Simple and efficient synthesis of belinostat

Article abstract of DOI:10.1080/00397910903277870

A novel synthesis of belinostat (1) starting from 3-nitrobenzaldehyde has been developed. The key step in this sequence involves the conversion of (2E)-3-(3-aminophenyl)acrylic acid methyl ester to (2E)-3-(3- chlorosulfonylphenyl)acrylic acid methyl ester via diazotization and sulfonylation. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903277870

This article was downloaded by: [Pennsylvania State University]
On: 20 May 2013, At: 23:31
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Simple and Efficient Synthesis of
Belinostat
Lei Yang a b , Xiaowen Xue a & Yihua Zhang b
a Department of Medicinal Chemistry, China Pharmaceutical
University, Nanjing, China
b Center of Drug Discovery, China Pharmaceutical University,
Nanjing, China
Published online: 05 Aug 2010.
To cite this article: Lei Yang , Xiaowen Xue & Yihua Zhang (2010): Simple and Efficient Synthesis of
Belinostat, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 40:17, 2520-2524
To link to this article: http://dx.doi.org/10.1080/00397910903277870
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 40: 2520–2524, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903277870
SIMPLE AND EFFICIENT SYNTHESIS OF BELINOSTAT
Lei Yang,1,2 Xiaowen Xue,1 and Yihua Zhang2
1Department of Medicinal Chemistry, China Pharmaceutical University,
Nanjing, China
2Center of Drug Discovery, China Pharmaceutical University, Nanjing, China
A novel synthesis of belinostat (1) starting from 3-nitrobenzaldehyde has been developed.
The key step in this sequence involves the conversion of (2E)-3-(3-aminophenyl)acrylic
acid methyl ester to (2E)-3-(3-chlorosulfonylphenyl)acrylic acid methyl ester via
diazotization and sulfonylation.
Keywords: Belinostat; sulfonylation; synthesis
Belinostat (PXD101, 1, Fig. 1), a new histone deacetylase (HDAC) inhibitor
developed by CuraGen=TopoTarget, is currently undergoing clinical trials as an
anticancer drug.[1,2] As a potent histone deacetylase inhibitor, belinostat has
shown great promise for the treatment of solid tumors and haematological malig-
nancies, used alone or in combination with other chemotherapeutics.[2,3] Bearing a
sulfonamide–hydroxamide structure, belinostat belongs to the hydroxamic acid class
of HDAC inhibitors. Although its structure is rather simple, the reported synthetic
methods are limited. To the best of our knowledge, only one method (developed
by Kalvinsh and coworkers) is available for the preparation of belinostat.[4,5] In
this method, benzaldehyde was used as starting material and first sulfonylated
with oleum, followed by Horner–Wadsworth–Emmons olefination with methyl
(dimethoxyphosphinyl) acetate and chlorination with SOCl2 to afford methyl (2E)-
3-(3-chlorosulfonyl-phenyl)prop-2-enoate as the key intermediate. This key inter-
mediate was then reacted with aniline, followed by hydrolysis, chlorination, and ami-
dation to provide belinostat with a 12% total yield. We report an improved synthesis
of belinostat with the following advantages. First, our synthesis avoids the use of the
extremely corrosive oleum and SOCl2 and therefore is possibly better for scaled-up
production. Second, our synthetic steps do not involve tedious separations and give a
better overall yield.
Scheme 1 delineates the novel synthesis of belinostat developed in our labora-
tories. This route emphasized the introduction of a chlorosulfonyl group into the
benzene ring via diazotization and thus avoids the use of extremely corrosive oleum
Received May 5, 2009.
Address correspondence to Xiaowen Xue, Department of Medicinal Chemistry, China
Pharmaceutical University, Nanjing 210009, China. E-mail: xwenxue@cpu.edu.cn
2520

