Synthesis, characterization and crystal structure of methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate

Article abstract of DOI:10.14233/ajchem.2015.18745

Methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate was synthesized from 4-hydroxy-3-methoxybenzoic acid. Firstly, 4-hydroxy-3-methoxybenzoic acid reacted with methanol in the presence of concentrated sulfuric acid at reflux temperature, then the product of the first step was transformed into benzyl bromide by the process of substitution reaction by using K₂CO₃. Finally, the product was obtained by nitration reaction with HNO₃. The product was characterized by ¹H NMR and LC-MS. The crystal structure of compound I was investigated using X-ray diffraction and SHELXTL-97 software. The results indicated that compound I crystallized in the monoclinic system, space group P2(1)/c with a = 5.590(2), b = 17.591 (7), c = 15.427(6) ?, V = 1516.9 (10) ?³; Z 4.

Full text of DOI:10.14233/ajchem.2015.18745

Asian Journal of Chemistry; Vol. 27, No. 7 (2015), 2647-2650
A
SIAN
J
OURNAL OF HEMISTRY
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http://dx.doi.org/10.14233/ajchem.2015.18745
Synthesis, Characterization and Crystal Structure of Methyl 4-(Benzyloxy)-5-methoxy-2-nitrobenzoate
1
1
1
1
3
2,*
KAI WANG , XIU-QIN ZHANG , JIAN ZHU , QIANG CHEN , ZHONG-QIANG ZHANG and LI FAN
1High Technology Research Institute of Nanjing University, Changzhou 213162, Jiangsu Province, P.R. China
2Gastroenterology Department Nanjing Medical University Affiliated Changzhou No. 2 Hospital, Changzhou 213000, Jiangsu Province, P.R. China
3School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210000, Jiangsu Province, P.R. China
*Corresponding author: E-mail: wkcoool@163.com
Received: 13 September 2014;
Accepted: 8 October 2014;
Published online: 30 March 2015;
AJC-17097
Methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate was synthesized from 4-hydroxy-3-methoxybenzoic acid. Firstly, 4-hydroxy-3-
methoxybenzoic acid reacted with methanol in the presence of concentrated sulfuric acid at reflux temperature, then the product of the
first step was transformed into benzyl bromide by the process of substitution reaction by using K2CO3. Finally, the product was obtained
1
by nitration reaction with HNO3. The product was characterized by H NMR and LC-MS. The crystal structure of compound I was
investigated using X-ray diffraction and SHELXTL-97 software. The results indicated that compound I crystallized in the monoclinic
system, space group P2(1)/c with a = 5.590(2), b = 17.591 (7), c = 15.427(6) Å, V = 1516.9 (10) Å3; Z 4.
Keywords: Vandetanid, Synthesis, Characterization, Crystal structure.
at 30 0.5 °C. The sample was dissolved in a 5 mm diameter
‘
INTRODUCTION
tube at a concentration of 20 mg/mL. X-ray diffraction was
Vandetanib1-5 is an orally active antagonist of vascular
performed on a Bruker APEXII CCD diffractometer. Mass
endothelial growth factor (VEGF) receptor-2 (VEGFR-2),
epidermal growth factor receptor (EGFR) and RET kinase. It
was approved for the treatment of metastatic medullary thyroid
cancer (MTC) by U.S. Food and Drug Administration (FDA)
on June 4, 2011.
Methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (I) is
a key intermediate compound for vandetanib. It was synthe-
sized from 4-hydroxy-3-methoxybenzoic acid through a three-
steps reaction.
Herein, we introduce a synthetic method of methyl 4-
(benzyloxy)-5-methoxy-2-nitrobenzoate (I) from compound
1 by methylation, substitution and nitration reactions (Scheme-
I), with an overall yield of about 79.5 %. Meanwhile, the crystal
structure of methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate
(I) was also investigated.
spectrum of (I) was analyzed using Trace DSQ LC/MS (Thermo
Electron Co., USA).
Synthesis of compound I: A 250 mL, round-bottomed
flask with a stirring bar, a solution of 4-hydroxy-3-methoxy-
benzoic acid (20 g, 118.94 mmol) was added slowly to a
solution of methanol (100 mL) and concentrated sulfuric acid
(10 mL).After being stirred for 12 h at reflux, saturated solution
of sodium bicarbonate was added to adjust the pH to 7. Dichloro-
methane was added and the mixture was then filtered and the
organic phase evaporated on a rotary evaporator and to obtain
the compound 2 (20.37 g, 94 %).
Compound 2 (20.4 g, 111.98 mmol) was added into a
500 mL, round-bottomed flask with a stirring bar, then benzyl
bromide (18 mL), potassium carbonate (22 g, 156.8 mmol),
DMF (200 mL) were added. It was stirred for 6 h at 80 °C.
Then the reaction system was poured into right amount of
water, white solid (3) was obtained by filtration (28.97 g,
95 %).
EXPERIMENTAL
4-Hydroxy-3-methoxybenzoic acid was supplied by Well
Chemical Co. Ltd of Jiangsu (Changzhou, People's Republic
of China), its mass content is 99 % determined by GC. Benzyl
bromide was purchased from Sinopharm Chemical Reagent
Co. Ltd of China. All other chemicals were of reagent grade
and used without purification as received.
Compound 3 (16.54 g, 60.74 mmol) was dissolved in
CH3COOH (50 mL) and then added into a 250 mL, round-
bottomed flask with a stirring bar. Then HNO3 (25 mL) was
added in to the system slowly to keep the temperature of the
reaction above 5 °C. The reaction temperature was raised to
50 °C and kept for another 2 h.After that the system was poured
1H NMR spectrum was obtained with Bruker AV-500
spectrometer at 500.13 MHz and measured in CDCl3 solution

