A New Synthesis of Cabozantinib

Full text of DOI:10.1080/00304948.2019.1615362

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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A New Synthesis of Cabozantinib
Ran Fang, Bin Wang, Zhiwei Zhao, Lingfeng Yin, Han Wang & Jingli Xu
To cite this article: Ran Fang, Bin Wang, Zhiwei Zhao, Lingfeng Yin, Han Wang & Jingli Xu
(2019): A New Synthesis of Cabozantinib, Organic Preparations and Procedures International, DOI:
10.1080/00304948.2019.1615362
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Organic Preparations and Procedures International, 0:1–7, 2019
# 2019 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2019.1615362
OPPI BRIEF
A New Synthesis of Cabozantinib
Ran Fang, Bin Wang, Zhiwei Zhao, Lingfeng Yin, Han Wang,
and Jingli Xu
College of Chemistry and Chemical Engineering, Shanghai University of
Engineering Science, 333 Longteng Road, Shanghai 201620, China
R
Cabozantinib (1, Scheme 1) marketed as CometriqV is a small molecule inhibitor of the
tyrosine kinases c-Met and VEGFR2.1 It was developed by Exelixis Inc. and was
approved by the U.S. FDA in 2012 for medullary thyroid cancer and advanced renal
cell carcinoma in people who have received prior anti-angiogenic therapy.2
Two synthetic routes of cabozantinib have been developed so far.3–10 With regard
to preparation of the key intermediate 6,7-dimethoxyquinolin-4-ol (6), there are two
kinds of approaches, as shown in Scheme 1. A common route to prepare 6 is based on
Gould-Jacobs methodology,3,4 in which the Meldrum's acid derivative 4 is heated with
Dowtherm A at > 230 ꢀC for several hours to give 6. This method is short, but the
main problem is that the high reaction temperature leads to a complex and tedious pro-
cedure. Dowtherm A is a high boiling solvent which is difficult to recover, is harmful
to the environment and may cause allergic reactions in workers, an effect which we
have seen in our own experience.
Alternatively, 1-(2-aminophenyl)ethan-1-one 5 reacts with ethyl formate under
strong alkaline conditions to give the intermediate 6 in 55% yield.5,6 Generally,
t-
MeONa or BuONa and anhydrous solvents are used in the reaction. We consider the
overall yield to be unsatisfactory.
4-Chloro-6,7-dimethoxyquinoline (7) was then reacted successively with 4-amino-
phenol (8) and 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (10)7 to
give the final product cabozantinib (1) in about 60% over-all yield from com-
pound 6.8–10
We developed a new and practical synthetic route, as shown in Scheme 2. A reduc-
tion cyclization process was adopted to prepare the key 6,7-dimethoxyquinolin-4-ol (6)
from 1-(4,5-dimethoxy-2-nitrophenyl)-3-(dimethylamino) prop-2-en-1-one (13).11
Commercially available 1-(3,4-dimethoxyphenyl)ethan-1-one (11) was nitrated in
HOAc/HNO3 to give 1-(4,5-dimethoxy-2-nitrophenyl)ethan-1-one (12) in 86% isolated
yield. Compound 12 was then reacted with N,N-dimethylformamide dimethyl acetal
(DMF-DMA) in toluene to obtain 13 in 79% yield.12 Through nucleophilic substitution
Received November 14, 2017; in final form January 5, 2019.
Address correspondence to Han Wang, College of Chemistry and Chemical Engineering,
Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, China. E-mail:
wanghan@sues.edu.cn
1

2
Wang et al.
Scheme 1
reactions, DMF-DMA can react with benzophenone, 3-oxo-3-phenylpropanenitrile, or
3-oxo-3-phenylpropanoate compounds to give the 3-(dimethylamino)-1-prop-2-en-1-one
intermediates for preparation of 4-hydroxyquinoline compounds.13,14 Since DMF-DMA
has higher reactivity, in general the reaction temperature is lower and the isolated yield
is higher than if using ortho-formate.15,16 Compound 6 was then obtained by treating
compound 13 with H2/Ni at room temperature in 89% yield and 99.1% purity (HPLC)
after purification. Compound 6 was subsequently chlorinated by POCl3 to give 4-chlor-
oquinoline 7 in 78% yield.
t-
Compound 7 was then reacted with 4-aminophenol (8) in BuOK/DMAC to give
4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (9) in 87% isolated yield.7 1-((4-
Fluorophenyl)carbamoyl) cyclopropane-1-carboxylic acid (16) was prepared in high
yield by reaction of cyclopropane-1,1-dicarboxylic (14) with SOCl2 and 4-fluoroaniline
(15) successively.8 Compound 16 was then treated with (COCl)2, followed by com-
pound 9 in K2CO3/THF/H2O to give cabozantinib (1).9 Compound 1 was purified by
heating and stirring in 50% EtOH/EtOAc in 82% overall yield and > 99.0% pur-
ity (HPLC).

