A scalable and facile process for the preparation of N-(pyridin-4-yl) piperazine-1-carboxamide hydrochloride

Article abstract of DOI:10.3184/174751916X14546711471143

A scalable and facile synthetic process for N-(pyridin-4-yl)piperazine-1-carboxamide hydrochloride, a novel Rho kinase inhibitor with an unsymmetrical urea structure currently under investigation for the treatment of central nervous system disorders, was established. After optimisation of the reaction conditions, N-(pyridin-4-yl)piperazine-1-carboxamide hydrochloride was synthesised from 4-aminopyridine and N,N'-carbonyldiimidazole through acylation, deprotection and salt formation. This new procedure affords the product in 53% overall yield with high purity and it can be easily scaled up for production.

Full text of DOI:10.3184/174751916X14546711471143

152 RESEARCH PAPER
VOL. 40 MARCH, 152–155
JOURNAL OF CHEMICAL RESEARCH 2016
A scalable and facile process for the preparation of N-(pyridin-4-yl)
piperazine-1-carboxamide hydrochloride
Daiyan Weia, Ligong Chenb, Xilong Yanb, Yang Lib, Jianye Lia and Donghua Wanga*
aSchool of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P.R. China
bSchool of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P.R. China
A scalable and facile synthetic process for N-(pyridin-4-yl)piperazine-1-carboxamide hydrochloride, a novel Rho kinase inhibitor with an
unsymmetrical urea structure currently under investigation for the treatment of central nervous system disorders, was established. After
optimisation of the reaction conditions, N-(pyridin-4-yl)piperazine-1-carboxamide hydrochloride was synthesised from 4-aminopyridine
and N,N’-carbonyldiimidazole through acylation, deprotection and salt formation. This new procedure affords the product in 53% overall
yield with high purity and it can be easily scaled up for production.
Keywords: N-(pyridin-4-yl)piperazine-1-carboxamide hydrochloride, Rho kinase inhibitor, asymmetric urea, N,N’-carbonyldiimidazole
Multiple sclerosis (MS), a chronic inflammatory demyelinating
disease of the central nervous system (CNS),1–3 is characterised
by the destruction of myelin and axons leading to progressive
disability.4 Some reports have demonstrated that intervention in
the CNS by Rho kinase inhibitors can improve clinical symptoms
and pathological changes.5 Rho kinases, which play important
roles in a series of cellular activities, are serine/threonine
kinases and are downstream substrates of the Rho protein.6–8
A comparative study showed that the efficacy of Rho kinase
inhibitors reduced leukocyte infiltration in damaged areas of the
CNS was better than a conventional dose of methylprednisolone.9
Research on experimental autoimmune encephalomyelitis (EAE)
and phagocytic cell culture confirmed that Rho kinase inhibitors
could inhibit leukocyte migration, infiltration and phagocytosis,
which significantly reduced demyelination.10 Rho kinase
activation contributes to neurite retraction,11 while Rho kinase
inhibitors enhance axonal regeneration.12
Rho kinase inhibitors fall into four structural categories:
4-aminopyridine, 1H-indazole, isoquinoline and phthalimide
derivatives. Since the discovery13 of the novel 4-aminopyridine
Rho kinase inhibitor N-(pyridin-4-yl)piperazine-1-carboxamide
hydrochloride (1) and its potent action14 as a potential agent for
neurological disorders, multikilogram quantities of compound
1 were required to support further pharmacological profiling
and clinical trials. X. Wang et al.13 first synthesised N-(pyridin-
4-yl)piperazine-1-carboxamide (5), however, the process was
found unsuitable for large-scale manufacture as it required
column chromatography and suffered from prolonged reaction
times and harsh reaction conditions etc. The promise shown by
N-(pyridin-4-yl)piperazine-1-carboxamide hydrochloride (1)
prompted the search for a better synthetic route that is efficient,
simple and robust to meet the needs for future clinical trials.
mixture and optimisation of the reaction conditions did not
provide promising results. Consequently, it was difficult to
obtain the pure compound by a simple separation. These
problems may possibly be attributed to the high reactivity of
the isocyanate, which led to the generation of impurities. We
therefore theorised that use of substrates with controllable
reactivity may work better. Based on this consideration, we
decided to use the approach of X. Wang et al.,13 in which the
isocyanate group was replaced by a carbamate function21
(Scheme 1) and the reaction was achieved in a stepwise manner.
Ethyl chloroformatewas usedtoform theintermediate carbamate
4 that subsequently reacted with piperazine to give compound 5.
