An efficient scale up process for synthesis of N-arylpiperazines

Article abstract of DOI:10.1016/j.tetlet.2015.06.003

An efficient protocol for the synthesis of various substituted phenylpiperazines was developed using sulfolane as solvent. The protocol was clean, high yielding and products were obtained in high purities (≥99%). It was also fast and convenient, as the final products were precipitated as hydrochloride salts and could be obtained by filtration. Sulfolane, an aprotic, dipolar, high boiling and recoverable solvent was used as a substitute for common organic solvents.

Full text of DOI:10.1016/j.tetlet.2015.06.003

Accepted Manuscript
An Efficient Scale up Process for Synthesis of N-Arylpiperazines
Lokesh Ravilla, N. Venkata subba Naidu, Kuppuswamy Nagarajan
PII:
S0040-4039(15)00975-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.06.003
TETL 46395
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 April 2015
1 June 2015
2 June 2015
Please cite this article as: Ravilla, L., Venkata subba Naidu, N., Nagarajan, K., An Efficient Scale up Process for
Synthesis of N-Arylpiperazines, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.06.003
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An Efficient Scale up Process for Synthesis of N-Arylpiperazines
Lokesh Ravillaa,b , N. Venkata subba Naidub , Kuppuswamy Nagarajana,*
a Alkem laboratories Ltd. R&D Centre, Peenya Ind. Area, 3rd stage, Banglore-560 058, India.
b Department of Chemistry, S.V.University, Tirupati-517 502, India.
ABSTRACT
An efficient protocol for the synthesis of various substituted phenylpiperazines was
developed using sulfolane as solvent. The protocol was clean, high yielding and products
were obtained in high purities (≥99%). It was also fast and convenient, as the final products
were precipitated as hydrochloride salts and could be obtained by filtration. Sulfolane, an
aprotic, dipolar, high boiling and recoverable solvent was used as a substitute for common
organic solvents.
Keywords:
N-Arylpiperazines
Scale up
High purity
Sulfolane
*Corresponding Author. Tel.: +91 9886713958
E-mail address: dknb69@yahoo.com (Kuppuswamy Nagarajan)

N-Arylpiperazines are an important class of organic compounds with prime
importance in the field of medicinal chemistry.1 These moieties are known to possess
antihistaminic, antihypertensive, adrenolytic and anti inflammatory activities.2
Arylpiperazines are also used in the field of neuroscience in particular, they are often found
in ligands for serotonin (5-hydroxytryptamine, 5-HT)3,4 dopamine receptors5 and monoamine
transporters.6,7 Apart from their intrinsic biological activities N-arylpiperazines serve as vital
building blocks for many drugs like aripiprazole, cariprazine, trazodone and nefazodone
(Figure 1) and brepiprazole, an antipsychotic under development. Hence, there is an ongoing
quest from the discovery and process chemists for their synthesis.
Cl
Cl
Cl
N
N
N
N
N
N
N
O
N
H
O
O
Aripiprazole
Trazadone
Cl
Cl
Cl
N
N
N
N
O
N
N
N
HN
O
O
N
Cariprazine
Nefazodone
Figure 1. Some N-arylpiperazine based drugs
Interestingly the first report on the synthesis of N-arylpiperazines was by Prelog
wherein aniline was condensed with N,N-bis(2-haloethyl)amine in presence of base.8,9
During the last decade, the synthesis of N-arylpiperazines has witnessed enormous
developments in terms of modifications of reaction conditions and evolution of newer
approaches. Substitution of an aryl halide (SnAr) with unsubstituted piperazine facilitated by
electron withdrawing group on the aromatic ring has been practiced for decades, while
substitution of even unactivated halogen atoms by piperazines using a palladium catalyst 10 is
a more recent development known as Buchwald11 and Hartwig coupling.12 The role of solvent
is critical in this transformation, low boiling solvents are not preferred for this condensation,
as products are obtained in low yields. Modifications involving the use of high boiling
solvents at elevated temperatures in the presence of K2CO3 gave desired products in
moderate yields. A few examples of solvents are 2-butoxyethanol (21% yield),13
chlorobenzene (54% yield),14 DMF (15% yield),15 diglyme (76% yield)16 and n-butanol (50-
72% yield).17,18 As these procedures involve extractions with an organic solvent and
subsequent treatment with HCl gas to give the desired N-aryl piperazine salts, there is a need
for developing alternatives where the use of an external base can be avoided to make them
industrially viable. However, there are only a couple of reports19,20 on the synthesis of N-
arylpiperazines without base using xylene as solvent, PTSA as catalyst and ethanol for

