Synthesis of macrocyclic urea kinase inhibitors

Article abstract of DOI:10.1055/s-2007-991083

An efficient and convergent route was developed for the synthesis of a novel class of urea-based macrocyclic kinase inhibitors. The synthesis is featured with an efficient urea formation by using a key carbamate intermediate and with a smooth ring-closure olefin metathesis. Furthermore, the hydrogenations of the resulting olefins were investigated in this complex macrocyclic ring system. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-991083

LETTER
2855
Synthesis of Macrocyclic Urea Kinase Inhibitors
S
ynthesis of Ma
h
crocyclic
U
r
i
ea
K
in
-
ase Inhib
F
itors u Tao,* Thomas J. Sowin, Nan-Horng Lin
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA
Fax +1(847)9355165; E-mail: Zhi-Fu.Tao@abbott.com
Received 19 June 2007
Cl
Cl
5
Abstract: An efficient and convergent route was developed for the
synthesis of a novel class of urea-based macrocyclic kinase inhibi-
tors. The synthesis is featured with an efficient urea formation by
using a key carbamate intermediate and with a smooth ring-closure
olefin metathesis. Furthermore, the hydrogenations of the resulting
olefins were investigated in this complex macrocyclic ring system.
O
O
N
1
3
N
H
NH
X
N
H
NH
2'
2
R2
N
N
N
R6'
6'
Key words: metathesis, urea, macrocycles, hydrogenations, kinase
inhibitors
5'
X = H, CN
1a
1
X
Scheme 1
Small-molecule kinase inhibitors have great potential as
novel therapeutics in the treatment of cancer and inflam-
mation. With the success of Gleevec and Iressa as revolu-
tionary anticancer drugs, currently there is overwhelming
interest in the design and development of new kinase
inhibitors.1 Due to their unique binding mode and kinase
inhibition profile, urea-based protein kinase inhibitors
have been a major focus of medicinal chemists.2 We have
been interested in a class of diaryl ureas as checkpoint
kinase 1 (Chk1) inhibitors, exemplified by 1.3 The Chk1
inhibitors have been demonstrated to significantly poten-
tiate the cytotoxicity of DNA-damaging agents in cancer
cells, and they are believed to be a new generation of ad-
juvant therapeutics that may greatly improve the efficacy
and selectivity of DNA-damaging agents in the clinic.4
Based on the X-ray crystallographic analysis and molecu-
lar modeling of 1 complexed with Chk1, we designed
macrocyclic ureas 1a as a new class of kinase inhibitors
by connecting R2 group at the 2-position of the phenyl
ring and R6¢ at the C6¢ position of the pyrazinyl ring
(Scheme 1). It has been well documented that restriction
of conformation through macrocylization can produce
potent inhibitors and can improve pharmacokinetic prop-
erties.5 Described herein is an efficient and convergent
route for the construction of cyanopyrazine-containing
macrocyclic urea kinase inhibitors.6
Cl
Cl
4: R = NO2
a
b
R
2a: R = NH2
NO2
O
F
3
Cl
O2N
Cl
O2N
c
NH2
O
2b
NH2
OH
5
Cl
Cl
Cl
Cl
Cl
SEMO
e
HO
HO
d
NO2
NO2
6
7
8
Cl
Cl
Cl
SEMO
SEMO
f
g
NH2
NO2
O
O
9
2c
Scheme 2 Reaction conditions: (a) NaH, 3-buten-1-ol, THF, 0 °C,
97%; (b) Fe powder, NH4Cl, EtOH, H2O, 80 °C, 86%; (c) allyl
bromide, K2CO3, DMF, r.t., 90%; (d) HNO3, CCl4, 0 °C to r.t., 62%;
(e) SEMCl, DIPEA, CH2Cl2, r.t., quantitative yield; (f) allylic alcohol,
NaH, THF, r.t., 55%; (g) SnCl2, EtOH, Et3N, 70 °C, 47%.
The synthesis of the various aniline intermediates 2a–c
that were used for the formation of the urea olefins is
shown in Scheme 2. The amino and hydroxyl groups at
the 4-position of these aniline intermediates would be use-
ful handles for further elaborations of the macrocyclic
urea kinase inhibitors. Fluoride was displaced from 3 by
but-3-en-1-ol in the presence of sodium hydride to afford
4 in quantitative yield. Reduction of 4 was effected by
iron powder in the presence of ammonium chloride in
aqueous ethanol to produce 2a in excellent yield. The
alkylation of phenol 5 occurred exclusively at the hydrox-
yl group to yield 2b quantitatively. The nitration of phenol
6 predominantly occurred para to the hydroxyl group to
provide 7. The hydroxyl group was then protected with a
SEM group in the presence of Hünig’s base to yield 8
SYNLETT 2007, No. 18, pp 2855–2858
x
x
.x
x
.2
0
0
7
Advanced online publication: 12.10.2007
DOI: 10.1055/s-2007-991083; Art ID: S04707ST
© Georg Thieme Verlag Stuttgart · New York

2856
Z.-F. Tao et al.
