Synthesis and crystal structure of trifluoromethyl-containing bendamustine hydrochloride

Article abstract of DOI:10.1177/1747519819868202

A simple strategy to afford trifluoromethyl-containing bendamustine hydrochloride in 34% overall via nine simple steps including substitution, selective reduction, N-acylation, cyclization, esterification, nitro-reduction, N-dihydroxyethylation, chlorinat

Full text of DOI:10.1177/1747519819868202

8
research-arti
6cle2019 8202CHL0010.1177/1747519819868202Journal of Chemical ResearchYin et al.
Research Paper
Journal of Chemical Research
–7
1
Synthesis and crystal structure of
trifluoromethyl-containing bendamustine
hydrochloride
© The Author(s) 2019
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Yue Yin, Huailiang Liu, Tangxin Xiao, Xiaoqiang Sun,
Ke Yang and Zhengyi Li
Abstract
A simple strategy to afford trifluoromethyl-containing bendamustine hydrochloride in 34% overall via nine simple steps
including substitution, selective reduction, N-acylation, cyclization, esterification, nitro-reduction, N-dihydroxyethylation,
chlorination, and acid-catalyzed hydrolysis from commercially available 2,4-dinitrochlorobenzene is described. The
structures of the intermediates and target product are established on the basis of infrared, nuclear magnetic resonance,
and high resolution mass spectrometer. Moreover, the structure of target product is also confirmed by X-ray crystal
analysis, and further studies indicate that the existence of intermolecular O–H···Cl and N–H···Cl hydrogen bonds are
effective in stabilization of the crystal structure.
Keywords
bendamustine hydrochloride, crystal structure, synthesis, trifluoromethyl group
Date received: 28 April 2019; accepted: 16 July 2019
Introduction
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology,
School of Petrochemical Engineering, Changzhou University, Changzhou,
P.R. China
Bendamustine hydrochloride (Figure 1(a)) is a bifunctional
molecule that combines the alkylating activity of a bis(2-
chloroethyl)amine moiety and the antimetabolite activity of
a benzimidazole group. It causes DNA damage that is
thought to lead to cell death, including inhibition of mitotic
1
–5
Corresponding authors:
Ke Yang, Jiangsu Key Laboratory of Advanced Catalytic Materials
and Technology, School of Petrochemical Engineering, Changzhou
University, Changzhou 213164, P.R. China.
Email: keyang@cczu.edu.cn
6
–8
checkpoints and induction of mittic catastrophe. In the
960s, bendamustine hydrochloride was designed with the
1
aim of creating a compound which possesses similar prop-
erties but less toxicity than nitrogen mustard agents. This
Zhengyi Li, Jiangsu Key Laboratory of Advanced Catalytic Materials
and Technology, School of Petrochemical Engineering, Changzhou
University, Changzhou 213164, P.R. China.
9
alkylating agent has been used against a number of malig-
1
0
nancies since the 1970s in Germany. It was approved by Email: zyli@cczu.edu.cn

2
Journal of Chemical Research 00(0)
Figure 1. The chemical structures of (a) bendamustine hydrochloride and (b) trifluoromethylated bendamustine hydrochloride.
the US Food and Drug Administration (FDA) for the treat- 2,2,2-trifluoroethylamine hydrochloride as a nucleophile,
ment of chronic lymphocytic leukemia in March 2008 and the desired product 2 was obtained in 95% yield. Moreover,
for rituximab-refractory indolent B-cell non-Hodgkin lym- the regioselective reduction of the ortho-nitro group could
9
,11,12
phoma (NHL) in October 2008.
be realized in the presence of Na S·9H O and EtOH, which
2 2
The small and highly electronegative fluorine atom can provided the corresponding nitrophenyldiamine 3 in 81%
play a significant role in medicinal chemistry, biochemistry, isolated yield. Next, to construct the imidazole ring and
1
3,14
and agrochemicals.
Around 20%–30% of medicines con- install the n-butyric acid group, glutaric anhydride was
15
tain at least one fluorine atom. Among the various fluorine- used to produce the desired amide product 4 in 92% iso-
containing groups, the trifluoromethyl group (CF ) has lated yield. To our delight, the imidazole ring was then
3
received significant attention as its introduction into phar- smoothly formed through an intramolecular cyclization
maceuticals has a major impact on the physical and chemical reaction using concentrated hydrochloric acid at room
properties of the molecule such as lipophilicity, pharmacoki- temperature, affording the desired product 5 in 82% iso-
16–20
netics, and the binding properties of molecules.
