An improved and efficient synthesis of panobinostat

Article abstract of DOI:10.3184/174751918X15357309308931

An improved and efficient method for the synthesis of panobinostat was developed. The commercially available starting material 4-(chloromethyl)benzaldehyde was converted to (E)-methyl 3-[4-(chloromethyl)phenyl]acrylate via the Wittig-Horner reaction and was then directly condensed with 2-(2-methyl-1H-indol-3-yl)ethanamine to afford the key intermediate (E)-methyl 3-[4-({[2-(2-methyl-1H-indol- 3-yl)ethyl]amino}methyl)phenyl]acrylate in a one-pot synthesis reactor. Subsequently a nucleophilic substitution reaction was carried out smoothly to generate the desired compound. The key intermediate and target compound were characterised by HRMS, ¹H NMR and ¹³C NMR. This procedure is operationally simple and would be more suitable for industrial production.

Full text of DOI:10.3184/174751918X15357309308931

JOURNAL OF CHEMICAL RESEARCH 2018
VOL. 42 SEPTEMBER, 471–473
RESEARCH PAPER 471
An improved and efficient synthesis of panobinostat
Shanwen Chena,b, Peiming Zhanga,b, Huali Chena,b, Pu Zhanga,b, Yu Yua,b* and Zongjie Gana,b*
aDepartment of MedicinalChemistry, College of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China
bChongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing 400016, P.R. China
An improved and efficient method for the synthesis of panobinostat was developed. The commercially available starting material
4-(chloromethyl)benzaldehyde was converted to (E)-methyl 3-[4-(chloromethyl)phenyl]acrylate via the Wittig–Horner reaction and was
then directly condensed with 2-(2-methyl-1H-indol-3-yl)ethanamine to afford the key intermediate (E)-methyl 3-[4-({[2-(2-methyl-1H-indol-
3-yl)ethyl]amino}methyl)phenyl]acrylate in a one-pot synthesis reactor. Subsequently a nucleophilic substitution reaction was carried out
1
smoothly to generate the desired compound. The key intermediate and target compound were characterised by HRMS, H NMR and 13
C
NMR. This procedure is operationally simple and would be more suitable for industrial production.
Keywords: panobinostat, histone deacetylase inhibitor, synthesis, Wittig–Horner reaction
Histone deacetylases (HDACs) are a class of enzymes that
catalyse the removal of acetyl groups from the ε-amino groups of
lysine residues that are present within the N-terminal extension
of the core histones, leading to chromatin condensation and
transcriptional repression.1,2 So far, 18 HDACs have been
identified in humans, and they are subdivided into four
structurally and functionally different phylogenetic classes.
Among them, Class I HDACs (1, 2, 3 and 8) and Class II HDACs
(4, 5, 6, 7, 9 and 10) are zinc-dependent proteases, which play
important roles in the modulation of chromatin topology and
the regulation of gene transcription.2–5 Consequently, it has been
widely recognised that histone deacetylase inhibitors (HDACi)
could be a new class of antitumour agents that can inhibit the
proliferation of tumour cells in culture and in vivo by inducing
cell cycle arrest, differentiation and/or apoptosis.6,7
haematological and solid tumours.11 Therefore, improvement in
the preparation of panobinostat is of practical significance.
Results and discussion
Considerable synthetic work has recently been devoted to the
synthesis of panobinostat.12–14 Among the available methods,
the most common strategies to prepare this compound employ
1-bromo-4-methylbenzene or 4-bromobenzaldehyde as the
starting material. For example, as shown in Scheme 1, 1-bromo-
4-methylbenzene is transformed to compound 2 by a Suzuki
coupling reaction, followed by bromation of the methyl group in
the presence of NBS/CCl4 to form intermediate 3. Condensation
of 3 with 2-(2-methyl-1H-indol-3-yl)ethanamine (1) affords the
intermediate (E)-methyl 3-[4-({[2-(2-methyl-1H-indol-3-yl)
ethyl]amino}methyl)phenyl]acrylate (4), which is subsequently
Over the past decade there have been extensive efforts to
identify and design novel small-molecule HDACi to address
unmet medical needs. There are already approved HDACi
for the treatment of cancer, such as lymphoma and multiple
myeloma (Fig. 1).8,9 Panobinostat (also known as LBH589,
trade name Farydak®) is a novel and potent small molecule
nonselective inhibitor of the HDACs, and was approved by the
US Food and Drug Administration (FDA) for the treatment
of relapsed multiple myeloma in certain patients in February
2015.10 Panobinostat is in various stages of clinical development
worldwide and shows great potential for curing a range of
attacked by NH2OH to generate the target compound
panobinostat. However, these reported methods often suffer
from several drawbacks, such as vigorous conditions, use of
expensive or toxic reagents, and the requirement for column
chromatography or complicated workups.
In view of this, we have designed an alternative synthetic
route for the synthesis of panobinostat (Scheme 2). Initially
this route involved a three-step process. The inexpensive
and readily available starting material 4-(chloromethyl)
benzaldehyde (5) was utilised and it was converted to (E)-
methyl 3-[4-(chloromethyl)phenyl]acrylate via the Wittig–
O
H
O
N
H
O
H
O
N
N
H
H
O
Vorinostat (SAHA)
HN
N
N
H
N
N
H
NH2
H
N
N
Panobinostat (Farydak
)
O
Mocetinostat
Fig. 1 Structures of some selective inhibitors of HDACs.
* Correspondent. E-mail: gzj@cqmu.edu.cn, yuyu3519@163.com