LETTER
quantitatively. The chlorine ortho to the nitro group was tion conditions was not undertaken, several phenomena
selectively displaced by anionic allylic alcohol to produce were observed. First, for a specific substrate 17a–e, the
9 in 55% yield. The nitro group was selectively reduced in catalysts (Figure 1) exhibited activity in the order of
the presence of the olefin by tin chloride to give 2c in good Hoveyda–Grubbs catalyst > Grubbs II catalyst > Grubbs I
yield.
catalyst. Second, although the Grubbs olefin metathesis
has been reported to be incompatible with cyano groups in
some cases, the cyano group in our substrates (17a–e) was
very stable under our reaction conditions and did not show
any adverse effect on the ring-closure reaction. Third, the
length of the carbon spacers of the olefin side chains in
17a–c did not show significant effects on the ring-closure
yield. However, it did affect the conformation of the cy-
clized product. For example, 17a and 17b predominantly
produced cis-conformation products 19a and 19b, respec-
tively, and only trace of their trans counterparts were de-
tected by LC-MS. In contrast, substrate 17c produced a
4:1 mixture of cis/trans isomers, indicating that the longer
chain length allows for the formation of a trans double
bond whereas the shorter alkene moieties would result in
ring sizes that disallow a trans double bond due to geo-
metrically strain. Fourth, although the unprotected amino
group has been reported troublesome in Grubbs cycliza-
tions, olefin 17e bearing an amino group at the 4-position
was cyclized in the presence of Grubbs II catalyst in good
yield although the unprotected amine did make it more
difficult to remove the green color that presumably origi-
nated from the Grubbs catalysts.12 Finally, the substrate
17d with a SEM protecting group was macrocyclized in
excellent yield. This high efficiency may be due to its
good solubility in dichloromethane.
Scheme 3 outlines the synthesis of the advanced olefin in-
termediates. Cyanopyrazine 14 was obtained in four steps
from the commercially available methylpyrazine 10 by
following a patent literature procedure with modifica-
tions.7 Nucleophilic displacement of chloride by an alco-
hol provided the aminopyrazinyl ethers 15a,b. The direct
coupling of 15a,b with phenyl isocyanates failed to pro-
duce ureas. This failure may be attributed to the deactiva-
tion of the amino group by the electron-withdrawing
cyano group on the pyrazine ring. Consequently, the ver-
satile intermediate carbamates 16a,b were synthesized by
coupling 15a,b with phenyl chloroformate.8 Carbamates
16a,b are stable, easily stored colorless solids that have
greatly facilitated the synthesis of ureas. The coupling of
16a,b to anilines 2a–c went smoothly in DMF or toluene
(less favorable) under heating, and the pure urea products
17a–e were simply obtained by trituration in most cases.9
Since the Grubbs olefin metathesis ring-closure reaction
was first applied to the synthesis of macrocyclic peptides,
it has been a very powerful macrocyclization methodolo-
gy for the construction of synthetically challenging natu-
ral products and medicinally significant molecules.10
X-ray crystallographic analysis indicates that diaryl urea
1 has an intramolecular hydrogen bond (shown as a dotted
line between an urea NH and N1 of pyrazine of 1. This H
bond is also indicated in the general scaffold (17a–e in
Scheme 4) which potentially could facilitate a favorable
conformation for the metathesis ring closure. The ureas
17a–e were therefore cyclized by olefin metathesis in the
presence of Grubbs catalysts to provide the desired prod-
ucts 19a–f in moderate to excellent yield (Scheme 4).11
Although systematic and careful optimization of the reac-
With the unsaturated macrocycles 19a–e in hand, we per-
formed the hydrogenation of the olefin in the presence of
platinum or palladium catalysts (Scheme 4).13 We found
that the 5-Cl substituent of phenyl ring and the 5¢-CN sub-
stituent of the pyrazinyl ring were both stable to our reac-
tion conditions (Pt/C or Pd/C as catalyst). The ring size of
19a–e significantly affected the hydrogenation. Com-
Cl
N
NH2
Cl
N
Cl
Cl
N
N
N
NH2
a
c
Me
N
N
N
Cl
Cl
HON
11
12
13
10
O
NH2
NH2
Ph
O
HN
e
N
d
N
f
N
N
N
( )n
O
Cl
N
( )n
14
CN
O
CN
15a: n=1
15b: n=2
Cl
CN
16a: n = 1
16b: n = 2
R
O
17a: m = 1, n = 2, R = H (58%)
17b: m = 1, n = 1, R = H (75%)
17c: m = 2, n = 2, R = H (89%)
17d: m = 1, n = 2, R = OSEM (88%)
18: m = 1, n = 2, R = NO2 (93%)
g
N
H
NH
O
N
( )m
N
h
O
17e: m = 1, n = 2, R = NH2 (71%)
( )n
CN
Scheme 3 Reaction conditions: (a) Cl2, AcOH, 110 °C, 25%; (b) NH2OH–HCl, NaOH, H2O, EtOH, pH 7.5, 95 °C, 29%; (c) 1 N NaOH, Ac2O,
20 °C, 82%; (d) o-xylene, 160 °C, 75%; (e) but-3-en-1-ol (or allyl alcohol), NaH, dioxane, 100 °C, 80–90%; (f) phenyl chloroformate, pyridine,
CH2Cl2, 0 °C to r.t., 80–90%; (g) 2a–c, DMF (or toluene), 90 °C; (h) iron powder, NH4Cl, EtOH, H2O, 80 °C, 71%.