Currently, lated yield. In order to reduce the nitro to an amino group,
the late-stage introduction of CF in drug-like compounds is the ester 6 was first obtained in 94% yield by the reaction
3
a well-known practice in medicinal chemistry and widely of 5 in ethanol with catalytic sulfuric acid at 75°C via a
2
1,22
used in the treatment of diseases.
For example, lansopra- Fischer esterification process. Next, in the presence of
zole and omeprazole are popular proton pump inhibitors
Pd/C and hydrazine hydrate, the corresponding amino
product 7 was formed. However, a hydrazide by-product
appeared when the dropwise hydrazine hydrate addition
was too fast. Therefore, hydrazine hydrate was added
slowly at 50°C, leading to a 94% yield of amino product
2
3
(
PPIs) used as anti-ulcer drugs. The difference between
these drugs is that lansoprazole contains a trifluoromethyl
group, which can significantly improve drug stability and
help to enhance its inhibitory effect on gastric acid secretion
mechanism, thereby significantly improving the effect of
7
. Moreover, with the view of introducing dichloroethyl
24,25
clinical disease control.
groups, first of all, reaction of excess oxirane with 7 in
HOAc as the solvent resulted in the dihydroxyethyl com-
pound 8 in 90% yield. Subsequently, the hydroxyl groups
were exchanged for chlorine groups through the reaction
In this context, in view of the importance of bendamus-
tine hydrochloride as an anti-tumor agent as well as the
positive effect of CF in organic molecules, it would be
3
meaningful to introduce a CF group on bendamustine
3
of disubstituted product 8 with POCl at 80°C. The
3
hydrochloride (Figure 1(b)). In our continuing efforts for
preparing important bioactive compounds,26 herein, using
,4-dinitrochlorobenzene as a raw material, trifluoromethyl-
containing bendamustine hydrochloride has been designed
and synthesized by a series of organic synthesis steps includ-
ing substitution, selective reduction, N-acylation, cycliza-
tion, esterification, nitro-reduction, N-dihydroxyethylation,
chlorination, and acid-catalyzed hydrolysis (Scheme 1).
This synthetic route involves simple operations and mild
reaction conditions affording a 34% total yield.
dichloroethyl product 9 was isolated in 79% yield. Finally,
refluxing compound 9 in concentrated hydrochloric acid
led to trifluoromethylated bendamustine hydrochloride 10
in 92% yield. It is also noteworthy that both compounds 9
and 10 may exhibit the potential toxicities acting as
alkylation agents.
With the desired product 10 in hand, we successfully
grew a single crystal from the mixture solvents of MeCN
and EtOH, and the structure was confirmed by the X-ray
crystal analysis (Figure 2(a), Cambridge Crystallographic
Data Centre (CCDC) 1827727).
2
Compound 10 crystallizes in the P2 /c space group and
its molecular structure contains one protonated trifluoro-
1
Results and discussion
In order to introduce a trifluoromethyl group into bendamus- methyl-containing bendamustine cation and one free chlo-
tine hydrochloride, our investigation began with the con- rine anion. Furthermore, the dihedral angle between the
version of 2,4-dinitrochlorobenzene (1) into N-substituted benzene ring and imidazole ring is 3.4(86)°, indicating that
dinitroaniline 2 via nucleophilic aromatic substitution S Ar these rings are basically coplanar. Intermolecular O(1)–
N
with 2,2,2-trifluoroethylamine. In 2016, Machara group H(1O)···Cl(1) and N(1)–H(1N)···Cl(1) hydrogen bonds
reported a pathway to prepare the N-substituted dini- (Table 1) are formed between the free chlorine anions and
troaniline 2 and nitrophenyldiamine 3; however, only 7% trifluoromethyl-containing bendamustine and carboxyl car-
overall yield was obtained.27 To our delight, employing boxylic cations, and link the molecules forming a zig-zag

Yin et al.
