An investigation of the synthesis of vilazodone

Article abstract of DOI:10.1177/1747519819893293

A novel synthetic route toward vilazodone is described by using 4-cyanoaniline and 5-bromo-2-hydroxybenzaldehyde as starting materials, with an overall yield of 24% and 99% purity. First, the intermediate (3-(4-chlorobutyl)-1H-indole-5-carbonitrile) is synthesized via diazotization of 4-cyanoaniline, followed by Fischer indole cyclization with 6-chlorohexanal. Subsequently, another intermediate, 5-(piperazin-1-yl)benzofuran-2-carboxamide, is generated via aromatic nucleophilic substitution of 5-bromobenzofuran-2-carboxamide with piperazine. Finally, vilazodone is obtained via nucleophilic substitution of the above two key intermediates by treatment with Et₃N/K₂CO₃. In comparison to the original process, this route avoids the use of expensive and toxic reagents and resolves issues such as safety, environmental concerns, and high costs.

Full text of DOI:10.1177/1747519819893293

893293CHL0010.1177/1747519819893293Journal of Chemical ResearchHu and Su
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An investigation of the synthesis of vilazodone
https://doi.org/10.1177/1747519819893293
DOI: 10.1177/1747519819893293
journals.sagepub.com/home/chl
Fan Hu1 and Weike Su1,2
Abstract
A novel synthetic route toward vilazodone is described by using 4-cyanoaniline and 5-bromo-2-hydroxybenzaldehyde
as starting materials, with an overall yield of 24% and 99% purity. First, the intermediate (3-(4-chlorobutyl)-1H-indole-5-
carbonitrile) is synthesized via diazotization of 4-cyanoaniline, followed by Fischer indole cyclization with 6-chlorohexanal.
Subsequently, another intermediate, 5-(piperazin-1-yl)benzofuran-2-carboxamide, is generated via aromatic nucleophilic
substitution of 5-bromobenzofuran-2-carboxamide with piperazine. Finally, vilazodone is obtained via nucleophilic
substitution of the above two key intermediates by treatment with Et3N/K2CO3. In comparison to the original process,
this route avoids the use of expensive and toxic reagents and resolves issues such as safety, environmental concerns,
and high costs.
Keywords
cyclization, diazotization, nucleophilic substitution, synthetic route, vilazodone
Date received: 6 August 2019; accepted: 16 November 2019
toward compound 3 (Scheme 2). 5-Cyanoindole (1) was pro-
tected using TsCl to give compound 8, which was then
reacted with 4-chlorobutanoyl chloride under catalysis of
AlCl3 to afford compound 9 in 90% yield. Compound 9 was
reduced to compound 10 by treatment with NaBH4/
CF3COOH in 95% yield.3 Finally, 3-(4-chlorobutyl)-1H-in-
dole-5-carbonitrile (3) was obtained via hydrolysis of com-
pound 10. Vilazodone (7) was obtained via nucleophilic
Introduction
Vilazodone (7), a new type of antidepressant drug, is widely
used for the treatment of major depression in adults. To date,
several efficient methods for synthesis of vilazodone have
been reported. For example, in 2004, Timo Heinrich’s group
described a synthetic route for the preparation of vilazodone
by using 5-cyanoindole and 5-nitrobenzofuran-2-carboxam-
ide as starting materials, with an overall yield of 10%–20%
being obtained.1,2 First, 5-cyanoindole (1) was reacted with
substitution reaction of compounds 3 and 6, using the same
method as Tim Heinrich’s group.1–3
4-chlorobutanoyl chloride under catalysis by isobutyl-AlCl2
to afford the chloride 2, which was then reduced to
3-(4-chlorobutyl)-1H-indole-5-carbonitrile (3) by treatment
1Key Laboratory for Green Pharmaceutical Technologies and Related
Equipment of Ministry of Education, College of Pharmaceutical
Sciences, Zhejiang University of Technology, Hangzhou, P.R. China
2Collaborative Innovation Center of Yangtze River Delta Region Green
Pharmaceuticals, Zhejiang University of Technology, Hangzhou, P.R.
