The Development of an Effective Synthetic Route of Belinostat

Article abstract of DOI:10.1021/acs.oprd.6b00170

A practical synthetic route of belinostat is reported. Belinostat was obtained via a five-step process starting from benzaldehyde and including addition reaction with sodium bisulfite, sulfochlorination with chlorosulfonic acid, sulfonamidation with aniline, Knoevenagel condensation, and the final amidation with hydroxylamine. Key to the strategy is the preparation of 3-formylbenzenesulfonyl chloride using an economical and practical protocol. The main advantages of the route include inexpensive starting materials and acceptable overall yield. The scale-up experiment was carried out to provide 169 g of belinostat with 99.6% purity in 33% total yield.

Full text of DOI:10.1021/acs.oprd.6b00170

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Full Paper
The Development of an Effective Synthetic Route of Belinostat
Xuefei Bao, Dake Song, Xuejun Qiao, Xuan Zhao, and Guoliang Chen
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00170 • Publication Date (Web): 12 Jul 2016
Downloaded from http://pubs.acs.org on July 13, 2016
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The Development of an Effective Synthetic Route of
Belinostat
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Xuefei Bao, Dake Song, Xuejun Qiao, Xuan Zhao, Guoliang Chen*
Key Laboratory of StructureꢀBased Drug Design & Discovery, Ministry of Education, Shenyang
Pharmaceutical University, Shenyang 110016, China
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Table of Contents Graphic:
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O
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inexpensive starting materials
hundreds gram scale
O S ONa
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OH
HOSO2Cl
K2SO4
Na2S2O5
5 total steps, 33% overall yield
CHO
H
O
O
S
CHO
N
OH
N
O
H
SO2Cl
Belinostat
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ABSTRACT: A practical synthetic route of belinostat is reported. Belinostat was obtained via a
fiveꢀstep process starting from benzaldehyde and including addition reaction with sodium
bisulfite, sulfochlorination with chlorosulfonic acid, sulfonamidation with aniline, Knoevenagel
condensation, and the final amidation with hydroxylamine. Key to the strategy is the preparation
of 3ꢀformylbenzenesulfonyl chloride using an economical and practical protocol. The main
advantages of the route include inexpensive starting materials and acceptable overall yield. The
scaleꢀup experiment was carried out to provide 169 g of belinostat with 99.6% purity in 33%
total yield.
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KEYWORDS: Belinostat, Synthesis, chlorosulfonation, histone deacetylase inhibitor.
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INTRODUCTION
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Belinostat (1, Figure. 1), a small molecule histone deacetylase (HDAC) inhibitor developed by
CuraGen/TopoTarget, has been approved in the U.S for the treatment of relapsed or refractory
peripheral Tꢀcell lymphoma in July 2014.1 Recently, the drug is in clinical development for the
treatment of cutaneous Tꢀcell (CTCL), other Tꢀcell nonꢀHodgkin's lymphomas (NHL) and
thymic epithelial tumors.2
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Figure 1. The chemical structure of belinostat (1).
Several researchꢀscale synthetic methods have been reported for the preparation of 1 (Scheme
1). Initially, Andrianov et al. disclosed a method for its synthesis in the early stage of drug
discovery (Route A).3 In this method, benzaldehyde was used as starting material and first
sulfonylated with oleum, followed by six steps process to provide 1 with a 12% total yield. Qian
et al. developed another method (Route B) to obtain 1 from sodium 3ꢀsulfoꢀbenzoic acid via six
steps with total yield of 13%.4 These two methods suffered from long synthetic procedure, low
yield and laborious workups. Besides, the use of extremely corrosive oleum required tedious
separation and caused a large amount of wastewater. Yang et al. reported a synthetic route
(Route C) of 1 starting from 3ꢀnitrobenzaldehyde with the overall yield of 33% and the key step
in this procedure involved the conversion of (E)ꢀ3ꢀ(3ꢀaminophenyl)acrylic acid methyl ester to
(E)ꢀ3ꢀ(3ꢀchlorosulfonylphenyl) acrylic acid methyl ester via diazotization and sulfonylation.5 The
method, producing subꢀgram scale 1 in a single batch, had two drawbacks, limiting the largeꢀ
scale synthesis of 1: (a) complicated purification process, (b) the employment of environmentally
unfriendly SO2. Recently, Wang et al. reported a process (Route D) for the preparation of
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belinostat cisꢀisomer starting from 3ꢀformylꢀNꢀphenylbenzenesulfonamide 5.6 In the process,
belinostat would be the main by product, but starting material 5 was not commercially available.