3
Scheme 1. The synthetic pathway to trifluoromethylated bendamustine hydrochloride 10.
Figure 2. (a) The molecular structure of trifluoromethylated bendamustine hydrochloride 10 showing 30% probability of
displacement ellipsoids and the atom-numbering scheme. (b) One-dimensional array running along the c-axis. Hydrogen bonds are
shown as dashed lines.
chain along the c-axis, which is effective in stabilization of hydrochloride was designed and synthesized. The target
the crystal structure (Figure 2(b)).
compound 10 was prepared from 2,4-dinitrochlorobenzene
in nine steps in 34% overall yield. A study of the crystal
structure of trifluoromethyl-containing bendamustine
hydrochloride indicates that intermolecular hydrogen bond-
Conclusion
In summary, using bendamustine hydrochloride as an ing interactions are effective in stabilization of the crystal
original drug, trifluoromethyl-containing bendamustine structure, which may contribute evidence for studies of

4
Journal of Chemical Research 00(0)
Table 1. Distances and angles of possible weak interactions for
compound 10.
1
Preparation of 4-nitro-N -(2,2,2-
trifluoroethyl)benzene-1,2-diamine (3)
Atoms involved
Distance/Å
Angle/°
A mixture of compound 2 (26.51g, 100mmol) and
Na S·9H O (60.00g, 250mmol) in ethanol (200mL) was
–
D···A
H···A
2.22(2)
D–H···A
2
2
stirred at 25°C for 2h. Aqueous NaHCO solution
3
O(1)–H(1O)···Cl(1)a
N(1)-H(1N)···Cl(1)
3.020(2)
3.012(2)
156(4)
166(3)
−1
(
2.5mol·L , 100mL) was added dropwise under stirring,
2.185(14)
and the mixture was stirred for 3h. The crude product was
precipitated from ice water and was washed with distilled
water. Product 3 was obtained as a red-brown solid (18.94g,
a
Symmetry codes: x,–y+3/2, z−1/2.
2
7
8
(
1%); m.p. 163–165°C (m.p. 156–158°C); IR (KBr)
drug designs and mechanisms. Detailed biological activity
studies of the title product are currently underway in our
laboratory.
−1
vmax cm ): 3393, 3354, 1594, 1533, 1504, 1328, 1302,
1
257, 1164, 1139, 1110, 946, 876, 828, 807, 745, 675;
1
H NMR (300MHz, DMSO-d ): δ 7.51–7.48 (m, 2H), 6.79
6
(
(
d, J = 8.6 Hz, 1H), 6.34 (s, 1H), 5.27 (s, 2H), 4.17
13
q, J=9.6Hz, 2H); C NMR (75MHz, DMSO-d ): δ 140.9,
1
6
Experimental
38.2, 135.1, 125.5 (q, J=279.4Hz), 114.7, 108.5, 108.0,
1
9
General information
43. 6 (q, J = 32.5 Hz); F NMR (282 MHz, DMSO-d
6
):
+
δ −70.1 (s, 3F); HRMS (ESI) m/z calcd for C H F N O
8
9
3
3
2
Unless noted otherwise, all the reagents were commercial
available and were used without further purification.
Column chromatography was performed on EMD Silica
Gel 60 (200–300 Mesh) using a forced flow of 0.5–1.0 bar.
Melting points were measured with an X4-A microscopic
melting point apparatus. Nuclear magnetic resonance
+
[M+H] : 236.0647; found: 236.0649.
