Novel method for the synthesis of lenvatinib using 4-nitrophenyl cyclopropylcarbamate and their pharmaceutical salts

Article abstract of DOI:10.1007/s11696-020-01402-z

4-Nitrophenyl cyclopropylcarbamate was deployed as a novel synthon for the synthesis of anticancer drug lenvatinib. 4-Nitrophenyl cyclopropylcarbamate was prepared by the reaction of 4-nitrophenyl chloroformate and cyclopropyl amine in acetonitrile at room temperature. Furthermore, lenvatinib was synthesized by reacting 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide with 4-nitrophenyl cyclopropylcarbamate in good yields. Apart from the synthesis of lenvatinib, citrate, phosphate, malate and oxalate salts of?lenvatinib were also reported in good yields.

Full text of DOI:10.1007/s11696-020-01402-z

Chemical Papers
https://doi.org/10.1007/s11696-020-01402-z
ORIGINAL PAPER
Novel method for the synthesis of lenvatinib using 4‑nitrophenyl
cyclopropylcarbamate and their pharmaceutical salts
Ravi Kumar Sadineni1,2 · Rajesh Kumar Rapolu1,2 · V. V. N. K. V. Prasada Raju1 · N. Srinivasu2 · Sireesha Malladi2 ·
Naveen Mulakayala3
Received: 22 June 2020 / Accepted: 20 October 2020
© Institute of Chemistry, Slovak Academy of Sciences 2020
Abstract
4-Nitrophenyl cyclopropylcarbamate was deployed as a novel synthon for the synthesis of anticancer drug lenvatinib.
4-Nitrophenyl cyclopropylcarbamate was prepared by the reaction of 4-nitrophenyl chloroformate and cyclopropyl amine
in acetonitrile at room temperature. Furthermore, lenvatinib was synthesized by reacting 4-(4-amino-3-chlorophenoxy)-
7-methoxyquinoline-6-carboxamide with 4-nitrophenyl cyclopropylcarbamate in good yields. Apart from the synthesis of
lenvatinib, citrate, phosphate, malate and oxalate salts of lenvatinib were also reported in good yields.
Keywords Synthesis · Process · Lenvatinib · Salts · Analysis
Introduction
2016 for the treatment of advanced renal cell carcinoma.
FDA approved lenvatinib for the treatment of patients with
advanced endometrial carcinoma along with pembrolizuma.
(Makker et al. 2020).
Cancer is one of the leading death causing disease globally.
According to World Health Organization (WHO) the cancer
patients will increases to 27.5 million by 2040. Lenvatinib
is an anticancer drug used for the treatment of thyroid can-
cer and also acts as a kinase inhibitor against VEGFR1,
VEGFR2 and VEGFR3 (Zschäbitz and Grüllich 2018).
Lenvatinib inhibits efectively in the tumor progression
by preventing phosphorylation and subsequent activation of
many tyrosine kinases taking part in tumor cell prolifera-
tion and neo-angiogenesis. (Scott et al. 2015) Lenvatinib
was approved for medical use in the United States from
On the other hand, it is important to develop high quality,
commercially viable and cost-efcient methods for an exist-
ing active pharmaceutical ingredients (API). Many research-
ers from academic as well as industry have focused to
develop commercially viable novel methods for the new and
existing API molecules. In this regard, we plan to develop
a novel method for the synthesis of lenvatinib which is an
important anticancer compound (Fig. 1).
After thorough literature review, several synthetic meth-
ods were reported for the synthesis of lenvatinib which were
shown in Scheme 1. (Matsushima et al. 2005; Sakaguchi
et al. 2006; Funahashi et al. 2007; Naito et al. 2006; Naka-
mura et al. 2016; Gang 2015; Flick et al. 2015; Casar 2020).
Lenvatinib synthesis was shown in Scheme 1 using dif-
ferent approaches. We are using 4-nitrophenyl cyclopropyl
carbamate as unsymmetrical reactive carbamate for the syn-
thesis of lenvatinib. Most of the lenvatinib synthesis were
reported using 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropyl
urea as an intermediate which is prepared by the reaction of
3-chloro-4-aminophenol and cyclopropyl amine using phe-
nylchloroformate or carbonyldiimidazole. In the same way
lenvatinib was synthesized by the reaction of 4-(4-amino-
3-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide
and cyclopropyl amine using phenylchloroformate or
Electronic Supplementary Material The online version of this
article (https://doi.org/10.1007/s11696-020-01402-z) contains
supplementary material, which is available to authorized users.