Scheme 1. Reported Researchꢀscale Synthetic Route of Belinostat
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For the largeꢀscale preparation of 1, Reisch et al. used 3ꢀbromobenzenesulfonyl chloride as
starting material (Scheme 2).7 By the method, 1 was obtained with high yield on hundreds gram
scale, but expensive palladium acetate was used and no industrialꢀscale 3ꢀbromobenzenesulfonyl
chloride was commercially available. These drawbacks made it unsuitable for industrialꢀscale
production. Luo et al. developed a manufacturing route of 1 based on route B (Scheme 1) by
changing some reagents.8 Some issues of the method for largeꢀscale synthesis are described
below: (1) the employment of expensive oxidant 1ꢀhydroxyꢀ1ꢀoxideꢀ1, 2ꢀBenziodoxolꢀ3(1H)ꢀ
one; (2) long synthetic procedure and laborious workups; (3) the relatively low 21.6% overall
yield. In this report, we discuss our attempts to develop an effective process for the hundredꢀ
gram scale preparation of belinostat.
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Scheme 2. Reported Largeꢀscale Synthetic Route of Belinostat.
RESULTS AND DISCUSSION
The synthetic route of 1, from commercially available benzaldehyde 2 and aniline, involved
addition reaction with sodium bisulfite to afford adduct 3. Then 3 was reacted with
chlorosulfonic acid to yield 3ꢀformylbenzenesulfonyl chloride 4. The reaction between 4 and
aniline in the presence of pyridine furnished 3ꢀformylꢀNꢀphenylbenzenesulfonamide 5.
Compound 5 was transformed into (E)ꢀ3ꢀ(3ꢀ((phenylamino)sulfonyl) phenyl)acrylic acid 6 by
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Knoevenagel condensation. 2ꢀPropenoyl chloride obtained from 6 was reacted with
hydroxylamine to afford belinostat (Scheme 3).
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Scheme 3. Novel Effective Synthetic Route of Belinostat
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O
O S ONa
CHO
aniline
CHO
chlorosulfonic acid
Na2S2O5
OH
EtOH, H2O
92%
K2SO4
69%
pyridine, EA
93%
SO2Cl
2
3
4
CHO
COOH
SOCl2, DBU
then NH2OH
malonic acid
piperidine, pyridine
83%
1
EA, THF, H2O
66%
SO2NHPh
SO2NHPh
5
6
Initially, in order to shorten the preparation process, our study was focused on the directly
preparation of 4 via the reaction between chlorosulfonic acid and benzaldehyde. As shown on
Table 1, however, only a small amount of 4 was obtained. The poor results were due to the
generation of benzal chloride as reported in literatures.9 Benzal chloride 7 and 8 were obtained
via column chromatography on silica gel, and they were generated in a low yield at low
temperature (entris 1ꢀ3). A plausible mechanism for the generation of 7 and 8 was shown in
Scheme 4. Besides, some unidentified strongꢀpolarity impurities were not eluted out from the
column.
Table 1. Reaction of Benzaldehyde with Chlorosulfonic Acid a
yield(%) b
entry
solvent
temp.(oC)
4
7
8
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2 c
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0
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4
DCM
CHCl3
THF
ꢀ
12
10
0
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6
7d
17
25
28
a Standard conditions: benzaldehyde (6.7 mmol), chlorosulfonic acid (53.4 mmol), solvent
(10 ml). b Isolated yield after chromatography. c Benzaldehyde 2 was recovered in 31% yield.
d Chlorosulfonic acid was increased to 80.0 mmol.