472 JOURNAL OF CHEMICAL RESEARCH 2018
O
H2N
NH
NH2
l
C
N
H
Et H
O
1
O
O
O
H
OC
3
H
Pd(OAc)2, PPh3, DMF
NBS, CCl4
N
H
OC
OCH3
3
r
B
H
OC
DMF, DIPEA
3
HN
Br
O
3
4
2
O
NH
H
2O
OH
N
H
H
N
MeOH, NaOH
HN
panobinostat
Scheme 1 The reported synthesis of panobinostat.
Scheme 2 An improved synthesis of panobinostat.
Horner reaction and was then condensed with 1 to afford the key
intermediate 4. A nucleophilic substitution reaction between
4 and NH2OH proceeded successfully to form the desired
compound in the presence of KOH. However, we accidentally
found that (E)-methyl 3-[4-(chloromethyl)phenyl]acrylate
reacted directly with 1 to afford 4 under the same conditions
(DBU/DMF) without purification. Thus, we employed a one-
pot synthesis strategy leading to 4, which had a simplified
workup and gave higher yield.
product were observed with higher mole equivalents, whereas
a decrease in mole equivalents ratios resulted in a lower yield
(Table 1, entries 6–8). Under the optimised conditions, effort
was made to increase the yield of the reaction using different
solvents such as DMF, THF, DCM, ACN and 1,4-dioxane. Out
of these solvents, DMF gave a maximum yield of the desired
product (Table 1, entry 7 versus entries 9–12). Hence, DMF
was chosen as the solvent for the reaction. Next, the reaction
temperature was also investigated, and the results showed that
25 °C is the optimal temperature (Table 1, entry 7 versus entries
13 and 14). Finally, panobinostat with the literature properties
was obtained efficiently from 5 with an overall yield of 40%
based on 1.
To increase the yield of this route, the reaction conditions
were investigated and optimised. First, as the base played
an important role in the reaction, a variety of bases such
as
1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU),
N,N-
diisopropylethylamine (DIPEA), t-BuOK, NaH and K2CO3
were examined as the catalyst for the reaction. As shown
in Table 1, it was observed that DBU gave the best outcome
compared with the other agents (Table 1, entries 1–5). With this
preliminary result in hand, the concentration of DBU and methyl
diethylphosphonoacetate (6) was further studied. As a result,
2.5 equiv. of DBU and 6 was found to be sufficient to obtain
a good yield, and no further improvements in the yield of the
In conclusion, we have developed a straightforward and
improved approach for the synthesis of panobinostat. This
synthetic route employed 4-(chloromethyl)benzaldehyde as
the starting materials to afford panobinostat via a two-step
reaction. The overall yield of this procedure was 40% based
on 2-(2-methyl-1H-indol-3-yl)ethanamine. This method shows
great potential for practical use in the synthesis of panobinostat
owing to its simple operating requirements and low cost.

