A new and improved process for N -(4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide

Article abstract of DOI:10.1021/op300260m

A new and improved synthetic route to N-(4-chloro-3-cyano-7-ethoxyquinolin- 6-yl)acetamide (1) is described on a kilogram scale. The key step is the basic cyclization of o-[(2-cyanovinyl)amino]benzoate (14) in ^tBuONa/ ^tBuOH system to give the 3-cyano-4-hydroxyquinoline (7). The final product 1 is obtained with 49% overall yield (seven steps) and 98.9% purity (HPLC), which makes it a cost-effective and commercially friendly process for scale-up operations.

Full text of DOI:10.1021/op300260m

Technical Note
pubs.acs.org/OPRD
A New and Improved Process for N‑(4-Chloro-3-cyano-7-
ethoxyquinolin-6-yl)acetamide
Yongjun Mao,†,§ Zheng Liu,‡,§ Xiaojun Yang,‡ Xiangfei Xia,‡ Rongxia Zhang,† Jianfeng Li,†
Xiangrui Jiang,† Kai Xie,‡ Jin Zheng,‡ Hui Zhang,‡ Jin Suo,‡ and Jingshan Shen*,†
†Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, P.R. China;
‡Topharman Shanghai Co., Ltd., 1088 Chuansha Road, Pudong, Shanghai 201209, P.R. China
ABSTRACT: A new and improved synthetic route to N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (1) is described on
t
a kilogram scale. The key step is the basic cyclization of o-[(2-cyanovinyl)amino]benzoate (14) in BuONa/tBuOH system to
give the 3-cyano-4-hydroxyquinoline (7). The final product 1 is obtained with 49% overall yield (seven steps) and 98.9% purity
(HPLC), which makes it a cost-effective and commercially friendly process for scale-up operations.
a
Scheme 1. Reported large-scale synthesis of 1
INTRODUCTION
■
4-Chloroquinolines are important precursors to a number of
anticancer,1 antimalarial,2 antidiabetic,3 and antiviral4 agents
and reversible (H+/K+) ATPase inhibitors.5 N-(4-Chloro-3-
cyano-7-ethoxyquinolin-6-yl)acetamide (1, Figure 1) was
a
Reagents and conditions: (a) AcOH, Ac2O, 60 °C; (b) C2H5Br,
K2CO3, DMF, 60 °C; (c) H2, Pd−C, MeOH, 71% (three steps); (d)
ethyl 2-cyano-3-ethoxyacrylate, toluene, 90 °C, 16 h, 90%; (e)
Dowtherm A, 260 °C, 20 h, 35−45%; (f) diglyme, POCl3, 100 °C, 1 h,
65%.
which are difficult to recover; they are harmful to the
environment and also cause allergic reactions in the operation
people based on our own experience. It only gave 16.6% yield
over six steps.
In order to develop a practical and commercial process of
preparing compound 1, a couple of synthetic routes were
designed and studied by us.8 The most efficient method9 was
based on the cyclization of the o-[(2-cyanovinyl)amino]-
benzoate (14) under strongly basic conditions to form the 3-
cyano-4-hydroxyquinoline (7). The target product 1 was
obtained in POCl3/EtOAc system with ∼90% isolated yield,
which is depicted in Scheme 2.
Figure 1. Chemical structures of 1, EKB-569 (2), and HKI-272 (3).
developed as an important intermediate for the preparation
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
The earlier work to prepare N-(4-chloro-3-cyano-7-ethox-
yquinolin-6-yl)acetamide (1) (Scheme 1)7 was based on
Gould−Jacobs methodology and involved the reaction of
cyanopropenoate 6 in through thermal cyclization at 250 °C for
20 h in Dowtherm A, which led to a messy and tedious
operation, and too much material was destroyed in the reaction
producing a tar or resin, which resulted in difficulties for
purification; thus, the overall yield was reduced dramatically
(only 35−45% was reached from 6 to 7). What’s more,
Dowtherm A and diphenyl ether are high-boiling point solvents
RESULTS AND DISCUSSION
■
Starting from methyl 3-amino-4-hydroxybenzoate (8), benzoate
10 was prepared by adopting the method described by
Wissner,10 with 88% overall yield (2 steps) and >99% purity
(HPLC) without extra purification operation. Nitration of 10 to
11 was carried out in good yield by using yhe fuming HNO3/
Received: September 18, 2012
© XXXX American Chemical Society
A
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Organic Process Research & Development
Technical Note
a
Scheme 2. Improved synthetic route of 1
a
Reagents and conditions: (a) AcOH, Ac2O, 60 °C, 3 h, 92%; (b) C2H5Br, K2CO3, DMF, 60 °C, 6 h, 96%; (c) fuming HNO3, CH3NO2, rt, 6 h,
89%; (d) H2, Raney Ni, 1 atm, rt, 12 h, 91%; (e) AcOH, rt, 4 h, 92%; (f) tBuONa, tBuOH, reflux, 3 h, 85%; (g) POCl3, DMAP (cat.), EtOAc, reflux,
2 h, 88%.