2648 Wang et al.
Asian J. Chem.
O
O
O
O
O
O
O
O
O
Ph-CH2Br
OH
CH3OH
HO
HO
2
1
3
O
O
O
O
O-
HNO3
N+
O
Scheme-I: Route for the synthesis of compound I
into water and pale yellow solid (I) was obtained6-8 (18.3 g, 95
%, m.p.: 134-135 °C).
TABLE-1
CRYSTALLOGRAPHIC DATA FOR COMPOUND (I)
ITEM
Formula
Formula weight
Temperature (K)
Wavelength (Å )
Crystal system
Space group
a (Å )
Data or description
C16H15NO6
317.29
296 (2)
0.71073
Monoclinic
P2(1)/c
5.590(2)
17.591(7)
15.427(6)
1516.9(10)
4
1.389
0.11
664
Crystals of I that suitable for X-ray diffraction were
obtained by slow evaporation of dichloromethane solution of I.
X-Ray crystallography: A colourless block-like crystal
of compound I grown in dichloromethane with dimensions of
0.35 mm × 0.25 mm × 0.16 mm was used for structural deter-
mination. Diffraction data were collected on a BrukerAPEXII
CCD diffractometer by using graphite monochromated MoKα
radiation (λ = 0.71073 Å). The structure was solved by direct
methods with SHELXS-97 and refined on the F2 by full-matrix
least-squares method with SHELXL-97. All non-hydrogen
atoms were refined anisotropically.
b (Å )
c (Å )
Volume (Å3)
Z
Calculated density (g/cm3)
Absorption coefficient (mm-1)
F(000)
RESULTS AND DISCUSSION
Crystal size (mm)
Theta range for data collection (°)
Reflections collected/unique
Completeness to theta = 25.38 (%)
Max. and min. transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
Largest diff. peak and hole (e. Å-3)
0.30 × 0.25 × 0.16
1.8 to 25.0
2671/1410 [Rint = 0.089]
99.7
0.968 and 0.983
Full-matrix least-squares on F2
2671/0/196
Identification of resonance in the spectra: In the 1H NMR
of compound I, the peak at 5.20 ppm was ascribed to the proton
of methylene which was substituted by phenyl group. The other
data was described as below, 1H NMR (CDCl3): δ 3.91 (3H,
s), 3.98 (3H, s), 5.20 (2H, s), 7.08 (1H, s), 7.26-7.46 (5H, m),
7.52 (1H, s).
In the LC spectrum peak at 4.930 min. ascribed to the
compound I. In the MS spectrum, the existence of the peaks
at right end showed the compound I, m/z 317.15 was ascribed to
molecular ion peak (M+), m/z 339.95 was ascribed to M+Na peak.
The crystal configuration of compound I was confirmed
by X-ray structural analysis. Experimental details for X-ray
data collection were presented in Table-1 and the geometric
parameters for compound I were listed in Table-2. Molecular
structure and packing plot of compound I were showed in
Figs. 1 and 2, respectively.
1.01
R1 = 0.0987, wR2 = 0.1191
R1 = 0.0547, wR2 = 0.1140
0.21 and -0.23
C14
O2
C12
O5
C5
C6
C2
C13
O1
C11
C15
C4
C1
C8
C10
C7
C9
O6
C3
C16
O4
N1
O3
Fig. 1. General appearance of compound I with the atoms represented by
thermal vibration ellipsoids of 50 % probability
Fig. 2. Packing diagram for compound I