SIMPLE AND EFFICIENT SYNTHESIS OF BELINOSTAT
2521
Figure 1. Structure of belinostat (1).
Scheme 1. Reagents and conditions: (a) (MeO)2P(O)CH2CO2CH3=K2CO3, rt, 0.5 h; (b) SnCl2 ꢀ 2H2O,
reflux, 2.5 h, 95% for two steps; (c) NaNO2=HCl=HOAc, ꢁ5 ꢂC to 10 ꢂC, 0.75 h; (d) SO2=CuCl=HCl=
HOAc; (e) aniline, rt, 2 h, 41% for three steps; (f) NH2OH ꢀ HCl=KOH, EtOH, 1 h, 84%.
and SOCl2 and tedious separation. More important, the total yield (33%) is signifi-
cantly improved.
The amine 3 was prepared from 3-nitrobenzaldehyde (2) using a two-step pro-
cedure carried out successively without purification in 95% overall yield. In the first
stage of the transformation, the Horner reaction of 2 with (MeO)2P(O)CH2
[6]
CO2CH3
in the presence of K2CO3 in water provided methyl (2E)-3-
(3-nitrophenyl)prop-2-enoate. The resulting crude was reduced with SnCl2[7] in anhy-
drous alcohol to yield methyl (2E)-3-(3-aminophenyl)prop-2-enoate (3). With amine
3 in hand, a three-step procedure was performed successively to convert 3 into sul-
fonamide 4. Diazotization of 3 with NaNO2 in dilute HCl, followed by substitution
with dilute SO2 in HCl and HOAc mixed solution,[8] provided the key intermediate
methyl (2E)-3-(3-chlorosulfonylphenyl) prop-2-enoate. Amination of the sulfo-
nylchloride with aniline in the presence of NaHCO3 afforded methyl (2E)-3-
{3-[(phenylamino)sulfonyl]phenyl}prop-2-enoate (4) with a overall yield of 41%
for three steps. The product 1 was finally obtained by oximation of 4 with
1
NH2OH ꢀ HCl in 84% yield.[9] The melting point and H NMR spectrum of 1 were
identical to those described in literature.[4]
In summary, we have successfully developed a novel synthetic route to prepare
belinostat from easily available 3-nitrobenzaldehyde with a considerable yield, and
the route has convenient and economic advantages.
EXPERIMENTAL
Reagents were purchased from commercial sources and used without further
purification unless otherwise indicated. Melting points were determined with a
1
XT4 melting-point apparatus and are uncorrected. H NMR spectra were recorded
on a Bruker AV-300 instrument (300 MHz) with CDCl3 and dimethylsulfoxide