CH3NO2 system.11 The crude 11 was purified by triturating in
warm water to give the product with >97% purity (HPLC).
Other nitration conditions had been studied also, including
fuming HNO3/CH2Cl2, 65% HNO3, and HNO3/H2SO4 mixed
acid, most of which gave lower yield and purity. The aniline 12
was obtained through catalytic hydrogenation of 11 under H2/
Raney Ni/MeOH condition, under 1 atm at room temperature.
The crude 12 was purified by heating and stirring in EtOAc,
giving 91% overall yield and >96% purity (HPLC). 3-
(Dimethylamino)acrylonitrile (13) was produced by condensa-
tion of cyanoacetic acid with N,N-dimethylformamide
dimethylacetal (DMF-DMA) in good yield based on Kraus’s
method.12 The key intermediate 14 was afforded in HOAc at
room temperature by condensation of aniline 12 with
acrylonitrile 13 in high yield,13 which contained both cis and
trans isomers as confirmed by HPLC and MS results. The two
isomers of 14 could both be converted to 4-hydroxyquinoline
compound 7 under strongly basic conditions. The crude 14 was
purified by suspending and stirring in 50% EtOH/H2O at room
temperature to obtain the product in 92% yield and >97%
purity (HPLC). Compound 3-cyano-4-hydroxyquinoline (7)
was produced by cyclization of 14 under strongly basic
practical, and commercial manufacture process of the title
compound 1, which gave 49% yield over 7 steps.
EXPERIMENTAL SECTION
■
Materials and Instruments. All commercially available
materials and solvents were used as received without any
further purification. 1H NMR spectra were recorded on a
Varian Gemini 300 spectrometer and 13C NMR spectra were
obtained from a Bruker AMX 400/600 at 100 MHz using TMS
as an internal standard. Infrared spectra were recorded using a
Thermo-Nicolet MAGNA-IR 750. Mass spectra were obtained
from a Finnigan MAT-95/711 spectrometer. Melting points
were measured on a Buchi-510 melting point apparatus, which
are uncorrected. The HPLC results were generated using a
Waters 2487 UV/Visible Detector and Waters 515 Binary
HPLC Pump. The purity measurements are on the basis of
HPLC UV Area%.
Methyl 3-Acetamido-4-hydroxybenzoate (9). To a
stirred solution of methyl 3-amino-4-hydroxybenzoate 8 (3.0
kg, 17.9 mol) in AcOH (15 L) at 60 °C was added Ac2O (2.6 L,
27.5 mol) over 30 min, and the mixture was stirred at this
temperature for 3 h. The mixture was poured into chilled water
(∼10 °C, 40 L) over 1 h and stirred. The resulting white solid
was filtered, washed with water (2 × 4 L), and dried at ordinary
pressure (50 °C, 6 h) to give product 9 (3.5 kg, 92%) as a white
conditions.14 The BuONa/tBuOH system was selected as the
t
reaction condition for the scale-up. Other conditions had also
been studied by us in detail. The experimental results showed
that NaOH/EtOH, NaOMe/MeOH, or NaOEt/EtOH system
gave more impurities. Although NaOEt/EtOH (produced by
metallic sodium and anhydrous ethanol) or DBU/MeCN
condition produced good results, the safety or cost factor
limited their application on a scale-up operation. The crude 7
was purified by heating and stirring in 50% EtOH/EtOAc to
give the compound with 85% overall yield and 99% purity
(HPLC). In the last step, 4-chloro-3-cyanoquinoline 1 was
obtained by reaction with POCl3 in EtOAc, catalyzed by 5 mol
% DMAP. Purification of 1 was carried out by triturating and
stirring in DMF at rt with 88% isolated yield and 98.9% purity
(HPLC).
1
powder, mp 181−183 °C. H NMR (300 MHz, DMSO-d6): δ
2.10 (s, 3H), 3.78 (s, 3H), 6.91 (d, J = 8.3 Hz, 1H), 7.58 (dd, J
= 2.0, 8.4 Hz, 1H), 8.45 (s, 1H), 9.35 (s, 1H), 10.82 (s, 1H).
