An improved synthesis of 4-(1-Piperazinyl)benzo[ b ]thiophene Dihydrochloride

Article abstract of DOI:10.1021/acs.oprd.5b00027

2-Chloro-6-fluorobenzaldehyde was converted to 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride (18), an intermediate in the synthesis of brexpiprazole, via a five-step sequence in 54% overall yield. This procedure requires no expensive catalyst and avoids the side products produced in the coupling step in the reported process. Several kilograms of compound 18 were prepared using this economical and scalable process.

Full text of DOI:10.1021/acs.oprd.5b00027

Technical Note
pubs.acs.org/OPRD
An Improved Synthesis of 4‑(1-Piperazinyl)benzo[b]thiophene
Dihydrochloride
Chunhui Wu,† Weiming Chen,‡ Dehui Jiang,‡ Xiangrui Jiang,*,† and Jingshan Shen†
†CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences (CAS), 555 Zuchongzhi Road, Shanghai 201203, China
‡Topharman Shanghai Co., Ltd., Shanghai 201209, China
S
* Supporting Information
ABSTRACT: 2-Chloro-6-fluorobenzaldehyde was converted to 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride (18), an
intermediate in the synthesis of brexpiprazole, via a five-step sequence in 54% overall yield. This procedure requires no expensive
catalyst and avoids the side products produced in the coupling step in the reported process. Several kilograms of compound 18
were prepared using this economical and scalable process.
piperazine-1-carboxylate (9) in N-methyl-2- pyrrolidinone in
the presence of N,N-diisopropylethylamine (DIPEA) (Scheme
2).5,6 Fluorine atom and chlorine atom are both active at the
ortho position of the aldehyde group, so the leaving group
ability (F− > Cl−) decides the regioselectivity of the SNAr
reaction. The amount of compound 9 has an important
influence on the reaction. Lower amounts of compound 9 gave
incomplete conversion of compound 11, and higher amounts
gave more of impurity 16 (Figure 3). Finally, optimum
equivalent of compound 9 was found to be 1.1 equiv, based on
compound 11. HPLC result indicated the reaction mixture
contained 93% of compound 12, approximate 5% of byproduct
15 and 1% of impurity 16. Fortunately, byproduct 15 was
subsequently converted to desired intermediate 13 in the
cyclization step, and impurity 16 can be conveniently removed
in the following purification.
INTRODUCTION
Brexpiprazole (1) (Figure 1), a serotonin−dopamine activity
modulator, is an investigational new drug currently in phase-III
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Figure 1. Brexpiprazole (1) and intermediate 18.
clinical trials for the treatment of depression, schizophrenia, and
attention deficit hyperactivity disorder.1 Brexpiprazole is also
considered to be a possible successor to the top-selling
antipsychotic agent aripiprazole.2
Alternative solvents for the SNAr reaction were evaluated.
The use of acetonitrile was avoided since very low conversion
of dihalide 11 to arylpiperazine 12 was observed even at its
boiling point (81 °C). N-Methyl-2-pyrrolidinone was found to
be a good solvent for this step in terms of both product yield
and quality. Potassium carbonate, sodium carbonate, and
triethylamine also worked as basic reagents giving good yields.
After completion of the reaction, the reaction mass was added
to a mixture of acetone and water. The ratio of acetone and
water was important for the precipitation of compound 12 from
the mixture, as a higher ratio of acetone resulted in a yield
reduction. The precipitated compound 12 was purified by
reslurrying in n-heptane, which can be recovered in high yield
and reused in the next batch, to give compound 12 as a white
solid in excellent yield (94%) containing 4% byproduct 15.
Cyclization of compound 12 with thioglycollic acid ethyl
ester in N,N-dimethylformide (DMF) in the presence of
potassium carbonate furnished compound 13, which was
hydrolyzed in situ and acidified to give compound 14.7−9
Several bases were evaluated for their effect on this cyclization
The synthesis of 4-(1-piperazinyl)benzo[b]thiophene hydro-
chloride (8) was originally accomplished by Yamashita and co-
workers (Scheme 1).3 In the first step, 4-bromobenzo[b]-
thiophene was coupled with unprotected piperazine using
tris(dibenzylideneacetone)dipalladium as the catalyst. However,
this process suffered from the formation of impurities 2 and 3
(Figure 2), which are difficult to remove via a crystallization
method. An alternative process using protected piperazine and
an expensive catalyst in order to minimize the generation of
impurities was reported by Shinhama and co-workers (Scheme
1).4
Herein we report a new process for producing 4-(1-
piperazinyl)benzo[b]thiophene hydrochloride. The strategy of
replacement rather than coupling was used to construct the
arylpiperazine in order to avoid the formation of impurities in
the reported coupling step and the use of an expensive catalyst.