Preparation of 5-({5-nitro-2-[(2,2,2-
trifluoroethyl)amino]phenyl}amino)-5-
oxopentanoic acid (4)
(
NMR) spectra were recorded on a 300 MHz spectrome-
Glutaric anhydride (12.55g, 110mmol) and compound 3
(23.52g, 100mmol) were dissolved in toluene (250mL)
and stirred under reflux for 2.5h. The precipitated product
was filtered through a fine filter paper and rinsed with tolu-
ene (50mL) three times. Product 4 was obtained as a deep-
ter with chemical shifts reported in ppm (in CDCl or
Dimethyl sulfoxide-d (DMSO-d ), with TMS as the
internal standard). High resolution mass spectrometer
(
(
(
MS). Infrared (IR) spectra were recorded using a Thermo
fisher Nicolet IS50 spectrometer. X-Ray single crystal
diffraction data were recorded on a Bruker Smart APEX
Ⅱ
3
6
6
HRMS) were obtained on a 6540 Ultra High Definition
UHD) Accurate-Mass Quadrupole Time-of-Flight
Q-TOF) liquid chromatography/mass spectrometry (LC/
yellow solid (32.03g, 92%); m.p. 222–224°C; IR (KBr)
−1
(
vmax cm ): 3398, 3249, 2925, 1717, 1674, 1601, 1545,
1
8
9
2
4
2
526, 1505, 1330, 1308, 1258, 1161, 1131, 1114, 944, 824,
1
14, 746; H NMR (300MHz, DMSO-d ): δ 12.18 (br s, 1H),
6
.38 (s, 1H), 8.11 (d, J=2.5Hz, 1H), 7.98 (dd, J=9.2Hz,
.5Hz, 1H), 7.03 (d, J=9.2Hz, 1H), 6.90 (t, J=6.3Hz, 1H),
.25–4.13 (m, 2H), 2.43 (t, J=7.4Hz, 2H), 2.29 (t, J=7.2Hz,
CCD.
1
3
H), 1.88–1.78 (m, 2H); C NMR (75 MHz, DMSO-d ):
6
Preparation of 2,4-dinitro-N-(2,2,2-
trifluoroethyl)aniline (2)
δ 174.6, 171.9, 148.0, 136.8, 125.4 (q, J=279.5Hz),
23.04, 122.97, 122.4, 110.2, 43.4 (q, J=32.7Hz), 34.9,
1
19
A mixture of 2,4-dinitrochlorobenzene (compound 1) 33.4, 20.4; F NMR (282MHz, DMSO-d ): δ −69.9 (s, 3F);
6
+
+
(
(
20.26g, 100mmol), 2,2,2-trifluoroethylamine hydrochloride HRMS (ESI) m/z calcd for C H F N O [M+H ] :
1
3
15
3
3
5
16.26g, 120mmol), and triethylamine (22.26g, 220mmol) 350.0964; found: 350.0961.
in ethanol was stirred in a high-pressure reactor at 75°C for
4
8h. After cooling, the solvent was evaporated under
Preparation of 4-[5-nitro-1-(2,2,2-
reduced pressure and the mixture was diluted with water
and extracted with dichloromethane. The combined extracts
were dried over Na SO and concentrated under reduced
trifluoroethyl)-1H-benzo[d]imidazol-2-yl]
butanoic acid (5)
2
4
pressure. Product 2 was obtained as a yellow solid (25.13 g, Compound 4 (17.46g, 50mmol) was added to a 12.0mol·L−1
2
7
9
5%); m.p. 114–115 °C (m.p. 119–121 °C); IR (KBr) HCl solution (1.5L) in batches, and the mixture was stirred
−
1
(
vmax cm ): 3366, 3110, 1620, 1592, 1523, 1367, 1343, at 25°C for 48h. After the reaction was complete, a large
1
1
321, 1294, 1253, 1165, 1128, 1057, 954, 928, 710, 674; H amount of a faint yellow precipitate was formed from
NMR (300MHz, CDCl ): δ 9.17 (d, J=2.6Hz, 1H), 8.79 (s, the filtrate when the pH was adjusted to 2.0–3.0 with
3
1
H), 8.38 (dd, J=9.5Hz, 2.6Hz, 1H), 7.10 (d, J=9.5Hz, ammonium hydroxide. The faint yellow solid was washed
1
3
1
H), 4.18–4.08 (m, 2H); C NMR (75 MHz, CDCl ): with ice-water (50mL) three times. Product 5 was obtained
3
δ 147.7, 137. 9, 132.0, 130.7, 123.9 (q, J=278.5Hz), 124.2, as a faint yellow solid (13.52 g, 82%); m.p. 225–227 °C;
1
9
−1
1
14.0, 44.9 (q, J=34.9Hz); F NMR (282MHz, CDCl ): IR (KBr) (vmax cm ): 3422, 2973, 1712, 1618, 1526, 1334,
3
δ –71.2 (s, 3F); HRMS (electrospray ionization (ESI)) 1269, 1228, 1175, 1144, 1067, 972, 836, 817, 786, 743,
−
−
1
m/z calcd for C H F N O [M−H] : 264.0232; found: 639; H NMR (300MHz, DMSO-d ): δ 12.17 (br s, 1H),
8
5
3
3
4
6
2
64.0238.
