Novel commercial scale synthetic approach for 5-cyanoindole: A potential intermediate for vilazodone hydrochloride, an antidepressant drug

Article abstract of DOI:10.14233/ajchem.2020.22717

Present work describes the synthesis of 5-cyanoindole, a common intermediate used in various synthetic route of the antidepressant vilazodone hydrochloride. The protocol is both robust and commercially viable, utilizing readily available and low-cost materials and the isomers are environmental friendly than previously reported routes through its evading use of cyanide reagents and heavy metals.

Full text of DOI:10.14233/ajchem.2020.22717

Asian Journal of Chemistry; Vol. 32, No. 10 (2020), 2460-2462
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2020.22717
Novel Commercial Scale Synthetic Approach for 5-Cyanoindole: A Potential
Intermediate for Vilazodone Hydrochloride, an Antidepressant Drug
1,*,
1,2
1
3
4
M. VENKATANARAYANA
, RAVI NUCHU , H. SHARATH BABU , GANGA SRAVANTHI GARREPALLI and SUDHAKAR TANGALLAPALL
1Department of Chemistry, GITAM School of Science, GITAM (Deemed to be University), Hyderabad-502329, India
2Mylan Laboratories Ltd, Bollaram Industrial Area, Hyderabad-502325, India
3Trinity College Pharmacy, Peddapalli-505172, India
4Department of Chemistry, Kakatiya Institute of Technology & Science, Warangal-506015, India
*Corresponding author: E-mail: vmuvvala2@gitam.edu
Received: 11 March 2020;
Accepted: 15 May 2020;
Published online: 25 September 2020;
AJC-20053
Present work describes the synthesis of 5-cyanoindole, a common intermediate used in various synthetic route of the antidepressant
vilazodone hydrochloride. The protocol is both robust and commercially viable, utilizing readily available and low-cost materials and the
isomers are environmental friendly than previously reported routes through its evading use of cyanide reagents and heavy metals.
Keywords: 5-Cyanoindole, Vilazodone hydrochloride, Ring closer reaction.
In this work, a systematic and robust process for the synth-
esis of 5-cyanoindole (1) by using inexpensive staring material
3-methyl-4-nitrobenzoic acid (6), which was converted to 3-
methyl-4-nitrobenzonitrile (4) [11]. From here ring closer
reaction was developed by modifying of Leimgruber-Batcho
protocol [5]. This approach is a robust, economically viable
and environmental free synthetic path.
INTRODUCTION
Heterocyclic compounds play a pivotal role in chemistry
due to their prevalence in natural and synthetic drug scaffolds
with significant pharmacological activity [1-3]. In particular,
the wide range of applications of substituted indole motifs
has drawn considerable attention due to their remarkable prop-
erties and prevalence in natural products. However, formation
of substituted indoles presents a significant challenge on comm-
ercial scale due to the use of harsh conditions, toxic reagents
and non-trivial starting materials. Many synthetic routes have
been reported for the synthesis of the indole ring such as the
classical Fisher-Indole synthesis [4], Leimgruber-Batcho indole
synthesis [5], various transition-metal-catalyzed syntheses and
multisteps one-pot synthesis [6-8] (Scheme-I).
A key starting material for synthesis of vilazodone hydro-
chloride is 5-cyanoindole (1) [9]. The present industrial and
commercial scale synthesis of 5-cyanoindole (1) involves conv-
ersion from 5-bromoindole (5) via various synthetic methods
that typically employ toxic chemicals such as CuCN, Zn(CN)2
and NaCN [6-8]. Because of this, conversion of 5-bromoindole
(5) to 5-cyanoindole (1) is a tedious process and not recom-
mended due to economical and environmental factors [10].
EXPERIMENTAL
Synthesis of 3-methyl-4-nitrobenzamide (7): 3-Methyl-
4-nitrobenzoic acid (6) (9 Kg) was charged with thionyl chloride
(18 L) and dimethyl formamide (90 mL). The mixture was heated
to reflux and maintained for 3 h. The progress of the reaction
was monitored by TLC. The reaction mixture was cooled to
below 25 ºC and aqueous NH3 solution (90 L) was added. The
mixture stirred at room temperature for 2 h. The precipitated
solid was collected by filtration, washed with water (9.0 L)
and dried at 50 ºC for 8 h to afford 3-methyl-4-nitrobenzamide
(7) (8.2 Kg). m.p. 148-150 ºC. Yield (theor./obtained): 0.99/
0.911 w/w (92%). 1H NMR (400 MHz, CDCl3, δ ppm): 2.51 (s,
3H), 7.62 (br, 1H), 7.84 (d, 1H, d, J = 8.2), 7.92 (s, 1H), 8.01
(d, 1H, J = 8.2), 8.19 (br, 1H); 13C NMR (100 MHz, CDCl3, δ
ppm): 19.79 (CH3), 124.81 (CH), 126.69 (CH), 132.30 (CH),
