Pirfenidone structural isosteres: Design, synthesis and spectral study

Article abstract of DOI:10.1515/hc-2012-0117

Series of 5-substituted arylpyridin-2(1 H )-ones and arylpyrimidin-4(3 H )-ones were designed and synthesized based on pirfenidone, a compound which shows promising therapeutic effects for treatment of fibrosis. The compounds 1a - c , 2a - c and 3a - c were obtained under mild conditions by arylation of the appropriate heterocyclic amines with arylboronic acids under Chan-Lam- Evans conditions. The synthesis of the useful synthon N -(4-methoxyphenyl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan- 2-yl)-(1 H )-pyridin-2-one ( 4 ) is also reported. All compounds were characterized by spectral and elemental analysis and structural elucidation by 1 H and 13 C NMR is discussed herein.

Full text of DOI:10.1515/hc-2012-0117

DOI 10.1515/hc-2012-0117ꢀ
ꢀHeterocycl. Commun. 2012; 18(4): 193–197
KPaimrefliea Fn. AibddoElnKaedesr*,tSreurrycAt.uA.rEal Bliailys, MoashmteourdeBs. E:l-Adshemsawigy annd,David W. Bo y k i n
synthesis and spectral study
Abstract: Series of 5-substituted arylpyridin-2(1H)-ones fibrous tissues after the removal of the fibrogenic stimu-
and arylpyrimidin-4(3H)-ones were designed and synthe- lus (Issa et al., 2001). Similar results were also observed
sized based on pirfenidone, a compound which shows in human patients with liver fibrosis due to autoimmune
promising therapeutic effects for treatment of fibrosis. hepatitis (Dufour et al., 1997) and biliary etiology (Hammel
The compounds 1a–c, 2a–c and 3a–c were obtained et al., 2001). However, the need for other means of treat-
under mild conditions by arylation of the appropriate het- ment is vital, especially when the removal of the causa-
erocyclic amines with arylboronic acids under Chan-Lam- tive factor is unlikely. Recently, the different antifibrotic
Evans conditions. The synthesis of the useful synthon agents that inhibit the accumulation or resolve the already
N-(4-methoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-diox- accumulated excess fibrous tissues in extracellular matrix
aborolan-2-yl)-(1H)-pyridin-2-one (4) is also reported. All (ECM) have been summarized (El Bialy et al., 2011a). These
compounds were characterized by spectral and elemental agents are thought to target one or more of the three stages
1
analysis and structural elucidation by H and 13C NMR is involved in the process of fibrosis formation, i.e., the trig-
discussed herein.
gering stage, fibrogenesis and ECM accumulation (El Bialy
et al., 2011a). One of these agents is pirfenidone (1a in
Keywords: arylboronic acid; Chan-Lam-Evans reaction; Scheme 1) that was recently approved for the treatment of
pirfenidone; pyridone; pyrimidone.
idiopathic pulmonary fibrosis (IPF) (Liu et al., 2009). Pirfe-
nidone showed promising results in a liver fibrosis model
by the inhibition of collagen synthesis, reduction of the
production of number of cytokines and fibroblast prolif-
eration (Di Sario et al., 2004). In the present investigation,
the design and synthesis of new compounds with possible
antifibrotic activity based on the structure of pirfenidone
are reported. Structural modifications were designed to
test the effect of altering the electronic character of phenyl
group (1a–c), replacing the methyl group with the approxi-
mately same size bromine substituent but with the bromine
being slightly more lipophilic (2a–c), and by replacing
the pyridone with the more hydrophilic pyrimidone ring
(3a–c). Although some of these compounds appeared pre-
viously in the literature (Stajer et al., 1987; Li and Dixon,
2004; Blatt et al., 2006; Kossen et al., 2009), we did not
find associated physical or spectral data.
