Synthesis and crystal structure of two diflunisal carboxamides

Article abstract of DOI:10.1007/s10870-010-9728-4

The title compounds, 2′,4′-difluoro-4-[(4-methylbenzoyl) oxy]-N-[4-nitro-3-(trifluoromethyl) phenyl]-[1, 10-biphenyl]-3-carboxamide 2a and 2′,4′-difluoro-4-[(4- chlorobenzoyl)oxy]-N-[4-nitro-3- (trifluoromethyl)phenyl]-[1, 1′-biphenyl]-3-carboxamide 2b, s

Full text of DOI:10.1007/s10870-010-9728-4

J Chem Crystallogr (2010) 40:735–739
DOI 10.1007/s10870-010-9728-4
ORIGINAL PAPER
Synthesis and Crystal Structure of Two Diflunisal Carboxamides
•
Guang-xiang Zhong Hong-dan Hu
•
•
Chun-nian Xia Jian-song Jiang Ting-ting Chen
•
Received: 18 November 2009 / Accepted: 11 February 2010 / Published online: 26 February 2010
Ó Springer Science+Business Media, LLC 2010
Abstract The title compounds, 20,40-difluoro-4-[(4-meth-
ylbenzoyl)oxy]-N-[4-nitro-3-(trifluoromethyl) phenyl]-[1,
10-biphenyl]-3-carboxamide 2a and 20,40-difluoro-4-[(4-
chlorobenzoyl)oxy]-N-[4-nitro-3-(trifluoromethyl)phenyl]-[1,
10-biphenyl]-3-carboxamide 2b, synthesized from diflunisal,
a registered anti-inflammatory drug, via amidation of car-
boxlic acid and esterification of phenolic hydroxy group and
recrystallized from butanone-ethanol, were confirmed by
single-crystal X-ray diffraction [CCDC 753735 and
753736]. The 2a crystallizes in triclinic space group P¯ı
inflammatory drugs [7–9] have been attractive for their
special properties. Diflunisal (1, CAS 22494-42-4), 20,40-
difluoro-4-hydroxybiphenyl-3-carboxylic acid, a registered
anti-inflammatory drug, has been approved worldwide as
therapeutics for the treatment of inflammation and pain
[10, 11]. Recently, the modifications of the chemical
structure of 1 were studied. For example, 3-(1,3-dihydro-
2H-isoindol-2-ylcarbonyl)-20,40-difluorobiphenyl-4-ol was
synthesized and reported to have the H3P-90 inhibition,
and H3P-90 in abnormal cells, such as in cancer cells
would damage the regulation of signal transduction net-
work [12]. Yu CX reported that esterification or amidation
of 1 could increase their solubility and absorption in vivo,
and some of them have even better analgesic activity than
that of 1 [13]. Some changes in the carboxyl group of 1
also showed good antimycobacterial, antiviral and antimi-
crobial activities [14]. Roberts found that O-aryl esters of
1, especially lipophilic esters possess large permeability
surface area and tissue distribution value [15]. Zhong GX
discovered that some amide derivatives of 1 exhibited
potent anti-inflammatory, analgesic and anti-tumor activity
[16–18].
˚
˚
with cell parameters a = 10.562(2) A, b = 10.696(2) A,
˚
c = 11.061(2) A, a = 80.503(7)°, b = 84.722(7)°, c =
73.553(7)° and Z = 2. The 2b crystallizes in triclinic
˚
space group P¯ı with cell parameters a = 9.348(3) A, b =
˚
˚
11.150(3) A, c = 11.798(4) A, a = 106.627(4)°, b =
93.223(4)°, c = 91.579(5)° and Z = 2. Their packing are
stabilized by intermolecular N–HꢀꢀꢀO hydrogen bonds.
Keywords Diflunisal derivative ꢀ Crystal structure ꢀ
X-ray diffraction ꢀ Amidation ꢀ Esterification
Introduction
A convenient synthetic route for title compounds (2)
was outlined in Scheme 1. Starting from 1, amidation of
carboxlic acid and esterification of phenolic hydroxy group
gave the desired product 2. The anti-tumor activity are
affected by the properties of R in compound 2 [18], so the
knowledge of the structural characteristic of these ana-
logues is of the utmost importance of the understanding of
the quantitative structure–activity relationships (QSARs)
underlying their biological activity. Encouraged by the
aforementioned information, it was considered valuable to
synthesize compounds 2a and 2b characterized by X-ray
studies.
