New Synthesis of 7-(3-chloropropoxy)-4-hydroxy-6-methoxyquinoline-3-carbonitrile, a Key Intermediate to Bosutinib

Article abstract of DOI:10.1002/jhet.2811

A new and convenient synthesis of 7-(3-chloropropoxy)-4-hydroxy-6-methoxyquinoline-3-carbonitrile, the key intermediate to bosutinib, is described on a hectogram scale. 5-Bromo-2-methoxyphenol is adopted as the starting material via the simple chemical process including Friedel-Crafts reaction, alkylation, bromination, cyano substitution, and so on to give the 3-amino-2-(2-bromobenzoyl)acrylonitrile compound 25, which underwent key intramolecular cyclization at K₂CO₃/DMF condition; the title product was obtained in 36.9% yield over 7 steps and 98.71% purity (HPLC).

Full text of DOI:10.1002/jhet.2811

Month 2017 New Synthesis of 7-(3-chloropropoxy)-4-hydroxy-6-methoxyquinoline-3-
carbonitrile, a Key Intermediate to Bosutinib
†
†
*
Guoqing Zhu, Mingchen Sun, Chunping Zhu, Han Wang, and Jingli Xu
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, China
*
E-mail: wanghansh@126.com
†Both authors contributed equally to this work.
Additional Supporting Information may be found in the online version of this article.
Received August 4, 2016
DOI 10.1002/jhet.2811
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
A new and convenient synthesis of 7-(3-chloropropoxy)-4-hydroxy-6-methoxyquinoline-3-carbonitrile,
the key intermediate to bosutinib, is described on a hectogram scale. 5-Bromo-2-methoxyphenol is adopted
as the starting material via the simple chemical process including Friedel-Crafts reaction, alkylation, bromi-
nation, cyano substitution, and so on to give the 3-amino-2-(2-bromobenzoyl)acrylonitrile compound 25,
which underwent key intramolecular cyclization at K2CO3/DMF condition; the title product was obtained
in 36.9% yield over 7 steps and 98.71% purity (HPLC).
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
temperature led to a messy and tedious operation, and
too many materials were destroyed in the reaction as
tar or resin, which resulted in difficulties for
purification, and thus the overall yield was reduced
dramatically (~40%).
Yin et al. [4] reported a new synthesis of 1, which started
with esterification of the material vanillic acid (3), followed
by alkylation and nitration reduction to give the methyl
Bosutinib (1, SKI-606, Fig. 1), marketed as Bosulif, is
an adenosine triphosphate (ATP)-competitive Bcr-Abl
tyrosine-kinase inhibitor with an additional inhibitory
effect on SRc family kinases (including Src, Lyn, and
Hck) for use in the treatment of cancer [1]. Bosulif
was originally developed by Wyeth Pharmaceuticals
(Pearl River, NY) and received the US Food and
Drug Administration (FDA) and European Union (EU)
European Medicines Agency approval on 2012 and
2013, respectively, for the treatment of adult patients
with Philadelphia chromosome-positive chronic myeloge-
nous leukemia with resistance or intolerance to prior
therapy [2].
A couple of synthetic routes of 1 were developed on a
multigram scale. The earlier and common work to
prepare 1 was based on the Gould-Jacobs methodology
through a thermal cyclization at 250°C for 4 hours in
Dowtherm A to synthesize the intermediate 7-fluoro-4-
hydroxy-6-methoxyquinoline-3-carbonitrile (2, Fig. 1)
[3]. The main problem was that the high reaction
2-amino benzoate 5. Condensation of
5 with 3,3-
diethoxypropanenitrile (6) in TFA, followed by cyclization
of 7 in NaOH/EtOH, gave the 3-cyano-4-hydroxyquinoline
compound 3 in around 40% overall yield from 4.
Compound 1 was eventually obtained in 16% yield from 3
after chlorination and 2 consecutive aminations (Scheme 1).