The improved process has a number of industrial advantages
such as economical material cost, convenient operation, and
relatively high yield.
RESULTS AND DISCUSSION
Substituted phenylpiperazine was constructed through the SNAr
reaction of 2-chloro-6-fluorobenzaldehyde (11) and tert-butyl
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Received: January 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.5b00027
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Organic Process Research & Development
Technical Note
Scheme 1. Reported synthetic routes for 4-(1-piperazinyl)benzo[b]thiophene hydrochloride (8)
In the published process for the decarboxylation of
benzothiophene-2-carboxylic acid, quinoline was used as the
solvent and catalyst as well.4 In the present process, the use of
quinoline is avoided, since it is a toxic and high-boiling-point
(238 °C) solvent, which made the recovery hazardous for the
working environment. Replacement of quinoline by DMF led
to almost the same yield, and the solvent can be conveniently
recovered under reduced pressure in situ.
Figure 2. Impurities 2 and 3.
The tert-butoxycarbonyl protecting group on piperazine in
compound 14 is not stable enough in heated DMF, so that
about a 6% yield of impurity 17 was found in the LC−MS
spectrum of the reaction mixture. To our delight, most of
impurity 17 can be removed simply by purification in ethanol,
and the remaining impurity 17 was converted to the desired
compound 18 in the deprotection step. After the purification in
ethanol, compound 10 was simply obtained in 85% yield with
excellent purity (98.7%).10,11
Compound 10 was treated with excess concentrated
hydrochloric acid in methanol. After the reaction end point,
methyl tert-butyl ether was added to the reaction mass as an
antisolvent to promote the precipitation of crude 4-(1-
piperazinyl)benzo[b]thiophene dihydrochloride (18), which
was further purified in methyl tert-butyl ether to give compound
18 with 99.8% purity on HPLC.
in DMF, such as DIPEA, potassium carbonate, and triethyl-
amine. When DIPEA was used as the base, the conversion of
compound 12 was only around 30%, even with excess
thioglycollic acid ethyl ester, as well as triethylamine.
Since it is tedious to recover DMF from mixtures of DMF
and water, to make the process greener we tried to use other
solvents, such as toluene, dioxane, acetonitrile, and ethanol.
However, the reactions in these solvents suffered from low
conversion of compound 12 and decreased yield.
Since 1 equiv of water (based on the charge of 12) was
generated in the cyclization, upon heating of the aqueous
reaction mixture in the presence of potassium carbonate, the
potassium salt of 14 was found in the reaction mass in a ratio of
10−20%. After completion of the cyclization, a solution of
potassium hydroxide in water was directly added to the cooled
reaction mixture to hydrolyze 13. Subsequently, the reaction
mass was extracted with ethyl acetate to remove some
impurities, and then the aqueous layer was acidified to furnish
14 as a white precipitate in satisfying yield (80% over two
steps) and purity (99.4%). The precipitate was directly used in
the next step without further purification.
CONCLUSION
■
An improved process for 4-(1-piperazinyl)benzo[b]thiophene
hydrochloride, including the replacement reaction of 2-chloro-
6-fluorobenzaldehyde with 1-tert-butoxycarbonylpiperazine, has
been provided. It affords a total yield of 54% over five steps and
a purity of 99.8%. Because of the good leaving ability of
fluorine, the synthesis of compound 18 was successfully
Alternatively, a more convenient and efficient cyclization of
compound 12 with thioglycollic acid was successful on a
several-gram scale in the presence of sodium hydroxide.
Scheme 2. Improved synthetic route for 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride (18)
B
DOI: 10.1021/acs.oprd.5b00027
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Organic Process Research & Development
Technical Note
Figure 3. Structures of 15−17.
accomplished by this new process. The resulting new
intermediates have some industrially favorable physical proper-
ties. For example, compounds 14 and 10 can be simply purified
from the reaction mixtures with satisfying purities. The
advantages ensure that the efficient, cost-effective, and
industrially convenient process will be employed for
commercial production.
aqueous solution (8.28 L, 16.56 mol) was added, and the
reaction mixture was stirred at 60 °C for 5 h, cooled to room
temperature, and extracted with ethyl acetate. Then the pH of
the aqueous phase was adjusted to 5 using 4 N HCl, and the
precipitate was collected by filtration, washed with water, and
dried to give compound 14 (2.68 kg, 80% yield over two steps).