*Corresponding author: Kamelia F. Abd El Kader, Department of
Medicinal Chemistry, Faculty of Pharmacy, Mansoura University,
Mansoura 35516, Egypt; and Department of Chemistry and Center
for Biotechnology and Drug Design, Georgia State University,
Atlanta, GA 30303-3083, USA, e-mail: k.fathy@hotmail.com
Serry A.A. El Bialy: Department of Pharmaceutical Organic
Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura
35516, Egypt
Mahmoud B. El-Ashmawy: Department of Medicinal Chemistry,
Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
David W. Boykin: Department of Chemistry and Center for
Biotechnology and Drug Design, Georgia State University, Atlanta,
GA 30303-3083, USA
Introduction
Liver fibrosis represents the results of a sustained wound
healing response to chronic hepatic cell injury that originates Results and discussion
due to various causes, including viral infections, e.g., hepa-
titis B and C viruses; and metabolic disorders such as that of Synthesis of compounds 1a–c, 2a–c and 3a–c was achieved
alcohol ingestion (Friedman, 2003; Guzman, 2008). The end- employing a one-step coupling reaction performed under
stage progression of hepatic fibrosis is known as cirrhosis mild reaction conditions known as the Chan-Lam-Evans
and it is characterized by regenerative nodules surrounded reaction (Chan and Lam, 2005; Rauws and Maes, 2012). The
by dense functionless fibrotic tissue (Guzman, 2008).
reaction involved the use of different arylboronic acids and
Several studies on experimental animal models of CuII-containingcatalystinCH2Cl2 atroomtemperature(Chan
liver fibrosis showed possible spontaneous resolution of and Lam, 2005; Sanjeeva Rao and Wu, 2012) (Scheme 1).
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194ꢀ
ꢀK.F. Abd El Kader et al.: Pirfenidone structural isosteres
Boronic acids are synthesized from other boron-con- compared to an apparent triplet at δ 7.51 in the unsubsti-
taining compounds (Hall, 2005) and used in many reac- tuted compound 2a.
tions forming C C bonds in the presence of a palladium
Similarly, the strong deshielding effect of the -CN
catalyst as in Suzuki-Miyaura coupling reaction (Suzuki, group in compounds 1c, 2c and 3c on the neighboring
2005), or C-heteroatom (N or O) bonds using copper cat- protons is obvious. For example, a doublet peak equiva-
alyst as in Chan-Lam coupling reaction (Chan and Lam, lent to two protons appears at δ 8.02 (H-3′-5′) in the 1H NMR
2005; Rauws and Maes, 2012; Sanjeeva Rao and Wu, 2012). spectrum of compound 3c compared to an apparent triplet
Herein, the appropriate arylboronic acid was allowed at δ 7.55 for the unsubstituted compound 3a.
to react with the N-containing system (pyridone/pyrimi-
Structures of all compounds were also confirmed by
done), in the presence of Cu(OAc)2 as a catalyst. The reac- studying their 13C NMR spectra. Peaks that represent classi-
tion is thought to start with a transmetalation step where cal aromatic carbons appear at δ 126.7–129.2 in compounds
the aryl moiety is transferred from the boronic acid to the 1a, 2a and 3a corresponding to five unsubstituted phenyl
Cu(OAc)2 forming ArCuIIOAc. Another portion of Cu(OAc)2 carbons (C2′/6′), (C3′/5′) and C4′. The sixth carbon C1′ signal
oxidizes the produced ArCuII(OAc) into ArCuIII(OAc)2. The appears deshielded at δ 137.1–141.0 due to its direct attach-
latter CuIII species easily forms the C N bond in the final ment to the heterocyclic N atom. Compounds 1b, 2b and 3b
product with reductive elimination of CuIOAc. The final were characterized by having a peak at δ 55.4 correspond-
step represents the oxidation of the produced CuIOAc ing to the -OCH3 group, whereas compounds 1c, 2c and 3c
into CuII(OAc)2 completing the catalytic cycle (King et al., have a peak at δ 116.4–118.3 corresponding to the -CN group.
2009).
