New synthesis of N -(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide

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New Synthesis of N-(4-Chloro-3-cyano-7-
ethoxyquinolin-6-yl)acetamide
Yongjun Maoa, Fuqiang Zhub, Weiming Chenb, Jingshan Shena &
Xiangrui Jianga
a Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, Pudong, Shanghai, P. R. China
b Topharman Shanghai Co., Ltd., Pudong, Shanghai, P. R. China
Published online: 18 Mar 2015.
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To cite this article: Yongjun Mao, Fuqiang Zhu, Weiming Chen, Jingshan Shen & Xiangrui Jiang
(2015) New Synthesis of N-(4-Chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide, Organic Preparations
and Procedures International: The New Journal for Organic Synthesis, 47:2, 161-167, DOI:
10.1080/00304948.2015.1005987
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Organic Preparations and Procedures International, 47:161–167, 2015
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2015.1005987
New Synthesis of N-(4-Chloro-3-cyano-7-
ethoxyquinolin-6-yl)acetamide
Yongjun Mao,1 Fuqiang Zhu,2 Weiming Chen,2 Jingshan Shen,1
and Xiangrui Jiang1
1Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Pudong,
Shanghai, P. R. China
2Topharman Shanghai Co., Ltd., Pudong, Shanghai, P. R. China
4-Chloroquinolines are key synthetic precursors for anticancer,1 anti-malarial,2 antidia-
betic,3 antiviral4 agents and reversible (HC/KC) AT Phase inhibitors.5 For example, N-(4-
chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (1) was developed as an important
intermediate for the preparation of pelitinib (2) and neratinib (3) [Fig. 1], which act as
irreversible inhibitors of epidermal growth factor receptor (EGFR) and human epidermal
growth factor receptor-2 (HER-2) kinases.6–8
Previous reports 9,10 described the preparation of 1 based on Gould-Jacobs methodol-
ogy 11 using 2-amino-5-nitrophenol (4) as the starting material (Scheme 1). Treatment of
5 with ethyl (E)-2-cyano-3-ethoxypropenoate afforded the corresponding ethyl cyanopro-
penoate 6. 3-Cyano-4-hydroxyquinoline (7) was obtained in » 40% yield through thermal
cyclization at 250 ꢀC for 20 h in Dowtherm A. After chlorination with POCl3 in diglyme,
1 was produced in 65% yield. While this route was straightforward, the high temperature
required for the cyclization of 6 to 7 on a kilogram scale proved to be disadvantageous
because of the formation of tars and resins as well as low overall yield.
Scheme 1
Received July 12, 2014; in final form November 4, 2014.
Address correspondance to Xiangrui Jiang, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, 501 Haike Road, Pudong, Shanghai 201203, P. R. China. E-mail:
jiangxiangrui@simm.ac.cn
161

162
Jiang et al.
Fig. 1. Structures of 1, pelitinib (2) and neratinib (3)
Recently, we developed new methods for the synthesis of 7.12–15 The key step in the
first route (Scheme 2)12,13 is the base-induced cyclization of o-[(2-cyanovinyl)amino]ben-
zoate (11) using t-BuONa/t-BuOH to give 7 on a kilogram scale, in 51% yield over six
steps (HPLC purity: 98.8%). In the second route (Scheme 3),14,15 3-(dimethylamino)-2-
(2-nitrobenzoyl) acrylonitrile (15) was converted to 7 through a reductive cyclization
method using a Zn/AcOH/EtOH. Since the solubility of compounds 15 and 7 are poor,
operations with these compounds are not convenient and the overall yield of this reduc-
tive cyclization is about 30% over ten steps.
