Tetraphenylborate Salt of Bambuterol (Bambec): Synthesis, Characterization and X-ray Structure of N-(2-(3,5-bis((dimethylcarbamoyl)oxy)phenyl)-2-hydroxyethyl)-2-methylpropan-2-aminium tetraphenylborate

Article abstract of DOI:10.1007/s10870-015-0592-0

The title compound tetraphenylborate salt of bambuterol (Bambec), N-(2-(3,5-bis((dimethylcarbamoyl)oxy)phenyl)-2-hydroxyethyl)-2-methylpropan-2-aminium tetraphenylborate (4), was prepared in 73 % yield by the reaction of 5-(2-(tert-butylamino)-1-hydroxyet

Full text of DOI:10.1007/s10870-015-0592-0

J Chem Crystallogr
DOI 10.1007/s10870-015-0592-0
ORIGINAL PAPER
Tetraphenylborate Salt of Bambuterol (BambecÒ): Synthesis,
Characterization and X-ray Structure of N-(2-(3,5-
bis((dimethylcarbamoyl)oxy)phenyl)-2-hydroxyethyl)-2-
methylpropan-2-aminium tetraphenylborate
Gamal A. E. Mostafa1 Hazem A. Ghabbour1 Obaid S. AlRuqi1
•
•
•
Hoong-Kun Fun1,2 Hatem A. Abdel-Aziz1,3
•
Received: 2 February 2015 / Accepted: 6 May 2015
Ó Springer Science+Business Media New York 2015
Abstract The title compound tetraphenylborate salt of
bambuterol N-(2-(3,5-bis((dimethylcar-
(BambecÒ),
obtained by slow evaporation from acetonitrile. Compound 4
crystallizes in the monoclinic, space group P21/c, with
˚
a = 8.8931 (2) A, b = 20.4639 (6) A, c = 21.4393 (6) A,
˚
3
˚
bamoyl)oxy)phenyl)-2-hydroxyethyl)-2-methylpropan-2-
aminium tetraphenylborate(4), was preparedin73 % yield by
the reaction of 5-(2-(tert-butylamino)-1-hydroxyethyl)-1,3-
phenylene bis(dimethylcarbamate) hydrochloride (bam-
buterol hydrochloride) (2) with sodium tetraphenylborate (3)
in deionized water, at ambient temperature, through anion
exchange reaction. The structure of the title borate salt was
characterized by IR, mass and 1H NMR analyses. Colorless
crystals of 4 suitable for an X-ray structural analysis were
˚
b = 93.640 (2)°, V = 3893.81 (18) A , Z = 4.
Graphical Abstract Synthesis, characterization and X-ray
structure of tetraphenylborate salt of bambuterol (Bam-
becÒ), the drug for the treatment of asthma, bronchospasm,
emphysema, and chronic obstructive pulmonary disease.
Keywords Bambuterol Á (BambecÒ) Á Anion exchange Á
Tetraphenylborate salt Á Crystal structure Á X-ray analysis
N
O
O
H
O
O
N
O
_
B
N
H
+
H
Introduction
& Hatem A. Abdel-Aziz
hatem_741@yahoo.com
Bambuterol hydrochloride is an oral a long acting beta-
adrenoceptor agonist (LABA), it has been approved for the
treatment for once-daily treatment of the symptoms of
asthma, bronchospasm, emphysema, and chronic obstruc-
tive pulmonary disease in 28 countries. It is produced in
marketing by AstraZeneca pharmaceutical company as
BambecÒ. Bambuterol, a biscarbamate ester prodrug of the
b2 adrenergic agonist terbutaline, is available in 10 and
1
Department of Pharmaceutical Chemistry, College of
Pharmacy, King Saud University, P.O. Box 2457,
Riyadh 11451, Saudi Arabia
2
3
X-ray Crystallography Unit, School of Physics, Universiti
Sains Malaysia (USM), 11800 Gelugor, Penang, Malaysia
Department of Applied Organic Chemistry, National
Research Center, Dokki, Cairo 12622, Egypt
123