Cabozantinib
3
Scheme 2
In summary, we have developed a new and practical synthetic route of cabozanti-
nib (1), adopting a reduction cyclization process to prepare the key 4-hydroxyquinoline
compound 6 from 13. Commercially available 11 was used as the starting material. The
final product 1 was obtained in 31% yield over seven steps and > 99% purity (HPLC).
The reduction cyclization method was developed13–16 in recent years and we also
expanded its application for the preparation of bosutinib17,18 and tivozanib.19,20 During
the design and synthesis of cabozantinib, the key intermediate 6 was obtained through
this method. Common and inexpensive regents and mild reaction conditions are used in
the new route, in order to simplify the operation, enhance the overall yield, and
decrease the preparation cost; as a result the new process is efficient, practical, and suit-
able for commercial manufacture.
Experimental Section
All commercially available chemicals and solvents were used as received without any
1
further purification. H NMR spectra were recorded on a Bruker UltraShield 400 Plus
spectrometer using TMS as an internal standard. Mass spectra were obtained on a
Finnigan MAT-95/711 spectrometer. Melting points were measured on a Shenguang

4
Wang et al.
WRS-1B melting point apparatus and are uncorrected. The HPLC results were gener-
ated using a Waters 2487 UV/Visible Detector and Waters 515 Binary HPLC Pump.
1-(4,5-Dimethoxy-2-nitrophenyl)ethan-1-one (12)
A mixture of 1-(3,4-dimethoxyphenyl)ethan-1-one 11 (180 g, 1.0 mol) and HOAc
(1.5 L) was stirred and heated to 60 ꢀC to give a clear solution. 65% HNO3 (110 mL,
1.5 mol) was added over 30 min and the mixture was stirred for another 3 h to give a
yellow solution. The reaction mixture was poured slowly into ice-water (5 L) while stir-
ring constantly. The yellow solid that formed was filtered off and washed with cold
water (600 mL ꢁ 2), dried at 60 ꢀC for 4 h to give crude product 12 (210 g). The crude
12 (210 g) was stirred and heated with EtOAc: petroleum ¼ 1:1 (v:v) (800 mL) at reflux
for 2 h then cooled to room temperature, the resulting solid was filtered off and washed
with EtOAc: petroleum ¼ 1:1 (v:v) (100 mL ꢁ 2), dried at 50 ꢀC for 4 h to afford 12
(193.7 g, 86%) as a yellow solid, mp 131.3 ꢂ 133.1 ꢀC (lit mp21 130 ꢂ 132 ꢀC). 1H
NMR (DMSO-d6): d 2.52 (s, 3H), 3.90 (s, 3H), 3.93(s, 3H), 7.23 (s, 1H), 7.64 (s, 1H).
ESI-MS (m/z): 226.1 (M þ H)þ, 473.2 (2M þ Na)þ.
Anal: Calcd for C10H11NO5 : C; 53:33; H; 4:92: Found : C; 53:42; H; 4:89:
1-(4,5-Dimethoxy-2-nitrophenyl)-3-(dimethylamino) prop-2-en-1-one (13)
A solution of 12 (160.0 g, 0.71 mol), DMF-DMA (119.2 g, 1.0 mol) and toluene (1.5 L)
was stirred and heated to reflux for 4 h, then cooled to room temperature. The resulting yel-
low solid was filtered, washed with toluene (150 mL ꢁ 2) and dried at 60 ꢀC for 4 h to
afford 13 (157.1 g, 79%) as a yellow solid, mp 140.5 ꢂ 143.1 ꢀC (lit mp22 142 ꢂ 145 ꢀC).
1H NMR (CDCl3): d 2.87 (br s, 3H), 3.10 (br s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 6.86 (s,
1H), 7.60 (s, 1H). ESI-MS (m/z): 281.2 (Mþ H)þ, 561.3 (2M þ H)þ, 583.2 (2M þ Na)þ.
Anal: Calcd for C13H16N2O5 : C; 55:71; H; 5:75: Found : C; 55:93; H; 5:80:
6,7-Dimethoxyquinolin-4-ol (6)
Compound 13 (95.3 g, 0.34 mol) was stirred and dissolved in THF (1.1 L) at room tem-
perature. Raney Ni (wet, 30 g) was washed with THF and added to the reaction solu-
tion. The reaction mixture was stirred under a hydrogen balloon at atmospheric pressure
for 6 h to give a light-yellow solution. The resulting mixture was filtered through a
Celite pad, the filter cake was washed by THF (100 mL ꢁ 2). The combined filtrate
was concentrated to give the crude product 6 as a light yellow solid, which was stirred
and heated with EtOAc: EtOH ¼ 1:1 (v:v) (250 mL) at reflux for 2 h then cooled to
room temperature; the resulting solid was filtered off and washed with EtOAc: EtOH ¼
1:1 (v:v) (50 mL ꢁ 2), dried at 50 ꢀC for 4 h to afford 6 (62.1 g, 89%) as a grey solid,
23
1
mp 222.0 ꢂ 224.2 ꢀC (lit mp
224 ꢂ 225 ꢀC). H NMR (DMSO-d6): d 3.68 (s, 3H),
3.72 (s, 3H), 5.68 (d, J ¼ 12.0 Hz, 1H), 6.26 (s, 1H), 6.83 (s, 2H), 7.17 (s, 1H), 7.53 (d,
J ¼ 12.0 Hz, 1H). ESI-MS (m/z): 206.2 (M þ H)þ, 411.2 (2M þ H)þ, 433.2 (2M þ Na)þ.
Anal: Calcd for C11H11NO3 : C; 64:38; H; 5:40: Found : C; 64:51; H; 5:46:
HPLC Conditions— Column: Acclaim C18 (150 mm ꢁ 2.1 mm ꢁ 5 mm);
Detection: 220 nm; Flow rate: 0.8 mL/min; Temperature: 30 ꢀC; Injection load: 1 lL;