Scheme 4. Possible Mechanism for the Generation of Benzal Chloride.
The poor results from initial attempt compelled us to protect aldehyde before chlorosulfonation
and the protected benzaldehyde, 2ꢀphenylꢀ1,3ꢀdioxolane 9, was prepared according to a literature
procedure.10 It was noteworthy that, when chlorosulfonic acid was dropped into 9, the conversion
of compound 9 was 100%, but the product was not the target compound 4. Rather, the main
product was unexpected 10 (Scheme 5). However, when 9 was dropped into chlorosulfonic acid,
we obtained a mixture containing 4, 7 and 8. The amount of chlorosulfonic acid influenced the
generation of products. When there was only a small amount of chlorosulfonic acid, acetal 9
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converted to hemiacetal which was oxidized to ester 10 before additional chlorosulfonic acid was
added. And when there was enough chlorosulfonic acid, generated hemiacetal was hydrolysis to
aldehyde immediately.
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Scheme 5. Attempted Synthesis of 4 from 9
Aldehyde bisulfite adducts were often employed for the purification of aldehydes, we tested
benzaldehyde bisulfite adduct 3 in several experiments (Table 2). Starting material 3 was
obtained according to a literature procedure.11 When the reaction was deemed to be complete
monitored by TLC, the product was isolated by column chromatography. As shown in Table 2,
the reaction with incremental amount of chlorosulfonic acid afforded a higher yield, but the
amounts of 7 and 8 also increased (entries 1ꢀ4). Meanwhile, we investigated the influence of the
temperature: by lowering the temperature, a remarkable increase of 4 and decrease of 7 and 8
were observed (entries 6ꢀ9). When the amount of chlorosulfonic acid was less than 10 equiv, the
isolated yield was low (<45%), and it reached a maximum (53−56%) when treating 3 with 10
equiv of chlorosulfonic acid at 25 °C to 30 °C (entries 7ꢀ9). As a result, a reaction temperature of
30 °C was adopted.
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Table 2. Effects of Chlorosulfonic Acid Amount and Temperature on Chlorosulfonation
Reaction a
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yield(%)b
entry
HOSO2Cl(equiv)
temp.(oC)
4
13
7+8
<5
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2
3
4
5c
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9
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0
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35
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<5
<5
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a Standard conditions: no solvent, 3 was added to chlorosulfonic acid b Isolated yield after
chromatography. Reaction time was more than 20 h and benzaldehyde 2 was recovered in
c
63% yield.
Although entry 7 (Table 2) had shown an acceptable result, the high mole ratio of
chlorosulfonic acid (10 equiv) needs to be improved further. Encouraged by Lu et al.’s report
that potassium sulfate could be conducive to the preparation of benzenesulfonyl chloride,12 we
tried to add 0.1ꢀ1.0 equiv of potassium sulfate into the reaction mixture. As shown in Table 3,
the yield of 4 was increased and almost no 7 and 8 were generated when potassium sulfate was
more than 0.5 equiv (entries 1ꢀ5). The result might be due to the acidity of the reaction mixture
influenced by potassium sulfatet, then the bisulfite adduct did not convert to aldehyde smoothly
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and the chlorination of aldehyde was retarded. Based on the results, we reduced the ratio of
chlorosulfonic acid, and found that reduced ratio afforded lower yield (entries 6ꢀ7). When
repeated in dichloromethane, similar results were observed (entries 8−9).
