A practical synthesis of 7-(3-chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile, a key intermediate to bosutinib

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A Practical Synthesis of 7-(3-
Chloropropoxy)-6-methoxy-4-oxo-1,4-
dihydroquinoline-3-carbonitrile, a Key
Intermediate to Bosutinib
Yongjun Maoa, Xin Tiana, Luobin Jianga, Guoqing Zhua & Han Wanga
a College of Chemistry and Chemical Engineering, Shanghai
University of Engineering Science, 333 Longteng Road, Shanghai,
201620, P. R. China
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Published online: 13 May 2015.
To cite this article: Yongjun Mao, Xin Tian, Luobin Jiang, Guoqing Zhu & Han Wang (2015) A Practical
Synthesis of 7-(3-Chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile, a Key
Intermediate to Bosutinib, Organic Preparations and Procedures International: The New Journal for
Organic Synthesis, 47:3, 207-213, DOI: 10.1080/00304948.2015.1025014
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Organic Preparations and Procedures International, 47:207–213, 2015
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2015.1025014
A Practical Synthesis of 7-(3-Chloropropoxy)-
6-methoxy-4-oxo-1,4-dihydroquinoline-3-
carbonitrile, a Key Intermediate to Bosutinib
Yongjun Mao,x Xin Tian,x Luobin Jiang, Guoqing Zhu,
and Han Wang
College of Chemistry and Chemical Engineering, Shanghai University of
Engineering Science, 333 Longteng Road, Shanghai 201620, P. R. China
Bosutinib (5, SKI-606) marketed as bosulifÒ is an 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, 2 BosulifÒ has received approval of the
United States FDA and EU European Medicines Agency in 2012 and 2013 respectively
for the treatment of adult patients with Philadelphia chromosome-positive (PhC) chronic
myelogenous leukemia (CML) with resistance, or intolerance to previous therapy.3–5
A
couple of preparations of 5 on a multi-gram scale have been reported.6–12 However, a
practical synthetic process is still needed because commonly used method (Scheme 1) is
based on Gould-Jacobs methodology13 involving thermal cyclization 3 at 250 ꢀC for 4 h
in Dowtherm A to obtain the key intermediate 7-fluoro-6-methoxy-4-oxo-1,4-dihydroqui-
noli- ne-3-carbonitrile (4).6,7 Although this route is short, the high reaction temperature
required to convert 3 to 4 leads to the formation of tars and resins with attendant difficulty
in the purify- cation and lower yield of 4 from 3 (40%). Furthermore, Dowtherm A is a
high boiling solvent difficult to recover, harmful to environment and may also cause aller-
gic reaction to people handling it.
Withbroe et al.8 developed a streamlined process for the synthesis and isolation of
bosutinib monohydrate (5, Scheme 2). A three-component coupling reaction of 6 with
cyanoacetamide 7 and triethyl orthoformate led to 8 as a mixture of cis/trans isomers.
Cyclization of 8 using POCl3 in sulfolane provided the core structure of 5. Yin et al11, 12
also reported a new synthesis of 5 (Scheme 3), which started with esterification of the
material vanillic acid (9), followed by alkylation, nitration, reduction to give the methyl
2-amino- benzoate 10. Condensation of 10 with 3,3-diethoxypropanenitrile in TFA fol-
lowed by cyclization of 11 with NaOH in ethanol gave7-(3-chloropropoxy)-6-methoxy-
4-oxo- 1,4-dihydroquinoline-3-carbonitrile (12) in 40.6% overall yield from 9. Bosutinib
was eventually obtained in 16.7% yield from 9 after chlorination and two consecutive
aminations.
Received June 28, 2014; in final form January 1, 2015.
Address correspondence to Han Wang, College of Chemistry and Chemical Engineering,
Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, P. R. China.
E-mail: wanghansh@126.com
xY.M. and X.T. have contributed equally to this work.
207

208
Wang et al.