China
with 2-(methoxyethoxy)aluminum hydride. Subsequently,
5-nitrobenzofuran-2-carboxamide (4) was reduced to com-
pound 5 via hydrogenation with Pd/C and, then, further
transformed into 5-(piperazin-1-yl)benzofuran-2-carboxam-
ide (6) by reaction with bis(2-chloroethyl)amine. Vilazodone
(7) was finally obtained by through nucleophilic substitution
of compounds 3 and 6 with K2CO3/DMF (Scheme 1). This
synthetic route employed many expensive and toxic rea-
gents, leading to environmental and high cost issues.
Corresponding author:
Weike Su, Collaborative Innovation Center of Yangtze River Delta
Region Green Pharmaceuticals, Zhejiang University of Technology,
Hangzhou 310014, P.R. China.
Subsequently, Xu’s group provided another synthetic route Email: pharmlab@zjut.edu.cn

2
Journal of Chemical Research 00(0)
Scheme 1. Current synthesis of vilazodone (7).
Scheme 3. The retrosynthesis of vilazodone (7).
Scheme 2. Current optimal synthesis of 3-(4-chlorobutyl)-1H-
indole-5-carbonitrile (3).
Scheme 4. The efficient synthesis of the key intermediate 3.
The two above-mentioned synthetic routes both involve
environmentally unfriendly reagents,4,5 such as bis(2-chlo-
roethyl)amine and NaBH4. In addition, 5-cyanoindole (1)
and 5-nitrobenzofuran-2-carboxamide (4) were also dem-
onstrated to be expensive and difficult to synthesize.
Herein, we describe a novel synthetic route toward vilazo-
done (7) that is more suitable for industrial production. This
route is advantageous due to its low cost and high yield.
Scheme 5. The formation of by-product 20.
Results and discussion
obtained in 90% yield via reduction of 4-cyanoaniline
diazonium salt 17 with NaHSO3 at 85°C for 2h (Scheme 4).
However, there existed a problem in which a large quantity
of HCl (36.5%, triple the volume of the reaction solution)
was needed to salt out compound 11, which resulted in a lot
of waste acid. In order to solve this problem, the HCl was
recycled at least four times. The results indicated that the
yield of compound 11 using recycled HCl four times was
almost 80% and was reduced markedly after more than five
times (Figure 2).
Further, 6-chlorohexanal (12) could be obtained quite
conveniently from compound 18 in two steps by employing
SOCl2 and HCOOH and was isolated in a total yield of
85%. Compound 3 could be obtained via a Fischer reaction
between compound 11 and aldehyde 12. For the purpose of
increasing the yield of compound 3, a variety of parameters
such as the solvent, catalyst, temperature, and reaction time
were screened to determine the optimum reaction condi-
tion, and the results are summarized in Table 1. The experi-
mental results indicate that raising the reaction temperature
to 170°C led to a decrease in the yield, accompanied with
the formation of additional by-product, as detected by thin-
layer chromatography (TLC). Following this screening, it
was concluded that EtOH/H2O and 20% H2SO4 was a better
system to accomplish this Fischer transformation because
of the better yield (70%) and lower cost.9–12
A retrosynthesis of the new synthetic route is shown in
Scheme 3. Vilazodone (7) can be disconnected into interme-
diates 3 and 6. These intermediates 3 and 6 would give four
fragments a, b, c, and d, and these fragments can be discon-
nected into compounds 11, 12, 13, and 14. Compound 11
can be synthesized through diazotization and reduction of
amine 15, and compound 14 can be synthesized via cycliza-
tion of aromatic aldehyde 16 with BrCH2COOCH2CH3.