Subsequent salt formation by treatment with 36% hydrochloric
acid gave target compound 1. It was found that the nucleophilic
substitution of ethyl chloroformate with 4-aminopyridine proceeds
effectively to produce compound 4 in 89% yield, but the second
step does not work well and so we attempted to improve it
further. Catalysts, such as AlMe3 and 1-methylpyrrolidine were
examined for this reaction and the results obtained showed that
1-methylpyrrolidine exhibits better catalytic performance, while no
reaction is observed without a catalyst. Polar aprotic solvents were
preferable, so DMF, DMSO, DCM, THF and 1,4-dioxane were
evaluated. All the reactions were carried out at the boiling point
of the solvent to enhance the reaction. The results indicated that
1,4-dioxane was the best choice not only in terms of yield but also
in post-processing. 1,4-Dioxane was found to be a better solvent
than the higher boiling DMF and DMSO. This may possibly be
due to volatilisation of the catalyst. We obtained the pure target
compound 5 successfully via this method and prepared sufficient
product for evaluation, but this synthetic route is only suitable for
small scale production. Scaling up the production only produced
a yield of 38%, because, in the second step, a reaction time of
24 h was needed even under optimised conditions. Furthermore,
pure product could only be obtained by two chromatographic
separations.
Results and discussion
Although studies of 4-aminopyridine derivatives containing
a urea unit as Rho kinase inhibitors are of importance, the
synthesis of this class of compounds is seldom reported. In 2009,
Sebti and Hamilton15 successfully prepared 4-aminopyridine
derivatives as Rho kinase inhibitors from 4-isocyanatopyridine,
but no experimental details were mentioned, nor was the
synthesis of the isocyanate disclosed. Because this isocyanate
was commercially unavailable, we first tried to prepare it from
4-aminopyridine and triphosgene16–20 and found it was unstable
and difficult to separate from the reaction mixture. Hence,
we attempted to carry on the next step without separation.
Unfortunately, many impurities were detected in the reaction
A sealed reaction vessel was considered to raise the
temperature without volatilisation of the catalyst and an
autoclave was used to perform this reaction at 160 °C for 6 h
with a pressure of 1 MPa (Scheme 1). After this time, analysis
of the reaction mixture showed the reaction was complete, no
starting material was detected and the yield increased from
38% to 50%. However, a crystalline by-product had precipitated
from the reaction solution. Analysis of this solid revealed it to
be the bis-substituted piperazine 2.
Two methods were investigated to decrease the formation of
the bis-substituted by-product. Thus, when N-Boc-piperazine, in
* Correspondent. E-mail: dhwang022@163.com

JOURNAL OF CHEMICAL RESEARCH 2016 153
O
O
HN
N
N
HN
N
N
H
NH
•2H
N
N
l
C
O
N
1
2
O
HN
N
piperazine
NH
1-methylpyrrolidine
1,4-dioxane
N
5
O
O
O
O
NH2
HN
N
N
HN
N
N
piperazine
HN
O
36 HCl
%
l
C
O
NH
•2H
NH
1-methylpyrrolidine
1,4-dioxane 1.0 MPa
Et3N, CH2Cl2
EtOAc
l
C
N
N
1
5
3
4
O
HN
N
N
N-Boc-piperazine
N
O
1-methylpyrrolidine
1,4-dioxane 1.0 MPa
O
6
Scheme 1 Synthesis of compound 1 from ethyl chloroformate and 4-aminopyridine.
O
O
HN
N
HN
N
N
HN
N
N
O
Boc2O
HN
+
N
+
O
NH
NH
O
H
NaOH, 2O
O
1,4-dioxane
5
7
6
8
Scheme 2 Reaction of crude product with t-butyloxycarbonyl anhydride.
which one active site of the piperazine is blocked, was used as the
nucleophilic reagent, substitution on nitrogen by the Boc group led
to lower reactivity and conversion to the product was poor (Scheme
1). The amount of piperazine was increased in an attempt to avoid
by-products. It was found that none of the piperazine 2 was formed
with a 5:1 molar ratio of piperazine to compound 4.
toluene, acetonitrile, acetone, 1,4-dioxane, ethyl acetate, DCM
and THF. As a result, compound 6 and N-Boc-piperazine could
be effectively separated in acetone and 1,4-dioxane. Hence,
the reaction mixture was reacted with t-butyloxycarbonyl
anhydride (Scheme 2). This was followed by recrystallisation
from acetone to obtain the pure compound 6. Deprotection of
compound 6 by hydrogen chloride formed the target compound
1 in high purity. Thus we have developed a route to prepare the
target compound on a large scale.