Cabozantinib
5
Solvent: methanol; Run time: 15 min; Mobile phase: methanol/water ¼ 90/10, tR:
3.527 min, purity: 99.093%.
4-Chloro-6,7-dimethoxyquinoline (7)
A solution of 6 (50 g, 0.24 mol) in POCl3 (400 mL) was stirred at 100 ꢀC for 6 h. Most
of the solvent was recovered under vacuum. The residue was added slowly to cooled
water (500 mL) and adjusted with 10% K2CO3 to pH ꢃ 9, and stirred for another 1 h.
The resulting solid was filtered, washed with H2O (50 mL ꢁ 2), and dried at 55 ꢀC for
4 h to give 7 (41.8 g, 78%) as a light brown solid, mp 130.2 ꢂ 131.4 ꢀC (lit mp24
1
130 ꢂ 131 ꢀC). H NMR (DMSO-d6): d 3.96 (s, 3H), 3.97 (s, 3H), 7.35 (s, 1H), 7.44(s,
1H), 7.54 (d, J ¼ 5.2 Hz, 1H), 8.61 (d, J ¼ 5.2 Hz, 1H). ESI-MS (m/z): 223.2 (M þ H)þ,
245.2 (M þ Na)þ.
Anal: Calcd for C11H10ClNO2 : C; 59:07; H; 4:51: Found : C; 59:20; H; 4:46:
4-((6,7-Dimethoxyquinolin-4-yl)oxy)aniline (9)
Compound 7 (16.0 g, 0.071 mol) and 4-aminophenol 8 (11.0 g, 0.10 mol) were added to
dimethylacetamide (200 mL), and stirred for 10 min at room temperature; then a solu-
tion of t-BuOK (9.68 g, 0.09 mol) in dimethylacetamide (20 mL) was added slowly such
that the reaction temperature kept at or below 25 ꢀC; the reaction mixture was then
stirred at 100 ꢀC for another 4 h, then cooled to room temperature, and poured slowly
into water (400 mL) while stirring constantly. The solid formed was filtered off and
washed with cold water (50 mL ꢁ 2), dried at 60 ꢀC for 4 h to afford 9 (18.4 g, 87%) as
1
a light tan solid, mp 140 ꢀC (dec.). H NMR (DMSO-d6): d3 .93 (s, 3H), 3.94 (s, 3H),
5.16 (s, 2H), 6.37 (d, J ¼ 5.2 Hz, 1H), 6.67 (d, J ¼ 8.8 Hz, 2H), 6.93 (d, J ¼ 8.8 Hz, 2H),
7.37 (s, 1H), 7.51 (s, 1H), 8.43 (d, J ¼ 5.2 Hz, 1H). ESI-MS (m/z): 297.8 (M þ Na)þ.
Anal: Calcd for C17H16N2O3 : C; 68:91; H; 5:44: Found : C; 68:79; H; 5:49:
1-((4-Fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (16)
A suspension of cyclopropane-1,1-dicarboxylic acid 14 (10.0 g, 0.08 mol) in THF
(56 mL) was stirred in an ice-water bath and triethylamine (7.79 g, 0.08 mol) was added
slowly to keep the reaction temperature below 10 ꢀC. SOCl2 (9.16 g, 0.08 mol) was
added slowly to the reaction mixture to keep the reaction temperature below 8 ꢀC.
When the addition was complete, the mixture was stirred below 5 ꢀC for another 1 h.
4-Fluoroaniline 15 (7.77 g, 0.07 mol) in THF (20 mL) was added to the reaction
solution slowly to keep the reaction temperature below 8 ꢀC, and stirred on the ice-
water bath for another 3 h. The reaction solution was then diluted with ethyl acetate
(100 mL) and water (100 mL), stirred at room temperature for 30 min. The organic
phase was separated, washed with water (80 mL) and brine (80 mL). The solution was
concentrated under vacuum to give the solid, dried at 50 ꢀC for 4 h to give the product
16 as a cream solid (9.2 g, 92%). 1H NMR (DMSO-d6): d 1.41 (s, 4H), 7.14 (t,
J ¼ 8.8 Hz, 2H), 7.61 (dd, J ¼ 4.8, 8.8 Hz, 2H), 10.57 (s, 1H).
Anal: Calcd for C11H10FNO3 : C; 59:19; H; 4:52: Found : C; 59:30; H; 4:45:

6
Wang et al.
Cabozantinib (1)
A stirred suspension of 16 (10.3 g, 0.043 mol) and DMF (0.3 mL, 0.004 mol) in THF
(50 mL) was cooled in an ice-water bath. Oxalyl chloride (4.7 mL, 0.055 mol) was
added slowly to the suspension to keep the reaction temperature below 10 ꢀC. When the
addition was complete, the reaction mixture was stirred at room temperature for another
2 h. The solution was concentrated under vacuum to give 1-((4-fluorophenyl) carba-
moyl)cyclopropane-1-carbonyl chloride (10) as a light yellow soild, which was used
directly at the next step.
To a stirred suspension of 9 (8.4 g, 0.028 mol) in THF (80 mL) was added a solu-
tion of K2CO3 (8.3 g, 0.06 mol) in water (40 mL). The mixture was stirred at room tem-
perature for 2 h. Then the carbonyl chloride 10 (0.043 mol) was added at room
temperature and the reaction solution was stirred for 3 h. The stirring was stopped and
the phases of the mixture were allowed to separate. The lower aqueous phase was
removed and discarded. To the remaining upper organic phase was added water
(100 mL). Then the mixture was stirred at 15 ꢀC for 10 h. The solid was precipitated.
The product was filtered and washed with a mixture of 2:1 (v/v) water/THF (20 mLꢁ
2). The crude product was dried at 60 ꢀC for 4 h. The dried product was then taken up
in EtOAc: EtOH ¼ 1:1 (v:v) (50 mL) and heated to reflux for 30 min, then cooled to
room temperature for 1 h, the resulting solid was filtered off and washed with EtOAc
1
(20 mL ꢁ 2), dried at 50 ꢀC for 3 h to afford 1 (11.5 g, 82%) as an off-white solid. H
NMR (DMSO-d6): d 1.48 (s, 4H), 3.94 (s, 3H), 3.95 (s, 3H), 6.42 (d, J ¼ 5.2 Hz, 1H),
6.67 (d, J ¼ 9.2 Hz, 1H), 6.93 (d, J ¼ 9.2 Hz, 1H), 7.16 (t, J ¼ 8.8 Hz, 2H), 7.23 (d,
J ¼ 9.6 Hz, 2H), 7.39 (s, 1H), 7.51 (s, 1H), 7.65 (dd, J ¼ 4.8, 8.8 Hz, 2H), 7.77 (d,
J ¼ 9.6 Hz, 2H), 8.47 (d, J ¼ 5.2 Hz, 1H), 10.07 (s, 1H), 10.20 (s, 1H). ESI-MS (m/z):
502.2 (M þ H)þ.
Anal: Calcd for C28H24FN3O5 : C; 67:06; H; 4:82: Found : C; 67:25; H; 4:78:
HPLC Conditions— Column: Acclaim C18 (150 mm ꢁ 2.1 mm ꢁ 5 mm);
Detection: 220 nm; Flow rate: 0.8 mL/min; Temperature: 30 ꢀC; Injection load: 1 lL;
Solvent: methanol; Run time: 15 min; Mobile phase: methanol/water ¼ 90/10, tR:
4.143 min, purity: 99.1%.
Acknowledgment
This work was supported by the Key Laboratory of Tropical Medicinal Plant
Chemistry of Ministry of Education, Hainan Normal University (201604).
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