Synlett 2007, No. 18, 2855–2858 © Thieme Stuttgart · New York

LETTER
Synthesis of Macrocyclic Urea Kinase Inhibitors
2857
ate and with a smooth ring-closure olefin metathesis.
Furthermore, the hydrogenation of the resulting olefin
was investigated in this complex macrocyclic ring system.
The efficient synthetic methodology developed here
should facilitate the utilization of these macrocylic com-
pounds as anticancer agents in the field of kinase
inhibitors.
Mes
Cl
Cl
N
N Mes
Mes
Cl
Cl
N
N
Mes
Ph
PCy3
Cl
Ph
Ru
O
Ru
Ru
PCy3
Grubbs II Catalyst
Cl
PCy3
Grubbs I Catalyst
Hoveyda–Grubbs catalyst
Figure 1 Chemical structures of ruthenium catalysts.
References and Notes
(1) For reviews, see: (a) Meggers, E.; Atilla-Gokcumen, G. E.;
Bregman, H.; Maksimoska, J.; Mulcahy, S. P.; Pagano, N.;
Williams, D. Synlett 2007, 1177. (b) Noble, M. E. M.;
Endicott, J. A.; Johnson, L. N. Science 2004, 303, 1800.
(2) For reviews, see: (a) Dumas, J.; Smith, R. A.; Lowinger, T.
B. Curr. Opin. Drug Discovery Dev. 2004, 7, 600.
(b) Dumas, J. Curr. Opin. Drug Discovery Dev. 2002, 5,
718.
(3) Chen, Z.; Xiao, Z.; Gu, W.-Z.; Xue, J.; Bui, M.; Kovar, P.;
Li, G.; Wang, G.; Tao, Z.-F.; Tong, Y.; Lin, N.-H.; Sham, H.
L.; Wang, J. Y.; Sowin, T. J.; Rosenberg, S. H.; Zhang, H.
Y. Int. J. Cancer 2006, 119, 2784.
pounds 19a and 19b were reduced with hydrogen using
Pt/C or Pd/C as catalyst in minutes in moderate yield, and
longer reaction time resulted in extensive side reactions
with the formation of a major uncharacterized side prod-
uct. In contrast, the hydrogenation of 19c under the same
conditions went very well and provided the final product
20c in quantitative yield. Furthermore, the presence of
substituents on the 4-positon of the phenyl ring signifi-
cantly improved the hydrogenation. Olefins 19d and 19e
were reduced in the presence of Pd/C to give 20d (91%)
and 20e (80%), respectively.
(4) For a review, see: Tao, Z.-F.; Lin, N.-H. Anticancer Agents
Med. Chem. 2006, 6, 377.
Cl
(5) For a review, see: Chen, X.; Wang, W. Ann. Rep. Med.
Chem. 2003, 38, 333.
Cl
R
O
R
(6) All compounds were unambiguously characterized by 1H
NMR, MS, and analytical LC-MS.
O
N
H
NH
N
H
NH
CN
(7) Grabowski, E. J.; Tristram, E. W.; Tull, R. J. US 3625944,
1968.