HPLC for compound 14 (tR = 12.5 min, identical to authentic
sample) 99.4% purity; HPLC method A.
EXPERIMENTAL SECTION
Method B. A three-neck bottle was charged with compound
12 (3 g, 9.24 mmol), sodium hydroxide (1.48 g, 36.92 mmol)
and DMF (15 mL). Then the mixture was stirred for 20 min at
room temperature. Thioglycollic acid (0.77 mL, 11.08 mmol)
was added, and the reaction mixture was stirred at 105 °C
overnight, cooled to room temperature, and extracted with
ethyl acetate. Then the pH of the aqueous phase was adjusted
to 5, and the precipitate was collected by filtration, washed with
water, and dried to give compound 14 (2.61 g, 78% yield).
■
General Procedures. All commercially available materials
and solvents were used without any further purification. TLC
analyses were performed on Merck silica gel 60 F254 plates. H
1
NMR spectra were recorded at room temperature on a Bruker
AMX-400 using TMS as an internal standard. Mass spectra
were recorded on a Finnigan MAT-95/711 spectrometer.
Reversed-phase HPLC analyses were performed on an Agilent
1100 HPLC system with a DAD detector (area normalization).
HPLC method A: Waters XTerra Phenyl column (5 μm, 4.6
mm × 250 mm); flow rate = 1 mL/min; 30 °C; gradient elution
from 30:70 A/B to 80:20 A/B over 20 min, where A =
acetonitrile and B = 0.1% H3PO4 in water; UV detection at 210
nm. HPLC method B: Waters XTerra MS C18 column (4.6
mm × 150 mm); flow rate = 1 mL/min; 30 °C; gradient elution
from 10:90 A/B to 80:20 A/B over 20 min, where A =
acetonitrile and B = 0.02 M KH2PO4 (pH 6.0); UV detection at
210 nm.
1
13: H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 0.6 Hz,
1H), 7.69 (d, J = 8.2 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.00 (d,
J = 7.4 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.58 (s, 4H), 3.09−
2.97 (m, 4H), 1.43 (s, 9H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, DMSO-d6): δ 161.89, 153.84, 149.64, 142.74,
132.66, 131.57, 128.35, 127.93, 117.28, 113.49, 78.97, 61.44,
51.89, 28.03, 14.12. MS (ESI, eV): m/z = 391.2 [M + H]+.
14: 1H NMR (400 MHz, DMSO-d6) δ 13.49 (s, 1H), 7.99 (s,
1H), 7.67 (d, J = 8.1 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 6.98 (d,
J = 7.6 Hz, 1H), 3.57 (s, 4H), 3.10−2.96 (m, 4H), 1.43 (s, 9H).
13C NMR (100 MHz, DMSO-d6): δ 163.42, 153.83, 149.48,
142.79, 133.38, 132.85, 128.00, 127.47, 117.25, 113.28, 78.97,
51.87, 28.04. MS (ESI, eV): m/z = 363.1 [M + H]+, m/z =
361.1 [M − H]−.
tert-Butyl 4-(3-Chloro-2-formylphenyl)piperazine-1-
carboxylate (12). A mixture of 2-chloro-6-fluorobenzaldehyde
(5 kg, 31.52 mol), tert-butylpiperazine-1-carboxylate (6.46 kg,
34.67 mol), DIPEA (7.80 L, 47.28 mol), and N-methyl-2-
pyrrolidinone (25 L) was heated at 95 °C overnight under a
nitrogen atmosphere. The reaction mixture was cooled to room
temperature and poured into a prepared mixture of water (33
L) and acetone (17 L). The resulting suspension was stirred for
15 min and filtered, and the wet cake was washed with water
and dried to give a yellow solid, which was slurried in heated n-
heptane (30 L) to give compound 12 (9.62 kg, 94% yield) as a
white solid containing 4% compound 15. HPLC for compound
12 (tR = 14.4 min, identical to authentic sample) 94% purity,
compound 15 (tR = 7.6 min); HPLC method A. The 1H NMR
data were identical with those in the literature.5
tert-Butyl 4-(Benzo[b]thiophen-4-yl)piperazine-1-car-
boxylate (10). A reactor was charged with compound 14 (2.5
kg, 6.90 mol), cuprous oxide (250 g, 1.75 mol), and DMF (10
L). The mixture was purged with nitrogen three times and
stirred at 140 °C for 15 h. The reaction mass was cooled to
70−80 °C, and DMF was recovered under reduced pressure to
give a residue, which was cooled to ambient temperature and
dispersed in ethyl acetate (10 L). The resulting suspension was
stirred under reflux for 2 h after the addition of active carbon
(75 g) and then hot-filtered. The filtrate was concentrated to
obtain crude 10, which was further purified by reslurrying in
ethanol and dried to give compound 10 (1.87 kg, 85% yield).