Scheme 1
In order to devise a practical and commercial preparation of 5, a new and practical
route involving a reductive cyclization of 2-(o-nitrobenzoyl)-3-(dimethylamino)acryloni-
trile (20) with hydrogen and Raney Ni was developed to give key intermediate 12, as
shown in Scheme 4. Treatment of methyl vanillate (13) with 1-bromo-3-chloropropane
gave 14 in 91% yield. Nitration of 14 carried out in HNO3/AcOH, led to compound 15 in
81% yield. Hydrolysis of 15 under basic conditions (92% yield) followed by consecutive
reactions with oxalyl chloride (the use of thionyl chloride requires reflux and gave a col-
ored product) and ethyl cyanoacetate, provided 18, purified by recrystallization from hex-
ane/EtOAc in 79% yield from 16. Treatment of 18 in 1:9 aqueous DMSO led to 19
in 82% yield after recrystallization from hexane/EtOAc. Condensation of 19 with
DMF-DMA at room temperature gave compound 20 in 78% yield. The final reductive
cyclization was carried out by catalytic hydrogenation of 20 over Raney Ni/THF at room
temperature. A similar reductive cyclization had also be utilized by us during the synthe-
sis of N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide as the key intermediate for
the preparation of neratinib.13–17 The crude 12 was purified by digestion in 50% EtOH/
EtOAc to give the compound with 71% overall yield and 98.6% purity (HPLC).
In summary, we have developed a new and practical synthetic route of bosutinib interme-
diate 12 on a hectogram scale from commercially available methyl vanillate (13) as the start-
ing material in eight simple steps including alkylation, ester hydrolysis, nitration,
decarboxylation, and reductive cyclization to give the final product 12 in 24.3% yield and
98.6% purity (HPLC).
Scheme 2

7-(3-Chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile 209
Scheme 3
Experimental Section
All commercially available materials and solvents were used as received without any fur-
ther purification. 1H NMR and 13C NMR spectra were recorded on a Bruker UltraShield
400 Plus spectrometer using TMS as an internal standard. Mass spectra were obtained
from a Finnigan MAT-95/711 spectrometer. Melting points were measured on a Shen-
guang WRS-1B melting point apparatus and are uncorrected. The HPLC data were
acquired using a Waters 2487 UV/Visible Detector and Waters 515 Binary HPLC Pump.
The purity of the compounds were based on the areas of HPLC UV. Although compounds
12,11,12,18,19 14,11,12 15,11,12 and 1620 are mentioned in the literatures, they were not fully
characterized and no mps were reported.
Methyl 4-(3-Chloropropoxy)-3-methoxybenzoate (14)
1-Bromo-3-chloropropane (404 g, 2.57 mol) was added dropwise to a stirred mixture of
methyl vanillate (13, 360 g, 1.98 mol) and potassium carbonate (415 g, 3.0 mol) in DMF
(1.8 kg) at 60 ꢀC. The reaction mixture was stirred at this temperature for another 1 h
then cooled to room temperature, and poured slowly into ice-water (8 kg) while stirring
Scheme 4

210
Wang et al.
constantly. The solid formed was collected, washed with cold water (0.8 kg £ 2), and
dried at 60 ꢀC for 4 h. The white product was digested by stirring and heating with 2:1
hexane/EtOAc (1 kg) at 60 ꢀC for 2 h then cooled to room temperature. The resulting
solid was collected and washed with 1:1 hexane/EtOAc (300 g £ 2), dried at 50 ꢀC for
1
ꢁ
4 h to afford 14 (466 g, 91%) as a white solid, mp 106.5¡107 C. H NMR (CDCl3): d
2.29¡2.35 (m, 2 H, ClCH2CH2CH2O), 3.78 (t, J D 6.4 Hz, 2 H, ClCH2CH2CH2O), 3.90
(s, 3 H, OCH3), 3.91 (s, 3 H, OCH3), 4.23 (t, J D 6.0 Hz, 2 H, ClCH2CH2CH2O), 6.91 (d,
J D 8.4 Hz, 1 H, ArH), 7.55 (d, J D 2.0 Hz, 1 H, ArH), 7.67 (dd, J D 2.0, 8.4 Hz, 1 H,
ArH). MS-ESI (m/z): 281.0 (MCNa)C.