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Table 3. Effect of Potassium Sulfate on Chlorosulfonation Reaction a
Cl
Cl
O
Cl
Cl
CHO
O S ONa
HOSO2Cl
K2SO4
+
+
OH
SO2Cl
SO2Cl
SO2Cl
4
7
8
3
entry
1
K2SO4(equiv)
HOSO2Cl(equiv)
6
solvent
CHCl3
yield(%)b
0.1
0.2
0.5
1.0
0.7
0.7
0.7
0.7
0.7
0.7
4: 26, 7+8: <5
2
3c
4
6
6
6
6
4
5
6
5
6
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCM
4: 34, 7+8: <5
64
65
68
43
61
70
62
69
5
6
7
8
9
DCM
10 d
DCM
a Standard conditions: 3 (4.8 mmol), solvent (10 ml), 30 °C. b Isolated yield after flash column
chromatography. c Almost no 7 and 8 were observed on TLC. d The load of 3 was 300 g.
Though previous optimization greatly decreased the amount of 7 and 8, the unidentified
strongꢀpolarity impurities did not be eliminated, so our endeavors focused on the development of
a scaleꢀup workup and purification protocol. Several attempts were made to purify 4 including
distillation and aldehyde bisulfite adduct, but to no avail. We also tried to skip the purification of
4, instead the material was used directly into next reaction, and a very complicated mixture was
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obtained. Finally, we found a flash column chromatography could be a suitable workup protocol
to purify 4 with toluene as eluent.
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In view of the facts mentioned in INTRODUCTION: a) no commercially avaible material that
is suitable for hundredꢀgram scale preparation of belinostat, b) no method that is suitable for the
preparation of mꢀsulfonyl intermediates (e.g. 3ꢀbromobenzenesulfonyl chloride) in a larger scale,
which is the key step for the preparation of belinostat or starting material, though column
chromatography would increase the cost, it would be an acceptable method for preparation of 4.
And we verified the method in scaleꢀup experiments (entry 10, Table 3).
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With 4 in hand, we tried to synthesize 5 through a modified literature procedure.13 When 5 was
synthesized via sulfonamidation of 4 with aniline in the presence of triethylamine, we observed
that a small amount of N, Nꢀdisulfonylarylamine 11 was generated. Encouraged by Mali et al.’s
report14 that disulfonamide impurity was not formed when pyridine was used as a base in
combination with 2ꢀMeꢀTHF, we screened several bases and solvents. As shown in Table 4, the
amount of 11 was reduced by replacing triethylamine with pyridine and increasing the mole ratio
of aniline (entry 9). Considering of the higher mole ratio of aniline, which could act as both
reactant and acid binding agent, the next reaction was conducted without base, but the reactant 4
was always remnant even though the reaction time was prolonged to 51 h at ambient temperature
(entries 10ꢀ12). In order to assess the effect of pyridine, we screened the reaction using 0.8−1.5
equiv of pyridine. When the amount of pyridine was less than 1.2 equiv, starting material 4 could
be detected by TLC analysis (entries 13ꢀ15).
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Table 4. Reaction of aniline with 4 a
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yield(%)b
entry
1
aniline (equiv) base (equiv)
solvent
DCM
5
49
11
23
4
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.2
1.3
2
Et3N (1.5)
pyridine (1.5)
K2CO3 (1.5)
NaHCO3 (1.5)
pyridine (1.5)
pyridine (1.5)
pyridine (1.5)
pyridine (1.5)
pyridine (1.5)
ꢀ
ND c
2
3
DCM
THF
THF
THF
DMF
EA
57
Dd
D
14
D
ND
ND
ND
ND
ND
ND
ND
ND
D
4
D
5
D
D
6
D
D
7
D
D
8
EA
D
D
9
EA
93
D
ND
ND
ND
ND
ND
ND
ND
10
11
12
13
14
15
EA
2.2
2.5
1.3
1.3
1.3
ꢀ
EA
D
D
ꢀ
EA
D
D
pyridine (0.8)
pyridine (1.0)
pyridine (1.2)
EA
92
94
94
D
EA
D
EA
ND
a Standard conditions: 4 (24.5 mmol), solvent (50 ml), 0ꢀ5 °C then r.t. Isolated yield after
column chromatography. Entries 9 and 13ꢀ15 did not perform purification. c Not detected by the
TLC analysis. d Detected by the TLC analysis but not isolated.
b
After the reaction of 4 with aniline finished, the reaction mixture quenched with 2 N aqueous
hydrochloric acid and a light yellow solid 5 was obtained via a simple workup. Followed by the
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Knoevenagel condensation of 5 with propanedioic acid, according to a literature procedure,15 (E)
ꢀ3ꢀ(3ꢀ((phenylamino)sulfonyl)phenyl)acrylic acid 6 was successfully obtained. Next, we
intended to synthesize belinostat from acrylic acid 6 via the method reported by Reisch et al.,7
and an acceptable result was obtained (Scheme 6).