In recent years, our group also developed 2 routes to
prepare bosutinib (1) as well as its key intermediate 3
[5,6]. In the first route, as shown in Scheme 2,
commercially available methyl vanillate (4) was adopted
as the starting material through the simple and traditional
steps including alkylation, ester hydrolysis, nitration,
decarboxylation, and reductive cyclization to give the
final product 3 in 24.3% yield over 8 steps [5].
© 2017 Wiley Periodicals, Inc.

G. Zhu, M. Sun, C. Zhu, H. Wang, and J. Xu
Vol 000
Figure 1. Chemical structures of bosutinib 1, 2, and 3.
Scheme 1. Reagents and conditions: (A) TFA; (B) NaOH and EtOH.
Scheme 2. Reagents and conditions: (A) ClC3H6Br, potassium carbonate (K2CO3), DMF, 50°C, 1 hour, 91%; (B) NaOH, MeOH-H2O, 50°C, 12 hours,
92%; (C) nitric acid (HNO3), AcOH, 50°C, 6 hours, 85%; (D) oxalyl chloride ((COCl)2), DMF (cat), dichloromethane (CH2Cl2), RT, 4 hours; (E)
CNCH2CO2Et, sodium ethoxide (NaOEt), EtOH, 0°C, 79%; (F) DMSO-H2O, 110°C, 0.5 hour, 82%; (G) DMF-DMA, THF, RT, 2 hours, 78%; (H)
H2, Raney Ni, THF, RT, 6 hours, 71%.
Scheme 3. Reagents and conditions: (A) ClC3H6Br, K2CO3, DMF, 50°C, 1 hour, 91%; (B) nitric acid (HNO3), AcOH, 50°C, 6 hours, 81%; (C) bromine
2 (Br2), dichloromethane (CH2Cl2), RT, 12 hours; (D) sodium cyanide (NaCN), EtOH/DMSO, 0°C to RT, 78%; (E) H2, Raney Ni, THF, RT, 6 hours,
91%; (F) DMF-DMA, THF, RT, 2 hours, 71%.
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New Synthesis of Intermediate to Bosutinib
In the second route, as shown in Scheme 3,
acetovanillone (19) was used as the starting material
through alkylation, nitration, bromination, cyano
substitution, catalytic hydrogenation, and cyclization to
give product 3 in 37.1% yield over 6 steps. After another
3 steps including chlorination and condensation, the final
product 1 was given in 13.7% yield over 10 steps [6].
In summary, we have developed a new and practical
synthetic route of 7-(3-chloropropoxy)-4-hydroxy-6-
methoxyquinoline-3-carbonitrile (3), the key intermediate
of bosutinib (1), on a hectogram scale. Adopting the
easily commercially available 5-bromo-2-methoxyphenol
(19) as the starting material via the Friedel-Crafts
reaction, alkylation, bromination, and cyano substitution
gives the 3-oxo-3-phenylpropanenitrile compound 23
in 61.7% over 4 steps. After being substituted by
methoxymethylene and amino group successively,
3-amino-2-(2-bromobenzoyl)acrylonitrile compound 25
was obtained. Via the key intramolecular cyclization of
25 at K2CO3/DMF condition, the title 3-cyano-
4-hydroxyquinoline product 3 was obtained in 36.9%
yield over 7 steps (from 19) and 98.71% purity (HPLC).
Purification methods of the intermediates involved in the
route were also given.
RESULTS AND DISCUSSION
In this paper, we developed a new and practical
synthetic route to prepare the title compound 3, as shown
in Scheme 4. 5-Bromo-2-methoxyphenol (19),
a
commonly used chemical, was chosen as the starting
material. The acetophenone product 20 was obtained in
87% yield after recrystallization through a Friedel-Crafts
reaction from 19 at room temperature [7]. Compound 20
was reacted with 1-bromo-3-chloropropane in potassium
carbonate (K2CO3)/DMF to give compound 21 in 97%
yield based on the reported method [8]. The next
bromination was carried out by 1 equiv of bromine 2
(Br2) in trichloromethane (CHCl3) at room temperature;
compound 22 was obtained in 85% isolated yield [9].
