Synthesis and crystal structure of 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one

Article abstract of DOI:10.1177/1747519820907877

7-Bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one is prepared from 6-methoxybenzo[d]thiazol-2-amine and 2-(bromomethyl)-2-butylhexanoic acid as the key starting materials via five simple steps including hydrolysis, substit

Full text of DOI:10.1177/1747519820907877

907877CHL0010.1177/1747519820907877Journal of Chemical ResearchDu and Wu
research-article2020
Research Paper
Journal of Chemical Research
1–4
© The Author(s) 2020
Article reuse guidelines:
sagepub.com/journals-permissions
Synthesis and crystal structure of 7-bromo-3,3-
dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b]
[1,4]thiazepin-4(5H)-one
https://doi.org/10.1177/1747519820907877
DOI: 10.1177/1747519820907877
journals.sagepub.com/home/chl
Damin Du1 and Haijian Wu2
Abstract
7-Bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-oneispreparedfrom6-methoxybenzo[d]
thiazol-2-amine and 2-(bromomethyl)-2-butylhexanoic acid as the key starting materials via five simple steps including
hydrolysis, substitution, condensation, bromination, and aromatic amidation under microwave conditions. This new route
has reduced the reaction time and increased the overall yield to 43%. Moreover, the structure of the target product is also
confirmed by X-ray crystal analysis, and further studies indicate that the existence of an intramolecular C–H···Cg1 non-
classical hydrogen bond is effective in stabilization of the crystal structure.
Keywords
aromatic amidation, benzothiazepine, crystal structure, microwave irradiation
Date received: 26 November 2019; accepted: 27 January 2020
first bile acid transport inhibitor in Japan. Its generic name
Introduction
is Elobixibat hydrate.8
Constipation is a common digestive disease having a preva-
lence rate of about 20% in China. It occurs more frequently
in women than in men, and the prevalence rate is higher in
7-Bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-
dihydrobenzo[b][1,4]thiazepin-4(5H)-one is a key interme-
diate of Elobixibat hydrate and is the main bioactive group.
older people.1 Prucalopride succinate is now on the market
However, there are only a few studies reported that discuss
for the treatment of constipation in women.2,3 In addition,
the synthesis of the title compound in the literature.9,10
stool softeners increase water absorption by the faeces by
Herein, we report an efficient route to prepare the title com-
lowering the surface tension of the feces, a representative
pound. Compared with the original research patent, we
example being docusate.4 However, these stimulant laxa-
tives and stool softeners only provide temporary effects.
Recent medical research has demonstrated that the
have shortened the reaction time of the last step (from 17h
transfer of bile acids is one of the leading causes of consti-
pation. Benzothiazepine derivatives inhibit bile acid trans-
port that regulates bile acid reabsorption,5–7 thus increasing
bile acid flow to the colon, thereby promoting the intestinal
tract to secrete more water and facilitate defecation, so as to
naturally improve natural defecation in patients. On 19
April 2018, EA Pharma and Mochida launched the World’s
1Department of Physics, Taizhou University, Taizhou, P.R. of China
2Advanced Research Institute and Department of Chemistry, Taizhou
University, Taizhou, P.R. of China
Corresponding author:
Haijian Wu, Advanced Research Institute and Department of Chemistry,
Taizhou University, Taizhou 318000, P.R. of China.
Email: wuhaijian@tzc.edu.cn