Although we obtained the product in large scale with high
purity, there were also some drawbacks such as pressure and
the protection–deprotection reaction etc. Moreover, the reagent
ethyl chloroformate is highly toxic and difficult to store and
transport. Further study is needed to develop a more convenient
way to solve these problems. Thus, N,N’-carbonyldiimidazole
(CDI) was chosen to effect N-acylation of 4-aminopyridine.
CDI is comparatively stable, as available as ethyl chloroformate
and also can be used as the reagent to prepare unsymmetric
ureas.22–24 The newly designed route is shown in Scheme 3.
A number of solvents such as DMSO, acetonitrile, ethyl
acetate, DCM, toluene, THF, 1,4-dioxane and acetone were
The next step was to remove the large amount of excess
piperazine to meet the demands for pharmaceutical evaluation.
We found that upon acidification of the reaction mixture with
HCl gas, most of the piperazine hydrochloride precipitated from
the methanol solution while target compound 1 remained in
solution, but further recrystallisation gave little improvement.
Other solvents such as acetonitrile, ethanol, isopropyl alcohol,
acetone, 1,4-dioxane, ethyl acetate and methylene chloride were
selected to recrystallise the crude product, but compound 1
and piperazine hydrochloride exhibited similar solubility in all
solvents, so it was difficult to remove all of the piperazine.
Based on consideration of the structures of compound 5
and piperazine, we assumed the derivatisation of these two
compounds may change their solubility in certain solutions.
So, compound 6 and N-Boc-piperazine were dissolved in DMF,

154 JOURNAL OF CHEMICAL RESEARCH 2016
O
O
NH2
HN
N
N
HN
N
N
1. CDI, Et3N, acetone
36%
HCl
N
O
NH
•2HCl
2. N-Boc-piperazine
EtOAc
O
N
3
6
1
Scheme 3 Synthesis of compound 1 from CDI and 4-aminopyridine.
Synthesis
of
N-(pyridin-4-yl)
piperazine-1-carboxamide
examined, of which acetone showed particular promise, while
the reaction did not proceed in DMSO or in acetonitrile.
Although the reaction proceeded when ethyl acetate, DCM,
toluene, THF and 1,4-dioxane were used as solvents, it was
necessary to increase the amount of CDI. This route with mild
conditions can operate at room temperature without the need to
separate any of the intermediates. The use of N-Boc-piperazine
not only reduced the incidence of impurities, but also effectively
avoided column chromatography, because in the system only
compound 6 precipitated from the acetone solution. Compound
6 was recrystallised from acetone–water (5:1 v/v). In the last
step, in order to effectively save resources and time, 36%
hydrochloric acid was added in excess to give the hydrochloride
directly. The reaction cycle was shortened to 5 h and the whole
yield was raised to 53%.
hydrochloride (1) from 4 and piperazine
Compound 4 (100.00 g, 621.20 mmol) was added to a solution of
piperazine (66.26 g, 745.44 mmol) in 1,4-dioxane (300 mL) with
1-methylpyrrolidine (52.85 g, 621.20 mmol) as catalyst. The mixture
was refluxed for 24 h and then concentrated. The residue was purified
by column chromatography (ethyl acetate–methanol 5:1, v/v) to afford
compound 5 (47.14 g, 38% yield). The product 5 was dissolved in ethyl
acetate (400 mL) and converted to the hydrochloride 1 by introduction
of 36% hydrochloric acid (60 mL). The mixture was filtered off and
dried to obtain compound 1: Yield 59.78 g (94%); m.p. 196.8–197.4 °C;
1H NMR (600 MHz, MeOD): δ 8.54 (d, J = 6.8 Hz, 2H), 8.11 (d, J = 6.7
Hz, 2H), 3.95 (d, J = 4.5 Hz, 4H), 3.38–3.36 (m, 4H); 13C NMR (150
MHz, MeOD): δ 157.3, 154.5, 142.3, 115.4, 44.4, 42.7; HRMS (ESI) for
C10H14N4O: [M + H]+: calcd: 207.1246; found: 207.1249.