Anal. Calcd for C12H15ClO4: C, 55.71; H, 5.84; Found: C, 55.93; H, 5.80.
Methyl 4-(3-Chloropropoxy)-5-methoxy-2-nitrobenzoate (15)
A stirred suspension of 14 (317 g, 1.23 mol), 65% HNO3 (179 g, 1.85 mol) and AcOH
(1.5 kg) was stirred at 40–50 ꢀC for 6 h to form a white milky mixture which was poured
slowly into ice water (5 kg) over 20 min and stirred at the ambient temperature for
another 2 h. The resulting white solid was collected and washed with H2O (300 g £ 3)
and dried at 60 ꢀC for 5 h. The crude product was recrystallized from 1:1 hexane/EtOAc
1
ꢁ
(0.7 kg) to afford 15 (302 g, 81%) as a white solid, mp 101.5¡104.2 C. H NMR
(CDCl3): d 2.30¡2.36 (m, 2 H, ClCH2CH2CH2O), 3.78 (t, J D 6.0 Hz, 2 H,
ClCH2CH2CH2O), 3.91 (s, 3 H, OCH3), 3.96 (s, 3 H, OCH3), 4.25 (t, J D 6.0 Hz, 2 H,
ClCH2CH2CH2O), 7.08 (s, 1 H, ArH), 7.49 (s, 1 H, ArH). MS-ESI (m/z): 326.0
(MCNa)C.
Anal. Calcd for C12H14ClNO6: C, 47.46; H, 4.65; N, 4.61; Found: C, 47.58; H, 4.60;
N, 4.65.
4-(3-Chloropropoxy)-5-methoxy-2-nitrobenzoic Acid (16)
A mixture of 15 (470 g, 1.55 mol), NaOH (80 g, 2.0 mol) in MeOH (2 kg) and H2O
(2 kg) was stirred at 50–60 ꢀC for 12 h to form a colorless solution. It was cooled to
room temperature and conc. H2SO4 was added slowly into the reaction solution to pH 2–
3. The white suspension was stirred at the ambient temperature for 1 h. The resulting
solid was collected and washed with H2O (0.5 kg £ 3) and MeOH (0.3 kg £ 1), dried at
1
ꢁ
50 ꢀC for 5 h to give 16 (352 g, 92%) as a white solid, mp 134.6¡135.6 C. H NMR
(DMSO-d6): d 2.17¡2.24 (m, 2 H, ClCH2CH2CH2O), 3.78 (t, J D 6.0 Hz, 2 H,
ClCH2CH2CH2O), 3.92 (s, 3 H, OCH3), 4.23 (t, J D 6.0 Hz, 2 H, ClCH2CH2CH2O), 7.30
(s, 1 H, ArH), 7.62 (s, 1 H, ArH), 13.52 (br s, 1 H, COOH). 13C NMR (DMSO-d6): d
31.88, 42.17, 56.96, 66.59, 108.77, 111.97, 121.93, 141.89, 149.62, 152.43, 166.61. MS-
ESI (m/z): 312.0 (MCNa)C.
Anal. Calcd for C11H12ClNO6: C, 45.61; H, 4.18; N, 4.84; Found: C, 45.78; H, 4.22;
N, 4.80.
Ethyl 3-(4-(3-Chloropropoxy)-5-methoxy-2-nitrophenyl)-2-cyano-3-oxopropanoate
(18)
Oxalyl chloride (190 g, 1.5 mol) and DMF (7.3 g, 0.1 mol) were added consecutively to
a mixture of 16 (290 g, 1.0 mol) in CH2Cl2 (2 kg) at room temperature and the mixture
was stirred for 4 h to give a homogeneous solution. Removal of the volatiles left 4-(3-

7-(3-Chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile 211
chloropropoxy)-5-methoxy-2-nitrobenzoyl chloride (17) as a light brown oil (315 g,
102.2%).