Treated with 1 equiv of sodium cyanide (NaCN) in
EtOH/DMSO solution at room temperature [10],
compound 22 was transferred to the 3-oxo-3-
phenylpropanenitrile inter-mediate 23 in 86% yield after
recrystallization from hexane/EtOAc. Compound 23 was
condensed with trimethyl orthoformate (CH(OMe)3) in
acetic anhydride (Ac2O) to give the intermediate 24,
which was then substituted by ammonia (NH3) in MeOH
to give the 3-amino-2-benzoylacrylonitrile compound 25
in 82% yield [11]. The intramolecular cyclization of 25
was carried out in K2CO3/DMF condition to afford 3
[12], which was purified by heating and stirring in 1/1
(vol/vol) EtOH/EtOAc to give the final compound 3 in
73% overall yield and 98.71% purity (HPLC).
EXPERIMENTAL
All commercially available chemicals and solvents were
used as received without any further purification. Proton
nuclear magnetic resonance and 13C-NMR spectra were
recorded on a Bruker UltraShield 400 Plus spectrometer
(Billerica, MA) by using TMS as an internal standard.
Mass spectra were obtained from a Finnigan MAT-95/711
spectrometer (San Jose, CA). Melting points were
measured on
a Shenguang WRS-1B melting point
apparatus (Minhang, Shanghai, China) and are uncorrected.
The HPLC results were generated by using a Waters 2487
UV/Visible Detector and Waters 515 Binary HPLC Pump
(Milford, MA).
1-(2-Bromo-4-hydroxy-5-methoxyphenyl)ethan-1-one
(20).
Anhydrous aluminum chloride (AlCl3) (263.0 g,
1.97 mol) was suspended and stirred in CHCl3 (3 kg)
under nitrogen and cooled to 5 to 10°C. Acetyl chloride
(AcCl) (108.3 g, 1.38 mol) was added to the mixture
Scheme 4. Reagents and conditions: (A) acetyl chloride (AcCl), aluminum chloride (AlCl3), CHCl3, RT, 20 hours, 87%; (B) ClC3H6Br, K2CO3, DMF, 50°C,
2 hours, 97%; (C) bromine 2 (Br2), CHCl3, RT, 16 hours, 85%; (D) sodium cyanide (NaCN), EtOH, DMSO, 5°C to RT, 86%; (E) trimethyl orthoformate
(CH(OMe)3), acetic anhydride (Ac2O), 110°C, 2 hours; (F) ammonia (NH3), MeOH, RT, 2 hours, 82%; (G) K2CO3, DMF, 120°C, 3 hours, 73%.
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G. Zhu, M. Sun, C. Zhu, H. Wang, and J. Xu
Vol 000
dropwise over 1 hour and stirred at 5 to 10°C for another
1 hour. A solution of 5-bromo-2-methoxyphenol 19
(200.2 g, 0.985 mol) in CHCl3 (1.2 kg) was added
dropwise to the previous AlCl3 solution over 1 hour, and
the reaction temperature was kept below 25°C. A brown
solution was obtained and stirred at the ambient
temperature for another 20 hours. The reaction solution
was then poured into a mixture of ice-water (5 kg) and
CHCl3 (1.5 kg) and stirred for 1 hour. The organic
layer was separated and washed with water (3 kg × 2)
and saturated sodium bicarbonate (NaHCO3) solution
(3 kg × 1), respectively, and dried over anhydrous
sodium sulfate (Na2SO4). The solvent was recovered to
give an off-white solid, which was dried at 60°C for
4 hours to give the crude product 20 (232 g). The crude
product was stirred and heated with 2/1 (vol/vol)
hexane/EtOAc (1.0 kg) at 60°C for 2 hours then cooled
to room temperature; the resulting solid was filtered off
and washed with 2/1 (vol/vol) hexane/EtOAc (300 g × 2)