2522
L. YANG, X. XUE, AND Y. ZHANG
(DMSO-d6) as the solvents, and mass spectra (MS) were performed on Agilent
G1956B and Shimadzu GCMS-QP2010 instruments.
Methyl (2E)-3-(3-Aminophenyl)prop-2-enoate (3)
Methyl (2E)-3-(3-aminophenyl)prop-2-enoate (3) was prepared by a modified
literature method. m-Nitrobenzadehyde (26.2 g, 174 mmol) was added to a mixture
of methyl (dimethoxyphosphinyl) acetate (34.6 g, 208 mmol) and K2CO3 solution
(48 g of K2CO3 in 80 ml of water). The formed mixture was stirred at room tempera-
ture for 0.5 h. The precipitate was filtered, washed with 1N HCl and water, and dried
to yield 35.9 g of methyl (2E)-3-(3-nitrophenyl)prop-2-enoate as a yellowish powder.
It was used for the next step without further purification.
A mixture of methyl (2E)-3-(3-nitrophenyl)prop-2-enoate (16.6 g, 80 mmol)
and SnCl2 ꢀ 2H2O (62.1 g, 275 mmol) in anhydrous EtOH (200 ml) was heated at
80 ꢂC for 2.5 h. The mixture was allowed to cool to rt, and then the solvent was half
evaporated under reduced pressure. The residue was poured into ice water and
neutralized (pH ca. 7) with saturated Na2CO3 solution, and the resulting mixture
was extracted with ethyl acetate. The organic extract was washed with saturated
NaCl solution and dried over Na2SO4. The solvent was then evaporated under
reduced pressure to provide 3 (13.4 g, 95%) as a light yellowish solid. Mp
1
80–82 ꢂC; H NMR (300 MHz, CDCl3): d 3.69–3.79 (br, 5H), 6.37 (d, J ¼ 15.9 Hz,
1H), 6.69 (dd, J ¼ 1.8, 7.8 Hz, 1H), 6.80 (s, 1H), 6.91 (d, J ¼ 7.5 Hz, 1H), 7.15 (dd,
1
J ¼ 7.5, 7.8 Hz, 1H), 7.60 (d, J ¼ 15.9 Hz, 1H); MS: m=z ¼ 178.1 (M þ H)þ. The H
NMR spectrum was in good agreement with the reported data.[4]
Methyl (2E)-3-{3-[(Phenylamino)sulfonyl]phenyl}prop-2-enoate (4)
Methyl (2E)-3-(3-aminophenyl)prop-2-enoate (3) (8.41 g, 48 mmol) was added
to a mixture of concentrated HCl (40 ml) and glacial acetic acid (12 ml) under vigor-
ous stirring. The formed mixture was then cooled to ꢁ13 ꢂC with an ice–NaCl bath,
and a solution of sodium nitrite (3.61 g of NaNO2 in 12 ml of water) was added
dropwise at such a rate that the temperature did not exceed ꢁ5 ꢂC. After addition,
the stirring was continued for 45 min with the temperature below ꢁ5 ꢂC.
In another flask, sulfur dioxide was introduced to 45 ml of glacial acetic acid
with vigorous stirring at 0 ꢂC until saturation. Cuprous chloride (1.45 g, 15 mmol)
was then added to the solution, and sulfur dioxide was added until the yellow-green
suspension became blue-green. Sulfur dioxide solution was added to the diazotiza-
tion reaction mixture in portions. After all the diazonium salt had been added,
the mixture was poured into 500 ml of ice water and stirred until the ice melted,
and then the crude sulfonamide was extracted with ethyl acetate. The organic extract
was then washed with saturated sodium bicarbonate and dried over anhydrous
sodium sulfate. The solvent was removed under reduced pressure to afford a black
oil, which was used directly for the next step.
A solution of the black oil (obtained the previous step) in 40 ml of 1,4-dioxane
was added dropwise to a solution of aniline (2.56 g, 28 mmol) in 1,4-dioxane (10 ml)
and 10% aqueous sodium bicarbonate solution (50 ml), and the mixture was stirred
at room temperature for 10 h. The solvent was then evaporated, and 80 ml of water