HPLC for compound 10 (tR = 15.1 min, identical to authentic
12: 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.54 (t,
J = 8.1 Hz, 1H), 7.20 (s, 1H), 7.18 (s, 1H), 3.49 (s, 4H), 2.96
(s, 4H), 1.42 (s, 9H). 13C NMR (100 MHz, DMSO-d6): δ
189.24, 155.69, 153.80, 134.62, 134.34, 125.38, 124.31, 118.70,
79.05, 52.88, 43.77 (br), 42.72 (br), 28.03. MS (ESI, eV): m/z
= 325.1 [M + H]+.
1
sample) 98.7% purity; HPLC method A. The H NMR data
were identical with those in the literature.4
1
10: H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 5.5 Hz,
1H), 7.64 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 5.5 Hz, 1H), 7.28 (t,
J = 7.8 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 3.56 (s, 4H), 3.07−
2.93 (m, 4H), 1.43 (s, 9H). 13C NMR (100 MHz, DMSO-d6):
δ 153.87, 147.94, 140.41, 133.51, 126.03, 125.02, 121.82,
117.03, 112.40, 78.92, 51.60, 28.04. MS (ESI, eV): m/z = 319.1
[M + H]+.
4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)benzo[b]-
thiophene-2-carboxylic Acid (14). Method A. A three-neck
bottle was charged with compound 12 (3 kg, 9.24 mol),
potassium carbonate (5.11 kg, 36.96 mol), and DMF (15 L).
The mixture was stirred for 20 min at room temperature, and
thioglycollic acid ethyl ester (1.21 L, 11.04 mol) was added.
The reaction mixture was stirred at 90 °C overnight to give the
reaction mass containing compound 13. Potassium hydroxide
1-(Benzo[b]thiophen-4-yl)piperazine Dihydrochloride
(18). Compound 10 (1.5 kg, 4.71 mol) was dissolved in
C
DOI: 10.1021/acs.oprd.5b00027
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Organic Process Research & Development
Technical Note
(11) Cadot, S.; Rameau, N.; Mangematin, S.; Pinel, C.; Djakovitch, L.
Green Chem. 2014, 16, 3089−3097.
methanol (6.8 L), and concentrated hydrochloric acid (2.27 L,
27.27 mol) was added. The reaction mixture was stirred at 50
°C for 1 h. After completion of the reaction, methyl tert-butyl
ether (10 L) was added to the reaction mixture, which was then
stirred 30 min. The precipitates were collected by filtration,
washed with methyl tert-butyl ether, and then dried to give
compound 18 (1.17 kg, 85% yield). HPLC for compound 18
(tR = 6.3 min, identical to authentic sample) 99.8% purity;
HPLC method B.
18: 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.65 (s,
2H), 7.75 (d, J = 5.5 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.53 (d,
J = 5.5 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.6 Hz,
1H), 3.30 (s, 8H). 13C NMR (100 MHz, DMSO-d6): δ 146.92,
140.62, 133.40, 126.50, 125.06, 121.91, 117.73, 112.56, 48.52,
43.00. MS (ESI, eV): m/z = 219.1 [M + H]+.
ASSOCIATED CONTENT
* Supporting Information
NMR spectra for compounds 7, 8, 10, and 12−18. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*Address: Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang
Hi-Tech Park, Shanghai 201203, China. Fax: +86-21-20231000-
2407. Telephone: +86-21-2023100-2407. E-mail:
jiangxiangrui@simm.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the Science
and Technology Commission of Shanghai Municipality
(14431905500) and the National Natural Science Foundation
of China (81273366).
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DOI: 10.1021/acs.oprd.5b00027
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