Fluorine-containing drugs, such as tegadifur [1, 2], flu-
tamide [3, 4], ciprofloxacin [5, 6], non-steroid anti-
G. Zhong (&) ꢀ H. Hu ꢀ C. Xia ꢀ J. Jiang ꢀ T. Chen
College of Pharmaceutical Science, Zhejiang University of
Technology, Hangzhou 310032, People’s Republic of China
e-mail: drzhonggx@sohu.com
123

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J Chem Crystallogr (2010) 40:735–739
Scheme 1 Route of synthesis
of diflunisal carboxamides 2
Experimental
J = 8.5 Hz, 50-H), 7.39 (d, 2H, J = 8.0 Hz, 3000,5000-H),
7.41 (d, 1H, J = 8.5 Hz, 5-H), 7.48 (q, 1H, J = 8.5 Hz, 60-
H), 7.61 (s, 1H, 200-H), 7.78 (d, 1H, J = 8.5 Hz, 6-H), 7.92
(d, 1H, J = 8.0 Hz, 600-H), 8.06 (d, 1H, J = 8.5 Hz, 500-H),
8.13 (d, 2H, J = 8.0 Hz, 2000,6000-H), 8.19 (s, 1H, 2-H), 8.89
(s, 1H, –NH). MS: m/z 556 (M?, 0.11), 391 (0.52), 351
(2.09), 232 (3.89), 204 (5.86), 175 (6.04), 119 (100.00), 91
(56.85); Anal. Calcd. for C28H17F5N2O5: C, 60.44; H, 3.08;
N, 5.03. Found: C, 60.29; H, 3.02; N, 4.93.
20,40-Difluoro-4-Hydroxy-N-[4-Nitro-3-
(Trifluoromethyl)phenyl]-[1,10-Biphenyl]-3-
Carboxamide (4)
A mixture of compound diflunisal 1 12.7 g (0.05 mol) and
SOCl2 11.9 g(0.1 mol)in70 mltoluenewasreactedfor7 hat
80 °C prior to work up to give compound 3. The compounds 4
(18.2 g) was prepared by reaction of 3 with 4-nitro-3-(tri-
fluoromethyl)phenylamine 10.3 g (0.05 mol) and K2CO3
12.4 g (0.05 mol) in 120 ml THF at room temperature for
12 h, in 83% total yields based on the diflunisal. Recrystal-
lized with butanone to get white solid. m.p. 175–176 °C. 1H
NMR (CDCl3): d 6.96 (t, 1H, J = 8.5 Hz, 30-H), 6.99 (t, 1H,
J = 8.5 Hz, 50-H), 7.16(d, 1H, J = 8.5 Hz, 5-H), 7.40(q, 1H,
J = 8.5 Hz, 60-H), 7.63(d, 1H, J = 8.0 Hz, 6-H), 7.68 (s, 1H,
2-H), 8.05 (d, 1H, J = 8.0 Hz, 500-H), 8.09 (s, 1H, 200-H), 8.11
(d, 1H, J = 8.0 Hz, 600-H, 8.29 (s, 1H, –NH), 11.30 (s, 1H,
–OH). MS: m/z 438(M?, 12.93), 233(100), 232 (89.69), 204
(18.02), 177 (28.11), 151 (25.23), 63 (4.45), 53 (16.24); Anal.
Calcd. for C20H11F5N2O4: C, 54.81; H, 2.53; N, 6.39. Found:
C, 54.69; H, 2.48; N, 6.30 [18].
Compounds 2b (R = Cl): yield 79%, yellowish crys-
1
talline solid, m.p. 198–200 °C. H NMR (CDCl3): d 6.97
(t, 1H, J = 8.5 Hz, 30-H), 7.01 (t, 1H, J = 8.5 Hz, 50-H),
7.39 (d, 1H, J = 8.5 Hz, 5-H), 7.48 (q, 1H, J = 8.5 Hz, 60-
H), 7.54 (d, 2H, J = 8.5 Hz, 3000,5000-H), 7.76 (d, 1H,
J = 8.0 Hz, 6-H), 7.77 (s, 1H, 200-H), 7.93 (d, 1H,
J = 8.5 Hz, 600-H), 7.99 (d, 1H, J = 8.5 Hz, 500-H), 8.04
(s, 1H, 2-H), 8.15 (d, 2H, J = 8.5 Hz, 2000,6000-H), 8.56 (s,
1H, -NH). IMS: m/z 576 (M?, 0.08), 420 (3.14), 371 (1.29),
232 (4.31), 204 (4.99), 175 (6.03), 139 (100), 111 (26.33),
75 (9.67). Anal. Calcd. for C27H14ClF5N2O5: C, 56.22; H,
2.45; N, 4.86. Found: C, 56.11; H, 2.36; N, 4.79.