13C NMR (100 MHz, DMSO-d6): δ 23.7, 51.5, 114.9, 120.0,
123.3, 126.5, 126.6, 152.3, 166.0, 169.2. ESI-MS (m/z): 210.1
(M + H).
Methyl 3-Acetamido-4-ethoxybenzoate (10). To a
stirred suspension of 9 (3.5 kg, 16.7 mol) and K2CO3 (3.5
kg, 25.3 mol) in DMF (25 L) at 60 °C was added C2H5Br (1.5
L, 19.9 mol) over 1 h, and the mixture was stirred at this
temperature for 6 h. The mixture was poured into chilled water
(∼10 °C, 50 L) and stirred for 1 h at rt. The resulting white
solid was filtered, washed with water (2 × 4 L), and dried at
ordinary pressure (50 °C, 6 h) to provide 10 (3.8 kg, 96%) as a
white powder, mp 153−155 °C. 1H NMR (300 MHz, CDCl3):
δ 1.50 (t, J = 6.9 Hz, 3H), 2.20 (s, 3H), 3.90 (s, 3H), 4.25 (q, J
= 6.9 Hz, 2H), 6.95 (d, J = 8.4 Hz, 1H), 7.75 (br s, 1H), 7.80
(dd, J = 2.0, 8.4 Hz, 1H), 9.05 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 14.7, 24.8, 51.8, 64.3, 109.8, 120.7, 122.6, 126.0,
127.1, 150.8, 166.6, 168.1. ESI-MS (m/z): 238.1 (M + H),
260.1 (M + Na). HPLC conditions: Column: ZORBAX SB-
CONCLUSIONS
■
In this article, we developed a new and kilogram scale of a
synthetic process for N-(4-chloro-3-cyano-7-ethoxyquinolin-6-
yl)acetamide (1). In the new synthetic route, common and
inexpensive regents and mild reaction conditions were used in
order to simplify the operation, enhance the overall yield, and
decrease the preparation cost, which made it as an efficient,
B
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Organic Process Research & Development
Technical Note
C18, 150 mm × 4.6 mm × 5 μm; Detection: 254 nm; Flow
rate: 1.0 mL/min; Temperature: 30 °C; Injection load: 10 μL;
Solvent: acetonitrile; Concentration: 0.5 mg/mL; Run time: 25
min; Mobile phase A: water (0.1% H3PO4); Mobile phase B:
acetonitrile; Gradient program: time (min): 0, 10, 20, 25; % of
mobile phase A: 80, 60, 10, 10; % of mobile phase B: 20, 40, 90,
90, tR: 10.754 min. Purity: 99.3%.
EtOH/H2O (10 L) and stirred at rt for 1 h. The resulting solid
was collected by suction filtration, washed by 50% EtOH/H2O
(2 × 2 L), and dried at 10−20 mmHg (50 °C, 4 h) to give
product 14 (2.8 kg, 92%) as a white solid, which contained
both cis and trans isomers as confirmed by LC−MS results. 1H
NMR (300 MHz, DMSO-d6): δ 1.39 (t, J = 6.9 Hz, 3H), 2.06
(s, 3H), 3.82 (s, 3H), 4.25 (q, J = 6.9 Hz, 2H), 5.14 (d, J = 13.2
Hz, 1H), 7.05 (s, 1H), 8.21 (t, J = 13.2 Hz, 1H), 8.41 (s, 1H),
9.02 (s, 1H), 10.41 (d, J = 13.2 Hz, 1H). 13C NMR (100 MHz,
DMSO-d6): δ 14.6, 23.9, 52.3, 65.1, 72.0, 98.1, 104.6, 120.9,
121.4, 125.2, 141.2, 146.3, 155.4, 167.9, 168.9. ESI-MS (m/z):
303.9 (M + H), 326.0 (M + Na). HPLC conditions: Column:
ShinoChrom ODS-BP, 250 mm × 4.6 mm × 5 μm; Detection:
254 nm; Flow rate: 1.0 mL/min; Temperature: 30 °C;
Injection load: 5 μL; Solvent: 60% acetonitrile/water;
Concentration: 10 mg/mL; Run time: 35 min; Mobile phase
A: 0.02 M aqueous KH2PO4; Mobile phase B: acetonitrile;
Gradient program: time (min): 0, 5, 15, 35; % of mobile phase
A: 60, 60, 30, 30; % of mobile phase B: 40, 40, 70, 70, tR: 12.355
min (59.9%), tR: 12.564 (37.7%), Combined purity: 97.6%.