A suspension of NaOEt (95 g, 1.4 mol) in anhydrous EtOH (0.8 kg) was stirred at
40–50 ꢀC for 1 h; then CNCH2CO2Et (170 g, 1.5 mol) was added to the solution. The
resulting white suspension was heated to reflux for another 0.5 h and then cooled to –5
ꢀC in an ice-salt bath and treated dropwise with a solution of the above 17 (315 g,
1.0 mol) in THF (0.8 kg) over 2 h, keeping the reaction temperature below 0 ꢀC. The
reaction mixture was then added to chilled water (6 kg), stirred and acidified to pH 2–3
with H2SO4. The resulting solid was collected, washed with H2O (400 g £ 3), and dried
at 50 ꢀC for 5 h to give crude 18, which was recrystallized from 3:1 hexane/EtOAc
1
ꢁ
(1 kg) to afford 18 (304 g, 79%) as an off-white solid, mp 85.2¡88.2 C. H NMR
(CDCl3): d 0.99 (t, J D 7.0 Hz, 3 H, OCH2CH3), 2.20¡2.26 (m, 2 H, ClCH2CH2CH2O),
3.80 (t, J D 6.4 Hz, 2 H, ClCH2CH2CH2O), 3.87 (q, J D 7.0 Hz, 2 H, OCH2CH3), 3.89
(s, 3 H, OCH3), 4.26 (t, J D 6.0 Hz, 2 H, ClCH2CH2CH2O), 7.09 (s, 1 H, ArH), 7.78 (s, 1
H, ArH), 10.35 (br s, 1 H, OH, enolization). 13C NMR (CDCl3): d 14.32, 31.96, 42.20,
57.17, 60.00, 66.49, 80.85, 108.70, 111.86, 117.23, 127.75, 138.58, 148.34, 154.24,
164.17, 181.77. MS-ESI (m/z): 407.1 (MCNa)C.
Anal. Calcd for C16H17ClN2O7: C, 49.94; H, 4.45; N, 7.28; Found: C, 49.78; H, 4.49;
N, 7.20.
3-(4-(3-Chloropropoxy)-5-methoxy-2-nitrophenyl)-3-oxopropanenitrile (19)
A mixture of 18 (300 g, 0.78 mol), DMSO (900 g) and H2O (100 g) was stirred at 100–
110 ꢀC for 30 min. Then the brown solution was cooled to around 50 ꢀC, poured into
chilled water (4 kg), and stirred for 1 h. The resulting precipitate was collected, washed
with H2O (300 g £ 3) and 50% EtOH/H2O (200 g £ 1), dried at 60 ꢀC for 4 h to give a
brown solid, which was recrystallized from 1:1 hexane/EtOAc (0.8 kg) to afford 19
1
ꢁ
(200 g, 82%) as light-tan solid, mp 149.5¡151.9 C. H NMR (DMSO-d6): d 2.19¡2.26
(m, 2 H, ClCH2CH2CH2O), 3.79 (t, J D 6.8 Hz, 2 H, ClCH2CH2CH2O), 3.94 (s, 3 H,
OCH3), 4.27 (t, J D 6.0 Hz, 2 H, ClCH2CH2CH2O), 4.52 (s, 2 H, CH2CN), 7.32 (s, 1 H,
ArH), 7.76 (s, 1 H, ArH). 13C NMR (DMSO-d6): d 31.75, 33.02, 42.06, 57.18, 66.57,
108.71, 110.67, 115.47, 128.97, 138.73, 149.41, 154.21, 191.71. MS-ESI (m/z): 335.0
(MCNa)C.
Anal. Calcd for C13H13ClN2O5: C, 49.93; H, 4.19; N, 8.96; Found: C, 49.68; H, 4.15;
N, 8.89.