Synthesis of N-(pyridin-4-yl)piperazine-1-carboxamide hydrochloride
(1) from 4 and piperazine in an autoclave
Ultimately, through the optimisation of the process, a
scalable and facile process for the synthesis of the novel Rho
kinase inhibitor N-(pyridin-4-yl)piperazine-1-carboxamide
hydrochloride, an unsymmetrical urea derivative, was
established in overall yield of 53.8%. The use of an autoclave
can shorten the time from 24 h to 5 h, however, the process of
removing the impurities was cumbersome. The use of N-Boc-
piperazine and CDI not only reduced the incidence of impurities,
but also effectively avoided column chromatography. The
reaction operated with acetone as solvent at room temperature
furnishing a pilot-scale synthesis of 3 kg quantities of high
quality active pharmaceutical ingredient, which provided
convenience for future clinical trials.
Compound 4 (96.60 g, 581.44 mmol) was added to a solution of
piperazine (258.42 g, 2907.17 mmol) in 1,4-dioxane (400 mL)
with 1-methylpyrrolidine (49.47 g, 581.44 mmol) as catalyst. The
mixture was placed in an autoclave for 6 h with a pressure of 1 MPa,
temperature of 160 °C and a rotation speed of 385 r min–1 and then
concentrated. The residue was purified by column chromatography
(ethyl acetate–methanol 5:1, v/v) to afford compound 5 (61.65 g,
50% yield). The product 5 was converted to the hydrochloride 1 and
precipitated from the ethyl acetate (500 mL) after 36% hydrochloric
acid (75 mL) was added dropwise. The mixture was filtered off and
dried to obtain compound 1 (93% yield).
Synthesis of N1,N4-di(pyridin-4-yl)piperazine-1,4-dicarboxamide (2)
from 4 and piperazine
Experimental
Solvents and reagents were obtained from commercial sources and
used without further purification unless otherwise noted. Solvents
were dried and purified according to standard procedures before use.
The course of the reactions was monitored by TLC (silica gel GF254s).
Flash chromatography was performed using 200–300 mesh silica
Compound 4 (96.00 g, 577.83 mmol) was added to a solution
of piperazine (59.65 g, 693.39 mmol) in 1,4-dioxane (400 mL)
with 1-methylpyrrolidine (49.47 g, 581.44 mmol) as catalyst. The
mixture was placed in an autoclave for 6 h with a pressure of 1 MPa,
temperature of 160 °C and a rotation speed of 385 r min–1. The solid
that precipitated from the solution was purified by recrystallisation
from methanol to give compound 2: Yield 35.92 g (19%); m.p.
220.1–221.6 °C; 1H NMR (600 MHz, DMSO-d6): δ 9.04 (s, 2H), 8.32
(d, J = 4.5 Hz, 4H), 7.49 (d, J = 4.8 Hz, 4H), 3.53 (s, 8H); 13C NMR (150
MHz, DMSO-d6): δ 154.1, 149.8, 147.4, 113.0, 43.6; HRMS (ESI) for
C16H18N6O2: [M + H]+: calcd: 327.1569; found: 327.1570.
1
gel. H and 13C NMR spectra were measured in CDCl3, MeOD and
DMSO-d6 solutions and recorded on INOVA 600 MHz and Bruker 400
MHz spectrometers with TMS as an internal standard. HRMS were
recorded with a Bruker MicrOTOF-QII spectrometer. IR spectra were
obtained using KBr disks on the FTIR Bruker Tensor 27.
Ethyl pyridin-4-ylcarbamate (4)
Synthesis of N-(pyridin-4-yl)piperazine-1-carboxamide hydrochloride
(1) from 4 and N-Boc-piperazine in an autoclave
Triethylamine (1295.23 g, 12.75 mol) and ethyl chloroformate
(1153.12 g, 10.63 mol) were added to a solution of 4-aminopyridine
(1000.06 g, 10.62 mol) in anhydrous DCM (1.2 L) at –8 °C over 2 h.
The resulting mixture was stirred at –8 °C for 3 h. The reaction mixture
was adjusted to pH 5–6 by 5% hydrochloric acid. Then the aqueous
phase was extracted with DCM (3 × 1 L). The DCM phases were
combined, dried over MgSO4 and concentrated to afford 4 as: White
solid; yield 1574.64 g (89%); m.p. 126.7–127.4 °C (lit.25 127–128 °C);
1H NMR (600 MHz, CDCl3): δ 8.72 (s, 1H), 8.46 (d, J = 5.1 Hz, 2H),
7.45 (d, J = 5.1 Hz, 2H), 4.25 (q, J = 6.9 Hz, 2H), 1.31 (t, J = 7.0 Hz,
3H); 13C NMR (150 MHz, CDCl3): δ 153.4, 150.1, 146.3, 112.7, 61.6,
14.4; HRMS (ESI) for C8H10N2O2: [M + H]+: calcd: 167.0821; found:
167.0821.