J Chem Crystallogr
20 mg (25 and 50 lmol) tablets as the hydrochloride salt
[1, 2]. It has been demonstrated that both of bambuterol
enantiomers are potent in the treatment of asthma [3].
QueryOn the other hand, sodium tetraphenylborate is the
organic compound with the formula NaB(C6H5)4. It is a salt,
wherein the anion consists of four phenyl rings bonded to
boron. This white crystalline solid is used to prepare other
tetraphenylborate salts, which are often highly soluble in
organic solvents. The compound is used in inorganic and
organometallic chemistry as a precipitating agent. Further-
more, tetraphenylborate recently was used as a precipitating
agent for radioactive ion extraction [4]. It is also used as
precipitating agent for formation of new active materials
which were used as ion sensing material for some drug [5–9].
Many pharmaceutical salts are not chemically equiva-
lent and such chemical differences causes differences in
their therapeutic prosperities and increase their chemical
stability. Salt selection is now a common standard op-
eration in drug development and in most cases the drug
salts show preferential properties as compared with the
parent agent. Consequently, there has been a huge interest
in the production of drug salts. Almost half of the clinically
used drugs are salts and many drugs are now produced in
more than one salt form [10].
hydrochloride) (2) (0.4039 g, 1 mmol) in deionized water
(10 mL) a solution ofsodiumtetraphenylborate(3) (0.3422 g,
1 mmol) in deionized water (10 mL) was added. The formed
white precipitate was filtered off, washed with cold deionized
water. The precipitate was dried under vacuum to give the title
ion-pairs complex. Recrystallization from methanol the title
compound in 73 %; m.p. 198–200 °C; IR m 3502–3045
1
(2NH?OH), 1670–1654 (2C=O) cm-1; H NMR (DMSO–
d6, 500 MHz) d 1.30 (s, 9H, –C(CH3)3, 2.92, 3.05 (s, 12H, 2 –
N(CH3)2), 3.10–3.13 (m, 2 H, CH2), 4.84–4.87 (m, 1H, CH),
6.33(bs, D2O exchangeable, 1H, OH), 6.79–6.82 (m, 4H, 4H4
of tetraphenyl borate), 6.92–6.95 (m, 9H, H4 of benzene ring
of bambuterol, 4H3 and 4H5 of tetraphenyl borate), 7.11 (d,
2H, J = 3.0 Hz, H2 and H6 of benzene ring of bambuterol),
7.18–7.20 (m, 8, 4H3 and 4H5 of tetraphenyl borate), 8.50
(2bs, D2O exchangeable, 2H, 2NH); 13C NMR (DSMO-d6,
125 MHz) d 25.55 (3C, –C(CH3)3, 36.16 (2C, –N(CH3)2),
39.58 (2C, –N(CH3)2), 47.71 (CH2), 56.97 (–C(CH3)3), 68.92
(–C(OH)–), 115.90 (C4 of benzene ring of bambuterol),
116.83 (C2 and C6 of benzene ring of bambuterol), 121.98
(4C4 of tetraphenyl borate), 125.73, 125.75, 125.77, 125.79
(4C3 and 4C5 of tetraphenyl borate), 136.00 (4C2 and 4C6 of
tetraphenyl borate), 144.21 (C1 of benzene ring of bam-
buterol), 152.09 (C=O), 154.11 (C=O), 163.25, 163.64,
164.03, 164.42 (4C1 of tetraphenyl borate); ESI-MS (?ve) m/
z: 368.1 (M?–(Ph)4B), 294.0.
In this study we hope to report herein the synthesis,
characterization and X-structure of tetraphenylborate salt
of bambuterol (BambecÒ).
X-ray Crystallography
Experimental
Chemistry
General
General
Single crystals of 4 were obtained by slow evaporation from
acetonitrile. A good crystal of a suitable size was selected for
X-ray diffraction analysis. Data were collected on a Bruker
APEX-II CCD diffractometer equipped with graphite
monochromatic CuK\a radiation (k = 1.54178) at 296 (2) K.
Cell refinement and data reduction were done by Bruker
SAINT; program used to solve structure and refine structure is
SHELXS-97 [11]. The final refinement was performed by
full- matrix least-squares techniques with anisotropic thermal
data for non-hydrogen atoms on F2. All the hydrogen atoms
were placed in calculated positions and constrained to ride on
their parent atoms. Multi-scan absorption correction was ap-
plied byuse of SADABS software. The crystal and refinement
data are given in Table 1, selected geometric parameters are
listed in Table 2, and selected torsion angles are given in
Table 3 and hydrogen-bond geometry are listed in Table 4.1
Melting point was determined on a Gallenkamp melting point
apparatus and it is uncorrected. Infrared (IR) Spectrum was
recorded as KBr disks using the Perkin Elmer FT-IR Spectrum
BX apparatus. NMR Spectra were scanned in DMSO-d6 on a
Brucker NMR spectrometer operating at 500 MHz for 1H and
125 MHz for 13C. Chemical shifts are expressed in d-values
(ppm) relative to TMS as an internal standard. Coupling con-
stants (J) are expressed in Hz. D2O was added to confirm the
exchangeable protons. Mass spectrum was measured on an
Agilent Triple Quadrupole 6410 QQQ LC/MS equipped with
an ESI (electrospray ionization) source.
N-(2-(3,5-bis((dimethylcarbamoyl)oxy)phenyl)-2-
hydroxyethyl)-2-methylpropan-2-aminium
tetraphenylborate (4)
1
Crystallographic data for the structure 4 has been deposited with the
Cambridge Crystallographic Data Center (CCDC) under the numbers
CCDC 1037897-1037898. Copies of the data can be obtained, free of
charge, on application to CCDC 12 Union Road, Cambridge CB2
1EZ, UK [Fax: ?44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk/
http://www.ccdc.cam.ac.uk].
To a solution of 5-(2-(tert-butylamino)-1-hydroxyethyl)-1,3-
phenylene bis(dimethylcarbamate) hydrochloride (bambuterol
123