There have been several routes reported for synthesis of
compound 3.6–8 One of the most suitable routes, which was
developed by Xu’s group,3 employed 1H-indole-5-
carbonitrile (1) as the starting material. We have developed an
efficient synthetic route to prepare compound 3 (Scheme 4),
which is inexpensive and uses commercially available rea-
gents. First, because of the strong electron-withdrawing
substituent, it proved difficult to convert 4-aminobenzoni-
trile (15) into the corresponding salt with HCl. In order to
increase the yield of 4-cyanobenzenediazonium hydrochlo-
ride (17), 3 equiv. of HCl and 1.1 equiv. of NaNO2 were
required, and the extent of conversion of 4-aminobenzoni-
trile (15) was almost 90%. However, the by-product 20
(Scheme 5) was also observed during this process.9 To
decrease the formation of 20, the effect of the reaction tem-
perature on this reaction was investigated. Fortunately, it
was observed that increasing the reaction temperature
reduced the quantity of by-product 20, and a temperature of
2°C proved to be the best choice (Figure 1). Subsequently,
4-cyanophenylhydrazine hydrochloride (11) was easily
With compound 3 in hand, we next attempted to explore
an efficient route to synthesize carboxamide 6 by using

Hu and Su
3
(7) by employing 4-aminobenzonitrile and 5-bromo-2-
hydroxybenzaldehyde as starting materials. This novel syn-
thetic route involves diazotization, a Fischer reaction,
cyclization, and substitution to afford vilazodone in an
overall yield of 24% and with 99% purity. It is noteworthy
that the reagents and materials used in this synthetic route
are inexpensive, and the process should be suitable for
industrial production.
Experimental
Melting points were determined using a Buchi digital melt-
ing point apparatus and are uncorrected. 1H and 13C NMR
spectra were recorded on a Varian spectrometer at working
frequencies of 400 and 100MHz, respectively, in DMSO-d6
using tetramethylsilane (TMS) as an internal standard. All
chemical shifts are reported as δ values (ppm) relative to
TMS and observed coupling constants (J) are given in
Hertz (Hz). MS data were obtained on an instrument of
Agilent 6545 Q-TOF. All reagents were purchased from
commercial sources and used without prior purification.
Column chromatography was performed on silica gel (200–
300 mesh) eluting with n-hexane/ethyl acetate.
Figure 1. Change in the yield of by-product 20 based on the
reaction temperature during diazotization. Reaction conditions:
1 equiv. of 4-aminobenzonitrile, 3 equiv. of HCl, 1.1 equiv. of
NaNO2, 1h.
4-Hydrazinylbenzonitrile
hydrochloride
(11):
4-Aminobenzonitrile (118g, 1.0mol) was dissolved in
hydrochloric acid (36.5%, 300g, 3.0mol in 500mL of
H2O). NaNO2 (79.5g, 1.1mol) and H2O (200mL) were
added into the solution slowly for 1h at 2°C. Then, reaction
mixture was filtered, and the residue was dried for 12h and
identified as by-product 20 (12.3g). The filtrate was trans-
ferred to a new vessel and NaHSO3 (520g, 5.0mol) was
added, and the mixture was stirred at 85°C for 2h. After
filtering, the filtrate was distilled to remove one-third of the
solvent, and then, 36.5% HCl (1L) was added to the residue
solution. After stirring at 50°C for 30min, the mixture was
filtered, and the product was obtained as a white solid.
Yield 137g (81%). High-performance liquid chromatogra-
phy (HPLC) purity 94.2%. m.p. 238.8–240.5°C. (Lit17
Figure 2. Change in the yield of compound 11 with recycled
times of HCl during salting out. Recycled HCl was used directly
without any purification.
5-bromo-2-hydroxybenzaldehyde (16) as the starting material
(Scheme 6). Initially, acid 21 was easily prepared via conden-
sation between compound 16 and ethyl 2-bromoacetate and
was isolated in an excellent yield (90%).13,14 The piperazine
moiety can be easily introduced through a C–N cross-coupling
reaction under basic conditions to give the intermediate 22.
Although the yield of 22 was not satisfactory, we found that
any unconverted compound 21 could be easily recycled. After
the reaction, HCl was added to the reaction solution, and the
unreacted compound 21 was salted out, while the intermediate
22 stayed in the reaction solution. Finally, intermediate 22 was
transformed into carboxamide 6 in 80% yield by treatment
with SOCl2 and NH3 (two steps without isolation).15,16
Subsequently, vilazodone (7) was prepared via nucleo-
philic substitution between chloride 3 and carboxamide 6
(Scheme 7). The experimental results indicated that the
Et3N/K2CO3 system was very effective for this transforma-
tion, and the desired product vilazodone (7) was obtained in
65% yield.1
1
240°C). H NMR (400MHz, D2O): δ 7.54–7.32 (m, 2H),
6.93–6.83 (m, 2H), 4.67 (s, 1H), 3.33 (s, 2H). 13C NMR
(100MHz, D2O): δ 158.7, 134.6, 134.6, 122.3, 114.5, 114.5,
103.3. HRMS (ESI): m/z [M+H]+ calculated for
C7H8ClN3: 170.0480, found: 170.0477.