The effect of the presence of the methoxy group in
The structures of all compounds 1a–c, 2a–c and 3a–c compounds 1b, 2b and 3b on the directly attached carbon
were verified using microanalytical and spectral analysis. (C-4′) and on carbons in its ortho positions (C3′/C5′) is
The 1H NMR spectra show peaks at δ 7.55–7.37 integrated as evident; where C-4′ appears as more deshielded and C3′/
five protons to confirm the presence of an unsubstituted C5′ as a more shielded peak than their corresponding
phenyl group incorporated into the pyridone and pyrimi- carbons in the unsubstituted phenyl-containing com-
done ring systems in compounds 1a, 2a and 3a. Com- pounds 1a, 2a and 3a. Conversely, the carbon directly
pounds with para-methoxyphenyl group (1b, 2b and 3b) attached to -CN in compounds 1c, 2c and 3c is more
exhibit in their 1H NMR spectra the characteristic singlet of shielded, whereas carbons at ortho positions (C3′/C5′)
methoxy group at δ 3.8. The shielding effect of this group appear to be more deshielded than their corresponding
is noticeable especially on the adjacent protons in its ortho carbons in compounds 1a, 2a and 3a (Tables 1–3).
positions, where, for example, a doublet peak equivalent
In anticipation of performing further modifications
to two protons (H-3′-5′) appears at δ 7.03 in compound 2b of the pirfenidone structure, the synthesis of a useful
synthon 4 was achieved using the method adopted pre-
viously (El Bialy et al., 2011b) as outlined in Scheme 2.
HO
The previously prepared compound 2b was boronated
B
R
HO
No
R
by palladium catalyzed cross-coupling reaction via its
interaction with bis(pinacolato)diboron in the presence
of bis(dibenzylideneacetone)palladium, [Pd(dba)2] as
catalyst, tricyclohexylphosphine (PCy3) as ligand, KOAc
as base and anhydrous dioxane as solvent, at 80–90°C (El
Bialy et al., 2011b).
NH
NH
N
N
1a
1b
1c
H
OMe
CN
(i)
O
O
R
R
1a-c
Br
Br
HO
B
R
No
R
HO
2a
2b
2c
H
OMe
CN
The structure of compound 4 was verified by micro-
(i)
1
O
O
analytical and spectral analysis. Its H NMR spectrum
exhibits the presence of the three peaks at δ 7.67, 7.56 and
6.45, of one proton each, characteristic for the three pyri-
done protons. It also shows the two doublet peaks, of two
protons each, showing an AB-system pattern at δ 7.33 and
7.03, characteristic for the four protons of the substituted
phenyl group, which is also consistent with the results of
compound 2b. In addition, it shows one singlet at δ 1.25,
equivalent for 12 protons assigned for the four methyl
groups of the boronate ester.
2a-c
HO
B
R
No
R
N
N
HO
3a
3b
3c
H
OMe
CN
NH
N
(i)
O
O
R
3a-c
Scheme 1ꢁSynthesis of compounds 1a–c, 2a–c and 3a–c. Reagents
and conditions: (i) Cu(OAc)2‧H2O, pyridine, molecular sieves 4 Å, CH2Cl2.
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K.F. Abd El Kader et al.: Pirfenidone structural isosteresꢀ
ꢀ195
C2
C3
C4
C5
C6
C1′
C2′,6′
C3′,5′
C4′
CH3
Extra C
1a
1b
1c
160.4
160.6
160.1
120.2
120.1
120.3
136.1
133.9
135.2
114.0
113.8
110.7
143.0
142.9
144.6
141.0
136.4
143.5
126.7
127.8
128.0
129.0
114.1
133.1
127.9
158.6
114.6
16.3
16.3
16.3
–
55.4 OCH3
118.3 CN
13
Table 1ꢀ C NMR data of compounds 1a–c.
13C NMR spectrum of compound 4 shows eight peaks
in the aromatic region equivalent to ten carbons. In the
aliphatic region, it shows three different peaks which
match the proposed structure, bearing in mind that the
carbon atom directly attached to boron atom does not
appear in the spectrum, which is consistent with the pre-
viously reported results for similar compounds (El Bialy
et al., 2011b).
employing a Bruker Avance 400 MHz spectrometer. Elemental analy-
ses were obtained from Atlantic Microlab Inc. (Norcross, GA, USA).