Vol. 27, No. 7 (2015)
Bond
Synthesis, Characterization and Crystal Structure of Methyl 4-(Benzyloxy)-5-methoxy-2-nitrobenzoate 2649
TABLE-2
GEOMETRIC PARAMETERS FOR COMPOUND I
Dist. (Å)
Bond
Dist. (Å)
C1-C2
C1-C6
C1-H1
C2-C3
C2-H2
C3-C4
C3-H3
C4-C5
C4-C7
C5-C6
C5-H5
C6-H6
C7-O1
C7-H7A
C7-H7B
C8-O1
C8-C9
C8-C13
C9-C10
C9-H9
1.3900
1.3900
0.9300
1.3900
0.9300
1.3900
0.9300
1.3900
1.4926
1.3900
0.9300
0.9300
1.442(2)
0.9700
0.9700
1.356(3)
1.360(3)
1.408(3)
1.386(3)
0.9300
C10-C11
C10-N1
1.378(3)
1.456(3)
1.385(3)
1.501(4)
1.379(4)
0.9300
1.350(3)
1.431(3)
0.9600
0.9600
0.9600
1.192(3)
1.305(4)
1.446(3)
0.9600
C11-C12
C11-C15
C12-C13
C12-H12
C13-O2
C14-O2
C14-H14A
C14-H14B
C14-H14C
C15-O5
C15-O6
C16-O6
C16-H16A
C16-H16B
C16-H16C
N1-O4
0.9600
0.9600
1.220(3)
1.220(3)
N1-O3
Angle
Data (º)
Angle
Data (º)
C2-C1-C6
C2-C1-H1
C6-C1-H1
C3-C2-C1
C3-C2-H2
C1-C2-H2
C4-C3-C2
C4-C3-H3
C2-C3-H3
C5-C4-C3
C5-C4-C7
C3-C4-C7
C4-C5-C6
C4-C5-H5
C6-C5-H5
C5-C6-C1
C5-C6-H6
120.0
120.0
120.0
120.0
120.0
120.0
120.0
120.0
120.0
120.0
119.0
120.9
120.0
120.0
120.0
120.0
120.0
C9-C10-N1
C10-C11-C12
C10-C11-C15
C12-C11-C15
C13-C12-C11
C13-C12-H12
C11-C12-H12
O2-C13-C12
117.9(2)
118.0(2)
124.7(2)
117.2(2)
121.1(2)
119.4
119.4
124.8(2)
115.6(2)
119.7(3)
109.5
109.5
109.5
109.5
109.5
109.5
125.0(3)
124.3(3)
110.4(3)
109.5
109.5
109.5
109.5
109.5
109.5
123.2(2)
118.9(2)
117.9(2)
116.97(18)
118.6(2)
116.4(3)
1.5(4)
-0.2(4)
179.4(3)
-179.8(3)
-0.2(4)
-108.8(4)
75.2(4)
77.4(4)
-98.6(3)
3.2(4)
O2-C13-C8
C12-C13-C8
O2-C14-H14A
O2-C14-H14B
H14A-C14-H14B
O2-C14-H14C
H14-C14-H14C
H14B-C14-H14C
O5-C15-O6
C1-C6-H6
O1-C7-C4
120.0
106.81(11)
110.4
110.4
110.4
O5-C15-C11
O6-C15-C11
O1-C7-H7A
C4-C7-H7A
O1-C7-H7B
C4-C7-H7B
H7A-C7-H7B
O1-C8-C9
O1-C8-C13
C9-C8-C13
C8-C9-C10
C8-C9-H9
C10-C9-H9
C11-C10-C9
C11-C10-N1
C6-C1-C2-C3
C1-C2-C3-C4
C2-C3-C4-C5
C2-C3-C4-C7
C3-C4-C5-C6
C7-C4-C5-C6
C4-C5-C6-C1
C2-C1-C6-C5
C5-C4-C7-O1
C3-C4-C7-O1
O1-C8-C9-C10
C13-C8-C9-C10
O6-C16-H16A
O6-C16-H16B
H16A-C16-H16B
O6-C16-H16C
H16A-C16-H16C
H16B-C16-H16C
O4-N1-03
O4-N1-C10
O3-N1-C10
C8-O1-C7
C13-O2-C14
110.4
108.6
125.9(2)
114.7(2)
119.4(2)
120.0(2)
120.0
120.0
121.8(2)
120.3(2)
0.0
0.0
0.0
-177.0
0.0
177.1
0.0
0.0
C15-O6-C16
C11-C12-C13-C8
O1-C8-C13-O2
C9-C8-C13-O2
O1-C8-C13-C12
C9-C8-C13-C12
C10-C11-C15-O5
C12-C11-C15-O5
C10-C11-C15-O6
C12-C11-C15-O6
C11-C10-N1-O4
C9-C10-N1-O4
C11-C10-N1-O3
C9-C10-N1-O3
-70.11(16)
106.96(16)
179.2(3)
-0.4(4)
-175.4(3)
-179.4(3)
2.0(4)