SIMPLE AND EFFICIENT SYNTHESIS OF BELINOSTAT
2523
were added. The resulting mixture was stirred for 1 h and extracted with ethyl
acetate. The organic extract was washed successively with 1N HCl solution, water,
and saturated brine. After removing the solvent, the residue was purified by column
chromatograph to afford 4 as a yellowish powder (4.43 g, 41% for three steps). Mp
144–146 ꢂC; 1H NMR (300 MHz, CDCl3): d 3.81 (s, 3 H), 6.00–6.38 (br, s, 1H), 6.41
(d, J ¼ 15.6 Hz, 1H), 7.09–7.15 (m, 3 H), 7.22–7.27 (m, 2 H), 7.45 (t, J ¼ 7.8 Hz, 1H),
7.59–7.64 (m, 2 H), 7.77 (d, J ¼ 7.5 Hz, 1H), 7.92 (s, 1H); MS: m=z ¼ 317 [M]þ, 318
[M þH]þ.
(2E)-N-Hydroxy-3-{3-[(phenylamino)sulfonyl]phenyl}prop-2-enamide
(Belinostat, 1)
Potassium hydroxide (2.2 g, 39.0 mmol) was added to a solution of hydroxyla-
mine hydrochloride (2.70 g, 39.0 mmol) in dry ethanol (10 ml), and the resulting
mixture was cooled to 0 ꢂC and filtered. Potassium hydroxide (0.35 g, 6.39 mmol)
and 4 (0.37 g, 1.17 mmol) were added to the filtrate, and the mixture was stirred at
0 ꢂC for 1 h. Then 25 ml of water were added to quench the reaction, and the mixture
was then neutralized with 2 N HCl solution. The precipitate was filtered and
dried under vacuum to provide 1 as an off-white solid (0.31 g, 84% yield). Mp
170–172 ꢂC; 1H NMR (300 MHz, DMSO-d6): d 6.52 (d, J ¼ 15.9 Hz, 1H),
6.81–7.12 (m, 6H), 7.33 (d, J ¼ 15.9 Hz, 1H), 7.47–7.67 (m, 3 H), 7.87 (s, 1H),
9.00–11.20 (br, 3H); HRMS calcd. for C15H14N2O4SNa, m=z: 341.0567 (M þ Na)þ;
; found, m=z: 341.0578.
ACKNOWLEDGMENT
This work was supported by funding from the China Pharmaceutical
University (No. 211080).
REFERENCES
1. Steele, N. L.; Plumb, J. A.; Vidal, L.; Tjornelund, J.; Knoblauch, P.; Rasmussen, A.; Ooi,
C. E.; Buhl-Jensen, P.; Brown, R.; Evans, T. R. J.; De Bond, J. S. A phase 1 pharmacoki-
netic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients
with advanced solid tumors. Clin. Cancer Res. 2008, 14, 804–810.
2. Qian, X.; Ara, G.; Mills, E.; LaRochelle, W. J.; Lichenstein, H. S.; Jeffers, M. Activity of
the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate
cancer. Int. J. Cancer 2008, 122, 1400–1410.
3. Qian, X.; LaRochelle, W. J.; Ara, G.; Wu, F.; Petersen, K. D.; Thougaard, A.; Sehested,
M.; Lichenstein, H. S.; Jeffers, M. Activity of PXD101, a histone deacetylase inhibitor,
in preclinical ovarian cancer studies. Mol. Cancer Ther. 2006, 5(8), 2086.
4. Finn, P.W.; Bandara, M.; Butcher, C.; Finn, A.; Hollinshead, R.; Khan, N.; Law, N.;
Murthy, S.; Romero, R.; Watkins, C.; Andrianov, V.; Bokaldere, R. M.; Dikovska, K.;
Gailite, V.; Loza, E.; Piskunova, I.; Starchenkov, I.; Vorona, M.; Kalvinsh, I. Novel
sulfonamide derivatives as inhibitors of histone deacetylase. Helv. Chim. Acta 2005, 88,
1630–1656.
5. Watkins, C. J.; Romero-Martin, M. R.; Moore, K. G.; Ritchie, J.; Finn, P. W.; Kalvinsh, I.;
Loza, E.; Dikovska, K.; Gailite, V.; Vorona, M.; Piskunova, I.; Starchenkov, I.; Adrianov, V.;

2524
L. YANG, X. XUE, AND Y. ZHANG
Harris, C. J.; Duffy, J. E. S. Carbamic acid compounds comprising a sulfonamide linkage
as HDAC inhibitors. US Patent 6,888,027, May 3, 2005.
6. Pavri, N. P.; Trudell, M. L. An efficient method for the synthesis of 3-arylpyrroles. J. Org.
Chem. 1997, 62, 2649–2651.
7. Marques, M. A.; Doss, R. M.; Urbach, A. R.; Dervan, P. B. Toward an understanding of
the chemical etiology for DNA minor-groove recognition by polyamides. Helv. Chim. Acta
2002, 85, 4485–4517.
8. Hoffman, R. V. m-Trifluoromethylbenenesulfonyl chloride. Org. Synth. Coll. 1990, 7, 508.
9. Mai, A.; Massa, S.; Rotili, D.; Pezzi, R.; Bottoni, P.; Scatena, R.; Meranerd, J.; Brosch, G.
Exploring the connection unit in the HDAC inhibitor pharmacophore model: Novel
uracil-based hydroxamates. Bioorg. Med. Chem. Lett. 2005, 15, 4656–4661.