New and practical synthesis of N-(3-Cyano-7-ethoxy-4-oxo-1,4- dihydroquinolin-6-yl)acetamide

Article abstract of DOI:10.1002/jhet.1901

New and practical synthetic route of N-(3-cyano-7-ethoxy-4-oxo-1,4- dihydroquinolin-6-yl)acetamide (1) is described, through the cyclization of 2-aminophenyl-ethanone (12) with N,N-dimethylformamide dimethylacetal. The overall yield of 1 obtained from this process is 46% (five steps) with a purity of >99% (HPLC).

Full text of DOI:10.1002/jhet.1901

866
New and Practical Synthesis of N-(3-Cyano-7-ethoxy-4-oxo-1,
Vol 51
4-dihydroquinolin-6-yl)acetamide
Wenpeng Ma, Yongjun Mao, Kai Xie, Qifeng Zhu, Rongxia Zhang, Jingshan Shen, and Hongbin Sun
a
b
c
c
b
b
a
*
aChina Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
bShanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Pudong, Shanghai
201203, China
cTopharman Shanghai Co., Ltd., 1088 Chuansha Road, Pudong, Shanghai 201209, China
*
E-mail: hongbinsun@cpu.edu.cn
Received June 27, 2012
DOI 10.1002/jhet.1901
Published online 3 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
New and practical synthetic route of N-(3-cyano-7-ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)acetamide (1) is
described, through the cyclization of 2-aminophenyl-ethanone (12) with N,N-dimethylformamide dimethylacetal.
The overall yield of 1 obtained from this process is 46% (five steps) with a purity of >99% (HPLC).
J. Heterocyclic Chem., 51, 866 (2014).
INTRODUCTION
3-butyryl-8-methoxy-4-hydroxyquinoline and 6,7-substituted-
4-hydroxyquinolines, respectively, via formation of the
nitroenamine intermediates by condensation of N,N-
dimethylformamide dimethylacetal (DMF-DMA) with the
corresponding starting materials o-nitrophenylethanones.
Such approaches enlightened our direction, and we
designed a new route to obtain 3-cyano-4-hydroxyquinoline
(1) (Scheme 2). Starting from 4-hydroxy-3-nitrophenyl-
ethanone (7), phenylethanone (8) was prepared by using
the method described by Wissner [14]. Nitration of 8 to 9
was conducted in good yield by using fuming nitric
acid–nitromethane system [15]. Other conditions, such as
KNO3-H2SO4 [16], or 65% HNO3 [17] gave inferior yields
for this transformation. Compound 9 was then treated with
1 equiv of bromine in dichloromethane to give 10 [18],
and followed by 1.1 equiv of sodium cyanide in DMSO at
RT to afford 11 in 81% yield over two steps [19]. The nitro
compound 11 was reduced by using Fe-HCl or Zn-AcOH
system to give the aniline (12), which was then condensed
with DMF-DMA in DME to provide the final product 1
(70% from 11) [20]. DMF-DMA could be replaced by
trimethyl orthoformate or triethyl orthoformate, but this
required the reaction to be performed at 90–100ꢀC for 4–6 h.
In conclusion, a new route of making N-(3-cyano-7-
ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)acetamide (1) was
developed to simplify the process, improve the yield,
and make it cost-effective. The key step is the cyclization
reaction of the 2-aminophenyl-ethanone (12) with DMF-DMA.
The overall yield of 1 obtained from this process was 46%
(five steps) with HPLC purity >99%.
4-Hydroxyquinolines (equal to 4-oxo-1,4-dihydroquino-
lines) are the key synthetic precursors for anticancer [1],
antimalarial [2], antidiabetic [3], antiviral [4] agents, and
reversible (H+/K+) ATPase inhibitors [5]. N-(3-Cyano-7-
ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)acetamide (1) (Fig. 1)
was developed as an important intermediate for the prepara-
tion of EKB-569 (2) and neratinib (3), which were developed
as irreversible inhibitors of epidermal growth factor receptor
(EGFR) and human epidermal growth factor receptor-2
(HER-2) kinases [6–8].
The earlier work to prepare 1 (Scheme 1) [9] was based on
Gould–Jacobs methodology [10] and involved the reaction
of 4-acetamido-3-ethoxyaniline (5) with ethyl 2-cyano-3-
ethoxyacrylate to afford ethyl cyanopropenoate (6). Thermal
cyclization of 6 at 260ꢀC in Dowtherm A for 15–20 h then
yielded N-(3-cyano-7-ethoxy-4-oxo-1,4-dihydroquinolin-6-
yl)acetamide (1).