* Naveen Mulakayala
naveen071280@gmail.com
1
Granules India Limited, R&D Center, Plot No. 56,
Road No. 5, ALEAP Industrial Area, Pragathi Nagar,
Hyderabad 5000072, India
2
Division of Chemistry, Department of Sciences
and Humanities, Vignan’s Foundation for Science,
Technology and Research (VFSTR) (deemed to be)
University, Vadlamudi, Guntur 522 213, India
3
SVAK Life Sciences, ALEAP Industrial Area, Pragathi
Nagar, Hyderabad 500090, India
Vol.:(0123456789)
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Chemical Papers
Fig. 1 Structure of lenvatinib 1
4-nitrophenyl cyclopropylcarbamate as a novel intermediate.
Previously several researchers used 4-nitrophenyl cyclopro-
pylcarbamate for the construction of cyclopropylurea in the
literature. (Thomas et al. 2007; Harry et al. 2013; Michael
et al. 2003; Rapolu et al. 2019a, b). The importance of the
present study is to synthesize lenvatinib using novel pro-
cess followed by the preparation of diferent lenvatinib salts
which are having novel polymorphism. All the synthesized
compounds were characterized using 1H NMR, 13C NMR,
Mass spectra and HPLC method.
carbonyldiimidazole. (Reddy et al. 2017; Oruganti et al.
2017; Gang 2015).
Experimental procedure
Due to continuous eforts in the development of API
and API impurities (Gudisela et al. 2018; Rapolu et al.
2018; Rapolu et al. 2019a, b) by our team, we wish to
report a novel method for the synthesis of lenvatinib using
Solvents and reagents obtained from commercial sources
1
were used without any further purifcation. H NMR and
13C NMR were recorded in CDCl3, DMSO-d6 on a Varian
Scheme 1 Literature known synthetic schemes of lenvatinib 1
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Chemical Papers
Mercury spectrometer using TMS as an internal standard.
The mass spectrum (70 eV) was recorded on an HP 5989
A LC–MS spectrometer. TLC analyses were performed
on Merck silica gel 60 F254 plates. HPLC was performed
using waters 2695 model pump and 2996 PDA detector.
YMC C-18 column (4.6×150 mm, 5 μ) analytical column
and a mobile phase containing water and methanol in a
ration 30:70 isocratic systems was used to separate the len-
vatinib peak. PXRD was performed on Bruker D8 advance
instrument.
1H), 6.85 (d, J = 8.6 Hz, 1H), 6.46 (1 d, J = 5.3 Hz, 1H),
5.95 (brs, 1H), 4.12 (s, 3H), 4.11 (s, 2H); Mass (m/z):
Calculated-343.0, Found-343.9 (M + H) + .
Preparation of lenvatinib (4‑(3‑chloro‑4‑(3‑cyclopro‑
pylureido)phenoxy)‑7‑methoxy quinoline‑6‑carbox‑
amide) (1)
To a stirred solution of 4-(4-amino-3-chlorophenoxy)-
7-methoxyquinoline-6-carboxamide 4 (50 g, 0.145 mol)
in acetonitrile (500 mL) 4-nitrophenyl cyclopropylcarba-
mate 10 (63 g, 0.278 mol) was added, followed by pyri-
dine (34.5 g, 0.434 mol) at room temperature. The reaction
mixture was heated to 80–85 °C and stirred at the same
temperature for 13 h. Another lot 4-nitrophenyl cyclopro-
pylcarbamate 10 (10 g, 0.044 mol) was added and stirred
for 7–8 h at 80–85 °C. The reaction mixture was cooled
to room temperature and fltered. The obtained solid was
washed with acetonitrile (100 mL) and crude solid was
dissolved in methanol: DCM (1:1, 1560 mL). The solu-
tion was warmed to 40–45 °C, carbon (25 g) was added
and stirred for 1 h at the same temperature. After fltering
the reaction mass, the fltrate was evaporated under vac-
uum below 40 °C to furnish crude. The crude was slurried
in acetone (250 mL) and fltered to furnish lenvatinib 1
(4-(3-chloro-4-(3-cyclopropylureido) phenoxy)-7-methox-
yquinoline-6-carboxamide) (45.7 g, 74%).
Preparation of 4‑nitrophenyl cyclopropylcarbamate
(12)
To a stirred solution of 4-nitrophenyl chloroformate 13
(88.0 g, 0.436 mol) in acetonitrile (1000 mL) cyclopropyl
amine 3 (25.0 g, 0.437 mol) was added at 0–5 °C over a
period of 50–60 min. The reaction mixture was warmed to
room temperature and stirred for 24–26 h. After comple-
tion of the starting material (Checked by TLC), the reac-
tion mixture was fltered and washed with dichlorometh-
ane (100 mL). The fltrate was evaporated under reduced
pressure to obtain solid compound. The solid compound
was slurried in hexane (2× 500 mL), fltered and washed
with hexane (2×100 mL). The wet cake was dried to obtain
4-nitrophenyl cyclopropylcarbamate 12 (73.7 g, 76%) as an
of white solid.
Of white solid: mp: 203–206 °C; 1H NMR (DMSO-d6,
500 MHz): δ 8.29–8.20 (m, 3H), 7.40 (dd, J=7.1, 2.0 Hz,
2H), 2.62–2.56 (m, 1H), 0.69–0.64 (m, 2H), 0.52–0.50 (m,
2H). Mass (m/z): Calculated-222.25, Found-223.4 (M+H)+.
HPLC purity: 98.27%.Off white solid; 1H NMR
(DMSO-d6, 500 MHz): δ 8.67 (d, J = 5.2 Hz, 1H), 8.66
(s, 1H), 8.28 (d, J = 9.1 Hz, 1H), 7.99 (s, 1H), 7.85 (s,
1H), 7.74 (s, 1H), 7.52 (s, 1H), 7.50 (d, J = 2.8 Hz, 1H),
7.25 (dd, J = 9.1, 2.8 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H),
6.53 (d, J = 5.2 Hz, 1H), 4.04 (s, 3H), 2.62–2.56 (m, 1H),
0.70–0.64 (m, 2H), 0.46–0.40 (m, 2H); 13C NMR (DMSO-
d6, 100 MHz): δ 165.7, 162.2, 161.3, 158.4, 155.5, 152.7,
150.5, 147.4, 134.7, 125.3, 124.8, 122.1, 121.9, 121.8,
120.3, 11.4, 107.0,103.1, 56.2, 22.3, 6.2. Mass (m/z): Cal-
culated-426.85, Found-427.74 (M + H)+
Preparation
of 4‑(4‑amino‑3‑chlorophenoxy)‑7‑methoxyquino‑
line‑6‑carboxamide (8)
To a stirred solution of 4-chloro-7-methoxyquinoline-6-car-
boxamide 5 (50 g, 0.211 mol) in DMSO (250 mL) 4-amino-
3-chloro phenol 7 (42.5 g, 0.296 mol) was added at room
temperature. After 5–10 min, KOH (35.5 g, 0.633 mol)
in 70 mL water was added drop wise over a period of
30–40 min at room temperature. The reaction mixture was
warmed to 70–80 °C and stirred at the same temperature for
12–13 h. After consumption of starting material, the reac-
tion was cooled to room temperature and water (500 mL)
was added to obtain the solid. The contents were stirred for
60 min at room temperature, fltered, washed with water
(150 mL) and dried to aford 4-(4-amino-3-chlorophenoxy)-
7-methoxyquinoline-6-carboxamide 8 (54 g, 84%) as light
brown solid.
Purifcation of lenvatinib
Using DMSO‑IPA
To a stirred solution of lenvatinib 1 (32 g, crude) in
DMSO (640 mL) IPA (1600 mL) was added drop wise at
40–45 °C. The suspension was cooled to room tempera-
ture and stirred for 15–16 h. The suspension was fltered
and the solid was washed with water (50 mL) followed by
acetone (100 mL). The wet cake was dried at 50 °C under
vacuum to obtain lenvatinib 1 (23 g, 72%) with 99.54%
HPLC purity.
Light brown solid: 1H NMR (CDCl3, 400 MHz): δ 9.27
(s, 1H), 8.64 (d, J = 5.3 Hz, 1H), 7.79 (brs, 1H), 7.52 (s,
1H), 7.13 (d, J = 2.4 Hz, 1H), 6.92 (dd, J = 8.6, 2.6 Hz,
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Chemical Papers
Using DMSO‑acetone
mixture was heated to 60–65 °C and stirred for 6–7 h at
the same temperature. The suspension was cooled to room
temperature and stirred for 18–20 h. The suspension was
fltered, washed with acetone (15 mL) and dried to give
lenvatinib (l)-malate (4-(3-chloro-4-(3-cyclopropylureido)
phenoxy)-7-methoxyquinoline-6-carboxamide (S)-2-hydrox-
ysuccinate) 15 (5 g, 95%) as an of white solid.
To a stirred solution of lenvatinib 1 (7 g, crude) in DMSO
(140 mL) acetone (420 mL) was added dropwise at
40–45 °C. The suspension was cooled to room temperature
and stirred for 6 days. The suspension was fltered and the
solid was washed with water (20 mL) followed by acetone
(20 mL). The wet cake was dried at 50 °C under vacuum to
obtain lenvatinib 1 (1.7 g, 24%) with 99.55% HPLC purity.
1
Of white solid: mp: 157.5–161.0 °C; LOD: 0.9%; H
NMR (DMSO-d6, 500 MHz): δ 12.33 (broad, 1H), 8.67 (s,
1H), 8.66 (s, 1H), 8.27 (d, J = 9.1 Hz, 1H), 7.97 (s, 1H),
7.84 (s, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 7.48 (d, J=3.0 Hz,
1H), 7.24 (dd, J=9.0, 2.5 Hz, 1H), 7.18 (d, J=2.5 Hz, 1H),
6.53 (d, J=5.2 Hz, 1H), 4.28–4.23 (m, 1H), 4.03 (s, 3H),
2.64–2.56 (m, 2H), 2.57–2.40 (m, 1H), 0.70–0.64 (m, 2H),
0.46–0.40 (m, 2H); Mass (m/z): 426.9(M + H)+. HPLC
purity: 99.63%; Assay by HPLC: 73.2%; TGA (Method:
Ramp 5.00 °C/min to 300.00 °C, Equlibrate at 30.00 °C):(3
0.00 °C–100.00 °C):2.69%; DSC (Method: Ramp 5.00 °C/
min to 300.00 °C, Equlibrate at 30.00 °C):157.2–160.46 °C;
XRD: 4.012, 7.329, 8.125, 9.369, 10.840, 12.382, 14.285,
14.797, 15.514, 16.518, 18.048, 18.552, 18.928, 19.920,
19.866, 20.586, 21.481, 22.733, 22.986, 23.461, 24.043,
24.930, 25.864, 26.963, 27.861, 28.629, 29.030, 29.793,
30.552, 31.448, 33.917, 35.035, 36.275, 38.523.
Preparation of lenvatinib mesylate
(4‑(3‑Chloro‑4‑(3‑cyclopropylureido)
phenoxy)‑7‑methoxyquinoline‑6‑carboxamide
methanesulfonate
To a stirred suspension of 4-(3-chloro-4-(3-cyclopropy-
lureido) phenoxy)-7-methoxyquinoline-6-carboxamide 1
(5 g, 0.011 mol.) in IPA (50 mL) MSA (1.1 g, 0.011 mol.)
was added at room temperature. The reaction mixture was
heated to 80–85 °C and stirred at the same temperature for
7–8 h. The reaction mass was cooled to room temperature
and stirred for 15–18 h. The suspension was fltered, washed
with IPA (10 mL) and dried to yield lenvatinib mesylate 12
(4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methox-
yquinoline-6-carboxamide methane sulfonate) (5 g, 82%)
as an of white solid.
Process for lenvatinib oxalate
Of white solid: mp: 226.5–231.0 °C, LOD: 0.3%;1H
NMR (DMSO-d6, 500 MHz): δ 8.98 (d, J=6.5 Hz, 1H), 8.73
(s, 1H), 8.37 (d, J=9.1 Hz, 1H), 8.07 (s, 1H), 7.97 (broad,
1H), 7.91 (brs, 1H), 7.64 (s, 2H), 7.36 (d, J =9.1, 2.8 Hz,
1H), 7.27 (d, J=2.6 Hz, 1H), 6.95 (d, J=6.5 Hz, 1H), 4.09
(s, 3H), 2.62–2.56 (m, 1H), 2.35 (s, 3H), 0.71–0.60 (m,
2H), 0.47–0.41 (m, 2H). 13C NMR (DMSO-d6, 100 MHz):
165.7, 161.5, 158.0, 155.4, 153.2, 151.5, 147.5, 134.5,
124.9, 124.6, 121.8, 121.7, 120.3, 114.3, 107.8, 102.9,
101.5, 56.1, 22.3, 6.2. Mass (m/z): Calculated-426.85,
Found-427.20 (M + H) +, HPLC purity: 95.19%; TGA
(Method: Ramp 5.00 °C/min to 300.00 °C, Equilibrate at
30.00 °C): (30.00 °C–120.00 °C): 0.26%; DSC (Method:
Ramp 5.00 °C/min to 300.00 °C, Equilibrate at 30.00 °C):
225.8–229.3 °C.
4‑(3‑Chloro‑4‑(3‑cyclopropylureido)
phenoxy)‑7‑methoxyquinoline‑6‑carboxamide oxalate (16)
To a stirred suspension of 4-(3-chloro-4-(3-cyclopropy-
lureido)phenoxy)-7-methoxyquinoline-6-carboxamide 1
(5 g, 0.011 mol) in acetone (200 mL) oxalic acid (1.27 g,
0.014 mol) was added at room temperature. The reaction
mixture was heated to 60–65 °C and stirred for 6–7 h at
the same temperature. The suspension was cooled to room
temperature and stirred for 15–16 h. The suspension was
fltered, washed with acetone (30 mL) and dried to yield
lenvatinib oxalate 16(4-(3-chloro-4-(3-cyclopropylureido)
phenoxy)-7-methoxyquinoline-6-carboxamide oxalate)
(5.8 g, 96%) as an light brown solid.
Light brown solid: mp:170.0–173.2 °C; LOD:0.06%; 1H
NMR (DMSO-d6, 500 MHz): δ 8.71–8.68 (m, 1H), 8.67
(s, 1H), 8.28 (d, J=9.1 Hz, 1H), 7.99 (s, 1H), 7.85 (s, 1H),
7.73 (s, 1H), 7.52 (s, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.25
(dd, J=9.5, 3.0 Hz, 1H), 7.19 (d, J=3.0 Hz, 1H), 6.55 (d,
J=5.3 Hz, 1H), 4.03 (s, 3H), 2.61–2.56 (m, 1H), 0.70–0.64
(m, 2H), 0.46–0.40 (m, 2H); 13C NMR (DMSO-d6): δ 165.7,
162.2, 161.3, 158.4, 155.5, 152.7, 150.5, 147.4, 134.7,
125.3, 124.8, 122.1, 121.9, 121.8, 120.3, 114.4, 107.0,
103.1, 56.2, 22.3, 6.2., Mass (m/z): Calculated-426.85,
Found-427.15(M + H)+; HPLC purity: 99.26%. Assay
by HPLC: 77.1%; TGA (Method: Ramp 5.00 °C/min to
Process for lenvatinib (l)‑malate
4‑(3‑Chloro‑4‑(3‑cyclopropylureido)
phenoxy)‑7‑methoxyquinoline‑6‑carboxamide
(S)‑2‑hydroxysuccinate (15)
To a stirred suspension of 4-(3-chloro-4-(3-cyclopropy-
lureido)phenoxy)-7-methoxyquinoline-6-carboxamide 1
(4 g, 0.009 mol) in acetone (120 mL) (l)-malic acid (1.5 g,
0.011 mol) was added at room temperature. The reaction
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Chemical Papers
300.00 °C, Equilibrate at 30.00 °C):30.00 °C–120.00 °C:
3.46%,120.0–155.0 °C:3.12%, 155–200 °C:21.79%; DSC
(Method: Ramp 5.00 °C/min to 300.00 °C, Equilibrate at
30.00 °C):171.89 °C–188.71 °C(melting with decompose);
XRD: 3.495, 5.483, 8.034, 10.527, 11.105, 16.699, 18.047,
20.145, 24.016, 25.881, 27.109, 27.156, 28.642, 29.313.
temperature and stirred for 15–16 h. The suspension was
fltered, washed with acetone (20 mL) and dried to furnish
lenvatinib citrate (4-(3-chloro-4-(3-cyclopropylureido)
phenoxy)-7-methoxyquinoline-6-carboxamide-2-hydroxy
propane-1,2,3-tricarboxylate) 18 (6 g, 83%) as an of white
solid.
Of white solid: mp: 161.5–164.0 °C; LOD: 0.25%; 1H
NMR (DMSO-d6, 500 MHz): δ 12.21 (broad, 1H), 8.67 (s,
1H), 8.66 (s, 1H), 8.28 (d, J = 9.0 Hz, 1H), 7.97 (s, 1H),
7.84 (s, 1H), 7.71 (s, 1H), 7.50 (s, 1H), 7.49 (d, J=3.0 Hz,
1H), 7.24 (dd, J = 9.0, 2.5 Hz, 1H), 7.18 (d, J = 2.5 Hz,
1H), 6.53 (d, J = 5.3 Hz, 1H), 4.03 (s, 3H), 2.73, 2.64
(q, J = 15.5 Hz, 4H), 2.61–2.56 (m, 1H), 0.70–0.64 (m,
2H), 0.46–0.40 (m, 2H); Mass (m/z): Calculated-426.1,
Found-426.9(M + H) +; HPLC purity: 99.78%; TGA
(Method: Ramp 5.00 °C/min to 300.00 °C, Equilibrate at
30.00 °C):120.0 °C: 1.92%,150.0 °C: 14.29%, 200.0 °C:
14.75%; DSC (Method: Ramp 5.00 °C/min to 300.00 °C,
Equilibrate at 30.00 °C):150.94–160.2 °C; XRD: 3.993,
5.475, 6.827, 8.268, 10.301, 11.667, 12.480, 13.139, 13.654,
14.697, 14.931, 15.505, 16.827, 17.137, 17.880, 17.976,
18.525, 19.063, 20.128, 20.908, 22.468, 23.222, 23.453,
24.187, 24.699, 26.035, 26.748, 27.099, 27.232, 27.850,
28.859, 29.687, 30.929, 31.423, 32.983, 34.894, 35.485,
38.962, 39.010.
Process for lenvatinib phosphate
4‑(3‑Chloro‑4‑(3‑cyclopropylureido)
phenoxy)‑7‑methoxyquinoline‑6‑carboxamide phosphate
(17)
To a stirred suspension of 4-(3-chloro-4-(3-cyclopropy-
lureido)phenoxy)-7-methoxyquinoline-6-carboxamide 1
(5 g, 0.011 mol) in IPA (200 mL) phosphoric acid (1.37 g,
0.013 mol) was added at room temperature. The reaction
mixture was heated to 80–85 °C and stirred at the same
temperature for 4–5 h. The suspension was cooled to room
temperature and stirred for 15–16 h. The suspension was
fltered, washed with IPA (20 mL) and dried to obtain len-
vatinib phosphate(4-(3-chloro-4-(3-cyclopropylureido)
phenoxy)-7-methoxyquinoline-6-carboxamide phosphate)
17 (5.0 g, 82%) as an of white solid.
Of white solid: mp: 191.5–193.0 °C; LOD: 1.80%; 1H
NMR (DMSO-d6, 500 MHz): δ 8.67 (m, 1H), 8.66 (s, 1H),
8.27 (d, J=9.0 Hz, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.72 (s,
1H), 7.52 (s, 1H), 7.49 (d, J=3.0 Hz, 1H), 7.24 (dd, J=9.0,
2.5 Hz, 1H), 7.19 (d, J= 3.0 Hz, 1H), 6.53 (d, J= 5.2 Hz,
1H), 4.03 (s, 3H), 2.62–2.56 (m, 1H), 0.69–0.64 (m, 2H),
0.45–0.40 (m, 2H); Mass(m/z): Calculated: 426.15, Found:
426.9(M + H) +; HPLC purity: 99.57%; Assay by HPLC:
72.7%; TGA (Method: Ramp 5.00 °C/min to 300.00 °C,
Equilibrate at 30.00 °C):120.0 °C:2.69%, 180.0 °C:10.42%,
230.0 °C:4.07%; DSC (Method: Ramp 5.00 °C/min to
300.00 °C, Equlibrate at 30.00 °C):185.8–192.9 °C; XRD:
3.154, 4.030, 4.469, 6.151, 6.099, 6.633, 9.715, 10.269,
11.020, 12.268, 12.490, 13.936, 16.456, 16.896, 17.004,
17.145, 18.976, 19.461, 19.944, 20.892, 21.609, 23.199,
23.496, 26.634, 27.575, 28.200, 28.729, 29.327.
Results and discussion
After thorough literature analysis, following retrosynthetic
analysis of lenvatinib was proposed (Scheme 2).
After going through the retrosynthetic route we proceeded
to use 4-nitrophenyl cyclopropylcarbamate 12 as a key start-
ing material for the synthesis of lenvatinib. 4-Nitrophenyl
cyclopropylcarbamate 12 which is a good leaving group can
be used for the synthesis of lenvatinib. It was prepared by the
reaction of 4-nitrophenyl chloroformate 14 with cyclopropyl
amine 3.
The key starting material, 4-nitrophenyl cyclopropyl-
carbamate 12 was prepared starting from commercially
available 4-nitrophenol. 4-Nitrophenol 14 on reaction with
triphosgene in toluene at 0–5 °C for 1–2 h aforded Com-
pound 13 in 95% yield. (Onozuka et al. 2011) (Scheme 3).
After synthesizing 4-nitrophenyl chloroformate 13, we
focused on the synthesis of 4-nitrophenyl cyclopropyl-
carbamate 12 which was synthesized by the reaction of
4-nitrophenyl chloroformate 13 and cyclopropyl amine
3. To optimise this reaction, we conducted a preliminary
reaction using literature procedure between 4-nitrophenyl
chloroformate and cyclopropyl amine in THF using diiso-
propylethyl amine as a base at room temperature. Only 10%
of the desired product 12 was formed at room temperature.
(Arcari et al. 2007).
Process for lenvatinib citrate
4‑(3‑Chloro‑4‑(3‑cyclopropylureido)
phenoxy)‑7‑methoxyquinoline‑6‑carboxamide
2‑hydroxypropane‑1,2,3‑tricarboxylate (18)
To a stirred suspension of 4-(3-chloro-4-(3-cyclopropy-
lureido)phenoxy)-7-methoxyquinoline-6-carboxamide
1 (5 g, 0.011 mol) in acetone (200 mL) citric acid (2.7 g,
0.014 mol) was added at room temperature. The reaction
mixture was heated to 60–65 °C and stirred for 6–7 h at
the same temperature. The suspension was cooled to room
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Chemical Papers
Scheme 2 Retrosynthetic analy-
sis of lenvatinib 1
Scheme 3 Preparation of
4-nitrophenyl cyclopropylcar-
bamate 12
To optimize the reaction conditions for the synthesis of
4-nitrophenyl cyclopropyl carbamate 12, we tried the reac-
tion with diferent bases such as TEA, DIPA, Pyridine,
NaOH, K2CO3 and found there is no improvement in the
yield of the reaction. When the reaction was tried without
using any base in DCM we observed an improvement in the
formation of the desired product with 57% yield. The same
reaction when performed in acetonitrile at room temperature
for 24 h the yield of the desired product was increased to
76% yield (Table 1).
Table 1 Optimization of reaction conditions for the synthesis of
4-nitrophenyl cyclopropylcarbamate 12
Entry
Base
Solvent
Time/tempera-
ture (h/RT)
Yield
(isolated)
(%)
1
2
3
4
5
6
7
8
DIPEA
TEA
DIPA
Pyridine
NaOH
K2CO3
No base
No base
THF
THF
THF
THF
DCM
DCM
DCM
MeCN
12
12
12
12
12
12
12
24
10
16
18
26
6
11
57
76a
After the synthesis of Compound 12, we started to opti-
mize the reaction between Compound 7 and Compound 5 to
get Compound 8. By following the literature references we
screened the reaction using diferent bases such as cesium
carbonate, potassium carbonate, sodium hydride, potassium
tertiary butoxide and potassium hydroxide. In all the above
bases potassium hydroxide was efective in DMSO by giving
84% of Compound 8 at 70–80 °C for 12–14 h. (Nakamura
et al. 2016; Reddy et al. 2019) (Scheme 4).
aReaction conditions. Compound 13 (0.436 mol.) in acetonitrile (12
vol.), cyclopropylamine 3 (0.437 mol.), 0–5 °C, 1 h then 30–35 °C,
24–26 h
TEA, pyridine, DIPEA, DIPA and KOH. In most of the
bases the reaction was either incomplete or formation of by-
products was observed. Among all the above bases TEA and
pyridine were efective in getting the fnal compound in good
yield. Better yields were obtained when the reaction was
Now we focused on the optimization of critical reaction
between Compound 8 and Compound 12 which is the novel
reaction for the synthesis of lenvatinib 1. The reaction was
screened using diferent bases such as cesium carbonate,
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Chemical Papers
Scheme 4 Synthesis of lenvatinib
Table 2 Optimization of reaction conditions for the synthesis of
Compound 1
To increase the solubility of lenvatinib, we converted the
free base into its mesylate salt using methane sulfonic acid
in IPA (or) methanol. During the preparation of mesylate
salt we used one equivalent of methane sulfonic acid which
controls the formation of mutagenic alkyl-sulfonate impuri-
ties. (Snodin and Teasdale 2015; Snodin et al. 2019).
After the synthesis of mesylate salt of lenvatinib, we
focused on the preparation of diferent salts of lenvatinib.
After thorough screening we synthesized four diferent salts
of lenvatinib, i.e., lenvatinib (l)-malate 15, lenvatinib oxalate
16, lenvatinib phosphate 17, lenvatinib citrate 18. (Fig. 2).
Lenvatinib (l)-malate 15, lenvatinib oxalate 16 are novel
salts and lenvatinib phosphate 17, lenvatinib citrate 18 are
novel polymorphic forms when compared with the literature
references.
Entry
Base
Solvent
Yield
1
2
3
4
5
6
7
8
Cs2CO3
TEA
Pyridine
DIPEA
DIPA
KOH
TEA
DCM
DCM
DCM
DCM
DCM
DCM
Acetonitrile
Acetonitrile
32
56
64
43
37
28
62
74
Pyridine
Reaction conditions. Compound 5 (0.211 mol.), Compound 7
(0.296 mol.), in DMSO (5 vol.), KOH (0.633 mol.), 70–80 °C,
12–13 h
Lenvatinib phosphate 17 which is a novel polymorphic
form having characteristic values 9.7, 11.0, 20.8, 21.6 and
26.6 are diferent from the reported values 8.1; 11.3; 20.3;
21.5 and 25.8. (Zvatora et al. 2017) Differential Scan-
ning Calorimetry (DSC) was used to measure the melting
point of the synthesized salt. The melting point obtained is
185.8–192.9 °C which is diferent from the reported value
178 °C. The above two techniques confrm the formation of
novel polymorph of lenvatinib phosphate salt.
performed in acetonitrile using pyridine as base at 80–85 °C
for 13 h. The isolated yield of lenvatinib was 74% (Table 2).
The solubility of lenvatinib base 1 was poor in water and
most of the organic solvents. To get pure form of lenvatinib,
purifcation was attempted under several conditions. Most
of the common solvents like DCM, MeOH, IPA, DMF and
DMSO didn’t increase the purity of the lenvatinib. (Zheng
et al. 2020) Finally, purifcation was tried with a mixture
of solvents using DMSO (or) DMF as one of the solvents.
Excellent purity of lenvatinib was achieved when the purif-
cation was performed using a mixture of DMSO-IPA (1:2.5)
(or) DMSO-acetone (1:4).
Lenvatinib citrate 18 which is also having novel poly-
morphic form having characteristic peak values 12.4,
19.0, 22.4 and 29.6 in comparison with the reported val-
ues 12.3; 18.9; 21.6 and 29.3. (Zvatora et al. 2017) DSC
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Chemical Papers
Fig. 2 Structures of novel salts
of lenvatinib
thermogram is showing the melting point at 150.9–160.2
which is diferent from the reported value 227.7–270.0. It
confrms the formation of novel citrate salt of lenvatinib.
After synthesizing the citrate and phosphate salts we
also synthesized malate 15, oxalate 16. These two salts
are novel and have high solubility in water compared with
citrate and phosphate slats. All the salts were confrmed by
their analysis using 1H NMR, PXRD and DSC.
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