All chemicals and solvents were purchased from Aldrich Chemical
Co. or VWR.
Preparation of 5-methyl-N-aryl-(1H)-
pyridin-2-ones 1a–c
A mixture of 5-methylpyridin-2(1H)-one (1.09 g, 0.01 mol), the appro-
priate aryl boronic acid (0.012 mol), Cu(II) acetate monohydrate
(2.74 g, 0.014 mol), pyridine (1.6 mL, 0.02 mol), molecular sieves 4
Å (7 g) and CH2Cl2 (25 mL) was stirred for 24 h at room temperature.
The solvent was evaporated and the residue was stirred with EtOAc
(2×200 mL) and filtered. The combined organic layers were trans-
ferred into a separating funnel, washed with water and brine solu-
tion, dried over anhydrous MgSO4 and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel, using EtOAc/hexanes (9:1) as eluent. The three targeted
compounds 1a–c appeared previously in the literature (Li and Dixon,
2004; Blatt et al., 2006; Kossen et al., 2009) respectively; however, no
physical or spectral data were reported.
Conclusion
The synthesis of 1a–c, 2a–c and 3a–c obtained under
mild conditions by arylation of the appropriate heterocy-
clic amines with aryl boronic acids under Chan-Lam-Evans
conditions is reported and analysis of their 1H and 13C NMR
spectral data is presented. The biological evaluation of
the possible antifibrotic activity of these compounds will
be completed and published elsewhere.
5-Methyl-N-phenyl-(1H)-pyridin-2-one (1a, pirfenidone) Yield
1
12%; mp 99–101°C; H NMR: δ 7.52 (s, 1H, H-6), 7.49 (d, 1H, Jꢀ=ꢀ8 Hz,
H-4), 7.44–7.37 (m, 5H, Ar-H), 6.43 (d, 1H, Jꢀ=ꢀ8 Hz, H-3), 2.05 (s, 3H,
CH3); 13C NMR: δ 160.4 (C-2), 143.0 (C-6), 141.0 (C-1′), 136.1 (C-4), 129.0
(C-3′-5′), 127.9 (C-4′), 126.7 (C-2′-6′), 120.2 (C-3), 114.0 (C-5), 16.3 (CH3).
Anal. Calcd for C12H11NO (185.22): C, 77.81; H, 5.99; N, 7.56. Found: C,
77.52; H, 6.17; N, 7.36.
Experimental
Melting points were recorded using a Thomas-Hoover (Uni-Melt)
capillary melting point apparatus and are uncorrected. Thin layer
chromatography (TLC) analysis was carried out on silica gel 60 F 254
1
precoated aluminum sheets and detected under UV light. H NMR
5-Methyl-N-(4-methoxyphenyl)-(1H)pyridin-2-one (1b) Yield
1
(400 MHz) and 13C NMR (100 MHz) spectra were recorded in DMSO-d6 18%; mp 95–96°C; H NMR: δ 7.39 (s, 1H, C-6), 7.36 (d, 1H, Jꢀ=ꢀ9 Hz
C2
C3
C4
C5
C6
C1′
C2′,6′
C3′,5′
C4′
Extra C
2a
2b
2c
159.8
160.1
159.6
122.0
121.8
118.2
138.7
132.9
122.1
97.0
96.8
97.6
143.2
143.0
143.6
140.0
139.0
138.1
129.1
127.9
128.2
128.4
114.1
133.2
129.1
159.0
111.2
–
55.5 OCH3
116.4 CN
13
Table 2ꢀ C NMR data of compounds 2a–c.
C2
C4
C5
C6
C1′
C2′,6′
C3′,5′
C4′
Extra C
3a
3b
3c
153.6
159.4
153.3
159.8
160.0
159.2
115.7
114.3
115.5
152.0
152.3
151.1
137.1
128.3
140.7
127.1
129.8
128.1
129.2
115.5
133.0
129.0
153.5
111.7
–
55.5 OCH3
117.1 CN
13
Table 3ꢀ C NMR data of compounds 3a–c.