recrystallization, where the time taken for reaction was 27-48 hours, yield was 82% and the
product purity was not reported. Thus there was a need for the development of efficient
protocols for the synthesis of N-arylpiperazine salts without use of external base in the
reaction medium, avoiding solvent extraction and treatment with HCl gas. This would
ultimately lead to increase in efficiency of the process and result in higher yields, giving rise
to a scalable process. Herein we report an efficient procedure for synthesis of N-
arylpiperazines using sulfolane21 as high boiling solvent of reaction of anilines with bis(2-
chloroethyl)amine hydrochloride to give N-arylpiperazine salts directly which can be isolated
by simple filtration in excellent yields and high purity.
For the typical synthesis of N-arylpiperazine salts initially a few different solvents ,
polar, protic, aprotic and non-polar were tried to identify the best solvent for the conversion
of 2,3-dichloroaniline to 1-(2,3-dichlorophenyl)piperazine hydrochloride . The tabulated
results (Table 1) showed unambiguously that sulfolane was the one of choice.
Table 1.
Solvents used for reaction medium
Reaction mass
at 15 hrs
Entry
No
Product Isolated
yield
Solvent
Volumes
Temp°C
purity
1a %
3a %
1
2
3
4
5
6
Isopropyl alcohol
1,2-Dichloro benzene
Glycerol
10
10
3
80
55.9
35.2
15.3
12.9
12.6
1.2
1.7
--
--
150
150
150
140
150
42.5
50.4
48.2
50.2
91.8
88
40
34
47
50
89
92
Diglyme
3
90.1
67.6
99.1
Ortho Xylene
Sulfolane
10
3
After selecting sulfolane as solvent for the reaction, different solvents were tried to
precipitate the product from the reaction mixture. The yield and purity of isolated product
with each solvent is mentioned below in (Table 2). The results showed that the acetone was
the best solvent for isolation.
Table 2.
Solvents used for isolation
Entry No
Solvent
Isopropyl alcohol
n-heptane
Yield
47
Purity%
98.6
1
2
3
4
5
54
93.6
1,4-Dioxane
Methanol
57
97.2
64
98.8
Acetone
89
99.1

A typical preparation of a N-arylpiperazine is now described. The reaction of 2,3-
dichloroaniline and bis(2-chloroethyl)amine hydrochloride in sulfolane was conducted at
150°C for 14 hours. Completion of the reaction was monitored by HPLC. The reaction
mixture was cooled to about 45°C and diluted with acetone. Further cooling to 0°C resulted
in the precipitation of a solid which was filtered and the precipitate was washed with chilled
acetone to give the desired product 3a 1-(2,3-dichlorophenyl)piperazine hydrochloride, an
intermediate for aripiprazole, in 89% yield. The product was characterized by 1H NMR,
Mass and IR spectra and the data were matching well with the literature. The protocol was
simple and clean and could be extended to many other arylpiperazines. The products were
isolated with more than 99% purity. Since the prime aim was to have a scalable process, the
synthesis of 3a was carried out at 1 kg level and executed without any difficulties. The filtrate
in the 1 kg batch was distilled to recover acetone and sulfolane in good purity and yield.
Having optimized the reaction conditions, we then wanted to generalize the protocol by
screening different substrates to obtain various N-arylpiperazines which are incorporated in
various drugs. Substitution was varied in the aniline ring and the process was found to work
well, resulting in the formation of corresponding N-arylpiperazine hydrochlorides 3b-k in
excellent yields (Table 3).
R3
R2
NH2
R1
R2
R4
Cl
Cl
sulfolane, 150 oC
14 h, 85-90%
R1
R4
N
H
N
HCl
R3
N
H
HCl
1a-k
2
3a-k
Scheme 1. Synthesis of N-arylpiperazine hydrochlorides in sulfolane
Table 3.
Synthesis of various N-arylpiperazine hydrochlorides 3a-k
Entry
Purity (%)
by HPLC
Substrate
Product
Yield (%)
Drug
No
1
R1,R2=Cl
(1a)
R1,R2=Cl
(3a)
Aripiprazole
Cariprazine
89
90
99.21
99.88
R1=Cl
(1b)
R1=Cl
(3b)
2
3
Enpiprazole
Mepiprazole
Nefazodone
Trazodone
R2=Cl
(1c)
R2=Cl
(3c)
91
99.27
Etoperidone
R3=Cl
(1d)
R3=Cl
(3d)
4
5
89
87
99.96
99.09
R1=OH
(1e)
R1=OH
(3e)
Bifeprunox