Crystal Structure Determination of 2
20,40-Difluoro-4-[(4-Substitutedbenzoyl)oxy]-N-[4-
Nitro-3-(Trifluoromethyl)phenyl]-[1,10-Biphenyl]-3-
Carboxamide(2)
Single-crystal X-ray diffraction measurement for 2a of
dimensions 0.37 mm 9 0.37 mm 9 0.20 mm was carried
out Rigaku AFC10 Saturn 724 ? diffractometer with
˚
graphite-monochromated MoKa radiation (k = 0.71073A)
A solution of 4-substituted benzoyl chloride (0.02 mol) in
THF (20 mL) was added dropwise into a solution of 4 8.77 g
(0.02 mol) and K2CO3 2.77 g (0.02 mol) in CHCl3 (60 ml)
at room temperature, and the reaction was allowed to pro-
cessed with stirring for an additional about 12 h (monitored
by TLC). After filtrating and evaporation of THF in vacuum,
the crude material was washed with alcohol, recrystallized
with butanone and ethanol to afford crystal 2.
[19]. Intensity data were collected up to a hmax of 27.49° by
the x/2h scan. A total of 11876 reflections were collected,
resulting in 5345 independent reflections of which 3845 had
I [ 2r(I) and these are considered as observed. The ranges of
h, k, l are -13 B h B 13, -13 B k B 13, -14 B l B 14.
A single crystals of 2b of dimensions 0.57 mm 9
0.37 mm 9 0.37 mm was chosen for X-ray diffraction
studies on the same instrument. Intensity data were col-
lected up to a hmax of 27.49° by the x/2h scan. A total of
11915 reflections were collected, resulting in 5320 inde-
pendent reflections of which 4197 had I [ 2r(I) and these
Compound 2a (R = CH3): yield 84%, yellowish crys-
1
talline solid, m.p. 178–179 °C. H NMR (CDCl3): d 2.50
(s, 3H, CH3), 6.97 (t, 1H, J = 8.5 Hz, 30-H), 7.01 (t, 1H,
123

J Chem Crystallogr (2010) 40:735–739
737
Table 1 Crystal data and
experimental crystallographic
details
Compound
2a
2b
R
CH3
Cl
Empirical formula
Formula weight
Temperature (K)
Wavelength
C
28H17F5N2O5
C27H14ClF5N2O5
576.86
556.44
93(2)
93(2)
˚
˚
k = 0.71073 A
Triclinic
P¯ı
k = 0.71073 A
Crystal system
Space group
Cell dimensions
Triclinic
P¯ı
˚
a (A)
10.562(2)
7.6199(13)
32.133(6)
9.8079(17)
90
˚
b (A)
10.6958(17)
11.061(2)
˚
c (A)
a (°)
b (°)
c (°)
80.503(7)
84.722(7)
94.048(2)
90
73.553(7)
3
˚
Volume (A )
1180.7(4)
2395.5(7)
2
Z
2
Density(calculated) (Mg/m3)
Absorption coefficient (mm-1
F000
1.565
1.604
)
0.134
0.222
568
1176
Crystal size
0.37 9 0.37 9 0.20 mm
3.21–27.48
-13 B h B 13,
-13 B k B 13,
-14 B l B 14
11876/5345
[R(int) = 0.0268]
5345
0.53 9 0.37 9 0.37 mm
3.28–27.48
-9 B h B 9,
-41 B k B 36,
-12 B l B 12
19174/5479
[R(int) = 0.0295]
5479
h range for data collection
Index ranges
Reflections collected
Independent reflections
Completeness to h = 27.48
Absorption correction
98.6%
99.8%
Empirical
Empirical
0.9228 and 0.8906
Full-matrix least-squares on F2
Max. and min. transmission
Refinement method
0.9737 and 0.9524
Full-matrix least-squares on F2
5345/0/366
1.000
Data/restraints/parameters
Goodness-of-fit on F2
5479/0/365
0.999
Final R indices [I [ 2r(I)]
R1 = 0.0363,
wR2 = 0.0741
R1 = 0.0562,
wR2 = 0.0805
0.331 and -0.223
753735
R1 = 0.0338,
wR2 = 0.0752
R1 = 0.0433,
wR2 = 0.0795
0.379 and -0.376
753736
R indices (all data)
-3
)
˚
Largest diff. peak and hole (e A
CCDC deposit no.
are considered as observed. The ranges of h, k, l are
-11 B h B 12, -14 B k B 14, -15 B l B 15.
