Convenient synthesis of sorafenib and its derivatives

Article abstract of DOI:10.1080/00397911.2010.517372

This article describes a convenient synthesis of sorafinib and its derivatives from phenyl carbamates in good yields. This procedure, avoiding toxic phosgene, is especially suitable for large-scale preparation. Copyright

Full text of DOI:10.1080/00397911.2010.517372

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Convenient Synthesis of Sorafenib and Its
Derivatives
Lijuan Zhang a , Wenpin Xia a , Bo Wang a b , Yu Luo a & Wei Lu a
a Department of Chemistry , East China Normal University ,
Shanghai , China
b Shanghai Pu Yi Chem-Tech. Co., Ltd. , Shanghai , China
Published online: 27 Jul 2011.
To cite this article: Lijuan Zhang , Wenpin Xia , Bo Wang , Yu Luo & Wei Lu (2011) Convenient
Synthesis of Sorafenib and Its Derivatives, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 41:21, 3140-3146, DOI:
10.1080/00397911.2010.517372
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Synthetic Communications1, 41: 3140–3146, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.517372
CONVENIENT SYNTHESIS OF SORAFENIB AND ITS
DERIVATIVES
Lijuan Zhang,1 Wenpin Xia,1 Bo Wang,1,2 Yu Luo,1 and
Wei Lu1
1Department of Chemistry, East China Normal University, Shanghai, China
2Shanghai Pu Yi Chem-Tech. Co., Ltd., Shanghai, China
GRAPHICAL ABSTRACT
Abstract This article describes a convenient synthesis of sorafinib and its derivatives from
phenyl carbamates in good yields. This procedure, avoiding toxic phosgene, is especially
suitable for large-scale preparation.
Keywords Aminolysis; phenyl carbamate; sorafenib; unsymmetrical urea
INTRODUCTION
Hepatocelluar carcinoma (HCC) is a serious health problem that has been
neglected until recently. During the past decades, the heavy burden of viral hepatitis
C as well as the growing importance of nonalcoholic steatohepatitis have resulted in
dramatic increases in HCC incidence in Western countries.[1] Sorafenib (compound
1a) is an oral multikinase inhibitor that blocks tumor cell proliferation and
angiogenesis by targeting the serine=threonine kinases Raf-1=B-Raf and the tyrosine
kinases (RTKs) of VEGFR -2=-3 and PDGFR-b.[2] It was approved by the U.S.
Food and Drug Administration (FDA) for the treatment of advanced renal cell car-
cinoma in 2005[3] and hepatocelluar carcinoma in 2007.[4] Nowadays, several reports
have documented the preparation of sorafenib (Scheme 1). The key step is the con-
struction of the unsymmetrical urea moiety. The classical method was the reaction of
isocyanate 4 with the aniline 2. Another reported method was the direct coupling of
the amine 2 with aniline 3 in the presence of 1,10-carbonyldiimidazole (CDI). Because
the preparation of isocyanate 4 has to use very toxic phosgene, this process was not
appealing for large-scale preparation. Besides, in our preparation of the sorafenib’s
Received December 7, 2009.
Address correspondence to Yu Luo, Institute of Medicinal Chemistry, Department of Chemistry,
East China Normal University, North Zhongshan Road, Shanghai, 200062, China. E-mail: wlu@chem.
ecnu.edu.cn
3140

SYNTHESIS OF SORAFENIB
3141
Scheme 1. Two reported methods for synthesis of sorafenib. Reagents and conditions: (a) CH2Cl2, 92%
yield. (b) CH2Cl2, CDI, 91% yield.
derivatives, the second CDI procedure found that the yield was poor and the reac-
tion was rather complicated (Scheme 1).[5,6] Obviously, a harmless and convenient
synthetic method for sorafenib and its derivatives is still needed. In this article, we
describe an improved and practical synthetic method for sorafenib and its analogs.
RESULTS AND DISCUSSION
Sorafenib is a molecule possessing a structure of N,N-unsymmetrical substituted
urea. N,N-Unsymmetrical substituted ureas have so many applications in medicinal
chemistry that lots of methods have been reported for its preparation. Most of the
methods are based on phosgene, phosgene substitutes, carbonic acid derivatives,
and isocyanates.[7] However, these methods use highly toxic reagents such as phosgene.
Recently, some methods for the synthesis of unsymmetrical ureas without any
toxic reagents have been also developed.[8] One promising method was the aminoly-
sis of alkoxycarbonylated amines. Of the alkoxycarbonylated amines, Matsumura
together with his coworkers proved that phenyl carbamate was the better choice.[9]
Thus, it has inspired us to use this method to explore the synthesis of sorafenib
and its derivatives.
First, one substrate aniline 2 was prepared from 4-chloro-pyridine-2-carboxylic
acid methylamide via the substitution reaction.[6] Meanwhile, o-tolylamine was cho-
sen to synthesize the other substrate phenyl carbamate 6b by reacting with phenyl
chloroformate (Scheme 2).[10,11] Then we found the reaction of the substrate aniline
2 with phenyl carbamate 6b in the presence of base gave the desired unsymmetrical
Scheme 2. Method for synthesis of phenyl carbamate.

3142
L. ZHANG ET AL.
urea 1b in 52.2% yield. Based on the fact, several anilines, which contained either
electron-withdrawing group, electron-donating group, or heterocycle, were selected
to synthesize different phenyl carbamates 6c–6e by the same strategy (Scheme 2).
These phenyl carbamates 6c–6e were checked for whether they could react with
the substrate amine 2. As expected, all the synthesized phenyl carbamates 6b–6e
could react well with the substrate aniline 2 in good yields, as shown in Table 1.
Therefore, it could be concluded that the electronegativity of the anilines 5,
which were used to prepare phenyl carbamates 6, had little influence on the reactivity
between the phenyl carbamates 6 and the substrate aniline 2. Moreover, the
method had a considerable degree of applicability in the synthesis of unsymmetrical
ureas.
According to the synthesis of these unsymmetrical ureas, we developed a novel
route to synthesize sorafenib. First, phenyl carbamate 6a was obtained similar to
compounds 6b–6e. Subsequently, phenyl carbamate 6a was treated with the aniline
2 and ammonolyzed in the presence of base (Scheme 3) to produce sorafenib in
48.2% yield. After chromatography, sorafenib was obtained in better than 99% purity.
In the experiments, phenyl carbamate 6a reacts with aniline 2 smoothly regardless of
Table 1. Preparation of sorafenib’s derivatives
Carbonatea
Product
Yieldb
48.2%
52.2%
54.8%
54%
62.5%
aPrepared by the reported methods.
bYield after chromatography.

SYNTHESIS OF SORAFENIB
3143
Scheme 3. Our approach for synthesis of sorafenib.
whether the solvent was pyridine or other basic organic solution. The effectiveness
and robustness of this procedure were undiminished on a preparative scale.
In summary, a convenient and harmless method was developed for the syn-
thesis of sorafenib and its derivatives. Our approach avoided the toxic reagents.
The yield was good, and the route was suitable for large-scale preparation.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker DRX-500 (500 MHz) instruments.
13C NMR spectra were obtained on JNM-EX400 (400 MHz) and Bruker DRX-500
(500 MHz) instruments. All reagents were used directly as obtained commercially,
unless otherwise noted.
General Procedure for Phenyl Carbamate 6
Phenyl chloroformate 1.5 g (9.5 mmol) was added to a solution of aniline 2 1 g
(8 mmol) and pyridine 0.77 ml (9.5 mmol) in dichloromethane at 0 ꢀC, and then the
mixture was stirred at room temperature for 1 h. After the reaction was completed,
10 ml water and 1 ml dilute hydrochloric acid was added, extracted with dichloro-
methane, dried over sodium sulfate, and evaporated under vacuum to produce the
product.
(4-Chloro-3-trifluoromethyl-phenyl)-carbamic Acid Phenyl Ester 6a[12]
1
Yield 93.8%. H NMR (CDCl3): d 7.11 (s, 1 H), 7.18 (d, J ¼ 8 Hz, 2 H), 7.27
(m, 2 H), 7.41 (m, 2 H), 7.45, J ¼ 8 Hz, 1 H), 7.60 (d, J ¼ 8 Hz, 1 H), 7.81 (s, 1 H).
13C NMR (400 MHz, CDCl3): d 120.88, 121.46, 122.72, 126.08, 126.34, 129.51,
129.57, 132.09, 136.35, 150.24, 151.61. Mp: 109–111 ꢀC.
o-Tolyl-carbamic Acid Phenyl Ester 6b[13]
Yield 93%. 1H NMR (CDCl3): d 2.34 (s, 1 H), 6.73 (s, 1 H), 7.06 (m, 1 H), 7.22–
7.29 (m, 5 H), 7.41 (m, 2 H), 7.86 (s, 1 H). 13C NMR (400MHz, CDCl3): d 17.58,
120.84, 121.54, 124.58, 125.55, 126.91, 129.32, 130.45, 135.35, 150.68. Mp: 94–95ꢀC.

3144
L. ZHANG ET AL.
(4-Nitro-phenyl)-carbamic Acid Phenyl Ester 6c[14]
1
Yield 85%. H NMR (CDCl3): d 7.19 (d, J ¼ 8 Hz, 2 H), 7.28 (m, 2 H), 7.42
(m, 2 H), 7.62 (d, J ¼ 9 Hz, 2 H), 8.23 (d, J ¼ 9 Hz, 2 H). 13C NMR (500 MHz,
CDCl3): d 118.4, 120.95, 121.44, 125.25, 126.23, 129.59, 143.32, 143.39, 150.07,
151.11. Mp: 159–160 ꢀC.
(4-Methoxy-phenyl)-carbamic Acid Phenyl Ester 6d[15]
Yield 81%. 1H NMR (CDCl3): d 3.80 (s, 3 H), 6.72 (s, 1 H), 6.88 (d, J ¼ 9 Hz, 2
H), 7.18 (d, J ¼ 8 Hz, 2 H), 7.24 (d, J ¼ 7 Hz, 1 H), 7.35–7.40 (m, 4 H). 13C NMR
(500 MHz, CDCl3): d 55.47, 114.29, 120.64, 121.64, 125.58, 129.35, 150.63. Mp:
154–155 ꢀC.
Thiazol-2-yl-carbamic Acid Phenyl Ester 6e[16]
Yield 93%. 1H NMR (CDCl3): d 6.97 (s, 1 H), 7.27 (m, 3 H), 7.43 (m, 2 H), 7.50
(d, J ¼ 4 Hz, 1 H), 12.30 (s, 1 H). 13C NMR (500 MHz, CDCl3): d113.20, 121.46,
126.14, 129.56, 137.03, 150.44, 152.49, 161.64. Mp: 182–184 ꢀC.
General Procedure for Sorafenib and Its Derivatives
A 25-mL flask was charged with 5 mL pyridine, 200 mg amine 2 (0.822 mmol),
and 259.5 mg phenyl carbamate 5 (0.822 mmol), and then the mixture was heated to
80 ꢀC for 3 h. After the reaction was completed, pyridine was evaporated under
vacuum to give crude 1, which was purified by column chromatography with
dichloromethane=methanol (30:1).
4-f4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxyg-
pyridine-2-carboxylic Acid Methylamide 1a
1
Yield 48.2%. H NMR (CDCl3): d 3.04 (d, J ¼ 5 Hz, 3 H), 6.98 (d, J ¼ 9 Hz, 2
H), 7.18 (m, 1 H), 7.35 (m, 3 H), 7.53 (d, J ¼ 2 Hz, 1 H), 7.71 (m, 2 H), 8.05 (s, 1 H),
8.34 (s, 1 H), 8.39 (d, J ¼ 4 Hz, 1 H), 8.47 (d, J ¼ 6 Hz, 1 H). 13C NMR (400 MHz,
CDCl3): d 25.98, 108.65, 114.01, 120.51, 121.44, 122.33, 123.11, 131.99, 137.03,
139.30, 147.83, 150.36, 152.44, 152.46, 163.77, 165.95. Mp: 204–205 ꢀC.
4-[4-(3-o-Tolyl-ureido)-phenoxy]-pyridine-2-carboxylic Acid
Methylamide 1b
Yield 54%. 1H NMR (CDCl3): d 2.26 (s, 3 H), 2.78 (d, J ¼ 5 Hz, 3 H), 6.95 (m, 1
H), 7.15 (m, 5 H), 7.38 (d, J ¼ 3 Hz, 1 H), 7.58 (d, J ¼ 8 Hz, 2 H), 7.82 (d, J ¼ 8 Hz, 1
H), 7.95 (s, 1 H), 8.49 (d, J ¼ 5 Hz, 1 H), 8.75 (d, J ¼ 5 Hz, 1 H), 9.15 (s, 1 H).13C
NMR (400 MHz, CDCl3): d 17.93, 26.03, 108.67, 113.98, 119.71, 121.20, 121.54,
122.81, 126.20, 127.70, 130.23, 137.34, 137.81, 147.32, 150.37, 152.45, 152.71,
163.82, 166.08. HRMS (ESI): m=z calcd. for C21H20N4NaO3 [M þNaþ]: 399.1428.
Found: 399.1434. Mp: 189–190 ꢀC.

SYNTHESIS OF SORAFENIB
3145
4-f4-[3-(4-Nitro-phenyl)-ureido]-phenoxyg-pyridine-2-carboxylic
Acid Methylamide 1c
1
Yield 54.8%. H NMR (CDCl3): d 2.78 (d, J ¼ 5 Hz, 3 H), 7.15 (m, 1 H), 7.19
(d, J ¼ 9 Hz, 2 H), 7.38 (d, J ¼ 3 Hz, 1 H), 7.60 (d, J ¼ 8 Hz, 2 H), 7.70 (d, J ¼ 9 Hz, 2
H), 8.20 (d, J ¼ 9 Hz, 2 H), 8.50 (d, J ¼ 5 Hz, 1 H), 8.76 (d, J ¼ 5 Hz, 1 H), 9.08 (s, 1
H), 9.50 (s, 1 H). 13C NMR (400 MHz, CDCl3): d 26.03, 108.68, 114.05, 117.53,
120.49, 121.56, 125.19, 136.90, 141.05, 146.36, 147.96, 150.40, 152.05, 152.45,
163.80, 165.96. HRMS (ESI): m=z calcd. for C20H17N5NaO5 [M þNaþ]: 430.1122.
Found: 430.1111. Mp: 240–241 ꢀC.
4-f4-[3-(4-Methoxy-phenyl)-ureido]-phenoxyg-pyridine-
2-carboxylicacimethylamide 1d
1
Yield 52.2%. H NMR (CDCl3): d 2.78 (d, J ¼ 5 Hz, 3 H), 3.72 (s, 3 H), 6.87
(d, J ¼ 9 Hz, 2 H), 7.13 (m, 3 H), 7.37 (m, 3 H), 7.55 (d, J ¼ 9 Hz, 2 H), 8.50
(d, J ¼ 6 Hz, 2 H), 8.73 (d, J ¼ 7 Hz, 2 H). 13C NMR (400 MHz, CDCl3): d25.95,
55.12, 108.59, 113.90, 113.95, 119.76, 120.04, 121.37, 132.60, 137.77, 147.19,
150.30, 152.37, 152.72, þ154.46, 163.75, 166.01. HRMS (ESI): m=z calcd. for
C21H20N4NaO4 [M þNa ]: 415.1377. Found: 415.1382. Mp: 217–218 ꢀC.
4-[4-(3-Thiazol-2-yl-ureido)-phenoxy]-pyridine-2-carboxylic Acid
Methylamide 1e
1
Yield 62.5%. H NMR (CDCl3): d 2.78 (d, J ¼ 5 Hz, 3 H), 7.14 (m, 2 H), 7.19
(d, J ¼ 9 Hz, 2 H), 7.38 (t, 2 H), 7.60 (t, 2 H), 8.50 (d, J ¼ 5 Hz, 1 H), 8.76 (d,
J ¼ 5 Hz, 1 H), 9.11 (s, 1 H), 11.62 (br, 1 H).13C NMR (400 MHz, CDCl3): d
26.32, 109.06, 112.82, 114.35, 120.91, 121.87, 136.73, 136.81, 137.13, 137.21,
148.45, 150.78, 152.26, 152.58, 160.00, 164.29, 166.21. HRMS (ESI): m=z calcd.
for C17H15N5NaO3S [M þNaþ]: 392.0788. Found: 392.0781. Mp: 231–233 ꢀC.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from New Century Excellent
Talents in University (NCET). We also thank the Laboratory of Organic Functional
Molecules and the Sino-French Institute of ECNU for support.
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