Scheme 2
Scheme 3
Herein, we report a new synthetic approach to compound 1 (Scheme 4) from 1-(3-
amino-4-hydroxyphenyl)ethanone (16). Acetylation and ethylation of 16 afforded com-
pound 17 in 88% yield.6,7 Subsequent nitration was carried out in fuming HNO3/CH3NO2

N-(4-Chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide
163
Scheme 4
16
to give the resulting 1-(2-nitrophenyl)ethanone 18 in 81% isolated yield, which was
then condensed with N,N-dimethylformamide dimethyl acetal (DMF-DMA) in toluene at
100ꢀC to give the 3-(dimethylamino)-1-phenylprop-2-en-1-one 19 in 89% yield.17,18
Reductive cyclization of 19 using Raney-Ni in DME furnished an 87% yield of quinolin-
4(1H)-one 2019,20 which has better solubility than compound 7 in DME, THF, and
CH2Cl2. 3-Bromoquinolin-4(1H)-one 21 was produced in 89% yield from 20 through bro-
mination with Br2/AcOH.21 Displacement of Br using CuCN/CuI/DMF
22,23
affored 3-
cyano-4-hydroxy quinoline 7, which was purified by digestion in 50% EtOH/EtOAc to
provide a 75% overall yield (HPLC purity: 99.1%). Finally, 4-chloro-3-cyanoquinoline 1
was obtained by reaction with POCl3 in EtOAc, catalyzed by 5 mol% DMAP. Purifica-
tion of 1 was carried out by washing with DMF and EtOAc at room temperature in 88%
isolated yield (HPLC purity 98.9%).
In summary, we have developed a new synthetic route to 4-chloro-3-cyanoqui-
noline (1) on a hectogram scale. The key steps include the reductive cyclization pro-
cess to produce the quinolin-4(1H)-one 20 from 19, the bromination of 20 to give 3-
bromoquinolin-4(1H)-one 21, and substitution of the bromide at C3 by CN to give
compound 7. Final chlorination using POCl3 in EtOAc provided product 1 in 32.5%
yield over eight steps (HPLC purity 98.9%). Purification methods for 7 and 1 are
also given.
Experimental Section
All chemicals and solvents are commercially available and were used as received without
1
any further purification. H NMR spectra were recorded on a Varian Gemini 300 spec-
trometer and 13C NMR spectra were obtained from a Bruker AMX 400/600 at 400 MHz
using TMS as an internal standard. Infrared spectra were recorded using a Thermo-Nico-
let MAGNA-IR 750. Mass spectra were obtained from a Finnigan MAT-95/711 spec-
trometer. Melting points were measured on a Shenguang WRS-1B melting point
apparatus and are uncorrected. The HPLC results were generated using a Waters 2487
UV/Visible Detector and Waters 515 Binary HPLC Pump. Although compounds 17 and
18 are mentioned in the literature,13 they were not fully characterized and no mps were
reported.

164
Jiang et al.
N-(5-Acetyl-2-ethoxyphenyl)acetamide (17). To a stirred solution of 1-(3-amino- 4-
ꢀ
hydroxyphenyl)ethanone 16 (200 g, 1.32 mol) in AcOH (760 mL) at 60 C was added
Ac2O (148 mL, 1.57 mol) over 1 h, and the mixture was stirred at this temperature for
1 h. The mixture was poured into ice water (4 L) over 20 min and stirred. The resulting
ꢀ
tan solid was collected and washed with water (500 mL £ 2) and dried at 50 C to give
N-(5-acetyl-2- hydroxyphenyl)acetamide (235 g, 92%) as a white powder. This acety-
lated product was suspended with K2CO3 (250 g, 1.82 mol) in DMF (1.17 L) at 60 C,
ꢀ
C2H5Br (99 mL, 1.33 mol) was added over 1 h, and the mixture was stirred at this tem-
perature for 1 h. The mixture was poured into ice water (5 L) and stirred for 30 min. The
resulting grey solid was collected and washed with water (500 mL £ 2) and dried at 50
ꢀC to provide 17 (258 g, 96%) as a grey powder, which was used directly at the next step.