8.51 (d, J=2.1Hz, 1H), 8.22 (dd, J=9.0Hz, 2.2Hz, 1H),

Yin et al.
5
7
.88 (d, J = 9.0 Hz, 1H), 5.44 (q, J = 9.2 Hz, 2H), 2.99
+
δ −69.4 (s, 3F); HRMS (ESI) m/z calcd for C H F N O
1
5
19
3
3
2
(
(
1
t, J = 7.4 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H), 2.13–2.03
m, 2H); C NMR (75MHz, DMSO-d ): δ 174.2, 159.4,
+
[
M+H] : 330.1429; found: 330.1423.
1
3
6
43.2, 141.5, 139.9, 124.2 (q, J=278.5Hz), 118.2, 114.8,
1
9
Preparation of ethyl 4-{5-[bis(2-hydroxyethyl)
amino]-1-(2,2,2-trifluoroethyl)-1H-benzo[d]
imidazol-2-yl}butanoate (8)
111.2, 44.0 (q, J=33.7Hz), 32.8, 25.5, 21.7; F NMR
(
282MHz, DMSO-d ): δ −69.3 (s, 3F); HRMS (ESI) m/z
6
+
+
calcd for C H F N O [M+H ] : 332.0858; found:
3
13
13
3
3
4
32.0853.
Compound 7 (6.59g, 20mmol) was added to a mixture of
glacial acetic acid (50mL) and water (50mL) and stirred at
5
°C. Oxriane (5mL) was added dropwise under stirring and
Preparation of ethyl 4-[5-nitro-1-(2,2,2-
trifluoroethyl)-1H-benzo[d]imidazol-2-yl]
butanoate (6)
the mixture was stirred at 5°C for 24h in a closed system.
After removing the solvent under reduced pressure, the resi-
due was dissolved in dichloromethane, washed with dis-
tilled water, and dried over anhydrous Na SO . The solvent
was concentrated in vacuo, and the crude product was
adjusted to pH 7.0 with a saturated aqueous solution of
sodium bicarbonate, filtered, and washed with distilled
Compound 5 (16.56g, 50mmol) in ethanol (150mL) was
stirred at 40°C, concentrated sulfuric acid (5mL) was added
dropwise under stirring, and the mixture was then stirred
under reflux for 3.5h. After the reaction was complete, the
mixture was evaporated in vacuo to obtain a white solid. The
crude product was dissolved in dichloromethane and adjusted
to pH 7.0 with a saturated aqueous solution of sodium bicar-
bonate, filtered, and washed with distilled water (50mL).
Product 6 was obtained as a white solid (16.85g, 94%); m.p.
2
4
water (50mL). Product 8 was obtained as a white solid
−1
(7.48g, 90%); m.p. 115–116°C; IR (KBr) (vmax cm ): 3286,
2989, 2955, 2876, 1741, 1628, 1591, 1501, 1450, 1419,
1
1390, 1289, 1260, 1189, 1168, 1058, 991, 826, 788, 654; H
NMR (300MHz, CDCl ): δ 7.15 (d, J=8.8Hz, 1H), 7.03
(d, J=1.8Hz, 1H), 6.80 (dd, J=8.9Hz, 2.00Hz, 1H), 4.63
3
−1
7
5–76°C; IR (KBr) (vmax cm ): 3414, 3115, 3009, 2983,
1716, 1619, 1524, 1394, 1329, 1265, 1224, 1178, 1162,
(
(
q, J=8.4Hz, 2H), 4.30 (s, 2H), 4.11 (q, J=7.1Hz, 2H), 3.83
t, J=4.7Hz, 4H), 3.55 (t, J=4.7Hz, 4H), 2.86 (t, J=7.5Hz,
1
1146, 1115, 1065, 971, 886, 834, 744, 638; H NMR
(
300MHz, DMSO-d ): δ 8.52 (d, J=2.2Hz, 1H), 8.23 (dd,
6
2H), 2.47 (t, J = 6.8 Hz, 2H), 2.22–2.13 (m, 2H), 1.24
J=9.0Hz, 2.2Hz, 1H), 7.90 (d, J=9.0Hz, 1H), 5.46 (q,
J=9.2Hz, 2H), 4.06 (q, J=7.1Hz, 2H), 3.00 (t, J=7.4Hz,
13
(
1
1