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Scheme 6. Synthesis of Belinostat from 5
CHO
COOH
NH2OH
SOCl2, DBU
malonic acid
piperidine, pyridine
105-110 oC, 8.5 h
EA
EA, THF, H2O
25-30 oC, 9 h
SO2NHPh
SO2NHPh
25-30 oC, 15 h
6
5
66 %for three steps
83%
O
OH
N
EtOH, water
H
recrystallization
SO2NHPh
1
CONCLUSION
In conclusion, we provide an alternative method for the production of belinostat, and it is
acceptable from both product quality and yield standpoint. The method proceeds in five linear
steps with total yield of 33% on hundreds gram scale. The key step in this process is the
conversion of benzaldehyde to 3ꢀformylbenzenesulfonyl chloride, and the advantages of the
method are inexpensive starting materials and acceptable total yield.
EXPERIMENTAL SECTION
General. All of the starting materials, reagents and solvents are commercially available and
used without further purification. Analytical samples were obtained by column chromatography
on silica gel. Melting points were determined with a Xꢀ4 apparatus and were uncorrected. The
nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Ascend 400 (Billerica,
MA, USA) using tetramethylsilane (TMS) as an internal standard. Electrospray ionization mass
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spectrometry (ESIꢀMS) analyses was recorded in an Agilent 1100 Series MSD Trap SL (Santa
Clara, CA, USA). The reactions were monitored by thinꢀlayer chromatography (TLC;
HG/T2354ꢀ92, GF254), and compounds were visualized on TLC with UVꢀlight. The purity of
belinostat was determined by HPLC using a Shimadzu LCꢀ20A series instrument. The HPLC
analysis data was reported in relative area % and was not adjusted to weight %.
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Preparation of sodium αꢀhydroxybenzenemethanesulfonic acid (3). Sodium metabisulfite
(627 g, 3.3 mol) was dissolved in water (1.5 L), and a small amount of insoluble substance was
filtered off. Then the filtrate was added to a solution of benzaldehyde (500 g, 4.7 mol) in EtOH
o
(3 L) over 3 h under ambient temperature and then the reaction mixture was stirred at 45ꢀ50 C
under an atmosphere of argon overnight. After 18 h, the reaction mixture was sampled and
deemed to be complete with no benzaldehyde being detected by TLC. The heterogeneous
reaction mixture was cooled to ambient temperature, stirred for 4 h, and then isolated by vacuum
filtration. The product cake was washed with EtOH (two portions of 200 mL) to give the product
bisulphite adduct as a white solid (907 g, 92%), after drying under vacuum at 50 °C, m.p. 150–
152 °C, decomposition, (lit.16 153ꢀ156 °C, decomposition).
Preparation of 3ꢀformylbenzenesulfonyl chloride (4). A suspension of bisulphite adduct 3
(300 g, 1.4 mol) and anhydrous potassium sulfate powder (174 g; 1.0 mol) in DCM (3 L) was
stirred at 0ꢀ5 °C, and chlorosulfonic acid (560 mL, 8.6 mol) was added dropwise into the
suspension whilst maintaining the temperature below 30 °C (caution: highly exothermic). When
the addition completed over 6 h, the reaction mixture was further stirred at 25ꢀ30 °C for 22 h.