JOURNAL OF CHEMICAL RESEARCH 2018 473
Table 1 Optimisation of reaction conditions
(m, 2H), 7.25 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.2
Hz, 2H), 7.69 (d, J = 16.1 Hz, 1H), 7.80 (d, J = 8.2 Hz, 2H), 9.59 (brs, 2H),
10.90 (s, 1H); 13C NMR (150 MHz, DMSO-d6): δ 11.6, 21.0, 47.4, 49.8,
52.0, 66.8, 105.6, 111.0, 117.6, 118.7, 119.0, 120.6, 128.2, 128.9, 130.9, 133.1,
134.9, 135.6, 144.2, 167.0; MS (ESI) m/z [M + H]+: 349.0; HRMS m/z
calcd for C22H24O2N2 [M + H]+: 349.1911; found: 349.1914.
Catalyst
(equiv.)
6
Temperature Time
Yield
(%)a
Entry
Solvent
(equiv.)
(°C)
25
25
25
25
25
25
25
25
25
25
25
25
0
(h)
6
6
6
6
6
6
6
6
6
6
6
6
6
3
3
b
1
K2CO3 (3.0)
DBU (3.0)
DIPEA (3.0)
NaH (3.0)
t-BuOK (3.0)
DBU (1.0)
DBU (2.5)
DBU (1.5)
DBU (2.5)
DBU (2.5)
DBU (2.5)
DBU (2.5)
DBU (2.5)
DBU (2.5)
DBU (2.5)
3.0
3.0
3.0
3.0
3.0
3.0
2.5
1.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
DMF
DMF
DMF
THF
–
2
3
4
5
6
7
8
9
10
11
12
13
14
15
52
b
–
Trace
Synthesis of (E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]
amino}methyl)phenyl]acrylamide (panobinostat)
b
THF
–
DMF
DMF
DMF
THF
DCM
ACN
18
55
32
20
22
23
A solution of potassium hydroxide (1.17 g, 21 mmol) in methanol (5 mL)
was added to a stirred solution of hydroxylamine hydrochloride (0.97 g,
14 mmol) in methanol (10 mL) at 0 °C. The mixture was stirred at 0 °C
for 15 min. The precipitate was removed by filtration and the filtrate was
collected to provide fresh hydroxylamine solution. The ester (0.48 g, 1.4
mmol) was added to the above freshly prepared hydroxylamine solution
at 0 °C. The reaction mixture was then stirred at this temperature under a
nitrogen atmosphere for 4 h. After the reaction was completed, the mixture
was diluted with water and neutralised with NH4Cl aqueous solution to
pH = 7–8. The precipitate that formed was collected by filtration, washed
with water and recrystallised from MeOH/H2O to give the title compound
as: Off-white solid; yield 0.35 g (73%); m.p. 89–91 °C (lit. 12 86–88 °C);
1H NMR (600 MHz, DMSO-d6): δ 2.31 (s, 3H), 2.69 (t, J = 7.5 Hz, 2H),
2.81 (t, J = 7.5 Hz, 2H), 3.77 (s, 2H), 6.45 (d, J = 15.8 Hz, 1H), 6.90
(m, 1H), 6.95 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.38 (m, 3H), 7.44 (d,
J = 15.8 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 10.70 (brs, 1H); 13C NMR (150
MHz, DMSO-d6): δ 11.7, 24.7, 50.0, 52.8, 108.5, 110.8, 117.8, 118.4, 118.8,
120.3, 127.7, 128.8, 128.9, 132.2, 133.6, 135.6, 138.6, 142.7, 163.2; MS
(ESI) m/z [M + H]+: 350.0; HRMS m/z calcd for C21H23O2N3 [M + H]+:
350.1863; found: 350.1864.
1,4-Dixone 30
DMF
DMF
DMF
31
45
35
50
25
aIsolated yield.
bNo reaction.
Experimental
4-(Chloromethyl)benzaldehyde was obtained from ZhengZhou Alfa
Chemical Industrial Corporation. Other reagents were obtained from
Adamas and Tansoole and used without further purification unless
otherwise noted. Melting points were determined on X-4 microscopic
melting point apparatus and are uncorrected. H NMR and 13C NMR
1
spectra were obtained from solution in DMSO-d6 and CDCl3 with TMS as
internal standard using a Bruker-600 MHz spectrometer. MS spectra were
obtained with an Aglient 6470 Triple Quad LC-MS instrument. HRMS
spectra were acquired with an Agilent 6210 ESI/TOF mass spectrometer.
Acknowledgements
We appreciate the financial support from the National
Natural Science Foundation of China (No. 81172097), and the
Fundamental and Advanced Research Projects of Chongqing
City (No. cstc2017jcyjAX0228).
Synthesis of 2-(2-methyl-1H-indol-3-yl)ethanamine (1)
Compound 1 was prepared following the literature method.15 A mixture of
phenylhydrazine (19.8 mL, 200 mmol) and 5-chloro-2-pentanone (25 mL,
210 mmol) in EtOH (300 mL) was heated to reflux for 4 h. After cooling,
the solvent was removed under reduced pressure. Water (100 mL) was
added and the pH was adjusted to 2–3 with 2 M HCl. The aqueous layer
was washed with ethyl acetate (2 × 50 mL), then separated. The pH of the
aqueous layer was readjusted to 11–12 with 20% NaOH aqueous solution,
and the resulting solution was extracted with ethyl acetate twice, and the
organic layer was combined, successively washed with brine and dried
over anhydrous Na2SO4. It was filtered and concentrated under reduced
pressure to afford compound 1 as: Red oil; yield 23.9 g (69%); 1H NMR
(600 MHz, CDCl3):δ 1.72 (brs, 2H), 2.32 (s, 3H), 2.84 (t, J = 6.6 Hz, 2H),
2.94 (t, J = 6.6 Hz, 2H), 7.09 (m, 2H), 7.11 (d, J = 7.2 Hz, 1H), 7.23 (d,
J = 7.2 Hz, 1H), 8.14 (brs, 1H); HRMS m/z calcd for C11H14N2 [M + H]+:
175.1230; found: 175.1231.
Electronic Supplementary Information
The ESI associated with this paper can be found at:
http://ingentaconnect.com/content/stl/jcr/2018/00000042/00000009/art00006
Received 11 July 2018; accepted 22 August 2018
Paper 1805518
https://doi.org/10.3184/174751918X15357309308931
Published online: 6 September 2018
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