2
Journal of Chemical Research 00(0)
to 30min) and reduced the reaction temperature (from did not require an amine ligand (like ethylenediamine,
190°C to 130°C). In the aromatic amidation step,11–13 we cyclohexanediamine, or 1,10-phenanthroline). Thus, we
have reduced the amount of amine ligand, which is more optimized the reaction conditions for this step (Table 1). As
conducive to large-scale production (Scheme 1). This syn- can be seen from Table 1, the presence of amine ligands had
thetic route afforded a 43% overall yield. Furthermore, a no effect on the yield of the product. The reaction time was
single crystal of the title compound was obtained and the shortened from 17h to 30min under microwave irradiation,
molecular structure was determined by X-ray diffraction.
and the reaction temperature was reduced from 190°C to
130°C. In addition, we found that the reaction time and
microwave power have little effect on the yield, with a yield
of 79% being obtained.
Results and discussion
Meanwhile, we successfully grew a single crystal of
product 6 from n-hexane, and the structure was confirmed
by the X-ray crystal analysis (Figure 1, CCDC 1960860).
Compound 6 crystallizes in the P-1 space group and its
molecular structure consists of two benzene rings.
Furthermore, the dihedral angle between the two benzene
rings (Cg1 (C1–C2–C3–C4–C5–C6) and Cg2 (C18–C19–
C20–C21–C22–C23)) is 83.0(2)°, indicating that these rings
are not coplanar. The crystal structure was formed though a
C10–H10B···Cg1 non-classical hydrogen bonds. The dis-
tance between C10–H10B and the benzene ring centroid of
Cg1(x, y, z) was 3.509(4). Classical hydrogen bonds and
π–π stacking interactions were not found in the structure.
In order to prepare the target product, we first investigated
the original research patent.9 When compounds 2 and 3 were
synthesized with ethylene glycol as the solvent and without
protection in N2 atmosphere, the yield of compound 3
reached 92%. However, the original patent did not use the
protection of the NH2 group and the yield was only 51%.
Compound 3 was converted into compound 4 by reaction
with
2-(7-azabenzotriazol-1-yl)-N,
N,
N′,
N′-
tetramethyluronium hexafluorophosphate (HATU) and N,
N-diisopropylethylamine (DIPEA) in dichloromethane at
25°C for 2h.As a brominating reagent, N-bromosuccinimide
(NBS) was reacted with compound 4 to afford bromide 5 at
25°C in high yield. Finally, the title compound 6 was
obtained by the metal-catalyzed cross-coupling reaction of 5
with iodobenzene in dimethylsulfoxide (DMSO) at 130°C
for 30min under microwave conditions and with CuI as the
catalyst. In the original route, tris[2-(2-methoxyethoxy)
ethyl]amine was added as the amine ligand and the mixture
was heated at reflux at 190°C for 17h. After experimenting,
we found that this metal-catalyzed cross-coupling reaction
Conclusion
In summary, using 6-methoxybenzo[d]thiazol-2-amine as
a starting material, 7-bromo-3,3-dibutyl-8-methoxy-5-
phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one
was synthesized. By optimizing the original research
route, the overall yield of this five-step sequence was
43%. At the same time, the reaction efficiency was greatly
improved by using a microwave, and thus the use of
expensive ligands was reduced and production costs were
saved. A study of the crystal structure of the title com-
pound may contribute evidence for further studies on drug
designs and mechanisms.
Experimental
General information
Unless noted otherwise, all the reagents were commer-
cially available and were used without further purifica-
tion. The reactions were monitored by thin-layer
chromatography (TLC). Microwave irradiation was
Scheme 1. The synthetic route toward 7-bromo-3,3-dibutyl-
8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-
one.
Table 1. Optimization of the reaction conditions (ligand, temperature, mode of heating, and duration of reaction) for the
preparation of the title compound.
Entry
Ligand
Temperature (°C)
Time
Yield (%)
1
2
3
4
5
6
7
8
None (MWI: 400W)
None (MWI: 300W)
None (MWI: 400W)
Cyclohexanediamine (MWI: 400W)
None
Cyclohexanediamine
Tris[2-(2-methoxyethoxy)ethyl]amine
1,10-phenanthroline
130
130
130
130
130
130
190
140
30min
30min
40min
30min
12h
12h
18h
12h
78
75
79
77
62
67
64
63
MWI: microwave irradiation.