t, J=7.1Hz, 3H); C NMR (75MHz, CDCl ): δ 173.3,
54.4, 145.3, 143.5, 128.0, 123.6 (q, J=279.0Hz), 111.8,
09.7, 103.0, 60.6, 60.5, 56.1, 45.0 (q, J=35.5Hz), 33.1,
3
2
H), 2.52 (t, J=7.3Hz, 2H), 2.17–2.07 (m, 2H), 1.18 (t,
13
J=7.1Hz, 3H); C NMR (75MHz, DMSO-d ): δ 172.6,
19
6
26.0, 22.4, 14.3; F NMR (282MHz, CDCl ): δ −70.3 (s, 3F);
3
1
1
1
59.2, 143.2, 141.4, 139.8, 124.2 (q, J = 278.6 Hz), 118.2,
+
+
HRMS (ESI) m/z calcd for C H F N O [M+H ] :
19
27
3
3
4
14.8, 111.2, 59.9, 44.0 (q, J=33.8Hz), 32.7, 25.4, 21.7,
4.1; F NMR (282MHz, DMSO-d ): δ −69.3 (s, 3F);
418.1954; found: 418.1959.
19
6
+
+
HRMS (ESI) m/z calcd for C H F N O [M+H ] :
15
17
3
3
4
Preparation of ethyl 4-{5-[bis(2-chloroethyl)
amino]-1-(2,2,2-trifluoroethyl)-1H-benzo[d]
imidazol-2-yl}butanoate (9)
360.1171; found: 360.1175.
Preparation of ethyl 4-[5-amino-1-(2,2,2-
trifluoroethyl)-1H-benzo[d]imidazol-2-yl]
butanoate (7)
A mixture of POCl (20mL) and compound 8 (4.17g,
1
solvent under reduced pressure, the residue was dissolved
3
0mmol) was stirred at 80°C for 8h. After removing the
A mixture of 10% dry palladium on carbon (0.80g) and in dichloromethane, washed with a saturated aqueous solu-
compound 6 (17.97g, 50mmol) in ethanol (150mL) was tion of sodium bicarbonate, and dried over anhydrous
stirred at 35°C. A total of 80% hydrazine hydrate (9.00g) Na SO . The solvent was concentrated in vacuo, and the
2
4
was added dropwise over 30min under stirring, and the crude product was purified by column chromatography
mixture was stirred at 50°C for 3.0h. After filtration, the (PE: EtOAc=30: 1 v/v) to provide the pure compound.
filtrate was evaporated under reduced pressure to give a Product 9 was obtained as a white solid (3.58 g, 79%);
−1
solid. Product 7 was obtained as a white solid (15.42g, m.p. 68–69°C; IR (KBr) (vmax cm ): 3421, 2982, 2967,
−
1
9
3
1
(
(
(
4%); m.p. 112–114°C; IR (KBr) (vmax cm ): 3403, 3316, 1720, 1629, 1592, 1523, 1493, 1447, 1359, 1326, 1266, 1228,
220, 2981, 1736, 1627, 1513, 1496, 1459, 1393, 1333, 1180, 1154, 1111, 1024, 981, 834, 793, 757, 734, 657, 632;
264, 1230, 1154, 1023, 969, 861, 832, 655, 613; H NMR
300 MHz, DMSO-d ): δ 7.23 (d, J = 8.5 Hz, 1H), 6.74 7.08 (d, J=2.3Hz, 1H), 6.79 (dd, J=8.9Hz, 2.4Hz, 1H),
d, J=1.8Hz, 1H), 6.57 (dd, J=8.5Hz, 2.0Hz, 1H), 5.11 4.66 (q, J=8.4Hz, 2H), 4.13 (q, J=7.1Hz, 2H), 3.77–3.72
q, J=9.3Hz, 2H), 4.78 (s, 2H), 4.05 (q, J=7.1Hz, 2H), (m, 4H), 3.67–3.61 (m, 4H), 2.91 (t, J=7.5Hz, 2H), 2.51
1
1
H NMR (300MHz, CDCl ): δ 7.22 (d, J=8.8Hz, 1H),
3
6
2
.81 (t, J=7.4Hz, 2H), 2.46 (t, J=7.4Hz, 2H), 2.07–1.98 (t, J=6.8Hz, 2H), 2.29–2.20 (m, 2H), 1.25 (t, J=7.1Hz,
1
3
13
(
m, 2H), 1.18 (t, J=7.1Hz, 3H); C NMR (75MHz, 3H); C NMR (75MHz, CDCl ): δ 173.2, 154.7, 143.9,
3
DMSO-d ): δ 172.7, 153.9, 144.4, 143.3, 127.6, 124.5 (q, 143.1, 128.5, 123.5 (q, J=278.8Hz), 110.8, 110.0, 103.0,