Compound 4 (100.38 g, 604.19 mmol) was added to a solution of
N-Boc-piperazine (154.10 g, 725.03 mmol) in 1,4-dioxane (400 mL)
with 1-methylpyrrolidine (51.41 g, 604.19 mmol) as catalyst. The
mixture was placed in an autoclave for 6 h with a pressure of 1 MPa,
temperature of 160 °C, rotation speed of 385 r min–1 and then the
reaction mixture was concentrated. The residue was purified by
column chromatography (dichloromethane–methanol 10:1, v/v). The
residue was slurried with acetone and water (1:5, v/v) and then the
mixture was filtered off and dried to afford compound 6 (31.62 g, 17%
yield). The solid product 6 was dissolved in ethyl acetate (350 mL) and
then 36% hydrochloric acid (30 mL) was added and the mixture stirred

JOURNAL OF CHEMICAL RESEARCH 2016 155
2
3
4
K.J. Peine, M. Guerau-de-Arellano, P. Lee, N. Kanthamneni, M. Severin,
G.D. Probst, H. Peng, Y. Yang, Z. Vangundy, T.L. Papenfuss, A.E. Lovett-
Racke, E.M. Bachelder and K.M. Ainslie, Mol. Pharm., 2014, 11, 828.
T. Tselios, V. Apostolopoulos, I. Daliani, S. Deraos, S. Grdadolnik, T.
Mavromoustakos, M. Melachrinou, S. Thymianou, L. Probert, A. Mouzaki
and J. Matsoukas, J. Med. Chem., 2002, 45, 275.
C.K. Wang, C.W. Gruber, M. Cemazar, C. Siatskas, P. Tagore, N. Payne, G.
Sun, S. Wang, C.C. Bernard and D.J. Craik, ACS Chem. Biol., 2014, 9, 156.
N. Wettschureck and S. Offermanns, J. Mol. Med., 2002, 80, 629.
G. Zalcman, V. Closson, G. Linarès-Cruz, F. Lerebours, N. Honoré, A.
Tavitian and B. Olofsson, Oncogene, 1995, 10, 1935.
T. Matozaki, H. Nakanish and Y. Takai, Cell. Signal., 2000, 12, 515.
K. Fujisawa, A. Fujita, T. Ishizaki, Y. Saito and S. Narumiya, J. Biol.
Chem., 1996, 271, 23022.
M. Hara, M. Takayasu, K. Watanabe, A. Noda, T. Takagi, Y. Suzuki and J.
Yoshida, J. Neurosurg.-Spine, 2000, 93, 94.
for 30 min. The product 6 was converted to the hydrochloride 1 in 91%
yield.
Synthesis of tert-butyl 4-(pyridin-4-ylcarbamoyl)piperazine-1-
carboxylate (6) from compound 5
Sodium hydroxide (2.34 g, 58.41 mmol) was added to a mixture of
compounds 5 and 7 (4.01 g, 19.47 mmol) in water–1,4-dioxane (3:1 v/v,
80 mL) at room temperature. Then, a solution of t-butyloxycarbonyl
anhydride (8.51 g, 38.94 mmol) in water–1,4-dioxane (3:1 v/v,
40 mL) was added dropwise at room temperature under stirring
and the resulting mixture was stirred for 1 h. The reaction mixture
was filtered and the filter cake was slurried with water–1,4-dioxane
(3:1 v/v, 40 mL) to give compound 6: White solid; yield 5.42 g; m.p.
5
6
7
8
1
9
200.8–201.4 °C; H NMR (400 MHz, MeOD): δ 8.31 (d, J = 6.4 Hz,
2H), 7.52 (d, J = 6.4 Hz, 2H), 3.53 (dd, J = 19.5, 5.5 Hz, 8H), 1.50
(s, 9H); 13C NMR (100 MHz, MeOD): δ 155.0, 154.9, 148.9, 148.4,
113.6, 80.3, 43.7, 27.3; HRMS (ESI) for C15H22N4O3: [M + H]+: calcd:
307.1770; found: 307.1770.
10 J. Greenwood, C.E. Walters, G. Pryce, N. Kanuga, E. Beraud, D. Baker and
P. Adamson, FASEB J., 2003, 17, 905.
11 E.-E. Govek, S.E. Newey and A.L. Van, Genes Dev., 2005, 19, 1.
12 A.E. Fournier, B.T. Takizawa and S.M. Strittmatter, J. Neurosci., 2003,
23(4), 1416.