and dried at 60°C for 4 hours to afford 20 (210.0 g,
87%) as a white solid, mp 109.9°C (dec). 1H NMR
(CDCl3, δ): 2.70 (s, 3H), 3.94 (s, 3H), 5.93 (s, 1H),
7.17 (s, 1H), 7.19 (s, 1H). 13C NMR (CDCl3, δ): 30.6,
56.2, 112.3, 112.4, 119.9, 132.5, 145.7, 148.8, and
199.7. ESI-MS (m/z) 247.1 (M + H)+.
respectively, and dried over anhydrous Na2SO4. The
solvent was recovered to give a light yellow solid, which
was dried at 60°C for 4 hours to give the crude product
22 (293 g). The crude product was stirred and heated
with 2/1 (vol/vol) hexane/EtOAc (1.2 kg) at 60°C for
2 hours then cooled to room temperature; the resulting
solid was filtered off and washed with 2/1 (vol/vol)
hexane/EtOAc (300 g × 2) and dried at 60°C for 4 hours
to afford 22 (255.0 g, 85%) as a white solid, mp 111.3 to
112.2°C. 1H NMR (CDCl3, δ): 2.30 to 2.36 (m, 2H),
3.79 (t, J = 6.4 Hz, 2H), 3.89 (s, 3H), 4.22 (t, J = 6.4 Hz,
2H), 4.61 (s, 2H), 7.10 (s, 1H), 7.15 (s, 1H). 13C NMR
(CDCl3, δ): 31.8, 34.3, 41.2, 56.2, 65.8, 111.6, 113.6,
117.5, 130.0, 148.7, 151.5, and 193.3. ESI-MS (m/z)
400.9 (M + H)+.
3-(2-Bromo-4-(3-chloropropoxy)-5-methoxyphenyl)-3-oxo
propanenitrile (23). A solution of 22 (218.3 g, 0.545 mol)
in DMSO (0.5 kg) and EtOH (0.5 kg) was cooled in an
ice-water bath to ~5°C then treated dropwise with NaCN
(26.8 g, 0.548 mol) in H2O (300 mL) over 1 hour. The
mixture was stirred for another 4 hours at ambient
temperature. The resulting solution was diluted with H2O
(2 kg) and filtered, and the filtrate was acidified with 2 M
H2SO4 to pH = 2 to 3 (carried out in an efficient fume
hood!). The resulting solid was collected via suction
filtration, washed with H2O (200 g × 2), and dried at
60°C for 4 hours to give the crude product 23 (190 g).
The crude product was stirred and heated with 1/1 (vol/
vol) hexane/EtOAc (0.8 kg) at 60°C for 2 hours then
cooled to room temperature; the resulting solid was
filtered off and washed with 1/1 (vol/vol) hexane/EtOAc
(200 g × 2) and dried at 60°C for 4 hours to afford 23
(147.3 g, 78%) as a faint yellow solid. 1H NMR (CDCl3,
δ): 2.34 (m, J = 6.0 Hz, 2H), 3.78 (t, J = 6.0 Hz, 2H),
3.90 (s, 3H), 4.22 (s, 2H), 4.24 (t, J = 6.0 Hz, 2H), 7.12
(s, 1H), 7.22 (s, 1H). 13C NMR (DMSO-d6, δ): 31.9,
32.7, 42.2, 56.6, 66.2, 111.5, 113.9, 117.3, 128.9, 148.6,
151.7, 170.9, and 190.0. ESI-MS (m/z) 369.9 (M + Na)+.