N-(3-Cyano-7-ethoxy-4-oxo-1,4-dihydroquinolin-6-
yl)acetamide (7). The benzoate 14 (2.0 kg, 6.6 mol) and
Methyl 5-Acetamido-4-ethoxy-2-nitrobenzoate (11).
To a stirred solution of compound 10 (3.6 kg, 15.2 mol) in
MeNO2 (40 L) at rt was added 95% fuming HNO3 (0.20 L, 4.6
mol) over 20 min. After the mixture was stirred at rt for 1 h,
another portion of 95% fuming HNO3 (1.2 L, 27.6 mol) was
added over 1 h, so that the reaction temperature stayed under
35 °C; the reaction solution was then stirred for another 6 h at
rt. Then the reaction solution was poured into cooled water
(∼10 °C, 40 L) and stirred for 1 h. The organic layer was
separated and washed by water (2 × 20 L). The solvent was
distilled off to give the crude 11 (4.1 kg) as a brown solid,
which was added to water (20 L) and stirred rapidly at rt for 1
h. The resulting solid was collected by suction filtration, washed
with water (2 × 4 L), and dried at ordinary pressure (50 °C, 8
1
h) to give product 11 (3.8 kg, 89%) as a light-yellow solid. H
t
tBuONa (1.3 kg, 13.5 mol) were added to BuOH (20 L,
NMR (300 MHz, DMSO-d6): δ 1.52 (t, J = 7.2 Hz, 3H), 2.25
(s, 3H), 3.89 (s, 3H), 4.23 (q, J = 7.2 Hz, 2H), 7.44 (s, 1H),
7.91 (br, 1H), 8.74 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
δ 14.6, 24.6, 53.4, 65.9, 108.1, 118.7, 120.8, 132.1, 144.1, 150.2,
165.4, 170.1. ESI-MS (m/z): 281.0 (M − H), 282.9 (M + H),
305.0 (M + Na). HPLC conditions: Column: ShinoChrom
ODS-BP, 250 mm × 4.6 mm × 5 μm; Detection: 230 nm; Flow
rate: 1.0 mL/min; Temperature: 30 °C; Injection load: 5 μL;
Solvent: 60% acetonitrile/water; Concentration: 0.5 mg/mL;
Run time: 50 min; Mobile phase A: water (0.1% H3PO4);
Mobile phase B: acetonitrile; Gradient program: time (min): 0,
5, 45, 50; % of mobile phase A: 90, 90, 0, 0; % of mobile phase
B: 10, 10, 100, 100, tR: 27.441 min. Purity: 97.7%.
warmed to liquid if needed). The reaction mixture was stirred
and heated to reflux for 3 h. The clear reaction solution was
cooled to ∼40 °C, concentrated to ∼8 L, and then diluted with
water (15 L). The pH was then adjusted to ∼4 with
concentrated HCl. The resulting suspension was stirred at
40−50 °C for another 1 h. The resulting solid was filtered,
washed with water, and dried to give the crude product 7 (1.7
kg), which was suspended in 50% EtOH/EtOAc (8 L) and
stirred and heated to 70 °C for 1 h. After cooling to rt, the
resulting solid was collected by suction filtration, washed by
50% EtOH/EtOAc (2 × 1 L), and dried at 10−20 mmHg (60
°C, 4 h) to give product 7 (1.5 kg, 85%) as a pale solid, mp
1
Methyl 5-Acetamido-2-amino-4-ethoxybenzoate (12).
Compound 11 (3.2 kg, 11.3 mol) and RTH-311 Raney-Ni
(wet, 0.30 kg) were added to MeOH (40 L), and the mixture
stirred for 12 h at rt under 1 atm hydrogen atmosphere. The
reaction mixture was then filtered through a Celite pad, and
then the filter cake was washed by methanol (2 × 3 L). The
combined filtrates were concentrated to give the crude aniline
product 12 (3.0 kg) as a brown solid, which was suspended in
EtOAc (8 L) and heated to reflux for 1 h. After cooling to rt,
the resulting solid was collected by suction filtration, washed
with EtOAc (2 × 1 L), and dried at ordinary pressure (50 °C, 4
>300 °C. H NMR (DMSO-d6, δ): 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, δ): 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 (M + H). HPLC
conditions: Column: Phenomenex Prodigy ODS3, 150 mm ×
4.6 mm × 5 μm; Detection: 230 nm; Flow rate: 1.0 mL/min;
Temperature: 30 °C; Injection load: 5 μL; 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%.