Synthesis of compound 1 from N,N′-carbonyldiimidazole (CDI) and
N-Boc-piperazine
13 X. Wang, L. Chen, H. Li, C. Sun, H. Qi and D. Wang, J. Heterocycl. Chem.,
2015, 52, 1212.
4-Aminopyridine (2000.15 g, 21.25 mol) was added to a solution
of CDI (3445.60 g, 21.25 mol) in acetone (4.0 L) with triethylamine
(2590.48 g, 25.50 mol) as base. The mixture was stirred for 4 h and
then N-Boc-piperazine (4516.56 g, 21.25 mol) was added and the
mixture stirred for 2.5 h. After filtration, the filter cake was slurried
with acetone and water (1:5, v/v), and then compound 6 was filtered
off and dried (3838.60 g, 59% yield). The solid product 6 was dissolved
in ethyl acetate (10 × 4 L) and then 36% hydrochloric acid (10 ×
350 mL) was added and the mixture stirred for 30 min. The product,
the hydrochloride 1, was obtained after filtration: m.p. 197.1–197.7 °C;
yield 91%.
14 Z.-b. Ding, H. Zhang, X.-w. Yang, H.-f. Zhang, J.-z. Yu, Y.-h. Li, C.-y. Liu,
W.-f. Yang, J.-l. Li, Q.-j. Feng, Y.-f. Zhao, B.-g. Xiao and C.-g. Ma, Chin. J.
Pathophysiol., 2014, 30, 1610.
15 S.M. Sebti and A.D. Hamilton, US Pat. Appl., 2009/0318684 A1.
16 X.D. Liu, M. Kimura, A. Sudo and T. Endo, J. Polym. Sci. A1, 2010, 48,
5298.
17 D. Liu, Z. Tian, Z. Yan, L. Wu, Y. Ma, Q. Wang, W. Liu, H. Zhou and C.
Yang, Bioorg. Med. Chem., 2013, 21, 2960.
18 S. Uesato, Y. Hashimoto, M. Nishino, Y. Nagaoka and H. Kuwajima, Chem.
Pharm. Bull., 2002, 50, 1280.
19 M. Yamanaka and R. Aoyama, Bull. Chem. Soc. Jpn., 2010, 83, 1127.
20 G. Guercio, S. Bacchi, A. Perboni, C. Leroi, F. Tinazzi, I. Bientinesi, M.
Hourdin, M. Goodyear, S. Curti, S. Provera and Z. Cimarosti, Org. Process
Res. Dev., 2009, 13, 1100.
21 R.S. Li, M.P. Martin, Y. Liu, B.L. Wang, R.A. Patel, J.Y. Zhu, N. Sun, R.
Pireddu, N.J. Lawrence, J.N. Li, E.B. Haura, S.S. Sung, W.C. Guida, E.
Schonbrunn and S.M. Sebti, J. Med. Chem., 2012, 55, 2474.
22 Y. Zhang, M. Anderson, J.L. Weisman, M. Lu, C.J. Choy, V.A. Boyd,
J. Price, M. Sigal, J. Clark, M. Connelly, F. Zhu, W.A. Guiguemde, C.
Jeffries, L. Yang, A. Lemoff, A.P. Liou, T.R. Webb, J.L. DeRisi and R.K.
Guy, Med. Chem. Lett., 2010, 1, 460.
Electronic Supplementary Information
The ESI (1H and 13C NMR spectra of compounds 1, 2, 4 and 6)
is available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
Received 2 September 2015; accepted 17 January 2016
Paper 1503572 doi: 10.3184/174751916X14546711471143
Published online: 11 February 2016
23 A. Velavan, S. Sumathi and K.K. Balasubramanian, Org. Biomol. Chem.,
2012, 10, 6420.
24 D.A. Walsh, J.J.B. Green, S.K. Franzyshen, J.C. Nolan and J.M. Yanni, J.
Med. Chem., 1990, 33, 2028.
References
25 D.T. Smith, R. Shi, R.B. Borgens, J.M. McBride, K. Jackson, S.R. Byrn,
Eur. J. Med. Chem., 2005, 40, 908.
1
M. Turvey, T. Koudelka, I. Comerford, J.M. Greer, W. Carroll, C.C.A.
Bernard, P. Hoffmann and S.R. McColl, J. Proteome Res., 2014, 13, 3655.