Du and Wu
3
Figure 1. ORTEP diagram of compound 6 with 50% ellipsoid probability (a axis, b axis, c axis).
performed in a MAS-1 microwave reactor apparatus
Preparation of 3,3-dibutyl-8-methoxy-2,3-
(Shanghai Sineo Microwave Chemistry Technology Co.,
Ltd). Melting points were measured with an X4-A micro-
scopic melting point apparatus. Nuclear magnetic reso-
nance (NMR) spectra were recorded on a Bruker BioSpin
400MHz spectrometer with chemical shifts reported in
ppm (in dimethyl sulfoxide-d6 (DMSO-d6), with tetra-
methylsilane (TMS) as the internal standard). High-
resolution mass spectrometry (HRMS) was performed
using a 6540 Ultra High Definition (UHD) Accurate-Mass
Quadrupole Time-of-Flight (Q-TOF) liquid chromatogra-
phy/mass spectrometry (LC/MS) instrument. X-ray sin-
gle-crystal diffraction data were recorded on a XtaLAB
Synergy, Dualflex, HyPix four-circle diffractometer.
dihydrobenzo[b][1,4]thiazepin-4(5H)-one
(4)
Compound 3 (13.0g, 0.038mol) in dichloromethane
(100mL) was stirred at 25°C, HATU (17.4g, 0.046mol)
was added dropwise under stirring, and the mixture was
then stirred for 10min. DIPEA (5.95g, 0.046mol) was
added slowly dropwise under stirring. The reaction pro-
gress was monitored by TLC with starting material 3 hav-
ing disappeared after stirring at room temperature for 2h.
The reaction mixture was washed with water and the
dichloromethane layer separated. The dichloromethane
layer was dried over anhydrous sodium sulfate, filtered,
and concentrated to afford a brown liquid. Hexane was
added with stirring to afford, after isolation, an off-white
crystalline solid (9.75g), yield 81%. m.p.: 70.2–72.2°C. 1H
NMR (400MHz, DMSO-d6): δ 9.52 (s, 1H), 7.03 (d, J =
8.8Hz, 1H), 6.97 (d, J = 2.5Hz, 1H), 6.86 (dd, J = 8.8,
2.6Hz, 1H), 3.73 (s, 3H), 2.98 (s, 2H), 1.66–1.55 (m, 2H),
1.54–1.40 (m, 2H), 1.25–1.09 (m, 8H), 0.82 (t, J = 6.7Hz,
6H). HRMS (ES+): m/z calcd for C18H28NO2S [M+H]+:
322.1762, found: 322.1565.
Preparation of 2-{[(2-amino-5-
methoxyphenyl)thio]methyl}-2-butylhexanoic
acid (3)
Under a nitrogen atmosphere, 6-methoxybenzo[d]thiazol-
2-amine (1) (9.00g, 0.05mol) was suspended in ethylene
glycol (12mL). To the suspension was added 50% potas-
sium hydroxide 50mL and the mixture heated to 120°C for
18h. The reaction was monitored by TLC to confirm the
formation of 2-amino-5-methoxybenzenethiol (2). After
cooling to 25°C, 2-bromomethyl-2-butylhexanoate (15.9g,
0.06mol) was added and the mixture stirred at 25°C for 8h.
The resulting solution was washed with 3 N HCl and the
pH was adjusted to 6.0 with 3 N HCl. Saturated sodium
chloride solution and ethyl acetate were added, and the
mixture was stirred for 30min and then the ethyl acetate
layer was separated. The ethyl acetate layer was dried over
anhydrous sodium sulfate, filtered, and concentrated. The
concentrated compound was washed with n-hexane and
then concentrated again. Compound 3 was obtained as a
yellow oily liquid (15.6g), yield 92%. 1H NMR (400MHz,
DMSO-d6): δ 6.86 (d, J = 2.0Hz, 1H), 6.72–6.64 (m, 2H),
3.64 (s, 3H), 2.98 (s, 2H), 1.64–1.46 (m, 4H), 1.21–1.10
(m, 4H), 1.09–0.90 (m, 4H), 0.79 (t, J = 7.2Hz, 6H).
HRMS (ES+): m/z calcd for C18H30NO3S [M+H]+:
340.1868, found: 340.2108.
Preparation of 7-bromo-3,3-dibutyl-8-
methoxy-2,3-dihydrobenzo[b][1,4]thiazepin-
4(5H)-one (5)
A mixture of compound 4 (4.47g, 0.014mol) and NBS
(2.67g, 0.015mol) in dichloromethane 50mL was stirred in
a dark reaction vessel at 25°C for 2h. Next, saturated
ammonium chloride solution was added and the dichlo-
romethane layer was separated. The dichloromethane layer
was dried over anhydrous sodium sulfate, filtered, and con-
centrated. The residue was charged with 100mL of a mix-
tureofhexaneandethylacetate(hexane/ethylacetate=30/1),
and the resulting solid was filtered to afford compound 5 as
1
a yellow solid (4.1g), yield 74%. m.p.: 120–122°C. H
NMR (400MHz, DMSO-d6): δ 9.60 (s, 1H), 7.33 (s, 1H),
7.11 (s, 1H), 3.83 (s, 3H), 3.00 (s, 2H), 1.70–1.56 (m, 2H),
1.54–1.41 (m, 2H), 1.27–1.10 (m, 8H), 0.83 (t, J = 6.8Hz,