An analytical sample of 17 was obtained by recrystallization from 1:1 hexane/EtOAc to
1
ꢀ
afford an off-white solid, mp: 98–99 C. H NMR (CDCl3): d 1.48 (t, 3 H, J D 7.2 Hz),
2.23 (s, 3 H), 2.57 (s, 3 H), 4.18 (q, 2 H, J D 7.2 Hz), 6.90 (d, 1 H, J D 8.7 Hz), 7.72 (dd,
1 H, J D 8.7, 1.8 Hz), 7.75 (br s, 1 H), 8.99 (d, 1 H, J D 1.8 Hz). 13C NMR (CDCl3): d
14.6, 24.9, 26.5, 64.5, 110.2, 120.4, 124.4, 127.2, 130.1, 150.53, 168.3, 197.3. ESI-MS
(m/z) 222.0 (MCH)C, 244.1 (MCNa)C, 260.0 (MCK)C.
Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.15; H, 6.86; N,
6.16.
N-(5-Acetyl-2-ethoxy-4-nitrophenyl)acetamide (18). To a stirred solution of 17
(230 g, 1.04 mol) in CH3NO2 (3.1 L) was added fuming nitric acid (119 mL, 2.6 mol) to
ꢀ
keep the reaction temperature below 30 C. The resulting solution was stirred at 20–30
ꢀC for another 4 h and diluted with chilled water (4 L) and stirred for 30 min. The organic
layer was separated, washed with water (2 L £ 2) and saturated NaHCO3 (2 L £ 2)
respectively, and dried over anhydrous Na2SO4. The solvent was removed under vacuum
to give the crude 18 as a brown solid, which was recrystallized from 1:1 hexane/EtOAc
1
(1.4 L) to afford 18 (224 g, 81%) as a light-yellow solid, mp: 78–79 ꢀC. H NMR
(CDCl3): d 1.52 (t, 3 H, J D 7.2 Hz), 2.25 (s, 3 H), 2.52 (s, 3 H), 4.23 (q, 2 H, J D
7.2 Hz), 7.53 (s, 1 H), 7.96 (br s, 1 H), 8.52 (s, 1 H). 13C NMR (CDCl3): d 14.4, 25.0,
30.3, 65.4, 106.2, 116.3, 132.1, 133.1, 139.9, 146.8, 168.7, 199.8. ESI-MS (m/z) 265.1
(M–H)¡, 267.0 (M C H)C.
Anal. Calcd for C12H14N2O5: C, 54.13; H, 5.30; N, 10.52. Found: C, 54.25; H, 5.36;
N, 10.46.
N-(5-(3-(Dimethylamino)acryloyl)-2-ethoxy-4-nitrophenyl)acetamide (19). To a
stirred suspension of 18 (200 g, 0.75 mol) in toluene (2.3 L) was added DMF-DMA
(401 mL, 3.02 mol). The mixture was stirred at 90–100 ꢀC for 24 h and then cooled to »
10 ꢀC. The resulting yellow solid was collected, washed with cooled toluene (115 mL £
3), and dried under reduced pressure to give 19 (214 g, 89%) as a bright-yellow powder,
1
ꢀ
which was used directly at the next step, mp: 174–175 C. H NMR (DMSO-d6): d 1.41
(t, 3 H, J D 7.2 Hz), 2.17 (s, 3 H), 2.83 (s, 3 H), 3.07 (s, 3 H), 4.24 (q, 2 H, J D 7.2 Hz),
5.18 (d, 1 H, J D 12.9 Hz), 7.58 (s, 1 H), 8.25 (s, 1 H), 9.42 (s, 1 H). MS-ESI (m/z): 322.1
(MCH)C, 344.1 (MCNa)C.
Anal. Calcd for C15H19N3O5: C, 56.07; H, 5.96; N, 13.08. Found: C, 56.19; H, 5.99;
N, 12.99.
N-(7-Ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)acetamide (20). Compound 19
(180 g, 0.56 mol) and Raney-Ni (wet, 20 g) were added to DME (4.6 L), and stirred for
12 h at rt under 1 atm of hydrogen. A yellow solid was generated during the reaction.