1
h) to give product 12 (2.6 kg, 91%) as a light-tan solid. H
NMR (300 MHz, DMSO-d6): δ 1.45 (t, J = 7.2 Hz, 3H), 2.16
(s, 3H), 3.82 (s, 3H), 4.06 (q, J = 7.2 Hz, 2H), 5.71 (br, 2H),
6.09 (s, 1H), 7.35 (br, 1H), 8.68 (s, 1H). 13C NMR (100 MHz,
DMSO-d6): δ 14.8, 23.9, 51.5, 64.1, 98.6, 101.0, 116.7, 126.3,
150.9, 155.9, 167.9, 168.5. ESI-MS (m/z): 252.9 (M + H).
Using HPLC conditions the same as those for compound 11,
tR: 20.267 min. Purity: 96.3%.
Methyl 5-Acetamido-2-[(2-cyanovinyl)amino]-4-
ethoxybenzoate (14). Compound 12 (2.5 kg, 9.9 mol) was
dissolved in glacial HOAc (18 L) at rt. 3-(Dimethylamino)-
acrylonitrile 13 (1.1 kg, 11.4 mol) was added over 1 h and
stirred at rt for another 4 h. A large amount of grey solid was
generated gradually. The mixture was poured into chilled water
(∼10 °C, 40 L) over 1 h and stirred. The resulting solid was
filtered, washed with water (2 × 2 L), and dried to give crude
product 14 (3.0 kg) as a grey powder, which was added to 50%
N-(4-Chloro-3-cyano-7-ethoxyquinolin-6-yl)-
acetamide (1). Compound 7 (1.4 kg, 5.1 mol) and DMAP
(30.0 g, 0.25 mol) were suspended in EtOAc (15 L) and stirred
at rt. To the mixture was added slowly over 1 h POCl3 (1.9 L,
20.8 mol), and the mixture was then heated to reflux for
another 2 h to give a clear solution. After cooling to rt, the
reaction solution was poured slowly into ice−water (20 L) and
stirred for 2 h. The resulting solid was filtered, washed with
water (2 × 2 L), and dried to give the crude product 1 (1.4 kg),
which was suspended in DMF (4 L) and stirred at rt for 1 h.
The solid was filtered, washed with EtOAc (3 × 1 L), and dried
at 10−20 mmHg (50 °C, 4 h) to give product 1 (1.3 kg, 88%)
as a faint brown solid, mp: 255−258 °C. 1H NMR (DMSO-d6,
δ): 1.50 (t, 3H, J = 6.3 Hz), 2.25 (s, 3H), 4.40 (q, 2H, J = 6.3
C
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Organic Process Research & Development
Technical Note
(13) (a) Abu-Shanab, F. A.; Elkholy, Y. M.; Elnagdi, M. H. Synth.
Commun. 2002, 32, 3493. (b) Dutta, M. C.; Chanda, K.; Karim, E.;
Vishwakarma, J. N. Indian J. Chem. B 2004, 43, 2471.
(14) (a) Duncan, S. M.; Pagan, M. A.; Floyd, M. B. U.S. Pat. Appl.
Publ. 20040204587, 2004; (b) Olszewski, J. D.; May, M. K.; Berger, D.
M. U.S. Pat. Appl. Publ. 20070208164, 2007.
Hz), 7.60 (s, 1H), 9.01 (s, 1H), 9.17 (s, 1H), 9.54 (s, 1H). ESI-
MS (m/z): 290.1 (M + H). 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): 3334.4, 2993.0, 2235.1, 1689.4, 1618.0, 1521.6, 1427.1,
1348.0, 1259.3, 1161.0, 1037.5, 694.3. HPLC conditions:
Column: Phenomenex Prodigy ODS3, 150 mm × 4.6 mm ×
5 μm; Detection: 230 nm; Flow rate: 1.0 mL/min; Temper-
ature: 30 °C; Injection load: 5 μL; Solvent: DMF;
Concentration: 0.5 mg/mL; Run time: 60 min; Mobile phase
A: water/acetonitrile/H3PO4 = 950:50:0.5; Mobile phase B:
water/acetonitrile/H3PO4 = 50:950:0.5; 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%.
AUTHOR INFORMATION
■
Corresponding Author
*Telephone: +86 21 20231962. Fax: +86 21 20231000. E-mail:
jsshen@mail.shcnc.ac.cn.
Author Contributions
§Y.M. and Z.L. have contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the National Science
and Technology Major Project (No. 2012ZX09301001-001).
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