J Chem Crystallogr
Table 1 Summary of X-ray crystallographic data for compound 4
Crystal data
Chemical formula
Mr
C18H30N3O5ÁC24H20
B
687.66
Crystal system, space group
Temperature (K)
Monoclinic, P21/c
296 (2)
˚
a, b, c (A)
8.8931 (2), 20.4639 (6), 21.4393 (6)
b (°)
V (A )
93.640 (2)
3
˚
3893.81 (18)
Z
4
Radiation type
l (mm-1
Cu Ka
)
0.61
Crystal size (mm)
Data collection
0.31 9 0.18 9 0.15
Diffractometer
Bruker APEX-II CCD diffractometer
Multi-scan SADABS Bruker 2014
0.827, 0.910
Absorption correction
T
min, Tmax
No. of measured, independent and observed [I [ 2r(I)] reflections 26859, 7277, 5221
Rint
0.049
Refinement
R[F2 [ 2r(F2)], wR(F2), S
No. of reflections
No. of parameters
No. of restraints
H-atom treatment
0.062, 0.191, 1.04
7277
478
0
H atoms treated by a mixture of independent and constrained refinement
-3
˚
Dqmax, Dqmin (e A
)
0.83, -0.41
Results and Discussion
Chemistry
˚
Table 2 Selected bond lengths (A) and angles (°) for compound 4
˚
Bond lengths (A)
O1–C2
1.39 (3)
1.21 (3)
1.20 (3)
1.40 (4)
1.32 (3)
N2–C14
N3–C16
C24–B1
N1–C8
1.45 (4)
1.33 (3)
1.64 (4)
1.49 (2)
The reaction of 5-(2-(tert-butylamino)-1-hydroxyethyl)-1,3-
phenylene bis(dimethylcarbamate) hydrochloride (bam-
buterol hydrochloride) (2) with sodium tetraphenylborate (3)
in deionized water, at ambient temperature, afforded the title
compound tetraphenylborate salt of bambuterol (BambecÒ),
N-(2-(3,5-bis((dimethylcarbamoyl)oxy)phenyl)-2-hydrox-
yethyl)-2-methylpropan-2-aminium tetraphenylborate (4) in
73 % yield through anion exchange reaction (Scheme 1).
The IR of compound 4 showed the absorption bands of
two carbonyl functions in the ring 1670–1654 cm-1 while
the absorption bands of –OH and 2 –NH appeared in the
O3–C13
O4–C16
O5–C7
N2–C13
Bond angles (°)
C2–O1–C13
C4–O2–C16
C8–N1–C9
C13–N2–C15
C13–N2–C14
C16–N3–C18
C17–N3–C18
C16–N3–C17
O1–C2–C3
O1–C2–C1
O2–C4–C3
117.85 (19)
121.02 (18)
117.37 (17)
118.50 (3)
123.40 (2)
119.60 (2)
117.10 (3)
123.30 (2)
120.60 (2)
117.20 (2)
121.67 (17)
O1–C13–O3
O3–C13–N2
O4–C16–N3
O2–C16–O4
O2–C16–N3
C19–C24–B1
O5–C7–C6
O5–C7–C8
N1–C8–C7
N1–C9–C12
O1–C13–N2
121.90 (2)
126.10 (2)
125.60 (2)
123.40 (2)
111.00 (2)
124.43 (19)
113.30 (2)
107.61 (19)
110.65 (16)
108.90 (2)
111.90 (2)
ring 3502–3045 cm-1
.
1
The HNMR (DSMO-d6, 500 MHz) of 4 revealed the
singlet signal of tert-butylamino protons at d 1.30 in ad-
dition to the singlet signals of dimethylcarbamate protons
which appeared at d 2.92 and 3.05. Th multiplet signals of
CH2 and CH protons appeared in the region d 3.10–3.13
123