3-(4-Chlorobutyl)-1H-indole-5-carbonitrile
(3):
Compound 11 (169g, 1mol) was dissolved in EtOH/H2O
(1:1, 100mL), and then, 20% H2SO4 (20mL) and 6-chlo-
rohexanal 12 (134g, 1.0mol) were added. The mixture was
stirred at 80°C for 4h. After the reaction was complete, the
aqueous was extracted with CH2Cl2. The combined CH2Cl2
fractions were evaporated to afford product 3 as a milky-
white solid. Yield 162g (70%), 97% purity. m.p. 97.6–
99.5°C. (Lit1 99–99.5°C) 1H NMR (400MHz, DMSO-d6):
δ 11.38 (s, 1H), 8.08 (s, 1H), 7.55–7.25 (m, 3H), 3.67 (t,
J=6.1Hz, 2H), 2.75 (t, J=6.7Hz, 2H), 1.77 (dd, J=6.3,
3.1Hz, 4H). 13C NMR (100MHz, DMSO-d6): δ 137.8,
127.2, 124.8, 124.5, 123.2, 120.7, 117.1, 111.9, 102.2, 44.9,
32.4, 27.3, 24.2. HRMS (ESI): m/z [M+Na]+ calculated
for C13H13ClN2: 255.0659, found: 255.0657.
Conclusion
In conclusion, we have developed an efficient and poten-
5-Bromobenzofuran-2-carboxylic acid (21): 5-Bromo-2-
tially commercial process for the synthesis of vilazodone hydroxybenzaldehyde (16) (201g, 1.0mol) was dissolved in

4
Journal of Chemical Research 00(0)
Table 1. Optimization of the Fischer indole reaction in the synthesis of compound 3.
Entry
Solvent
Catalyst
Temperature (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
n-butanol/H2O
n-butanol/H2O
n-butanol/H2O
n-butanol/H2O
Ethylene glycol/H2O
Ethylene glycol/H2O
Ethylene glycol/H2O
Ethylene glycol/H2O
20% CH3COOH
36.5% HCl
20% H2SO4
10% TFA
20% CH3COOH
36.5% HCl
20% H2SO4
10% TFA
20% CH3COOH
36.5% HCl
20% H2SO4
10% TFA
80
80
80
4
4
4
4
4
4
4
4
2
2
2
2
–
35
70
68
–
34
65
68
–
80
110
110
110
110
170
170
170
170
9
10
11
12
23
47
51
NMR (400MHz, DMSO-d6): δ 10.58 (s, 1H), 8.19–7.28
(m, 4H), 3.02 (d, J=4.2Hz, 4H), 2.86 (s, 4H), 2.51 (s, 1H).
13C NMR (100MHz, DMSO-d6): δ 159.6, 149.6, 148.2,
126.8, 117.9, 110.9, 109.6, 107.7, 107.3, 52.3(2), 45.5(2).
HRMS (ESI): m/z [M+H]+ calculated for C13H14N2O3:
247.1077, found: 247.1080.
5-(Piperazin-1-yl)benzofuran-2-carboxamide
(6):
Compound 22 (246g, 1.0mol) was dissolved in
ClCH2CH2Cl, and SOCl2 (119g, 1mol) was added slowly
to the solution and the resulting mixture was stirred at 60°C
for 4h. After filtration, the solid was dissolved in tetrahy-
drofuran (THF) (1L), and then, NH3 gas (0.3MPa in high-
pressure reactor) was poured into the solution. The resulting
mixture was stirred at 25°C for 30min. After the reaction
was complete, the mixture was concentrated under vacuum
to provide the product 6. Yield 196g (80%) with 97%
Scheme 6. The efficient synthesis of key intermediate 6.
1
purity. m.p. 251.3–254.3°C. (Lit19 253–255°C). H NMR
Scheme 7. Synthesis of vilazodone (7).