J=279.1Hz), 111.6, 110.2, 102.2, 59.8, 43.6 (q, J=33.5Hz), 60.5, 54. 6, 45.0 (q, J=35.6Hz), 40.6, 33.1, 26.0, 22.2,
6
1
9
19
3
2.9, 25.1, 22.2, 14.1; F NMR (282 MHz, DMSO-d ): 14.2; F NMR (282MHz, CDCl ): δ −70.3 (s, 3F); HRMS
6
3

6
Journal of Chemical Research 00(0)
Table 2. Crystallographic characteristics, experimental and
refinement data for compound 10.
X-Ray structure determination
Single crystals suitable for X-ray diffraction were selected,
glued on fiberglass, and mounted on a Bruker APEX II CCD
diffractometer equipped with a graphite-monochromatic
Mo-Kα radiation at 296K (λ=0.71073Å). Data collection
and reduction were performed using the APEX2 software
suite. Empirical absorption corrections were carried out using
SADABS. The structure was solved by direct methods and
expanded by difference Fourier techniques. The non-hydro-
gen atoms were refined anisotropically and the hydrogen
atoms were added according to the theoretical models with
U (H)=1.2 (1.5 for methyl) U (C). The structure was
Empirical formula
C H C F N O
17 21 l3 3 3 2
−1
Formula weight (g·mol )
462.72
Crystal system
Space group
Z
Monoclinic
P2 /c
1
4
a (Å)
b (Å)
c (Å)
β (°)
11.1969(11)
13.8329(13)
14.2207(14)
110.192(2)
2067.2(3)
1.487
V (Å3)
Density (calc. g·cm )
Absorption coefficient (mm )
F(000), e
iso
eq
−3
2
refined by full-matrix least-squares method on F with
SHELXL-97. The crystallographic data for the compound 10
−1
0.488
952
(CCDC, 1827727) is summarized in Table 2.
Temperature (K)
Crystal size (m )
θ range for data collection
296(2)
0.24×0.16×0.10
1.94–25.01
3
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.
Collection range
−13⩽h⩽12
−
13⩽k⩽16
14⩽l⩽16
−
Reflections collected/unique
11262/3636
Rint
0.0346
Funding
Refinement method
Full-matrix least-
squares on F2
3636/2/259
R1 =0.0623,
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 National Natural Science
Foundation of China (grant nos. 21572026, 21702019, and
Data/restraints/parameters
Final R indices (I>2sigma(I))
wR =0.1712
2
2
1702020), the Advanced Catalysis and Green Manufacturing
R indices (all data)
R1 =0.0721,
Collaborative Innovation Center, and the Priority Academic
Program Development of Jiangsu Higher Education Institutions.
wR =0.1837
2
2
Goodness-of-fit on F
Δρmax/Δρmin (e·Å )
1.039
0.743/−0.723
3
ORCID iD
Ke Yang
https://orcid.org/0000-0001-9506-4338
+
+
(
ESI) m/zcalcdfor C H Cl F N O [M+H ] :454.1276;
1
9
25
2
3
3
2
Supplemental material
found: 454.1271.
Supplemental material ( H, 13C and 19F NMR spectra of com-
1
pound 2–10) for this article is available online.
Preparation of 4-{5-[bis(2-chloroethyl)amino]-
1
-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-
-yl}butanoic acid hydrochloride (10)
2
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