2-(4-(3-Chloropropoxy)-5-methoxy-2-nitrobenzoyl)-3-(dimethylamino)acrylonitrile
(20)
To a stirred suspension of 19 (131 g, 0.42 mol) in THF (0.5 kg) was added DMF-DMA
(65.7 g, 0.55 mol). The mixture was stirred at room temperature for 2 h to give a light-
yellow suspension. Hexane (0.5 kg) was added and the mixture was stirred at room tem-
perature for 1 h, then cooled to around 10 ꢀC in an ice-water bath. The resulting solid
was collected, washed with 50% hexane /THF (100 g £ 2), and dried at 40 ꢀC to give a
1
ꢁ
yellow solid 20 ( 127 g, 82%), mp 145.5 C (dec.). H NMR (DMSO-d6): d 2.19¡2.26
(m, 2 H, ClCH2CH2CH2O), 3.33 (br s, 6 H, NC2H6), 3.80 (t, J D 6.4 Hz, 2 H,
ClCH2CH2CH2O), 3.92 (s, 3 H, OCH3), 4.25 (t, J D 6.0 Hz, 2 H, ClCH2CH2CH2O), 7.02
(s, 1 H, ArH), 7.72 (s, 1 H, ArH). 13C NMR (DMSO-d6): d 31.93, 42.08, 47.96, 57.17,

212
Wang et al.
66.21, 71.55, 99.10, 92.87, 108.67, 111.02, 138.73, 148.22, 148.33, 154.20, 181.06. MS-
ESI (m/z): 390.1 (MCNa)C.
Anal. Calcd for C16H18ClN3O5: C, 52.25; H, 4.93; N, 11.43; Found: C, 52.01;
H, 4.99; N, 11.55.
7-(3-Chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (12)
Compound 20 (184 g, 0.50 mol) and Raney Ni (wet, 30 g) were added to THF (2 kg), and
stirred for 6 h at room temperature under a hydrogen atmosphere (balloon) to form a
brown solution which was then filtered through a pad of Celite, the filter cake was washed
by THF (150 g £ 2). The combined filtrate was concentrated to give the product 12 as a
brown solid, which was digested with 1:1 EtOH/EtOAc (250 g) at 60 ꢀC for 2 h then
cooled to room temperature, the resulting solid was collected and washed with 1:1 EtOH/
EtOAc (50 g £ 2), dried at 60 ꢀC for 4 h to afford 12 (104 g, 71%) as an off-white solid,
1
ꢁ
mp > 300 C. H NMR (DMSO-d6): d 2.23¡2.30 (m, 2 H, ClCH2CH2CH2O), 3.80¡3.85
(m, 2 H, ClCH2CH2CH2O), 3.88 (s, 3 H, OCH3), 4.17¡4.21 (m, 2 H, ClCH2CH2CH2O),
7.07 (s, 1 H, ArH), 7.46 (s, 1 H, ArH), 8.59 (s, 1 H, PyH), 12.50 (br s, 1 H, OH, enoliza-
tion). 13C NMR (DMSO-d6): d 31.77, 42.23, 56.27, 65.89, 93.21, 101.54, 104.93, 117.62,
119.73, 135.18, 145.33, 148.54, 153.17, 173.77. MS-ESI (m/z): 315.1 (MCNa)C.
Anal. Calcd for C14H13ClN2O3: C, 57.44; H, 4.48; N, 9.57; Found: C, 57.58; H, 4.44;
N, 9.52. HPLC Conditions: Column: Acclaim C18 (150 mm £ 2.1 mm £ 5 mm); Detec-
tion: 280 nm; Flow rate: 0.8 mL/min; Temperature: rt; Injection load: 2 mL; Solvent:
acetonitrile; Run time: 5 min; Mobile phase: acetonitrile/water D 80/20, tR: 0.490 min,
purity: 98.6%.
Acknowledgment
This work was supported by the Special Scientific Foundation for Outstanding Young
Teachers in Shanghai Higher Education Institutions (ZZGJD13017), and the Undergradu-
ate Innovative Training Project of Shanghai (cs1404011, cs1404013).
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