J Chem Crystallogr
Table 3 Selected torsion
angles (°) for compound 4
Torsion angle
(°)
175.10 (2)
Torsion angle
(°)
C6–C1–C2–O1
C13–O1–C2–C3
C13–O1–C2–C1
C2–C3–C4–O2
C16–O2–C4–C5
C16–O2–C4–C3
C2–C1–C6–C5
C5–C6–C7–O5
C1–C6–C7–C8
C5–C6–C7–C8
C9–N1–C8–C7
O5–C7–C8–N1
C6–C7–C8–N1
C8–N1–C9–C12
C8–N1–C9–C10
C8–N1–C9–C11
C15–N2–C13–O1
C2–O1–C13–O3
C2–O1–C13–N2
C18–N3–C16–O4
C17–N3–C16–O4
C18–N3–C16–O2
C17–N3–C16–O2
C4–O2–C16–O4
C32–C31–C36–B1
C38–C37–C42–B1
C40–C41–C42–C37
C40–C41–C42–B1
C37–C42–B1–C24
C41–C42–B1–C24
C37–C42–B1–C30
C41–C42–B1–C30
C37–C42–B1–C36
C41–C42–B1–C36
C19–C24–B1–C42
C23–C24–B1–C42
C19–C24–B1–C30
C23–C24–B1–C30
C19–C24–B1–C36
C23–C24–B1–C36
C29–C30–B1–C42
C25–C30–B1–C42
C29–C30–B1–C24
C25–C30–B1–C24
C29–C30–B1–C36
C25–C30–B1–C36
C31–C36–B1–C42
C4–O2–C16–N3
176.20 (2)
177.00 (3)
1.50 (4)
-62.30 (3)
123.80 (2)
172.90 (2)
-132.90 (2)
55.00 (3)
-176.60 (3)
-110.80 (3)
67.20 (3)
0.80 (3)
9.90 (3)
-136.70 (2)
-79.70 (3)
102.00 (3)
168.20 (2)
57.20 (3)
-172.20 (2)
128.50 (3)
-53.50 (3)
-12.20 (3)
168.20 (2)
-132.20 (2)
48.30 (3)
-178.20 (2)
60.80 (3)
-62.10 (3)
179.60 (2)
-177.30 (3)
-8.40 (3)
173.60 (2)
-3.00 (4)
178.00 (3)
177.80 (3)
-1.30 (4)
2.40 (4)
107.90 (2)
-71.70 (3)
90.00 (2)
-86.50 (2)
-149.60 (2)
33.90 (3)
-28.80 (3)
154.70 (2)
145.80 (2)
-178.30 (2)
˚
Table 4 Hydrogen-bond geometry (A, °), Cg3 is (C25–C30)
125.79 (4C3 and 4C5), 136.00 (4C2 and 4C6), 163.25,
163.64, 164.03, 164.42 (4C1), respectively. Finally, the
signals of carbamate carbons appeared at d 152.09 and
154.11, respectively.
D–HÁÁÁA
D–H
HÁÁÁA
DÁÁÁA
D–HÁÁÁA
N1–H1BÁÁÁO4i
N1–H1CÁÁÁO3i
O5–H5BÁÁÁO3i
O5–H5BÁÁÁN1
C39–H39AÁÁÁCg3
0.90
0.90
0.82
0.82
0.97
2.00
1.91
2.48
2.32
2.71
2.88 (3)
2.79 (3)
3.28 (3)
2.78 (3)
3.54 (3)
170.00
166.00
171.00
117.00
150.00
The ESI-MS (?ve) of compound 4 revealed a peak at m/
z 368.1 equal to (M?– (Ph)4B) in addition to the peak at m/
z 294.0.
Symmetry code (i) x ? 1, y, z
X-ray crystallography
The title compound crystallizes with one cation and anion
in the asymmetric unit (Figs. 1, 2), that is a N-(2-(3,5-
bis((dimethylcarbamoyl)oxy)phenyl)-2-hydroxyethyl)-2-
methylpropan-2-aminium cation and a tetraphenylborate
anion. As typical for tetraphenylborate, the te-
traphenylborate anion is in a tetrahedral geometry around
the B atom [C–B–C angles of 108.80 (19)°–110.13 (18)°].
Regarding the bambuterol cation, the structure has chiral
center in C7 and the absolute configuration around this
carbon is S, all side substitutions attached to the phenyl
ring (C1–C6) were located in same direction and this
crystal structure seems to be the same of bambuterol hy-
drochloride which published in 2008 by Gao Cao et al. [2].
The crystal structure is stabilized by N–HÁÁÁO and O–HÁÁÁO
and 4.84–4.87, respectively. The protons of phenyl groups
of tetraphenyl borate anion and benzene ring of R-bam-
buterol apeared in the aromatic region while the two broad
D2O exchangeable signals of OH and 2 NHs apeared at d
6.33 and 8.50, respectively.
The 13C NMR (DSMO-d6, 125 MHz) of compound 4
exhibited the signals of aliphatic carbons at d 25.55 (3C, –
C(CH3)3, 36.16 (2C, –N(CH3)2), 39.58 (2C, –N(CH3)2),
47.71 (CH2), 56.97 (–C(CH3)3) and 68.92 (–C(OH)–), re-
spectively. Furthermore, 13C NMR of 4 showed the signals
of benzene ring of bambuterol at d 115.90 (C4), 116.83 (C2
and C6), 144.21 (C1), respectively, while it showed the
signals due to the carbons of four phenyl rings of te-
traphenyl borate at d 121.98 (4C4), 125.73, 125.75, 125.77,
123