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196ꢀ
ꢀK.F. Abd El Kader et al.: Pirfenidone structural isosteres
Hz, H-3′-5′), 7.69 (d, 2H, Jꢀ=ꢀ8 Hz, H-2′-6′), 7.65 (dd, 1H, Jꢀ=ꢀ3, 10 Hz, H-4),
6.50 (d, 1H, Jꢀ=ꢀ10 Hz, H-3); 13C NMR: δ 159.6 (C-2), 143.6 (C-6), 138.1
(C-1′), 133.2 (C-3′-5′), 128.2 (C-2′-6′), 122.1 (C-4), 118.2 (C-3), 116.4 (CN),
111.2 (C-4′), 97.6 (C-5). Anal. Calcd for C12H7BrN2O (275.10): C, 52.39;
H, 2.56; N, 10.18. Found: C, 52.64; H, 2.43; N, 10.00.
O
O
N
Br
B
O
O
O
B
B
O
N
O
(i)
O
OCH3
OCH3
2b
4
3
Preparation of N -aryl-pyrimidin-4-ones
Scheme 2ꢁSynthesis of compound 4. Reagents and conditions:
(i) bis(dibenzylideneacetone) palladium, tricyclohexylphosphine,
KOAc, dioxane, 80–90°C.
3a–c
Following the same procedure adopted for the preparation of
compounds 1a–c, compounds 3a–c were prepared using pyrimi-
din-4(3H)-one (0.96 g, 0.01 mol), as a starting material instead of
5-methylpyridin-2(1H)-one. Products were purified by column chro-
matography on silica gel, using EtOAc/hexane (7:3) as eluent. The
targeted compound 3a appeared in the literature (Stajer et al., 1987);
however, no spectral data were reported.
H-4), 7.29 (d, 2H, Jꢀ=ꢀ8 Hz, H-2′-6′), 7.02 (d, 2H, Jꢀ=ꢀ8 Hz, H-3′-5′), 6.40
(d, 1H, Jꢀ=ꢀ9 Hz, H-3), 3.80 (s, 3H, OCH3), 2.04 (s, 3H, CH3); 13C NMR:
δ 160.6 (C-2), 158.6 (C-4′), 142.9 (C-6), 136.4 (C-1′), 133.9 (C-4), 127.8
(C-2′-6′), 120.1 (C-3), 114.1 (C-3′-5′), 113.8 (C-5), 55.4 (OCH3), 16.3 (CH3).
Anal. Calcd for C13H13NO2 (215.25): C, 72.54; H, 6.09; N, 6.51. Found: C,
72.43; H, 6.21; N, 6.33.
3-Phenyl-(3H)-pyrimidin-4-one (3a) Yield 14%; mp 146–148°C (lit.
mp 147–149°C); 1H NMR: δ 8.41 (s, 1H, H-2), 7.99 (d, 1H, Jꢀ=ꢀ6 Hz, H-6),
7.55 (t, 2H, Jꢀ=ꢀ7 Hz, H-3′-5′), 7.513 (d, 1H, Jꢀ=ꢀ7 Hz, H-4′), 7.47 (d, 2H, Jꢀ=ꢀ7
Hz, H-2′-6′), 6.52 (d, 1H, Jꢀ=ꢀ6 Hz, H-5); 13C NMR: δ 159.8 (C-4), 153.6
(C-2), 152.0 (C-6), 137.1 (C-1′), 129.2 (C-3′-5′), 129.0 (C-4′), 127.1 (C-2′-6′),
115.7 (C-5).