The details of crystal data and refinement are given in
Table 1.
of all the non-hydrogen atoms were included in the full-
matrix least-squares refinement using SHELXL97 program
[21].
Table 2 gives the bond distances and angles of non-
hydrogen atoms for 2a and 2b, respectively. Figure 1
represents the ORTEP diagram [22] of the molecule 2a and
2b with thermal ellipsoids at 50% probability. H atoms
were included at calculated positions and refined using a
riding model. H atoms were given isotropic displacement
parameters equal to 1.2 times (1.5 times for methyl) the
Results and Discussion
Both structures were solved by direct methods procedures
as implemented in SHELXS97 program. [20] The positions
123

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J Chem Crystallogr (2010) 40:735–739
˚
Table 2 Selected lengths (A) and bond angles (°) of 2a versus 2b
Bond length
2a
Bond length
2b
C(17)–C(20)
F(1)–C(1)
1.506(2)
Cl(1)–C(17)
F(1)–C(1)
1.7375(16)
1.3554(17)
1.3592(18)
1.3449(17)
1.3465(17)
1.3394(18)
1.3548(18)
1.4076(17)
1.2098(19)
1.2220(17)
1.2314(16)
1.2304(17)
1.3682(19)
1.4038(18)
0.883(18)
1.3564(17)
1.3650(17)
1.3468(17)
1.3415(18)
1.3430(18)
1.3662(17)
1.4005(18)
1.2093(18)
1.2206(18)
1.2316(18)
1.2244(18)
1.3738(19)
1.4017(19)
0.878(19)
1.473(2)
F(2)–C(3)
F(2)–C(3)
F(3)–C(28)
F(4)–C(28)
F(5)–C(28)
O(1)–C(13)
O(1)–C(10)
O(2)–C(13)
O(3)–C(21)
O(4)–N(2)
O(5)–N(2)
N(1)–C(21)
N(1)–C(22)
N(1)–H(1N)
N(2)–C(25)
F(3)–C(27)
F(4)–C(27)
F(5)–C(27)
O(1)–C(13)
O(1)–C(10)
O(2)–C(13)
O(3)–C(20)
O(4)–N(2)
O(5)–N(2)
N(1)–C(20)
N(1)–C(21)
N(1)–H(1N)
N(2)–C(24)
1.4700(18)
Band angle
2a
Band angle
2b
Fig. 1 ORTEP of 2a (the upper molecule) versus 2b molecules at
50% probability
C(18)–C(17)–C(16) 117.76(15) C(18)–C(17)–C(16) 121.90(15)
C(18)–C(17)–C(20) 120.25(15) C(18)–C(17)–Cl(1) 119.47(13)
C(16)–C(17)–C(20) 122.00(15) C(16)–C(17)–Cl(1) 118.63(13)
equivalent isotropic displacement parameters of their par-
˚
ent atoms, and C–H distances were set to 0.95 A for the
˚
benzene H atoms and 0.98 A for the methyl H atoms. After
C(13)–O(1)–C(10)
C(21)–N(1)–C(22)
122.52(11) C(13)–O(1)–C(10)
126.73(13) C(20)–N(1)–C(21)
117.18(12)
125.84(12)
C(21)–N(1)–H(1N) 114.4(12)
C(22)–N(1)–H(1N) 117.5(12)
O(5)–N(2)–O(4)
C(20)–N(1)–H(1N) 119.0(12)
C(21)–N(1)–H(1N) 115.2(12)
refinement, the hydrogen atoms were placed at chemically
acceptable positions.