4
Journal of Chemical Research 00(0)
Table 2. Crystallographic data for compound 6.
fiberglass, and mounted on a Rigaku XtaLAB Synergy,
Dualflex, HyPix four-circle diffractometer equipped with a
mirror-monochromatic Cu–Kα radiation source at 293K (λ
= 1.54184Å). Data collection and reduction were per-
formed using the CrysAlisPro software suite.14 Empirical
absorption corrections were carried out using SCALE3.15
The structure was solved by direct methods and expanded
by difference Fourier techniques. The non-hydrogen atoms
were refined anisotropically and the hydrogen atoms were
added according to the theoretical models with Uiso(H) =
1.2 (1.5 for methyl) Ueq(C). The structure was refined by
the full-matrix least-squares method on F2 with
SHELXL-2015.16 The crystallographic data for the com-
pound 6 (CCDC, 1960860) are summarized in Table 2.
Formula
C24H30BrNO2S
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
a (Å)
b (Å)
c (Å)
Volume (Å)
476.46
293
1.54184
Triclinic
P-1
9.8322(4)
11.2888(3)
11.5601(6)
1196.55(9)
2
Z
Absorption coefficient (mm−1)
F(000)
3.298
496
Crystal size (mm3)
Goodness-of-fit on F2
θ range for data collection
Reflections collected/unique
Collection range
0.2×0.2×0.2
1.076
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.
3.9–75.7°
12,371/4763
−12⩽h⩽12
−13⩽k⩽13
−14⩽l⩽14
0.047
4763/0/265
0.0712, 0.1852
0.0761, 0.1907
0.56, −1.29
Funding
Rint
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
work was supported by the Nurturing Project from Taizhou
University (grant no. 2019PY016).
Data/restraints/parameters
R1, wRR2 (I>2σ(I))
R1, wRR2 (all data)
Δρmax/Δρmin (e·Å3)
Supplemental material
Supplemental material for this article is available online.
6H). HRMS (ES+): m/z calcd for C18H26BrNO2S [M+H]+:
400.0868, found: 400.1197.
References
1. WongBS, CamilleriM, McKinzieS, etal. AmJGastroenterol
2011; 106(12): 2154.
2. Bassotti G, Gambaccini D and Bellini M. Expert Rev
Gastroenterol Hepatol 2016; 10(3): 291–300.
3. Ke M, Zou D, Yuan Y, et al. Neurogastroent Motil 2012;
24(11): 999–e541.
4. McRorie JW, Daggy BP, Morel JG, et al. Aliment Pharm
Ther 1998; 12(5): 491.
5. Bariwal JB, Upadhyay KD, Manvar AT, et al. Eur J Med
Chem 2008; 43(11): 2279–2290.
6. Wang L, Zhang P, Zhang X, et al. Eur J Med Chem 2009;
44(7): 2815–2821.
7. Li W, Schlepphorst C, Daniliuc C, et al. Angew Chem Int Ed
2016; 55(10): 3300–3303.
8. Ymén I, Bohlin M and Larsson T. Patent application
15/519,808, USA, 2017.
9. Jung WH, Kim SI, Ji SH, et al. Patent application 15851901.7,
EP, 2015.
Preparation of 7-bromo-3,3-dibutyl-8-
methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]
thiazepin-4(5H)-one (6)
Compound 5 (2.0g, 0.005mol) in DMSO (30mL) was
charged with iodobenzene (1.2g, 0.006mol), copper
iodide (0.19g, 0.001mol) and potassium carbonate
(1.38g, 0.01mol). The mixture was stirred at 25°C for
about 5min and then heated in a microwave reactor
(400W) at 130°C for 30min. The resulting mixture was
cooled to room temperature, was washed with water, and
extracted with dichloromethane. The dichloromethane
layer was dried over anhydrous sodium sulfate, filtered,
and concentrated. The concentrated compound was
recrystallized from n-hexane to afford compound 6
(1.85g), yield 78%. m.p.: 96.8–97.8°C. 1H NMR
(400MHz, DMSO-d6): δ 7.43–7.35 (m, 3H), 7.29–7.24 10. Deepu C, Raghavendra G, Rekha N, et al. Curr Chem Lett
2015; 4(4): 133–144.
11. Gildner PG and Colacot TJ. Organometallics 2015; 34(23):
5497–5508.
12. Maaliki C, Thiery E and Thibonnet J. Eur J Med Chem 2017;
2017(2): 209–228.
(m, 1H), 7.12–7.05 (m, 3H), 3.88 (s, 3H), 3.16 (s, 2H),
1.44 (m, 4H), 1.19 (m, 8H), 0.81 (t, J = 6.0Hz, 6H).
HRMS (ES+): m/z calcd for C24H31BrNO2S [M+H]+:
476.1181, found: 476.1265.
13. Bhunia S, Pawar GG, Kumar SV, et al. Angew Chem Int Ed
2017; 56(51): 16136–16179.
14. CrysAlisProV.1.171.37.33(release27-03-2014CrysAlis171
.NET). Agilent Technologies, 2014.
15. SCALE3 ABSPACK scaling algorithm. CrysAlis RED, ver-
sion 1.171.31.8. Oxford: Oxford Diffraction.
X-Ray structure determination
A colorless block-like crystal of compound 6 was grown in
n-hexanewithdimensionsof0.20mm×0.20mm×0.20mm
and was used for structural determination. Single crystals
suitable for X-ray diffraction were selected, glued on 16. Sheldrick GM. Acta Crystall A: Crys 2015; 71: 3.