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Vol. 32, No. 10 (2020)
Novel Commercial Scale Synthetic Approach for 5-Cyanoindole 2461
NC
The mixture was cooled to 0 ºC and added iron lot wise at 0 ºC,
the reaction mixture heated again to 50-55 ºC for 8 h and the
progress of the reaction was monitored by TLC. The reaction
mixture was cooled to room temperature, filtered the reaction
mass and washed with methanol (3 × 3 L). The organic layer
was concentrated, charged with ethyl acetate (135 L) and stirred
at room temperature for 3 h. The precipitated solid was colle-
cted by filtration, washed with n-hexane (13 L) and dried at
50 ºC for 6 h to afford 5-cyanoindole (1) (Scheme-II). Yield
Br
NHNH2
2
N
H
5
[Ref. 9]
[Ref. 9]
Br
Pd/C, Zn(CN)2
NC
NC
DMF-DMA
[Ref. 5]
N
H
N
H
NO2
[Ref. 5]
[Ref. 6]
[Ref. 6]
1
5
4
1
(theor./obtained): 0.0876/0.841 w/w (96%). H NMR (400
CpRuCl(PPh3)2
[Ref. 7]
[Ref. 7]
MHz, CDCl3, δ ppm): 8.67 (br, 1H), 7.99 (s, 1H), 7.50-7.40
(m, 2H), 7.36-7.32 (m, 1H), 6.67-6.60 (m, 1H); 13C NMR (100
MHz, CDCl3, δ ppm); 137.59, 127.76, 126.58, 126.52, 124.97,
120.98, 112.12, 103.54, 102.88.
NC
NH2
3
RESULTS AND DISCUSSION
Scheme-I: Previously reported synthetic methods for 5-cyanoindole
The synthesis was initiated with commercially available,
starting with low-cost material such as 3-methyl-4-nitrobenzoic
acid (6) treated with thionyl chloride and catalytic amount of
DMF (to improve the rate of the reaction) under reflux condition
afforded the corresponding acid chloride, which was immedia-
tely converted to amide 7 by using aqueous NH3 in good yield.
The next following key challenging ring closer reaction was
performed by Leimgruber-Batcho protocol. Unfortunately, this
method was unsuccessful probably, the presence of free amide
group cause the ring closed reaction (TLC showed multiple spots).
To avoid this issue, amide 7 was converted into cyano func-
tional group by dehydration method with POCl3 under reflux
condition to furnish compound 4 in good yield. The POCl3 is
an expensive chemical and not recommended for the industrials
scale. However, thionyl chloride was used as dehydrating agent
instead of POCl3, which is a low-cost and commercially feasible
for large scale synthesis. This generation of cyanide function-
ality 4 worked effectively by using thionyl chloride.
After successful synthesis of compound 4, first ring closer
reaction was attempted with DMF-DMA and stoichiometric
ratio of pyrrolidine was used as an additive. The resulting
reaction mixture was heated at 55 ºC furnished an uncyclized
intermediate was isolated (not shown), which was reduced with
Na2S2O4 and MeOH at 50 ºC provided desired compound 1 in
low yield (Table-1, entry-1) [5]. During the reaction, the reducing
agent Na2S2O4 was not completely dissolved in MeOH which
133.02 (C), 138.62 (C), 150.83 (C), 166.65 (C); ESI: m/z calcd.
for C8H9O3N2+: 181.0613; found 181.0665.
Synthesis of 3-methyl-4-nitrobenzonitrile (4): 3-Methyl-
4-nitrobenzamide (7) (8.2 Kg) was dissolved in toluene (8.2 L)
and thionyl chloride (8.2 L). The mixture was heated to reflux
and maintained for 5-6 h. The progress of the reaction was
monitored by TLC. The reaction mixture was cooled to below
50 ºC and concentrated under reduced pressure. The resultant
residue was dissolved in toluene (33 L) and washed with 5%
sodium bicarbonate solution (2 × 8 L). The organic layer was
concentrated, charged with hexane (18 L) and stirred at room
temperature for 2-3 h. The precipitated solid was collected by
filtration, washed with n-hexane (4 L) and dried at 50 ºC for 5
to 6 h to afford 3-methyl-4nitrobenzonitrile (4, 7.5 Kg).Yield
1
(theor./obtained): 0.90/0.768 w/w (85.33%). H NMR (400
MHz, CDCl3, δ ppm): 8.10 (d, 1H, J = 8.5), 7.69-7.69 (m,
2H), 2.62 (s, 3H); 13C NMR (100 MHz, CDCl3, δ ppm); 152.6,
137.6, 134.5, 130.6, 125.2, 117.0, 116.7, 20.0
Synthesis of 5-cyanoindole (1): 3-Methyl-4-nitrobenzo-
nitrile (4) (6.3 Kg) was dissolved in methylene dichloride (14
L) and N,N-dimethylformamide dimethyl acetal (18 L). The
mixture was heated to 50-55 ºC and maintained for 8 h. The
progress of the reaction was monitored by TLC. The reaction
mixture was concentrated under reduced pressure at below 50
ºC and charged with methanol (90 L) and acetic acid (61 L).
O
i) SOCl2
Reflux
NC
H2NOC
POCl3
HO
Toluene
(82.7%)
ii) NH3
NO2
NO2
NO2
7
(91.5 %)
4
6
i) DMF-DMA
Pyrrolidine
ii) Fe/AcOH
(96%)
DMF-DMA
Pyrrolidine
NC
NC
N
H
N
H
1
1
Scheme-II: Novel synthetic strategy for 5-cyanoindole