J Chem Crystallogr
N
O
O
N
N
O
O
N
+
Na
O
O
H
O
O
H
_
O
O
B
HCl
+
N
H
N
H
+
_
Cl
H
1
3
2
- NaCl
N
O
H
O
O
N
O
_
B
N
H
+
O
H
4
Scheme 1 Synthesis of tetraphenylborate salt of bambuterol (BambecÒ) 4
Fig. 1 View of the two ions of
4 in the asymmetric unit
showing the atom-labelling
scheme. Ellipsoids are drawn at
the 50 % probability level with
H atoms represented by circles
of arbitrary size
hydrogen bonds into a three-dimensional framework
structure forming the chain extending along along the
a axis direction. The crystal packing is further stabilized by
weak C–HÁÁÁp (phenyl) interactions (Table 4) that links the
adjacent chains into a two dimensional structure along the
bc plane.
123

J Chem Crystallogr
Fig. 2 Crystal packing of 4
showing intermolecular
N–HÁÁÁO and O–HÁÁÁO hydrogen
bonds as dashed lines (H atoms
not involved in hydrogen
bonding are omitted for clarity)
4. Shinsuke T, Tetsuya S, Takahiro Y (2014) Jpn. Kokai Tokkyo
Koho, JP 2014181985 A
Conclusion
5. Ghaedi M, Shahamiri A, Hajati S, Mirtamizdoust BA (2014)
Novel PVC-membrane optical sensor for high sensitive and se-
lective determination of Cu2? ion based on synthesized (E)-N0-
(pyridin-2-ylmethylene)isonicotin-ohydrazide From. J Mol Liq
199:483–488
6. Yan Z, Wang S, Wang H, Wu S (2013) Bismuth (III) PVC
membrane ion selective electrodes based on two compounds:
acylhydrazone and thiosemicarbazone with 1,3,4-thiadiazole.
Mater Sci Eng C 33(5):2562–2568
7. Hefnawy MM, Homoda AM, Abounassif MA, Alanazi AM, Al-
Majed A, Mostafa GA (2014) Potentiometric determination of
moxifloxacin in some pharmaceutical formulation using PVC
membrane sensors. Chem Cent J 8:59
In conclusion, the title compound 4 was prepared effi-
ciently by the reaction of bambuterol hydrochloride 2 with
sodium tetraphenylborate (3) in deionized water at ambient
temperature. The structure of 4 was established under the
basis of its X-ray single crystal analysis.
Acknowledgments The authors would like to extend their sincere
appreciation to the Deanship of Scientific Research at King Saud
University for its funding of this research through the Research Group
Project no. RG-1436-024.
Conflict of interest The authors have declared that there is no
conflict of interest.
8. Mostafa GA, Hefnawy M, Al-Majed A (2010) Membrane sensors
for the selective determination of donepezil hydrochloride.
J AOAC Int 93:549–555
9. Mostafa GA, Al-Majed A (2008) Characteristics of new com-
posite- and classical potentiometric sensors for the determination
of pioglitazone in some pharmaceutical formulations. J Pharm
Biomed Anal 48:57–61
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