5-Methyl-N-(4-cyanophenyl)-(1H)-pyridin-2-one (1c) Yield 26%;
mp 188–189°C; H NMR: δ 7.99 (d, 2H, Jꢀ=ꢀ8 Hz, H-3′-5′), 7.66 (d, 2H,
Jꢀ=ꢀ8 Hz, H-2′-6′), 7.48 (s, 1H, H-6), 7.41 (d, 1H, Jꢀ=ꢀ9 Hz, H-4), 6.46 (d, 1H,
Jꢀ=ꢀ9 Hz, H-3), 2.05 (s, 3H, CH3); 13C NMR: δ 160.1 (C-2), 144.6 (C-6), 143.5
(C-1′), 135.2 (C-4), 133.1 (C-3′-5′), 128.0 (C-2′-6′), 120.3 (C-3), 118.3 (CN),
114.6 (C-4′), 110.7 (C-5), 16.3 (CH3). Anal. Calcd for C13H10N2O (210.23):
C, 74.27; H, 4.79; N, 13.33. Found: C, 73.98; H, 4.94; N, 13.18.
1
3-(4-Methoxyphenyl)-(3H)-pyrimidin-4-one (3b) Yield 25%; mp
212°C; H NMR: δ 8.40 (s, 1H, H-2), 7.97 (d, 1H, Jꢀ=ꢀ6 Hz, H-6), 7.38 (d,
2H, Jꢀ=ꢀ9 Hz, H-2′-6′), 7.07 (d, 2H, Jꢀ=ꢀ9 Hz, H-3′-5′), 6.49 (d, 1H, Jꢀ=ꢀ6 Hz,
H-5), 3.81 (s, 3H, OCH3); 13C NMR: δ 160.0 (C-4), 159.4 (C-2), 153.5 (C-4′),
152.3 (C-6), 129.8 (C-2′-6′), 128.3 (C-1′), 115.5 (C-3′-5′), 114.3 (C-5), 55.5
(OCH3). Anal. Calcd for C11H10N2O2 (202.21): C, 67.00; H, 3.58; N, 21.31.
Found: C, 67.21; H, 3.69; N, 21.04.
1
Preparation of 5-bromo-N-aryl-(1H)-pyridin-
2-ones 2a–c
3-(4-Cyanophenyl)-(3H)-pyrimidin-4-one (3c) Yield 10%; mp
1
Following the same procedure adopted for the preparation of com- 214°C; H NMR: δ 8.44 (s, 1H, H-2), 8.02 (d, 2H, Jꢀ=ꢀ8 Hz, H-3′-5′), 7.99
pounds 1a–c, compounds 2a–c were prepared using 5-bromopyri-
din-2(1H)-one (1.74 g, 0.01 mol), as a starting material instead of
5-methylpyridin-2(1H)-one. The targeted compounds 2a,b appeared
previously in the literature (Li and Dixon, 2004); however, no physi-
cal or spectral data were reported.
(d, 1H, Jꢀ=ꢀ6 Hz, H-6), 7.73 (d, 2H, Jꢀ=ꢀ8 Hz, H-2′-6′), 6.53 (d, 1H, Jꢀ=ꢀ6 Hz
H-5); 13C NMR: δ 159.2 (C-4), 153.3 (C-2), 151.1 (C-6), 140.7 (C-1′), 133.0
(C-3′-5′), 128.1 (C-2′-6′), 117.1 (CN), 115.5 (C-5), 111.7 (C-4′). Anal. Calcd
for C11H7N3O (197.19): C, 65.34; H, 4.98; N, 13.85. Found: C, 65.61;
H, 4.89; N, 13.71.