This route was straightforward, but the high temperature
required for cyclization of 6 to 1 on a kilogram scale
proved to be a disadvantage. The main problem was
that prolonged exposure of 6 to high temperature led to
extensive decomposition with significant tar formation.
This led to difficulties in purification, which dramatically
reduced the yield to 35–45%.
RESULTS AND DISCUSSION
When searching for a new synthetic route to produce 1
[11], we noted that Atkins [12] and Tois [13] had prepared
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New and Practical Synthesis of N-(3-Cyano-7-ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)
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acetamide
light orange solid in 78% (three steps), purity 99.08% (HPLC),
1
mp 96–97ꢀC. H-NMR (CDCl3, d): 1.48 (t, 3H, J = 7.2 Hz), 2.23
(s, 3H), 2.57 (s, 3H), 4.18 (q, 2H, J = 7.2 Hz), 6.90 (d, 1H,
J = 8.7Hz), 7.72 (dd, 1H, J = 8.7 Hz, 1.8 Hz), 7.75 (br s, 1H), 8.99
(d, 1H, J = 1.8 Hz). 13C-NMR (CDCl3, d): 14.63, 24.94, 26.53,
64.51, 110.19, 120.38, 124.36, 127.25, 130.13, 150.53, 168.33,
197.26. ESI–MS (m/z) 222.0 (M+ H), 244.1 (M+ Na), 260.0
(M+ K). Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83; N, 6.33.
Found: C, 65.15; H, 6.86; N, 6.16.
Fuming HNO3 (23.0 mL, 0.5 mol) was added to a stirred solu-
tion of 8 (45.0 g, 0.2 mol) in CH3NO2 (900 mL). The reaction
mixture was stirred at 25–35ꢀC for 4 h. The resulting solution
was washed with H2O, saturated NaHCO3, respectively, dried
(Na2SO4), and concentrated to give a dark brown solid. Recrystal-
lization from EtOAc to petroleum ether yielded 9 (44.2 g, 82%) as
a sand-like solid, purity 97.04% (HPLC), mp 78–80ꢀC. 1H-NMR
(CDCl3, d): 1.52 (t, 3H, J = 7.2 Hz), 2.25 (s, 3H), 2.52 (s, 3H),
4.23 (q, 2H, J = 7.2 Hz), 7.53 (s, 1H), 7.96 (br s, 1H), 8.52
(s, 1H). 13C-NMR (CDCl3, d): 14.42, 25.04, 30.28, 65.44, 106.25,
116.26, 132.07, 133.09, 139.90, 146.79, 168.66, 199.83. ESI–MS
(m/z) 265.1 (M– H), 267.0 (M + H).
Figure 1. Chemical structures of 1, EKB-569 (2), and HKI-272 (3).
EXPERIMENTAL
1-(5-Acetamido-4-ethoxy-2-nitrophenyl)-2-bromoethanone
All commercially available materials and solvents were used as
received without any further purification. 1H-NMR and 13C-NMR
spectra were recorded with a Gemini-300 spectrometer (EquipNet,
Inc., Hong Kong, China) using TMS as an internal standard. The
mass spectra were obtained from a Finnigan MAT-95/711 spec-
trometer (Thermo Fisher Scientific Inc. Barrington, IL). Melting
points were measured on a Buchi-510 melting point apparatus
and were uncorrected. The HPLC results were generated using a
Waters 2487 UV/Visible Detector and Waters 515 Binary HPLC
Pump Waters Corporation (Shanghai), China.
(10).
Br2 (5.0 mL, 0.1 mol) was added to a stirred solution
of 9 (26.6 g, 0.1 mol) in CH2Cl2 (500 mL). The reaction
mixture was stirred at 15–30ꢀC for 4 h. The resulting solution
was washed with saturated NaHCO3, dried (Na2SO4), and
concentrated to give 10 (33.1 g, 96%) as a pale yellow solid,
1
mp 104–106ꢀC. H-NMR (CDCl3, d): 1.55 (t, 3H, J = 7.2 Hz),
2.26 (s, 3H), 4.27 (q, 2H, J = 7.2 Hz), 4.30 (s, 3H), 7.64
(s, 1H), 7.88 (br s, 1H), 8.59 (s, 1H). 13C-NMR (CDCl3, d):
14.42, 25.07, 34.53, 65.60, 106.15, 117.36, 128.80, 133.59,
139.74, 147.26, 168.65, 193.79. ESI–MS (m/z) 344.9 (M + H),
368.9 (M + Na).
5-Acetamido-4-ethoxy-2-nitrophenylethanone (9). 3-Acetamido-
4-ethoxyphenyl-ethanone (8) was prepared from 4-hydroxy-3-
nitrophenyl-ethanone (7) using Wissner’s method [14] to give a
5-Acetamido-4-ethoxy-2-nitrobenzoylacetonitrile (11).
solution of 10 (10.4 g, 0.03 mol) in DMSO (30 mL) and EtOH
A
Scheme 1. Reagents and conditions: (a) AcOH, Ac2O, 60ꢀC; (b) C2H5Br, K2CO3, DMF, 60ꢀC; (c) H2, Pd-C, THF, 71% (three steps); (d) ethyl 2-cyano-
3-ethoxyacrylate, toluene, 90ꢀC, 16 h, 90%; and (e) Dowtherm A, 260ꢀC, 20 h, 35–45%.
Scheme 2. Reagents and conditions: (a) fuming HNO3, CH3NO2, 82%; (b) Br2, CH2Cl2, 96%; (c) NaCN, DMSO-H2O, 85%; (d) Fe, HCl, DME-EtOH,
70–80ꢀC, 79%; and (e) DMF-DMA, RT, DME, 88%.
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DOI 10.1002/jhet