After the reaction was completed, around 3.5 L DME was recovered and the residue was
dissolved into CH2Cl2 (3.8 L) to give a clear solution, which was then filtered through

N-(4-Chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide
165
celite pad, the filter cake was washed by CH2Cl2 (225 mL £ 2). The combined filtrate
was concentrated to give crude 20 as a tan solid, which was digested in 50% EtOH/EtOAc
(532 mL), stirred and heated to reflux for 1 h. After cooling to rt, the resulting solid was
collected, washed with 50% EtOH/EtOAc (70 mL £ 3), dried at 50 ꢀC to give 20 (119 g,
87%) as a faint yellow solid. An analytical sample of this solid was purified on a silica
column using hexane/EtOAc (2:1) as the eluent to give 20 as an off-white solid. mp: 269–
272 ꢀC. 1H NMR (DMSO-d6): d 1.44 (t, 3 H, J D 6.9 Hz), 2.12 (s, 3 H), 4.16 (q, 2 H, J D
6.9 Hz), 5.92 (d, 1 H, J D 7.5 Hz), 7.00 (br s, 1 H), 7.77 (d, 1 H, J D 7.5 Hz), 8.59 (s, 1
H), 9.06 (s, 1 H), 11.61 (br s, 1 H). 13C NMR (DMSO-d6): d 14.5, 23.4, 63.3, 91.6, 98.5,
111.8, 115.2, 126.0, 149.8, 152.64, 154.2, 168.1, 188.3. MS-EI (m/z): 247. IR (KBr):
3373, 3265, 1660, 1631, 1572.
Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C, 63.29; H, 5.79;
N, 11.30.
N-(3-Bromo-7-ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)acetamide (21). To
a
stirred suspension of 20 (105 g, 0.43 mol) in AcOH (1.9 L) was added dropwise of a solu-
tion of dry Br2 (23.2 mL, 0.45 mol) in AcOH (190 mL) over 1 h, keeping the reaction
temperature between 20–25 ꢀC. A tan solid was generated immediately. The mixture was
stirred at rt for another 1 h. The resulting solid was collected, washed with cooled EtOH
(100 mL £ 3), and dried under reduced pressure to give 21 (124 g, 89%) as a faint brown
powder, which was used directly at the next step. An analytical sample of this solid was
purified on a silica column using hexane/EtOAc (2:1) as the eluent to give 21 as an off-
white solid, mp: 216 ꢀC (dec.). 1H NMR (DMSO-d6): d 1.45 (t, 3 H, J D 6.9 Hz), 2.13 (s,
3 H), 4.17 (q, 2 H, J D 6.9 Hz), 7.02 (s, 1 H), 8.34 (d, 1 H, J D 5.7 Hz), 8.68 (s, 1 H),
9.12 (s, 1 H), 12.01 (br s, 1 H). MS-EI (m/z): 324.
Anal. Calcd for C13H13BrN2O3: C, 48.02; H, 4.03; N, 8.62. Found: C, 48.19; H, 4.07;
N, 8.58.
N-(3-Cyano-7-ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)acetamide (7). Compound
21 (110 g, 0.34 mol), CuCN (60.9 g, 0.68 mol) and CuI (19.0 g, 0.1 mol) were sus-
pended in DMF (742 mL) under nitrogen. The reaction mixture was stirred and heated to
130–140 ꢀC for 6 h and then cooled to rt. The resulting mixture was filtered through a cel-
ite pad, the filter cake was washed with DMF (53 mL £ 2). The combined filtrate was
concentrated and » 525 mL DMF was recovered. The residue was added to 1 L water
and stirred for 4 h at rt. The resulting white solid was collected, washed with water, and
dried to give the crude product 7 (80 g), which was suspended in 50% EtOH/EtOAc
(472 mL), stirred and heated to 70ꢀC for 1 h. After cooled to rt, the resulting solid was
collected, washed by 50% EtOH/EtOAc (36 mL £ 2), and dried at 50ꢀC to give the pure
7
1
ꢀ
product 7 (69 g, 75%) as a pale solid, mp > 300 ꢀC (lit. > 250 C). H NMR (DMSO-
d6): d 1.45 (t, 3 H, J D 6.6 Hz), 2.14 (s, 3 H), 4.20 (q, 2 H, J D 6.6 Hz), 7.05 (s, 1 H),
8.59 (d, 1 H, J D 6.3 Hz), 8.70 (s, 1 H), 9.18 (s, 1 H), 12.52 (d, 1 H, J D 6.3 Hz). 13C
NMR (DMSO-d6): d 14.1, 23.9, 64.6, 93.0, 99.7, 116.3, 117.0, 118.7, 126.5, 136.5, 145.4,
152.9, 168.7, 173.5. ESI-MS (m/z): 270.2 (M–H)¡, 272.2 (MCH)C.