1-(2-Bromo-4-(3-chloropropoxy)-5-methoxyphenyl)ethan-
1-one (21). Compound 20 (201.0 g, 0.820 mol), 1-bromo-
3-chloropropane (142.2 g, 0.903 mol), and K2CO3
(147.3 g, 1.066 mol) were mixed and stirred in DMF
(0.8 kg) at 50°C for 2 hours. The reaction suspension
was cooled to room temperature and poured into a
mixture of water (5 kg) and CHCl3 (4 kg) and stirred for
1 hour. The organic layer was separated and washed with
water (3 kg × 2) and brine (3 kg × 3), respectively, and
dried over anhydrous Na2SO4. The solvent was recovered
to give the product 21 (255.8 g, 97%) as a light brown
oil, which was used directly at the next step. 1H NMR
(CDCl3, δ): 2.28 to 2.34 (m, 2H), 2.67 (s, 3H), 3.77 (t,
J = 6.4 Hz, 2H), 3.87 (s, 3H), 4.20 (t, J = 6.4 Hz, 2H),
7.09 (s, 1H), 7.14 (s, 1H). 13C NMR (CDCl3, δ) 30.5,
31.9, 41.3, 56.2, 65.7, 111.6, 113.0, 117.8, 133.0, 148.4,
150.9, and 199.5. ESI-MS (m/z) 323.0 (M + H)+.
3-Amino-2-(2-bromo-4-(3-chloropropoxy)-5-methoxyben
zoyl)acrylonitrile (25). A mixture of 23 (104 g, 0.3 mol),
trimethyl orthoformate (CH(OMe)3) (64 g, 0.6 mol), and
Ac2O (500 g) was heated at 110°C for 2 hours. The
solvent was removed to give the 2-(2-bromo-4-(3-
chloropropoxy)-5-methoxybenzoyl)-3-
2-Bromo-1-(2-bromo-4-(3-chloropropoxy)-5-methoxyphe
nyl)ethan-1-one (22). Compound 21 (241.0 g, 0.749 mol)
was added to CHCl3 (5 kg), and the clear solution was
stirred at room temperature. Br2 (11.2 g, 0.07 mol) was
added to a solution, and the reaction mixture was stirred
at room temperature for 2 hours to give a colorless
solution. Another batch of Br2 (109.8 g, 0.687 mol) was
added dropwise to the previous reaction solution over
1 hour, and the resulting mixture was stirred at room
temperature overnight to give an almost colorless
solution. The reaction solution was washed with water
(3 kg × 2) and saturated NaHCO3 solution (3 kg × 2),
methoxyacrylonitrile (24) as a brown oil, which was used
at the next step without purification.
The previous product 24 (0.3 mol) was dissolved in
MeOH (0.7 kg) and cooled to ~10°C. NH3 gas was then
babbled to the solution until saturated, and the reaction
solution was stirred at 20°C for another 2 hours. The
resulting solid was collected by suction filtration, washed
with 50% MeOH/H2O, and dried under reduced pressure
to give 25 (92 g, 82%) as a pale solid. 1H NMR
(DMSO-d6, δ): 2.18 (m, J = 6.4 Hz, 2H), 3.78 (s, 3H),
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New Synthesis of Intermediate to Bosutinib
REFERENCES AND NOTES
3.80 (t, J = 6.4 Hz, 2H), 4.14 (t, J = 6.4 Hz, 2H), 6.95 (s,
1H), 7.21 (s, 1H), 8.81 (br s, 2H). 13C NMR (DMSO-d6,
δ): 32.1, 42.3, 56.4, 66.1, 89.2, 109.2, 112.3, 115.8,
117.1, 130.8, 148.8, 149.4, 160.9, and 186.4. ESI-MS
(m/z) 375.0 (M + H)+.
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suspended in 1/1 (vol/vol) EtOH/EtOAc (250 g), stirred
and heated to 70°C for 1 hour. After cooled to room
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(s, 3H), 4.19 (t, J = 3.6 Hz, 2H), 7.07 (s, 1H), 7.45 (s,
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acclaim C18 (150 mm × 2.1 mm × 5 μm); detection:
280 nm; flow rate: 0.8 mL/min; temperature: RT;
injection load: 2 μL; solvent: acetonitrile; run time:
5 minutes; mobile phase: acetonitrile/water = 80/20, tR:
0.490 minutes, purity: 98.71%.
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Acknowledgment. This work was supported by the
Undergraduate Innovative Training Project of Shanghai (nos
cs1504001 and cs1604004).
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