(400MHz, DMSO-d6): δ 8.19–7.28 (m, 4H), 7.15 (d,
J=6.6Hz, 2H), 3.02 (d, J=4.2Hz, 4H), 2.86 (s, 4H), 2.51
(s, 1H). 13C NMR (100MHz, DMSO-d6): δ 159.9, 149.2,
148.6, 127.5, 117.9, 111.4, 109.6, 107.3, 107.2, 51.0(2),
45.71, 45.7. HRMS (ESI): m/z [M+H]+ calculated for
C13H15N3O2: 246.1237, found: 246.1245.
ethyl acetate (1L), and then, BrCH2COOCH2CH3 (334g,
2mol) and K2CO3 (410g, 3mol) were added. The mixture
was stirred and refluxed for 6h. After the reaction was com-
plete, the liquid was filtered and the filtrate was concen-
trated under vacuum. KOH (84g, 1.5mol) and H2O (500mL)
were added to the residue, and the resulting mixture was
stirred at 80°C for 3h. Subsequently, HCl (3molL−1) was
added to adjust the pH to 2. After filtration, the product 21
was obtained as a white solid. Yield 217g (90%) with 94%
purity. m.p. 255.5–256.8°C. 1HNMR(400MHz, DMSO-d6):
δ 13.64 (s, 1H), 7.95 (d, J=1.9Hz, 1H), 7.77–7.46 (m, 3H).
13C NMR (100MHz, DMSO-d6): δ 159.4, 153.0, 146.9,
129.9, 128.8, 125.1, 115.8, 114.0, 112.5. HRMS (ESI): m/z
[M+H]+ calculated for C9H5BrO3: 240.9495, found:
240.9490.
5-(Piperazin-1-yl)benzofuran-2-carboxylic acid (22):
Compound 21 (241g, 1.0mol) and piperazine (430g, 5mol)
were dissolved in dimethylformamide (DMF), and the mix-
ture was stirred at 140°C for 6h. After the reaction was
complete, HCl (10molL−1, 500mL) was added. After filtra-
tion, KOH/H2O was added into the filtrate until pH 6–7.
The solution was extracted with CH2Cl2, and then, the
organic phase was concentrated under vacuum to obtain
product 22 as a faint yellow solid. Yield 221g (90%) with
95% purity. m.p. 275–278.2°C. (Lit18 274–276°C). 1H
Vilazodone (7): Compound 3 (233g, 1.0mol) and 6
(245g, 1.0mol) were dissolved in acetonitrile (3L), and
then, triethylamine (101g, 1.0mol) and K2CO3 (138g,
1.0mol) were added to the solution. The mixture was heated
at reflux for 12h. Subsequently, the reaction mixture was
poured into cold water (3L). After filtration, the solid was
dissolved in EtOAc, and then, HCl-EtOAc saturated solu-
tion was added to enable crystallization. Product 7 was
obtained as a white solid. Yield 287g (65%) with 99%
HPLC purity after the mixture was filtered. m.p. 276.5–
279.2°C (Lit1 277–279°C). 1H NMR (400MHz, DMSO-d6):
δ 11.35 (s, 1H), 8.04 (d, J=18.3Hz, 2H), 7.74–6.88 (m,
8H), 3.69–3.15 (m, 8H), 2.74 (t, J=7.2Hz, 2H), 2.37 (t,
J=7.2Hz, 2H), 1.80–1.61 (m, 2H), 1.54 (d, J=6.8Hz, 2H).
13C NMR (100MHz, DMSO-d6): δ 159.9, 148.8, 147.9,
138.6, 137.7, 127.8, 126.9, 124.7, 124.0, 123.3, 120.9,
117.8, 115.7, 112.4, 111.6, 109.5, 107.3, 100.0, 57.5,
52.8(2), 49.8(2), 27.7, 26.1, 24.1. HRMS (ESI): m/z
[M+H]+ calculated for C26H27N5O2: 442.2238, found:
442.2240.

Hu and Su
5
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Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
8. Ma YQ, Zhang B and Zhang G. Zhongguo Yaowu Huaxue
Zazhi 2013; 23: 292–294.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
study was supported by the National Natural Science Foundation
of China (21406200) and the Collaborative Innovation Center of
Yangtze River Delta Region Green Pharmaceuticals.
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