2462 Venkatanarayana et al.
Asian J. Chem.
resulted in the poor yield. To overcome the solubility problem,
reaction was performed with pre-dissolved reducing agent was
used in combination of MeOH and water to obtained compound
1 in moderate yield. The little improvement has been observed
(Table-1, entry-2). The next tuned by changing the different
solvents, such as dioxane, THF with various combination of
water (Table-1, entries-3, 4 and 5). However, did not observe
any significant improvement in yield of 5-cyanoindole (1).
Further evaluation of this reaction by tuning the solvent and
temperatures effect in ring closer reaction.
After successfully identification of the suitable reducing
agent, reactions were attempted in large scale with different
stoichiometric ratio of iron and AcOH (Table-1, entries 14-
17) [5,9]. During the addition of iron, highly exothermic has
been observed and the reaction was completed in 1 h at room
temperature (100 g scale reaction). It is also found that temp-
erature also plays a factor to improve the yield of 5-cyano-
indole. Reaction was tuned with lot wise addition of Fe at 0 ºC
to room temperature for 8 h provided lower the yield (Table-1,
entry 18). The addition of Fe at 0 ºC and raised the temperature
at 50-55 ºC for 8 h obtained in an excellent yield. Finally, we
have evaluated the best method for the ring closer reaction of
compound 1. Three batches in 5 kg level and same reaction
conditions as (Table-1, entry -17) in lab scale synthesis were
applied. The reproducibility of the yield was successfully
achieved (Table-1, entry 19-21) in all the three batches.
TABLE-1
OPTIMIZATION OF REACTION CONDITIONS
FOR RING CLOSER via MODIFICATION OF
LEIMGRUBER-BATCHOS PROTOCOL
Reducing
agent
Temp.
(°C)
Time
(h)
Yield
(%)
Entry
Solvent
1
2
3
4
5
6
7
8
9
MeOH
MeOH:AcOH
MeOH:H2O
THF:2O
Dioxane:H2O
MeOH
MeOH:H2O
AcOH
MeOH
Na2S2O4
Na2S2O4
Na2S2O4
Na2S2O4
Na2S2O4
Zn dust
Zn dust
Zn dust
N2H4 (Rani
Ni catalyst)
Fe (10 equiv)
Fe (10 equiv)
Fe (20 equiv)
Fe (20 equiv)
Fe (10 equiv)
Fe (10 equiv)
Fe (10 equiv)
Fe (10 equiv)
Fe (5 equiv)
Fe (5 equiv)
Fe (5 equiv)
Fe (5 equiv)
60
60
60
70
100
60
60
55
60
18
6
24
18
18
5
8
5
8
28
21
35
32
42
63
68
70
65
Conclusion
In this work, various reducing agents were screened to
develop a robust, economically viable and environmental free
synthetic protocol for 5-cyanoindole. By utilizing this method,
usage of toxic chemicals such as CuCN, Zn(CN)2 and NaCN
in the current industrial process can be avoided.
10
11
12
13
14
15
16
17
18
19
20
21
MeOH
MeOH
MeOH
MeOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
0
0
0
0
0
RT
50
50
50
50
50
50
18
24
12
9
3
8
4
6
8
8
73
65
69
75
83
75
90
92
96
95
96
96
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
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