Anal. Calcd for C14H13N3O3: C, 61.99; H, 4.83; N, 15.49. Found: C, 61.89; H, 4.87;
N, 15.56.
HPLC Conditions: Column: Phenomenex Prodigy ODS3, 150 mm £ 4.6 mm £
ꢀ
5 mm; Detection: 230 nm; Flow rate: 1.0 mL/min; Temperature: 30 C; Injection load:
5 mL; Solvent: DMF; Concentration: 0.5 mg/mL; Run time: 60 min; Mobile phase A:
water (0.1% H3PO4); Mobile phase B: acetonitrile; Gradient program: time (min): 0, 5,
45, 50, 52, 60;% of mobile phase A: 95, 95, 5, 5, 95, 95;% of mobile phase B: 5, 5, 95,
95, 5, 5; tR: 15.546 min; Purity: 99.1%.

166
Jiang et al.
N-(4-Chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (1). Compound 7 (61 g,
0.22 mol) and DMAP (0.85 g, 5 mol%) were suspended in EtOAc (565 mL) and stirred
at rt. POCl3 (60 mL, 0.65 mol) was added slowly to the mixture over 1 h, and the reaction
was heated to reflux for another 2 h to give a clear solution. After cooling to rt, the reac-
tion solution was poured slowly into ice-water (900 mL) and stirred for 1 h. The resulting
solid was collected, washed with water (80 mL £ 2), and dried to give the crude product
1 (60 g), which was suspended in DMF (180 mL) and stirred at rt for 1 h. The solid was
filtered, washed with EtOAc (39 mL £ 3), and dried at 50 ꢀC to give the pure product 1
(55 g, 88%) as a faint brown solid, mp: 255–258 ꢀC (lit.7 250 ꢀC). 1H NMR (DMSO-d6):
d 1.50 (t, 3 H, J D 6.3 Hz), 2.25 (s, 3 H), 4.40 (q, 2 H, J D 6.3 Hz), 7.60 (s, 1 H), 9.01 (s,
1 H), 9.17 (s, 1 H), 9.54 (s, 1 H). ESI-MS (m/z): 290.1 (MCH)C.
Anal. Calcd for C14H12ClN3O2: C, 58.04; H, 4.17; N, 14.50. Found: C, 57.81; H,
4.07; N, 14.18.
IR (KBr): 3334, 2235, 1689, 1618. HPLC Conditions: Column: Phenomenex Prodigy
ODS3, 150 mm £ 4.6 mm £ 5 mm; Detection: 230 nm; Flow rate: 1.0 mL/min; Temper-
ature: 30 ꢀC; Injection load: 5 mL; Solvent: DMF; Concentration: 0.5 mg/mL; Run time:
60 min; Mobile phase A: water/acetonitrile/H3PO4 D 950/50/0.5 (volume); Mobile phase
B: water/acetonitrile/H3PO4 D 50/950/0.5 (volume); Gradient program: time (min): 0, 5,
45, 50, 52, 60;% of mobile phase A: 100, 100, 0, 0, 100, 100;% of mobile phase B: 0, 0,
100, 100, 0, 0; tR: 26.018 min; Purity: 98.9%.
Acknowledgment
We are grateful to the Natural Science Foundation of Zhejiang province (No. 202095) and
the Natural Science Foundation of China (No. 20676123) for financial help.
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