R2=OH
(1f)
R2=OH
(3f)
6
85
88
87
99.74
99.66
99.17
Posaconazole
Itraconazole
Ketoconazole
Saperconazole
Levodropropizine
Oxypertine
R3=OH
(1g)
R3=OH
(3g)
7
8
R1,R2,R3,R5=H
(1h)
R1,R2,R3,R5=H
(3h)
Dropropizine
Niaprazine
Monatepil
R3=F
(1i)
R2= Me, R4=Br
(1j)
R2=SO2Me
(1k)
R3=F
(3i)
R2= Me, R4=Br
(3j)
R2=SO2Me
(3k)
9
90
91
92
99.96
99.71
99.74
10
11
When aminophenols 1e-g were subjected to our process, phenylpiperazine salts 3e-g
were obtained as hygroscopic solids which on washing with methanol/acetone (3:7) mixture
formed free flowing powders. All the phenylpiperazines made in the study are used as
intermediates for various drugs. The corresponding drugs are mentioned in table 3 in the last
column.
We have thus demonstrated a high yielding, scalable protocol for synthesis of
substituted phenylpiperazines using sulfolane, which has the following advantages.
Sulfolane is a versatile solvent and can be used for a wide range of synthesis. It is
highly polar, has a high boiling point and has excellent chemical and thermal stability. It is
completely miscible with water and hence kettles in which the reactions are performed can be
readily cleaned with water. It is totally miscible with aromatic hydrocarbons and hence can
be washed off from the precipitates by the later. It has very low skin penetration and high
dipole moment. It is an aprotic (no acidic hydrogen atoms), recoverable and recyclable
solvent. The procedure is clean and products are isolated by simple filtration as hydrochloride
salts. It is applicable to various substituted anilines to give corresponding N-phenylpiperazine
hydrochlorides (e.g. 3a-k) in excellent yields. All the products are found to be above 99%
pure by HPLC.
We propose to extend our study to the use of recently published aprotic dipolar
solvent, dihydrolevoglucosenone (cyrene) for piperazine formation.22
GENERAL
PRECEDURE
FOR
SYNTHESIS OF 1-ARYLPIPERAZINE
HYDROCHLORIDES
The following procedure for synthesis of 1-(2,3-dichlorophenyl)piperazine hydrochloride(3a)
is illustrative.
A 20 liter round bottom flask connected to scrubber was charged with 2,3-dichloroaniline
(1a) (1.0 kg, 6.17 mol) and bis(2-chloroethyl)amine hydrochloride(2) (1.43 kg, 8.02 mol) and

3.0 liters of sulfolane. The heterogeneous mixture was heated to 150°C to give a
homogeneous solution which was stirred at 150°C for 14 hours, by which the time the
reaction was completed as monitored by HPLC (see below Table 4). The reaction mixture
was cooled to 45°C and diluted with 5.0 liters of acetone and further cooled to 0°C. The
mixture was maintained at 0°C for 1 more hour to precipitate the desired product. This was
filtered under nitrogen atmosphere and washed with 1 liter of chilled acetone and dried at
60°C under vacuum for 8 hours to yield 1-(2,3-dichlorophenyl)piperazine hydrochloride (3a)
1.47 kg (89%); Purity by HPLC: 99.21%; MP: 245-247°C; Mass: m/z 231.1 (M+, 35Cl); 1H
NMR (400 MHz, DMSO-d6): 3.20 (s, 8H), 7.18 (dd, J =6.84, 2.76Hz, 1H), 7.32-7.36 (m,
2H), 9.50 (s, 2H) ppm; 13C NMR (DMSO-d6) δC: 149.960, 132.650, 128.545, 126.110,
125.111, 119.730, 47.680 and 42.889; IR (KBr, γmax, cm-1): 3447(N-H), 2900(Ar C-H),
1254(C-N), 543(C-Cl).
The filtrate was charged to a 20 liter round bottom flask with distillation setup. The
flask was heated upto100°C to distil out acetone at vapor temperature 50-52°C (85%
recovery). The flask temperature was then raised to 150°C, and a vacuum of 15-10 mm of Hg
applied to recover 93% of pure sulfolane (1H NMR) at vapor temperature 100-103°C.
Table 4. Reaction mass analysis by HPLC
1-(2,3-dichlorophenyl)
piperazine.HCl (Product)%
Time in Hrs
2,3-Dichloro aniline%
4
6
64.9
67.7
70.7
76.6
77.9
82.5
16.1
11.4
10.9
6.8
8
10
12
14
3.2
1.5
Acknowledgements
We thank Dr. K. Sundarraja Rao, Dr. K. Shridhara, Dr. Balachandra Bandodkar, Mr.
Suhas Chebbi and Mr. Pilla Pavan Kumar, Alkem Laboratories Ltd, Bangalore for their
encouragement and the Management for providing facilities.
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Graphical abstract
R3
R2
R1
NH2
R1
R2
R4
Cl
Cl
sulfolane, 150 oC
14 h, 85-90%
R4
N
H
N
HCl
R3
N
H
HCl