2650 Wang et al.
C8-C9-C10-C11
Asian J. Chem.
1.4(4)
-179.0(2)
178.08(19)
5.6(4)
-174.0(3)
6.1(5)
179.9(3)
-0.4(5)
178.2(3)
1.6(4)
-176.9(3)
-174.3(3)
7.2(5)
-2.2(4)
174.0(3)
-178.1(3)
C9-C8-O1-C7
C13-C8-O1-C7
C4-C7-O1-C8
C12-C13-O2-C14
C8-C13-O2-C14
O5-C15-O6-C16
C11-C15-O6-C16
C8-C9-C10-N1
C9-C10-C11-C12
N1-C10-C11-C12
C9-C10-C11-C15
N1-C10-C11-C15
C10-C11-C12-C13
C15-C11-C12-C13
C11-C12-C13-O2
Symmetry code: (i) x, y, z (ii) -x,1/2 + y, 1/2-z
According to the data from X-ray crystallographic
analysis, compound I crystallized in a P2(1)/c space group of
the triclinic system.All H atoms were positioned geometrically
and constrained to ride on their parent atoms, with C-H = 0.93
Å for aromatic H. Other H atoms were positioned geometrically
and refined using a riding model, with C-H = 0.96 Å for alkyl
H, with Uiso(H) =1.2Ueq(C) for aromatic H and Uiso(H)
=1.5Ueq(C) for other H. There are no intramolecular hydrogen
bonds in the structure. There is one intermolecular hydrogen
bonds in the structure and the hydrogen-bond geometry for
compound (I) was listed in Table-3. Unit cell parameters: a =
5.590(2), b = 17.591 (7), c = 15.427(6) Å, V = 1516.9 (10) Å3;
Z 4.
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TABLE-3
HYDROGEN-BOND GEOMETRY FOR COMPOUND I
D-H···A
D-H
H···A
D···A
D-H···A
171°
C9-H9···O3
0.93 Å
2.45 Å
3.371 (4) Å
ACKNOWLEDGEMENTS
This work was financially supported by the Science and
Technology Research Project of Changzhou City-Technology
Support Program (Industry) (CE20140028).