5-Bromo-N-phenyl-(1H)-pyridin-2-one (2a) Yield 56%; mp 76–
1
78°C; H NMR: δ 7.94 (d, 1H, Jꢀ=ꢀ2 Hz, H-6), 7.62 (dd, 1H, Jꢀ=ꢀ2, 10 Hz,
Preparation of N-(4-methoxyphenyl)-
5-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)-(1H)-pyridin-2-one (4)
Bis(dibenzylideneacetone) palladium (0.143 g, 0.25 mmol) and tricy-
clohexyl phosphine (0.168 g, 0.6 mmol) were added to a two-necked
flask containing degassed dioxane (30 mL). The solution was stirred
for 30 min at 25°C. Compound 2b (1.4 g, 5 mmol), KOAc (0.736 g,
7.5 mmol) and bis(pinacolato)diboron (1.4 g, 5.5 mmol) were added
sequentially, and the mixture was vigorously stirred. The mixture
was warmed to 90–100°C for 24 h, while stirring under nitrogen
atmosphere. After the completion of the reaction, the solvent was
removed under reduced pressure and the residue was dissolved in
EtOAc (150 mL). The solution was washed with water and brine, dried
H-4), 7.51 (t, 2H, Jꢀ=ꢀ7 Hz, H-3′,5′), 7.46 (t, 1H, Jꢀ=ꢀ7 Hz, H-4′), 7.42 (d,
2H, Jꢀ=ꢀ7 Hz, H-2′-6′), 6.48 (d, 1H, Jꢀ=ꢀ10 Hz, H-3); 13C NMR: δ 159.8 (C-2),
143.2 (C-6), 140.0 (C-1′), 138.7 (C-4), 129.1 (C-3′-5′), 128.4 (C-4′), 126.8
(C-2′-6′), 122.0 (C-3), 97.0 (C-5). Anal. Calcd for C11H8BrNO (250.09):
C, 52.83; H, 3.22; N, 5.60. Found: C, 53.12; H, 3.07; N, 5.52.
5-Bromo-N-(4-methoxyphenyl)-(1H)-pyridin-2-one (2b) Yield
37%; mp 97–99°C; 1H NMR: δ 7.90 (d, 1H, 2 Hz, H-6), 7.59 (dd, 1H, Jꢀ=ꢀ2,
9.8 Hz, H-4), 7.33 (d, 2H, Jꢀ=ꢀ9 Hz, H-2′-6′), 7.03 (d, 2H, Jꢁ=ꢁ 9 Hz, H-3′-5′),
6.45 (d, 1H, Jꢀ=ꢀ9.8 Hz, H-3), 3.80 (s, 3H, OCH3); 13C NMR: δ 160.1 (C-2),
159.0 (C-4′), 143.0 (C-6), 139.0 (C-1′), 132.9 (C-4), 127.9 (C-2′-6′), 121.8
(C-3), 114.1 (C-3′-5′), 96.8 (C-5), 55.5 (OCH3). Anal. Calcd for C12H10BrNO2
(280.12): C, 51.45; H, 3.60; N, 5.00. Found: C, 51.72; H, 3.59; N, 5.02.
5-Bromo-N-(4-cyanophenyl)-(1H)-pyridin-2-one (2c) Yield 15%; over anhydrous Na2SO4 and concentrated. The residue was purified
mp 196–200°C; 1H NMR: δ 8.03 (d, 1H, Jꢀ=ꢀ3 Hz, H-6), 8.00 (d, 2H, Jꢀ=ꢀ8 by column chromatography on silica gel, using EtOAc/hexanes (2:8)
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K.F. Abd El Kader et al.: Pirfenidone structural isosteresꢀ
ꢀ197
as eluent: yield 37%; mp 140°C; 1H NMR: δ 7.67 (s, 1H, H-6), 7.56 (d, 1H, (4 CH3). Anal. Calcd for C18H22BNO4 (327.18): C, 66.08; H, 6.78; N, 4.28.
Jꢀ=ꢀ9 Hz, H-4), 7.33(d, 2H, Jꢀ=ꢀ9 Hz, H-2′-6′), 7.03 (d, 2H, Jꢀ=ꢀ9 Hz, H-3′- Found: C, 66.23; H, 6.90; N, 4.31.
5′), 6.45 (d, 1H, Jꢀ=ꢀ9 Hz, H-3), 3.81 (s, 3H, OCH3), 1.25 (s, 12H, 4 CH3);
13C NMR: δ 161.6 (C-2), 158.9 (C-4′), 146.7 (C-6), 143.4 (C-1′), 133.3 (C-4), Received August 3, 2012; accepted August 23, 2012; previously
127.8 (C-2′-6′), 120.0 (C-3), 114.2 (C-3′-5′), 83.8 (2 C-O), 55.4 (OCH3), 24.6 published online September 15, 2012
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