After the completion of the reaction monitored by TLC, the reaction mixture was slowly poured
into crushed ice (3 kg) and stirred for 1 h. The aqueous phase was removed, and the organic
phase was washed with water (2 L) followed by 5% aqueous solution of sodium bicarbonate (1
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L) and brine (1 L) before dried over anhydrous sodium sulfate. The sodium sulfate was filtered
off and the filtrate was concentrated in vacuum (10ꢀ15 Torr, pot temperature of 20 °C) to afford
crude 4.
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The crude 4 was dissolved in toluene (300 mL) and then the solution was taken ahead as such
for the purification. The silica gel (1.2 Kg) was carefully poured into a column (diam: 10 cm),
and compressed air was used to pack the column. After 1 h, a portion of the solution (one sixth
of the total) was added and pressed into the dry silica gel using compressed air. When added
solution was all deposited on silica, another portion was added, and repeated until all six portions
were added. After the portionꢀwise addition, the column was eluted with toluene (7.3 L), and the
eluent was concentrated in vacuum (10−15 Torr, pot temperature below 35°C) to afford light
yellow oil 3ꢀformylbenzenesulfonyl chloride (203 g, 69%). (caution: 3-formylbenzenesulfonyl
chloride 4 was more likely to convert into strong-polarity impurities when the pot temperature
was higher than 40 °C).1HꢀNMR (CDCl3, 400 MHz) δ = 10.13 (s, 1H,), 8.53 (s, 1H), 8,31ꢀ8.26
(m, 2H), 7.85 (t, J = 8.0 Hz, 1H).
Preparation of 3ꢀformylꢀNꢀphenylbenzenesulfonamide (5). Pyridine (96 mL, 1.5 mol) was
added to a solution of aniline (118 mL, 1.3 mol) in EA (600 mL), and the mixture was stirred at
0ꢀ5oC. Then the solution of 3ꢀformylbenzenesulfonyl chloride 4 (200 g, 1.0 mol) in EA (400 mL)
was added slowly to the reaction mixture over 1.5 h while maintaining the reaction temperature
below 5 °C. The solution was stirred at 0ꢀ5 °C for 1 h and then at ambient temperature for 19 h.
When the reaction was deemed to be complete with no 4 detected by TLC. The reaction mixture
was washed with a 10% aqueous solution of hydrochloric acid (two portions of 500 mL)
followed by washing with water (500 L), 5% aqueous solution of sodium bicarbonate (500 mL)
and then brine (500 mL), dried with sodium sulfate anhydrous, filtered, and concentrated to
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afford yellow solid 3ꢀformylꢀNꢀphenylbenzenesulfonamide (242 g, 93%). Crude 5 was used
directly into next step. A sample of purified 5 as a white solid was analyzed as follows. 1HꢀNMR
(CDCl3, 400 MHz) δ = 10.38 (s, 1H), 10.00 (s, 1H), 8.29 (s, 1H), 8.05 (d, J =7.8 Hz, 1H), 8.00
(d, J = 7.8 Hz, 1H), 7.62 (t, J =7.8 Hz, 1H), 7.27ꢀ7.23 (m, 2H), 7.16ꢀ7.01 (m, 3H).
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Preparation of (E)ꢀ3ꢀ(3ꢀ((phenylamino)sulfonyl)phenyl)acrylic acid (6). Malonic acid (145
g, 1.4 mol) was added in batches to a solution of 3ꢀformylꢀNꢀphenylbenzenesulfonamide 5 (240
g, 0.9 mol) and piperidine (18 mL, 0.2 mol) in pyridine (700 mL), then the mixture was stirred at
105ꢀ110 °C for 8.5 h. When TLC analysis indicated the disappearance of 5, the reaction mixture
was cooled to ambient temperature and slowly poured into chilled 5% aqueous solution of
sodium hydroxide (2.4 L) below 20 °C (pH: 9ꢀ10). The reaction mixture was washed with EA
(1.2 L), and the separated organic layer was extracted with 5% aqueous solution of sodium
hydroxide (600 mL). The aqueous layers were combined and cooled to 10ꢀ20 °C, then it was
acidified slowly with 50% sulphuric acid (600 mL) below 20 °C (pH: 1ꢀ2). After an additional
30 min stirring at 15ꢀ20 °C, the solid obtained was collected by filtration, washed with water (2.4
L) followed by nꢀhexane (1 L). The filter cake was dried in a vacuum oven at 50 °C to afforded
colorless solid (E)ꢀ3ꢀ(3ꢀ((phenylamino)sulfonyl)phenyl)acrylic acid (244 g, 83%). mp 154−156
1
°C. H NMR (400 MHz, DMSOꢀd6) δ = 12.62 (bs, 1H), 10.32 (s, 1H), 8.01 (s, 1H), 7.94 (d, J =
7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.63ꢀ7.56 (m, 2H), 7.24 (m, 2H), 7.11ꢀ7.01 (m, 3H), 6.55
(d, J = 16.0 Hz, 1H). MS (ESI): m/z = 326.0 [M + Na] +.
