phase C18 column, and MeOH−H2O was used as the
mobile phase.
6-Hydroxyhexanal (10). ε-Caprolactone (9) is introduced
into a microreactor by pump A (0.8 mol/L in dichloromethane,
21 mL/min). DIBAL-H is introduced into the microreactor by
pump B (1.0 M solution in hexane, 20 mL/min). The two are
mixed by a T-shaped mixer and then allowed to react in the
microreactor; the residence time is 2 min and the reaction
temperature is −25 °C. After the reaction, the solution flows into
methanol (1.2 L) from the discharge port per 52 min, and then
1
89.3%). HPLC: 99.93% H NMR (600 MHz, DMSO-d6): δ
11.47 (s, 1H), 8.08 (s, 1H), 8.05 (s, 1H), 7.60 (s, 1H), 7.51 (d, J
= 8.4 Hz, 1H), 7.46 (d, J = 9.1 Hz, 1H), 7.42 (s, 1H), 7.39 (d, J =
2.6 Hz, 1H), 7.34 (s, 1H), 7.16 (d, J = 10.6 Hz, 2H), 3.29−3.17
(m, 2H), 3.10 (t, J = 4.8 Hz, 4H), 3.03 (t, J = 5.0 Hz, 1H), 2.87 (t,
J = 4.9 Hz, 1H), 2.74 (t, J = 7.5 Hz, 2H), 2.37 (t, J = 7.3 Hz, 2H),
1.68 (t, J = 7.6 Hz, 2H), 1.53 (t, J = 7.5 Hz, 2H). 13C NMR (150
MHz, DMSO-d6): δ 160.3, 149.9, 149.5, 148.8, 138.4, 128.1,
E
Org. Process Res. Dev. XXXX, XXX, XXX−XXX