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W. Ma, Y. Mao, K. Xie, Q. Zhu, R. Zhang, J. Shen, and H. Sun
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(30 mL) was cooled in an ice-water bath, then treated dropwise
with NaCN (1.6 g, 0.033 mol) in H2O (20 mL) over 1 h. The
mixture was stirred for another 4 h at 20–30ꢀC. The resulting
solution was diluted with H2O (200 mL) and filtered, and the
filtrate was acidified with 2M HCl to pH = 2–3. The resulting
solid was collected via suction filtration, washed with H2O,
and dried under reduced pressure to give 11 (7.4 g, 85%) as a
pale yellow solid, purity 96.23% (HPLC), mp 171–175ꢀC
(dec.). 1H-NMR (CDCl3, d): 1.56 (t, 3H, J = 5.4 Hz), 2.28
(s, 3H), 3.86 (s, 2H), 4.28 (q, 2H, J = 5.4 Hz), 7.88 (s, 1H), 8.01
(br s, 1H), 8.58 (s, 1H). 13C-NMR (DMSO-d6, d): 14.10, 24.20,
32.28, 65.40, 107.41, 115.26, 118.47, 126.94, 133.35, 140.49,
149.24, 169.69, 191.32. ESI–MS (m/z) 290 (M À H), 292.0
(M + H), 314.0 (M + Na).
Acknowledgments. This work was supported by grants from the
National Science and Technology Major Project (No.
2012ZX09301001-001) and the Key Project of Science and
Technology of Shanghai (No. 10431902800).
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5-Acetamido-2-amino-4-ethoxybenzoylacetonitrile (12). To
a mixture of 11 (29.0 g, 0.1 mol) and iron powder (28.0 g, 0.5 mol)
in DME (600 mL) and EtOH (100 mL) was added 2MHCl (50 mL,
0.1 mol). The resulting suspension was stirred at 70–80ꢀC for 5h.
The hot reaction mixture was filtered through celite pad; the filtrate
was concentrated to ~ 100 mL and diluted with H2O (500 mL). The
resulting product was filtered, washed with H2O, and dried under
reduced pressure to afford 12 (20.6 g, 79%) as a brown solid, purity
1
96.62% (HPLC), mp 213–216ꢀC (dec.). H-NMR (DMSO-d6, d):
1.35 (t, 3H, J = 6.6 Hz), 2.00 (s, 3H), 4.04 (q, 2H, J = 6.6 Hz), 4.43
(s, 2H), 6.35 (s, 1H), 7.32 (br s, 2H), 7.78 (s, 1H), 8.85 (s, 1H).
13C-NMR (DMSO-d6, d): 14.27, 23.29, 29.89, 63.76, 97.89,
107.41, 116.36, 126.69, 151.54, 157.02, 168.35, 187.57. EIMS
(m/z) 261 (MÀ H).
N-(3-Cyano-7-ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)
acetamide (1). To a stirred suspension of 12 (13.0 g, 0.05 mol)
in DME (250 mL) was added DMF-DMA (8.0 mL, 0.06 mol), and
the mixture was stirred at 15–30ꢀC for 1 h. The resulting solid
was collected via suction filtration, washed with EtOAc, and
dried under reduced pressure to give the product 1 (11.9 g,
88%) as a pale brown solid, purity 99.07% (HPLC) via slurring
in EtOH-EtOAc, mp >300ꢀC. 1H-NMR (DMSO-d6, d): 1.45
(t, 3H, J = 6.6 Hz), 2.14 (s, 3H), 4.20 (q, 2H, J = 6.6 Hz), 7.05
(s, 1H), 8.59 (d, 1H, J = 6.3 Hz), 8.70 (s, 1H), 9.18 (s, 1H),
12.52 (d, 1H, J = 6.3 Hz). 13C-NMR (DMSO-d6, d): 14.13,
23.98, 64.62, 92.97, 99.75, 116.32, 117.04, 118.67, 126.54,
136.55, 145.42, 152.86, 168.68, 173.49. ESI–MS (m/z)
270.2 (M À H), 272.2 (M + H). HPLC Conditions: Column:
Phenomenex Prodigy ODS3, 150 mm  4.6 mm  5mm; Detection:
230 nm; Flow rate: 1.0 mL/min; Temperature: 30ꢀC; Injection
load: 5 mL; Concentration: 0.5 mg/mL; Run time: 60 min;
Mobile phase A: H2O (0.1% H3PO4); Mobile phase B:
MeCN; Gradient program: time (min): 0, 5, 45, 50; % of
mobile phase A: 95, 95, 5, 5; % of mobile phase B: 5, 5,
95, 95, tR: 18.0 min.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet