An improved synthesis of sunitinib malate via a solvent-free decarboxylation process

Article abstract of DOI:10.1007/s11164-015-1939-z

To search for an economical and convenient synthesis of sunitinib and its malate salt, optimization of a scalable synthetic route was explored by designing a standard experimental protocol on laboratory scale using commercially available materials including acetyl ethyl acetate, 4-fluoroaniline, and N ¹,N ¹-diethylethane-1,2-diamine. The optimal conditions were established based on investigating the main reaction steps, including cyclization, hydrolysis, decarboxylation, formylation, and condensation, giving optimized yields for each step of 94.4, 97.6, 98.5, 97.1, 91.0, 86.3, 85.5, 88.2, 99.1, 97.3, and 58.7 %, respectively. The synthesis process of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid as the important intermediate was significantly improved by using solvent-free decarboxylation instead of the traditional process in a high-boiling-point solvent. The subsequent formylation was conducted directly using the dichloromethane solution of the crude product from decarboxylation, leading to an almost quantitative combined yield of these two steps. The overall yields of sunitinib and its salt using the optimal synthesis process were 67.3 and 40.0 % based on acetyl ethyl acetate. The obtained data could be used as reference for future industrialization, especially for avoiding expensive solvents and reducing reaction time.

Full text of DOI:10.1007/s11164-015-1939-z

Res Chem Intermed
DOI 10.1007/s11164-015-1939-z
An improved synthesis of sunitinib malate via a solvent-
free decarboxylation process
Ge Meng1 Chunyan Liu1 Shidong Qin1
•
•
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Mengshu Dong2 Xiaomi Wei1 Meilin Zheng1
Liwen Qin1 Huihui Wang1 Xiaoshuang He1
Zhiguo Zhang1
•
•
•
•
•
•
Received: 23 October 2014 / Accepted: 27 January 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract To search for an economical and convenient synthesis of sunitinib and
its malate salt, optimization of a scalable synthetic route was explored by designing
a standard experimental protocol on laboratory scale using commercially available
materials including acetyl ethyl acetate, 4-fluoroaniline, and N1,N1-diethylethane-
1,2-diamine. The optimal conditions were established based on investigating the
main reaction steps, including cyclization, hydrolysis, decarboxylation, formylation,
and condensation, giving optimized yields for each step of 94.4, 97.6, 98.5, 97.1,
91.0, 86.3, 85.5, 88.2, 99.1, 97.3, and 58.7 %, respectively. The synthesis process of
5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid as the important intermediate
was significantly improved by using solvent-free decarboxylation instead of the
traditional process in a high-boiling-point solvent. The subsequent formylation was
conducted directly using the dichloromethane solution of the crude product from
decarboxylation, leading to an almost quantitative combined yield of these two
steps. The overall yields of sunitinib and its salt using the optimal synthesis process
were 67.3 and 40.0 % based on acetyl ethyl acetate. The obtained data could be used
as reference for future industrialization, especially for avoiding expensive solvents
and reducing reaction time.
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-1939-z)
contains supplementary material, which is available to authorized users.
&
Ge Meng
mengge@mail.xjtu.edu.cn
1
2
School of Pharmacy, Health Science Center, Xi’an Jiaotong University, Xi’an 710061, Shaanxi,
People’s Republic of China
School of Software Engineering, Xi’an Jiaotong University, Xi’an 710049, Shaanxi,
People’s Republic of China
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G. Meng et al.
Keywords Sunitinib Á SU11248 Á Sutent Á Synthesis Á Optimization Á Solvent-free Á
Standard design
Introduction
Sunitinib (1, SU11248, SutentÒ, Sugen-Pfizer [1], Scheme 1) was approved by the
Food and Drug Administration (FDA) in 2006 for treatment of renal cell carcinoma
(RCC), gastrointestinal stromal tumor (GIST), and other tumors resistant to imatinib
[2]. The basis for its antitumor effect is multikinase inhibition, targeting a variety of
kinases [1] including vascular endothelial growth factor receptor (VEGFR)-1 [1],
VEGFR-2 [2], platelet-derived growth factor receptor b (PDGFRb), and FMS-like
tyrosine kinase 3 (FLT3) [3] involved in mutated forms of acute leukemia [3].
Having three hydrogen-bond donors and two hydrogen-bond acceptors, sunitinib
with molecular weight of 398.5 shows a clogP value of 5.2 [2], nicely satisfying
Lipinski’s four ‘‘rules of five’’ [4]. These good characteristics make 1 a very
promising molecule in many regards, such as for clinical use [2], for synthetic
improvements [5, 6], for use as a positron emission tomography (PET) tracer [7],
analytically [8], and for the design and synthesis of its derivatives [9].
The structure of 1 can be divided into three portions: A, B, and C (Scheme 1).
The 5-fluoroindolin-2-one ring (A) is connected to a substituted pyrrole ring
(B) with an attached amino side-chain (C). Retrosynthetic analysis of 1 indicated
that synthesis methods for building the target molecule could be divided into the
following three categories: ‘‘A ? (B ? C)’’ [6, 10], ‘‘B ? A ? C,’’ and
‘‘(A ? B) ? C’’ [6]. All three approaches involve the use of three main materials,
namely 5-fluoroindolin-2-one (2), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic
acid (3) and its derivatives, and N1,N1-diethylethane-1,2-diamine (4). Since
compound 4 is commercially available and synthesis of 2 can be easily achieved
Scheme 1 Retrosynthetic analysis of sunitinib (1)
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Improved synthesis of sunitinib malate
by traditional Sandmeyer isatin synthesis reaction, improvement of the synthesis of
3 has become the crucial element for the synthesis of 1 (Scheme 1).
Although there have been many reports on synthesis of 1 in literature [5, 9], the
methods involved share various shortcomings, such as long production period, high
production price, tedious manipulations, and expensive reagents and solvents.
Therefore, there is an urgent need to develop an optimized protocol suitable for
possible industrial application. To enhance the yield and decrease the price of the
product, it is still necessary to develop an efficient method to achieve 1 as well as
the related intermediates based on the ‘‘A ? (B ? C)’’ strategy, which seems to be
the most favorable for industrialization when comparing the different features of all
possible synthetic routes [11].
In this work, we developed a new, efficient solvent-free process to provide the
important intermediate 8 in high yield. The product of this process could be used
directly in the subsequent step, simplifying the workups during the purification
process. The combined yield of these two sequential steps was almost quantitative,
greatly benefiting the overall yield of 1. The reaction time is greatly shortened via
use of a rapid decarboxylation process under solvent-free conditions, and expensive
high-boiling-point solvents are omitted.
Moreover, other reaction conditions were also modified using a standard design
method; this work can be summarized as follows: The yield of the intermediate 6
was improved by strictly controlling the temperature in the addition process of
sodium nitrite and zinc powder during the Knorr reaction. The best condition for
synthesis of intermediate 7 was optimized by exploring the mole ratio, base
concentration, and reaction temperature. For the synthesis method of the building
block 10 (B ? C), workups for eliminating the main side-product 1,3-dicyclohexy-
lurea (DCU) were explored to enhance the yield of 10. The synthesis of 2 was
optimized via using a short, direct route from intermediate 13. Finally, different
solvents and catalysts were investigated to establish the best conditions to
synthesize 1. The transformation methods from sunitinib to its malate salt were
also investigated and optimized in this work.
Results and discussion
The main important synthons of 1 are parts A and B, i.e., the 5-fluoroindolin-2-one
(2) and pyrrole part (3), respectively. The synthesis of part A included Sandmeyer
isonitrosoacetanilide isatin and Wolff–Kishner–Huangminglong reaction. The
synthesis of part B included Knorr reaction, monohydrolyzation, decarboxylation,
Vilsmeier–Haack (V–H) reaction, and hydrolyzation, which were explored one by
one to search for good conditions to achieve higher yield and a convenient process
for each unit reaction. The results are discussed below.
For the synthesis of the substituted pyrrole part intermediates, diethyl-3,5-
dimethyl-1H-pyrrole-2,4-dicarboxylate (6) was first obtained via Knorr reaction
from acetyl acetate ethyl ester (5). Monohydrolyzation of 6 provided 4-(ethoxy-
carbonyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (7) as the intermediate. Direct
heating of 7 under N2 atmosphere provided ethyl 2,4-dimethyl-1H-pyrrole-3-
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G. Meng et al.
carboxylate (8). Formylation of 8 via Vilsmeier–Haack reaction gave ethyl
5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate (9). Further hydrolyzation of 9 in
basic condition produced 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3)
as the important intermediate to 1 (Scheme 2).
Compound 8 is usually obtained by heating in a suitable solvent with high boiling
point, such as dimethylformamide (DMF), triethyl phosphate (TEP). All these
methods share the shortcomings of difficult recovery and removal of the higher-
boiling-point solvent, tedious workups, as well as low yield. To solve this problem,
we used a solvent-free process to achieve this purpose successfully with a very high
yield to afford 8 from 7, which has not been reported before. Besides, ethyl
5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate (9) could also be obtained from 7
via a sequential semi-one-pot reaction without further purification of 8, offering a
quantitative yield for the combination of these two reaction steps (Scheme 2).
During the synthesis process of diethyl-3,5-dimethyl-1H-pyrrole-2,4-dicarboxy-
late (6), it should be noted that keeping the temperature between 0 and 10 °C was
crucial for a rapid and clean reaction. Portionwise addition of zinc powder was also
necessary to keep the temperature between 25 and 30 °C to prevent the evolution of
a large amount of hydrogen gas in a very short time, which could result in an
uncontrollable boiling reaction. Mechanical stirring should be adopted in large-scale
processing for better mixing effect.
Scheme 2 Synthesis route for sunitinib (1) malate via ‘‘A ? (B ? C)’’ method. Reagents and
conditions: (a) (i) NaNO2, AcOH, 0–10 °C; (ii) AcOH, Zn, 25–30 °C, reflux for 1 h; (b) (i) KOH,
50–60 °C, (ii) ice-water, HCl (2.0 mol/L), pH 4; (c) 200–202 °C, solvent-free; (d) DMF/POCl3 with
DCM at 0 °C, reflux, 1.5 h, 40–41 °C and then NaOH, reflux, 0.5 h; (e) Reflux, 82–83 °C, NaOH, 4.5 h,
HCl (2.0 mol/L), pH 2; (f) DMF (anhy.), 0 °C, DCC/DCM, DMAP, N,N-diethylethylenediamine (4), r.t.,
59 h, citric acid (5.0 %), NaOH, NaHCO3; (g) CCl3CH(OH)2, Na2SO4, NH2OH.HCl, HCl (conc.), 65 °C,
2 h; (h) H2SO4 (conc.), 50 °C, 75 °C, 20 min; (i) NH2NH2 (80 %), 140 °C, 6 h, HCl (2.0 mol/L), pH 2;
(j) Compound 10, toluene/piperidine, reflux, 3 h; (k) Malic acid, MeOH, CH3CN
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Improved synthesis of sunitinib malate
Regarding synthesis of 4-(ethoxycarbonyl)-3,5-dimethyl-1H-pyrrole-2-car-
boxylic acid (7), the reported method is reflux of 6 in ethanol and sodium
hydroxide. Double hydrolyzation of the diethyl ester might also occur in this basic
condition [12]. The results of standard experimental design indicated that the mole
ratio of 6 to KOH, concentration of the base in water, stirring method, temperature,
and reaction time were crucial factors determining the final yield and quality of 7
(Table 1).
The best mole ratio of diethyl-3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate (6) to
potassium hydroxide to achieve 7 was 2:5 (Table 1). The best basic concentration
was 0.83 mol/L with mechanical stirring. The best reaction temperature was
50–60 °C with shorter reaction time of 10 h (entry 8).
For the decarboxylation process from 4-(ethoxycarbonyl)-3,5-dimethyl-1H-
pyrrole-2-carboxylic acid (7) to synthesize ethyl 2,4-dimethyl-1H-pyrrole-3-
carboxylate (8), the available reported method is reflux of 7 in a solvent with
high boiling point, such as triethyl phosphate (TEP) [13], N,N-dimethylformamide
(DMF) [14]. Since TEP is very difficult to evaporate because of its high boiling
point (216 °C), the related workups usually require an extraction and then column
chromatography. The extracted liquid is liable to emulsify and then exhibit a very
dark color, leading to a tedious separation process that is almost impossible to
manipulate. The yield is also very low (less than 50 %). The reaction via reflux of 7
in DMF might last more than 1 day (30 h). The workup manipulations also require
an extraction and column chromatography, resulting in relatively low yield.
Therefore, the shortcomings of both method 1 and 2 are only too obvious for use in
possible industrial applications. Although the product from method 3 was very dark,
after being decolorized with active carbon, the product could be used directly in the
next step of V–H formylation. Sufficiently high product purity was obtained by
simply dissolving in absolute dichloromethane to elevate the overall yield of
sunitinib significantly. On the other hand, dissolving the product 8 in dichlor-
omethane for direct use in the subsequent formylation offers potential for large-
scale processing as the dissolution process would be helpful for collecting 8 spread
on the surfaces of the walls of a reaction container.
Method 3 was the best among the three tested decarboxylation processes. The
solvent-free condition offers many advantages over the other two methods due to
the shorter reaction time, energy efficiency, easy manipulation and workups, as well
as high yield (98.0 %) (Table 2).
During the process of synthesizing ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-
carboxylate (9), it was crucial to control the reaction temperature below 0 °C using
a salt-ice bath to avoid formation of dark-colored polymers leading to subsequent
tedious workups. Evaporation under vacuum after completion was also necessary to
eliminate dichloromethane and DMF, ensuring that the subsequent reaction system
was homogeneous after addition of aqueous sodium hydroxide solution to ensure
complete hydroxylation. Otherwise, the reaction system might get bumped, since
the possibility of formation of a heterogeneous system is not favorable for large-
scale synthesis processing, resulting in expensive economic loss.
Since both 9 and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3) share a
common aldehyde group in 5-position of the pyrrole skeleton, which might be
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Improved synthesis of sunitinib malate
Table 2 Yield of compound 8 for different reaction conditions
Method
Reaction condition
Reaction
temperature (°C)
Time
Yield (%)
M.p. (°C)
Method 1
Method 2
Method 3
Using TEP (b.p. 216 °C)
Using DMF (b.p. 153 °C)
Solvent-free condition
170–180
164–170
200–202
1.5 h
30 h
47.6
68.4
98.0
71–72
73–74
73–74
5 min
oxidized, the process for synthesis of 3 should be done under N2 atmosphere.
Double hydrolyzation, as in the reaction of the substrate 6, cannot occur, as there is
only one ethyl ester group in 9. Therefore, simply refluxing in aqueous sodium
hydroxide might be an easy way to achieve 3.
For synthesis of N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-
carboxamide (10), attempting to transform acid 3 to its acid chloride before reacting
with 4 could not provide the desired amide 10. The reaction via DCC condensation
should be conducted in anhydrous condition. The DCU formed from DCC is usually
difficult to remove, as all the reported methods do not work very well, especially for
full elimination of side-products [13]. Although the amide formation reaction could
not happen at r.t. without a catalyst, attempting to react at r.t. with DMAP catalyst
worked very well for both a small amount and in a large-scale reaction. Elimination
of DCU was successfully achieved by the procedures designed in the following. The
residue was washed with a large amount of aqueous citric acid solution (5.0 %) to
ensure 10 entered the aqueous phase completely, with monitoring of the organic
layer sample by TLC analysis. The aqueous layer was adjusted to pH 8 using
aqueous sodium bicarbonate and sodium hydroxide solution, which was extracted
with dichloromethane to give the organic phase, concentrated under vacuum to give
the desired product 10 as pale-yellow solid.
Many methods to synthesize the intermediate N-(4-fluorophenyl)-2-(hydroxyimi-
no)acetamide (12) have been reported, among which the Sandmeyer isonitrosoac-
etanilide isatin synthesis remains the best choice [15]. The reaction was explored in
terms of the mole ratio of the main materials, reaction temperature, and time
(Table 3).
During the cyclization process from 12 to 13 in H2SO4 (conc.), the temperature
should be controlled strictly around 75 °C. The reaction cannot occur below 50 °C.
Too many side-products were produced above 80 °C according to TLC analysis.
Adjusting pH of 2–4 could be an efficient way to purify 13, although crude 13 could
be used directly in the next step.
Synthesis of 5-fluoroindolin-2-one (2) could be achieved by two different
methods. Refluxing 13 in hydrazine hydrate (80 %) afforded 5-fluoro-3-hydra-
zonoindolin-2-one (14) in high yield, which reacted with sodium ethoxide to give 2
with very low yield. On the other hand, direct reflux of 13 in hydrazine hydrate
(80 %) for a relatively long time provided 2 via Wolff–Kishner–Huangminglong
reaction. Although the reaction time was very long, the workups were relatively
simple with elevated yield compared with the two-step method. Based on the
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G. Meng et al.
Table 3 Yield of compound 12 for different conditions
Method
Mole ratioa
Reaction
conditions
Notes
Method I
1.1:21.8:1:3
Reflux for
3 min
Large amounts of sodium sulfate left in the residue;
product was not very pure, as shown by a m.p. different
from literature
Method II 1.1:18.3:1:3
React at 65 °C Large amounts of sodium sulfate left in the residue; the
for 2 h
product purified from recrystallization showed a m.p. in
agreement with literature
Method III 1.1:11.2:1:3.2 React at
No sodium sulfate left in the residue; the product was not
very pure, as shown by a m.p. different from literature
60–70 °C
for 2 h
Method IV 1:10.6:1:3.3
Reflux for
3 min
No sodium sulfate left in the residue; the product was not
very pure, as shown by a m.p. different from literature
a
Mole ratio refers to the ratio of chloral hydrate/anhydrous sodium sulfate/4-fluoroaniline/hy-
droxylamine hydrochloride
Table 4 Yield of compound 2 under different conditions
Method
Reaction
temperature (°C)
Reaction
time (h)
Notes
Method I
140
140
145
120
8
6
6
6
Many black impurities in the yellow product 2
Yellow product 2 was pure, as shown by TLC analysis
Many black impurities in the yellow product 2
Reaction not complete, as shown by TLC analysis
Method II
Method III
Method IV
superior one-step method, the effects of temperature and reaction time on the yield
of 2 were investigated by a standard design (Table 4).
The suitable reaction time for synthesis of 2 should be no more than 6 h. Some
black side-products were produced when the reaction proceeded for more than 8 h,
which might decrease the yield. The suitable temperature range should be
130–140 °C. The reaction cannot complete below 120 °C. The higher the
temperature, the blacker the color of the side-products (Table 4).
The traditional Knoevenagel reaction was used for the final condensation
between 2 and 10 to provide (Z)-N-(2-(diethylamino)ethyl)-5-((5-fluoro-2-oxoin-
dolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (1, sunitinib). It
was established by our research group that slight excess of 5-fluoroindolin-2-one
should be used during the condensation process to facilitate the final workups to
purify the product 1. The effects of different solvents and catalysts as well as
reaction time on the yield of the final product were investigated (Table 5). The high,
sharp m.p. (222–223 °C) of the obtained product 1 indicated that the product was
very pure, showing a different polymorphic form to the original form reported in
literature (195–197 °C).
It was clearly seen that toluene could be used as the best solvent to achieve the
highest yield without using column chromatography as the purification method.
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Improved synthesis of sunitinib malate
Table 5 Yield of compound 1 under different conditions
Method
Solvent
Catalyst
Time (h)
Yield (%)
M.p. (°C)
Method I
Method II
Method III
a
Absolute ethanola
Absolute ethanola
Toluene
Triethylamine (pKa 11.02)
Piperidine (pKa 11.12)
Piperidine (pKa 11.12)
2
3
3
62.9
85.7
97.3
223–224
224–225
222–223
When ethanol was used as solvent, the product 1 might dissolve in ethanol. Purification of the product
requires column chromatography, which is not suitable for industrial purposes
Since 1 is insoluble in toluene, there was almost no product 1 left after filtration
except for unreacted 2. The purification could be easily manipulated by simply
washing with cold solvent. The results indicate that piperidine was better than
triethylamine as an organic basic catalyst.
Since ether is not a suitable solvent for industrial purposes [16], two different
methods using other solvent systems were investigated for the saltification process
of sunitinib (1) with malic acid. The results showed that methanol and acetonitrile
were superior to ethanol for higher yield and simple workups.
Experimental
All materials were obtained from commercial suppliers and used as received.
Melting points were taken on an X-1 digital melting point apparatus and are
uncorrected. Infrared (IR) spectra were recorded on a Nicolet FT-IR 360
1
spectrophotometer. H nuclear magnetic resonance (NMR) spectra were obtained
on a Bruker AM-300 (400 MHz) spectrometer with tetramethylsilane (TMS) as
internal standard; chemical shifts are reported in d. Mass spectra were measured on
a HP5988A instrument by direct inlet at 70 eV.
General procedures for the target molecule and intermediates
Diethyl-3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate (6) Ethyl 3-oxobutanoate (5,
30.0 mL, 236.0 mmol) and acetic acid (60.0 mL) were mixed in a flask. The
mixture was cooled down to 0–10 °C with an ice-water bath, and then aqueous
solution of sodium nitrite (12.0 mL, 9.8 mol/L) was added under stirring in 30 min,
while keeping the temperature below 10 °C. The reaction mixture was allowed to
rise to r.t. for 2.5 h before adding zinc powder (15.4 g, 236.0 mmol) portionwise.
The temperature should be kept between 25 and 30 °C during the process of zinc
addition. The reaction mixture was then heated to reflux for 1.0 h, until the reaction
was completed according to TLC monitoring. The mixture was then poured into ice-
water (400 mL) to form large amounts of yellow solids. After cooling in a
refrigerator for 2–3 h to allow complete precipitation, the solids were collected by
filtration and washed with ice-water, and dried under vacuum to provide the yellow
solids as the crude product 6 (6.70 g, 94.4 %), which was recrystallized from
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G. Meng et al.
ethanol to afford the pure product 6 with yield of 93.0 % [12], m.p. 133–134 °C (lit.
135–136 °C [17, 18]), yield 60.0 % (lit. [13]). Rf = 0.20 (eluent: petroleum ether/
ethyl acetate, v/v = 20:1, three times), Rf = 0.27 (eluent: chloroform/methanol,
1
v/v = 10:1). H NMR (CDCl3), d: 1.35–1.39 (m, 6H, 2CH3), 2.52 (s, 3H, CH3),
2.57 (s, 3H, CH3), 4.27–4.35 (m, 4H, 2CH2), 9.23 (s, 1H, NH-pyrrole).
4-(Ethoxycarbonyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (7) Compound 6
(0.48 g, 2.0 mmol) was added into a flask equipped with a stirrer, a thermometer,
and a condenser; absolute ethanol (3.0 mL) was added into the flask until partially
dissolving. Aqueous solution (6.0 mL) of potassium hydroxide (0.28 g, 5.0 mmol)
was added under mechanical stirring, being kept at 50–60 °C for 10 h with
monitoring by TLC (eluent: chloroform/methanol, v/v = 10:1) until reaction
completion. The reaction was then stopped by cooling down to r.t. The reaction
mixture was poured into ice-water (20 mL) to form an aqueous solution. A small
amount of insoluble substance was filtered under vacuum and was washed with
water (20 mL). The combined aqueous layers were adjusted with hydrochloride
(2 mol/L) to pH 4 to afford some white precipitates, which were collected via
filtering and washing with ice-water to provide 7 (0.41 g, 97.6 %), m.p. 169–170 °C
(lit. 235–236 °C [13]), yield 85.3 % (lit. [13]). Rf = 0.41 (eluent: chloroform/
methanol, v/v = 10:1). 1H NMR (DMSO-d6) d: 1.25 (t, 3H, J = 7.2 Hz, CH3), 2.38
(s, 3H, CH3), 2.43 (s, 3H, CH3), 4.15 (q, 2H, J = 7.2 Hz, CH2), 11.70 (s, 1H, NH-
pyrrole), 12.34 (s, 1H, COOH).
Ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate (8) 4-(Ethoxycarbonyl)-3,5-dimethyl-
1H-pyrrole-2-carboxylic acid (7, 5.0 g, 25.0 mmol) was heated in a flask to
200–210 °C with an oil bath for 12 min. The reactant gradually melted with
accompanying production of carbon dioxide. The heating was removed when there
was no more gas evolving. The reaction was allowed to cool down to r.t. and then
dried under vacuum to afford 8 as a pale-gray solid (3.90 g, 98.5 %), m.p. 75–76 °C
(lit. 74–76 °C [17]), yield 90.0 % (lit. [13]). Rf = 0.73 (eluent: chloroform/
methanol, v/v = 10:1).
Ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate (9) Anhydrous DMF
(2.0 mL, 24.4 mmol) in a dry flask was precooled to 0 °C with a salt-ice bath,
into which a solution of POCl3 (3.60 mL, 39.1 mmol) in anhydrous dichloro-
methane (8.2 mL) was added slowly dropwise. The temperature should be kept
below 3 °C during the whole addition process. The reaction mixture was stirred for
0.5 h using an ice-bath before dropwise addition of solution of ethyl 2,4-dimethyl-
1H-pyrrole-3-carboxylate (8) in anhydrous dichloromethane (10.0 mL, 2.27 mol/L).
The mixture was heated under reflux for 1.5 h before evaporating the excess
dichloromethane from the system. Aqueous sodium hydroxide (52.0 mL, 2.81 mol/
L) was then added before further reflux for 0.5 h. While cooling to r.t., a large
amount of pale-gray solid appeared from the system. The solid was filtrated and
washed with a small amount of cold water, and dried under vacuum to afford 9
(4.5 g, 100 %), m.p. 163–164 °C (lit. 166–167 °C [19]), yield 91.5 % (lit. [13]).
Rf = 0.71 (eluent: chloroform/methanol, v/v = 10:1). 1H NMR (400 MHz, CDCl3)
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Improved synthesis of sunitinib malate
d: 10.71 (s, 1H, CHO), 9.61 (s, 1H, pyrrole-1-H), 4.31 (q, 2H, CH3CH2O), 2.58 (m,
6H, 2 9 (CH3)), 1.38 (t, 3H, J = 8.0 Hz, CH3CH2O).
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3) To a three-necked flask
equipped with a thermometer, ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxy-
late (9, 1.17 g, 6.0 mmol) and methanol (6.0 mL) were added with stirring, to which
was added solution of sodium hydroxide (1.20 g) in water (10 mL). The reaction
mixture was kept under reflux at 82–83 °C for 4.5 h under nitrogen atmosphere. The
mixture was then cooled down to r.t. before being added into ice-water (20 mL).
The obtained mixture was extracted with dichloromethane (12 mL). The organic
layer was then washed with water (15 mL 9 3) until there was no absorption under
ultraviolet (UV) light. The aqueous layers were combined before being acidified
with hydrochloride (2.0 mol/L) to pH 2 until many precipitates appeared from the
mixture. The yellowish solids were obtained via filtrating under vacuum, washing
with water, and drying under vacuum to provide 3 (0.91 g, 91 %), m.p. [250 °C
(sublimes and decomposes) (lit. 275–277 °C [13]), yield 90.0 % (lit. [13]).
Rf = 0.28 (eluent: chloroform/methanol, v/v = 10:1 or petroleum ether/ethyl
acetate, v/v = 10:1). Electrospray ionization (EI) mass spectroscopy (MS) m/
1
z (%): 167.1 ([M]?, 100), 138.1 (20), 121.1 (60). H NMR (DMSO-d6) d: 1.35 (t,
3H, J = 7.3 Hz, CH3), 2.53 (s, 3H, CH3), 2.55 (s, 3H, CH3), 4.29 (q, 2H,
J = 7.3 Hz, CH2), 7.24 (s, 1H, pyrrole-1-NH), 9.97 (s, 1H, CHO).
N-(2-(Diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (10) To
a three-necked flask equipped with a thermometer, 5-formyl-2,4-dimethyl-1H-
pyrrole-3-carboxylic acid (3, 5.50 g, 32.7 mmol) and anhydrous DMF (13.1 mL)
were added while being cooled down to 0 °C with an ice-salt bath. To the above
mixture was added dropwise a solution of dicyclohexylcarbodiimide (DCC,
10.13 g, 49.0 mmol) in dichloromethane (78.4 mL) under stirring while keeping
the reaction temperature between 0 and 2 °C, to which were then added at r.t.
4-dimethylaminopyridine (DMAP, 1.65 g) and N1,N1-diethylethane-1,2-diamine (4,
5.03 mL, 35.9 mmol). The reaction mixture was then allowed to react at r.t. for 59 h
with TLC monitoring (eluent: chloroform/methanol, v/v = 5:1). The filtrate
obtained from filtration was added with water, which was extracted with
dichloromethane (15 mL 9 3). The organic layers were combined, washed with
saturated brine (65.7 mL), then dried over anhydrous sodium sulfate. The filtrate
was concentrated to give some solids, which were dissolved in a small amount of
dichloromethane (5.0 mL). The obtained organic phase was washed with aqueous
citric acid solution (5.0 %, 330 mL 9 3) until there was no product in the organic
layer (as monitored by TLC). The reason was that the weak basic product 10 could
form a water-soluble salt with citric acid. The aqueous phase was then basified with
saturated aqueous sodium hydroxide solution and a large amount of aqueous sodium
bicarbonate solution to pH 8, which was then extracted with dichloromethane
(330 mL 9 3). The combined organic layers were combined and concentrated to
provide brownish-red oily liquid. Further purification could be achieved with
stepwise column chromatography with petroleum ether/ethyl acetate eluent (v/
v = 3:1 to 1:1) to provide 10 as yellowish solid (8.11 g, 86.3 %), m.p. 153–154 °C
123

G. Meng et al.
(lit. 177–181 °C [13]), yield 42.5 % (lit. [13]). Rf = 0.60 (eluent: chloroform/
1
methanol, v/v = 5:1). H NMR (400 MHz, DMSO-d6) d: 11.85 (s, 1H, NH), 9.54
(s, 1H, CHO), 7.36–7.38 (t, 1H, CONH), 3.24–3.29 (m, 2H, NHCH2), 2.50–2.56 (m,
6H, 3 9 (N–CH2)), 2.32 (s, 3H, 4-CH3), 2.37 (s, 3H, 2-CH3), 0.95–0.99 (t, 6H,
2 9 (CH3)).
N-(4-Fluorophenyl)-2-(hydroxyimino)acetamide (12) To a three-necked flask equipped
with a thermometer were added chloral hydrate (4.55 g, 27.5 mmol) and water
(120 mL) with stirring until chloral hydrate dissolved completely. Sodium sulfate
(65.0 g, 457.7 mmol) was added into the mixture with full stirring, to which was
added 4-fluoroaniline (11, 2.43 mL, 25.0 mmol) until the mixture was milky white.
Hydroxylamine hydrochloride (5.20 g, 75.0 mmol) was added to the mixture. After
the solution became clear, hydrochloride (conc., 1.1 mL) was then added at r.t. with
stirring. The reaction mixture was heated under 65 °C for 2 h. The solution turned
milky white with precipitation of white crystals, which were collected by filtration
and washing with water. Yellow powders containing white and granular-like solids
were obtained after drying under vacuum. The solid was dissolved in ethyl acetate,
which was filtered to eliminate the insoluble inorganic sodium sulfate. The filtration
was stood overnight until some crystals precipitated from the solution system. Pale-
yellow crystal was obtained by filtering and drying as the desired product 12
(3.15 g), m.p. 161–164 °C (lit. 160 °C [15], 158–159 °C [20]), yield 87.9 % (lit.
[21]). Small amount of hexane (about 1.0 mL) was added into the filtration until
another portion of 12 was obtained as yellow solids (0.74 g), m.p. 158–160 °C. The
total amount of 12 thus reached 3.89 g with yield of 85.5 %. Rf = 0.56 (eluent:
chloroform/methanol, v/v = 10:1).
5-Fluoroindoline-2,3-dione (13) To a flask equipped with a thermometer, sulfuric
acid (conc., 3.26 mL) was added under 50 °C in a water bath. N-(4-fluorophenyl)-2-
(hydroxyimino)acetamide (12, 0.75 g, 4.11 mmol) was added portionwise to the
mixture under stirring. The reaction mixture was heated to 75 °C for 20 min, then
cooled down to r.t. before being poured into ice-water (10 mL). The mixture was
kept in an ice bath for 1 h; the precipitated brownish solid was collected by
filtration. The filter cake was washed with water until pH 7 to provide 13 as
brownish solid (0.60 g, 88.2 %), m.p. 223–226 °C (lit. 228–229 °C [13]), yield
1
92.6 % (lit. [21]). Rf = 0.52 (eluent: chloroform/methanol, v/v = 20:1). H NMR
(DMSO-d6) d: 6.89–6.93 (m, 1H, aryl-6-H), 7.39-7.49 (m, 2H, aryl-4,7-H), 11.05 (s,
1H, NH-indole).
5-Fluoroindolin-2-one (2) To a flask equipped with a thermometer were added
5-fluoroisatin (13, 4.60 g, 27.9 mmol), hydrazine hydrate (80 %, 19.3 mL, 386 m-
mol), and water (19.3 mL) with full stirring. The reaction mixture was kept at
140 °C in an oil bath for 6 h before cooling down to r.t., to which was added
hydrochloride (2.0 mol/L) to pH 2. The reaction mixture was stirred at r.t. for 12 h.
Brownish-gray solid was obtained by filtering under vacuum and washing with
water as the first portion of compound 2 (2.59 g), m.p. 131–133 °C. Some solid was
recovered from the filtration via extracting with ethyl acetate (30 mL 9 3) then
evaporating to give the second portion of compound 2 (1.58 g), m.p. 134–135 °C
123

Improved synthesis of sunitinib malate
(lit. 134–135 °C [21]). The total amount of 2 was 4.17 g with yield of 99.1 % (lit.
yield 80.8 % [21]). Rf = 0.51 (eluent: petroleum ether/ethyl acetate, v/v = 3:1). 1H
NMR (DMSO-d6) d: 3.49 (s, 2H, 3-CH2), 6.76–6.79 (m, 1H, aryl-6-H), 6.96–7.01
(m, 1H, aryl-4-H), 7.08–7.10 (m, 1H, aryl-7-H), 10.36 (s, 1H, NH-indole).
(Z)-N-(2-(Diethylamino)ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-
dimethyl-1H-pyrrole-3-carboxamide (1, sunitinib) To a flask equipped with a
condenser were added 10 (0.50 g, 1.89 mmol), 2 (0.32 g, 2.08 mmol), and toluene
(8.0 mL). The mixture was stirred to be fully dissolved before addition of a drop of
piperidine with stirring. The mixture was heated to reflux for 3 h before cooling
down with an ice-bath. The precipitates were collected by filtration. The filter cake
was washed with petroleum ether and dried under vacuum to give the free base of
the desired target molecule 1 as orange–yellow solid (0.73 g, 97.3 %), m.p.
222–223 °C (lit. 195–197 °C [13]), yield 90.0 % (lit. [13]). Rf = 0.24 (eluent:
chloroform/methanol, v/v = 10:1). 1H NMR (400 MHz, DMSO-d6) d: 13.69 (s, 1H,
NH-pyrrole), 10.90 (s, 1H, NH-indole), 7.75–7.78 (m, 1H, CONH), 7.72 (s, 1H,
alkenyl-H), 7.43–7.46 (m, 1H, aryl-7-H), 6.90–6.95 (m, 1H, aryl-4-H), 6.83–6.86
(m, 1H, aryl-6-H), 3.26–3.31 (m, 2H, NHCH2), 2.51–2.57 (m, 6H, 3 9 (N-CH2)),
2.43 (s, 3H, pyrrole-2-CH3), 2.44 (s, 3H, pyrrole-4-CH3), 0.96–1.00 (t, 6H,
2 9 (CH3)); EI MS m/z (%): 398.1 ([M]?, 5), 326.1 (2), 283.0 (4), 149.1 (8), 86.1
(100); the purity of sunitinib was 99.5 %.
Sunitinib malate (1Ámalate) To a flask were added sunitinib (1, 0.131 g,
0.331 mmol) and methanol (20.0 mL) with stirring, to which was added (2S)-
hydroxysuccinic acid (0.047 g, 0.351 mmol) under stirring. The solid dissolved
rapidly to afford clear pale-yellow solution. The methanol was evaporated under
vacuum. The residue was added with acetonitrile (5.0 mL) and kept stirring under
refluxing for 10 min. Yellow precipitates were obtained via filtration under vacuum
to provide sunitinib malate (1Ámalate, 0.103 g, 58.7 %) as orange–yellow crystals,
m.p. 200–201 °C (lit. 196 °C [21]), yield 86.0 % (lit. [21]). 1H NMR (DMSO-d6) d:
1.19 (t, 6H, 2 9 (CH3)), 2.45 (s, 3H, pyrrole-2-CH3), 2.47 (s, 3H, pyrrole-4-CH3),
3.07–3.09 (m, 6H, 3 9 (N-CH2)), 3.54 (m, 2H, NHCH2), 4.10 (q, 1H, malic acid-
CH), 6.84–6.87 (m, 1H, aryl-6-H), 6.92–6.95 (m, 1H, aryl-4-H), 7.75 (s, 1H, aryl-7-
H), 7.77 (m, 1H, alkenyl-H), 7.79 (dd, 1H, CONH), 10.94 (s, 1H, NH-indole), 13.75
(s, 1H, NH-pyrrole); the purity of sunitinib malate was 98.2 %.
Conclusions
Sunitinib malate was synthesized from commercially available materials through an
11-step reaction synthetic route with improved overall yield of 40.0 % (based on 5).
The best conditions for each reaction of the synthesis route were established via the
designed investigational research. The synthesis of the important intermediate 3 was
significantly improved by using a solvent-free decarboxylation process. By avoiding
expensive solvents, these processes with shorter reaction time might be beneficial
for possible industrial purposes. Direct use of intermediate 8 in the formylation
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process without purification enhanced the yield of the intermediate 9 as well as the
overall yield of the final product 1.
Acknowledgments The authors would like to thank the Returned Overseas Chinese Scholars, State
Education Ministry (SRF for ROCS, SEM), P.R. China (JWSL 20101561) and Technology Research and
Development Program of China, International Cooperation (2013KW31-04) for financial support. The
research work has also been sponsored by the National Undergraduate Innovative Experiment Program
(2012).
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