124.34(14) O(5)–N(2)–O(4)
124.26(12)
118.27(12)
117.38(13)
117.20(14)
118.96(13)
117.62(14)
119.38(14)
111.07(12)
105.97(12)
107.10(12)
106.12(12)
112.33(12)
117.94(13)
120.39(12)
122.86(13)
124.56(14)
112.58(13)
122.48(14)
117.96(12)
116.16(13)
122.16(13)
From Fig. 1, the atoms of C1–C6, F1 and F2 are almost
O(5)–N(2)–C(25)
O(4)–N(2)–C(25)
F(1)–C(1)–C(2)
118.46(14) O(5)–N(2)–C(24)
coplanar, deviating from the mean plane within 0.005(12)
˚
and 0.0139(13) A, respectively for 2a and 2b. The different
117.14(14) O(4)–N(2)–C(24)
117.24(14) F(1)–C(1)–C(2)
118.77(14) F(1)–C(1)–C(6)
118.08(15) F(2)–C(3)–C(2)
118.40(14) F(2)–C(3)–C(4)
110.40(12) F(3)–C(27)–C(23)
105.89(12) F(3)–C(27)–F(4)
107.50(12) F(5)–C(27)–F(4)
106.18(12) F(5)–C(27)–F(3)
113.02(13) F(4)–C(27)–C(23)
122.74(14) C(9)–C(10)–O(1)
115.48(13) C(11)–C(10)–O(1)
122.93(14) O(2)–C(13)–O(1)
126.85(14) O(2)–C(13)–C(14)
110.21(12) O(1)–C(13)–C(14)
123.88(14) C(26)–C(21)–N(1)
116.72(13) C(22)–C(21)–N(1)
116.65(13) C(25)–C(24)–N(2)
122.51(14) C(23)–C(24)–N(2)
para-substituent of the benzene rings C14–C19 can cause
the distinct configuration. In 2a, the benzene ring C14–C19
and C20, O1 are almost coplanar deviating within
˚
0.0703(12) A, and the deviation of the carbonyl O2 from
˚
the plane is 0.1441 (17) A. But the atoms C13, C14, O1 and
F(1)–C(1)–C(6)
F(2)–C(3)–C(2)
F(2)–C(3)–C(4)
F(3)–C(28)–C(24)
F(4)–C(28)–F(3)
F(4)–C(28)–F(5)
F(5)–C(28)–F(3)
F(4)–C(28)–C(24)
C(9)–C(10)–O(1)
C(11)–C(10)–O(1)
O(2)–C(13)–O(1)
O(2)–C(13)–C(14)
O(1)–C(13)–C(14)
C(27)–C(22)–N(1)
C(23)–C(22)–N(1)
C(26)–C(25)–N(2)
C(24)–C(25)–N(2)
O2 lie on the same plane. By contrary, in 2b, the atoms
C13–C19, O1, O2 and Cl1 are coplanar, deviating from the
˚
mean plane within 0.0448(9) A. There is an interesting
phenomenon that both adjacent substituent (C10 and C11
of the parent ring) remove away or reverse each other, and
the reason may be the Cl atom showing greater repulsive
force to the trifluromethyl group than methyl group.
From Fig. 2, [23] intermolecular hydrogen bonding
(Table 3) helps to stabilize the crystal structure. In both
crystal packing, N–HꢀꢀꢀO hydrogen bonds contribute to the
formation of the crystals. In 2a and 2b, two molecules form
stacks in a head-to-tail manner by N1–H1ꢀꢀꢀO2 intermo-
lecular hydrogen bonds to form dimer, and those dimers
interact other dimers to form network.
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J Chem Crystallogr (2010) 40:735–739
739
Fig. 2 Packing of 2a (the upper
molecule) versus 2b down c and
a-axis, respectively Dashed
lines represent the hydrogen
bonds
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Table 3 Hydrogen-bonding geometry (A, °)
Compound D–HꢀꢀꢀA D–H HꢀꢀꢀA
DꢀꢀꢀA
D–HꢀꢀꢀA
(°)
˚
(A)
˚
(A)
˚
(A)
2a
2b
N1–H1ꢀꢀꢀO2a 0.878 2.101(0) 2.967(1) 168.75(2)
N1–H1ꢀꢀꢀO2b 0.883 2.071(0) 2.950(1) 173.53(1)
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Supplementary Material
CCDC-753735 and 753736 contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html or from the Cambridge Crystallographic
Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ,
UK; fax: ?44(0)1223-336033; e-mail: deposit@ccdc.
cam.ac.uk.
13. Yu CX, Xu L (2008) WO Patent 2008 012 603
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Acknowledgments We are very grateful to the Zhejiang Povincial
Natural Science Foundation of China (grant no. Y4090271).
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