Preparation of (E)ꢀNꢀhydroxyꢀ3ꢀ((phenylamino)sulfonyl)phenyl)acrylamide (belinostat,
1). (E)ꢀ3ꢀ(3ꢀ((phenylamino)sulfonyl)phenyl)acrylic acid 6 (240 g, 0.8 mol) was added to a
solution of DBU (1.2 mL, 8 mmol) in EA (2.4 L), and the slurry was stirred at 15ꢀ20 °C. Thionyl
chloride (67 mL, 0.9 mol) was added to the reaction mixture and the mixture was stirred at 25ꢀ30
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°C. After 15 h, the reaction completed with no 6 detected by TLC. The resulting solution of 2ꢀ
propenoyl chloride was bubbled with argon for 1 h and then used directly into next step without
further workꢀup.
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THF (480 mL) was added to a solution of 50% (w/w) hydroxylamine (478 mL, 8 mol) in water
(1 L) and the mixture was stirred at 0ꢀ5 °C. The 2ꢀpropenoyl chloride solution was then slowly
added into the hydroxylamine solution over 2.5 h. The mixture was stirred at 25ꢀ30 °C for
additional 6.5 h and was monitored by TLC. After completion of the reaction, the aqueous layer
was separated and discarded. The organic layer was reduced in volume in vacuum while
maintaining the temperature below 30 °C until about 1L of solvent was distilled out. Then
petroleum ether (1L) was added and the precipitated product was collected by filtration, washed
with petroleum ether, dried at 45ꢀ55 °C under vacuum to afford light orange solid belinostat 1
(209 g, 82 %). mp 172−174 °C, (lit.3a 172 °C). 1H NMR (400 MHz, DMSOꢀd6) δ = 10.75ꢀ10.42
(m, 2H), 9.15 (s, 1H), 7.92 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.56 (d, J =
7.8 Hz, 1H),7.47 (d, J = 15.8 Hz, 1H), 7.24 (m, 2H), 7.10ꢀ7.01 (m, 3H), 6.51 (d, J = 15.8 Hz,
1H). MS (ESI): m/z = 318.6 [M + H] +.
The crude 1 (209 g, 0.66 mol) was dissolved in EtOH (840 mL) at 60 °C, and distilled water (2
L) was then added at a rate of 20 mL /min while keeping the temperature at 55ꢀ60 °C. After the
addition, the reaction mixture was then cooled to ambient temperature and stirred overnight. The
crystals were filtered and collected. The filter cake was washed with water (two portions of 200
mL) and dried at 45ꢀ55 °C in vacuum to afford a light orange solid (169 g, 81%) with a purity of
99.6% (relative area) by HPLC.
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ASSOCIATED CONTENT
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Supporting Information.
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HPLC information with chromatogram and1H NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: guoliang222@gmail.com
Present Addresses
Shenyang Pharmaceutical University, NO.103, Wenhua Road, Shenyang, P. R. CHINA.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by Discipline Construction Program of Shenyang
Pharmaceutical University (No. 52134606) and the program of the Education Department of
Liaoning Province (No. L2014378).
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