(8) A Typical Procedure for the Preparation of Phenyl
Chloroformate
O
N
O
a
N
( )m
N
( )m
N
O
O
( )n
CN
( )n
To a suspension of 15b (200 mg, 1.05 mmol) in pyridine
(0.17 mL, 2.1 mmol) and CH2Cl2 (10 mL) at 0 °C was
injected phenyl chloroformate (0.145 mL, 2.1 mmol)
dropwise. The reaction mixture was stirred at r.t. for 3 h and
directly applied to flash chromatography eluted with
CH2Cl2. Compound 16b was obtained in 86% yield; mp
140–141 °C (CH2Cl2). MS (DCI/NH3): m/z = 328.13 [M +
NH4]. 1H NMR (500 MHz, DMSO-d6): d = 2.56 (q, J = 6.71
Hz, 2 H), 4.49 (t, J = 6.71 Hz, 2 H), 5.11 (dd, J = 10.22, 1.68
Hz, 1 H), 5.19 (dd, J = 17.24, 1.68 Hz, 1 H), 5.88 (m, 1 H),
7.27 (d, J = 7.63 Hz, 2 H), 7.31 (t, J = 7.32 Hz, 1 H), 7.47 (t,
J = 7.93 Hz, 2 H), 8.73 (s, 1 H), 11.62 (s, 1 H) ppm.
(9) Typical Procedures for the Preparation of Acyclic Ureas
Preparation of Compound 17a
19a: m = 1, n = 2, R = H
19b: m = 1, n = 1, R = H
19c: m = 2, n = 2, R = H
19d: m = 1, n = 2, R = OSEM (92%)
19e: m = 1, n = 2, R = NH2 (77%)
(76%)
(85%)
(62%)
17a: m = 1, n = 2, R = H
17b: m = 1, n = 1, R = H
17c: m = 2, n = 2, R = H
17d: m = 1, n = 2, R = OSEM
17e: m = 1, n = 2, R = NH2
b
Cl
O
R
20a: m = 1, n = 2, R = H
20b: m = 1, n = 1, R = H
20c: m = 2, n = 2, R = H
20d: m = 1, n = 2, R = OSEM
20e: m = 1, n = 2, R = NH2
NH
N
N
H
CN
N
O
( )m
O
( )n
2-(Allyloxy)-5-chloroaniline (108.8 mg, 0.59 mmol) and
16b (116 mg, 0.37 mmol) in toluene (10 mL) were heated at
90 °C for 24 h. The reaction mixture was concentrated and
the residue was purified by flash chromatograghy eluting
with hexane–EtOAc (3:1) to give the title compound (86 mg,
58%) as colorless solid; mp 138–139 °C (EtOAc). MS (DCI/
NH3): m/z = 400.09 [M + H]+. 1H NMR (400 MHz, DMSO-
d6): d = 2.53 (q, J = 6.65 Hz, 2 H), 4.45 (t, J = 6.60 Hz, 2 H),
4.70 (m, 2 H), 5.10 (dd, J = 10.28, 1.99 Hz, 1 H), 5.17 (m, 1
H), 5.30 (m, 1 H), 5.42 (m, 1 H), 5.85 (m, 1 H), 6.07 (m, 1
H), 7.06 (d, J = 2.15 Hz, 1 H), 7.06 (s, 1 H), 8.19 (d, J = 2.15
Hz, 1 H), 8.86 (s, 1 H), 9.05 (s, 1 H), 10.69 (s, 1 H) ppm.
Preparation of Compound 17d
A mixture of 16b (1.925g, 6.21 mmol) and 2c (2.049g, 6.21
mmol) in DMF (25 mL) was stirred at 70 °C for 6 h. The
DMF was then removed by evaporation, and the residue was
suspended in a mixture of hexane and EtOAc. The
precipitates were collected by filtration and dried in vacuo.
The desired product (3 g, 88%) was obtained as colorless
solid; mp 167–168 °C (EtOAc). MS (DCI/NH3): m/z =
Scheme 4 Reaction conditions: (a) Grubbs II catalyst, CH2Cl2, re-
flux; (b) H2, Pd/C (10%), MeOH–THF (3:1), r.t.
The olefins 19a–e may also be further elaborated to gain
access to compounds not explored in this account of our
research. For example, they can be readily transformed
into dihydroxyl,14 aminohydroxyl,15 and epoxides.16 Fur-
thermore, the amino group (19d, 20d) and the protected
hydroxyl group (19e, 20e) at the 4-position of the phenyl
ring provide a handle, with which a large number of ana-
logues could be quickly synthesized in parallel fashion for
biological tests.
In summary, an efficient and convergent route was devel-
oped for the synthesis of a novel class of macrocyclic urea
kinase inhibitors. The synthesis is featured with an effi-
cient urea formation by using a key carbamate intermedi-
Synlett 2007, No. 18, 2855–2858 © Thieme Stuttgart · New York

2858
Z.-F. Tao et al.
LETTER
546.18 [M + H]+. 1H NMR (500 MHz, DMSO-d6): d = 0.00
(s, 9 H) 0.90–0.93 (m, 2 H), 2.56 (q, J = 6.76 Hz, 2 H), 3.75–
3.79 (m, 2 H), 4.47 (t, J = 6.55 Hz, 2 H), 4.71 (d, J = 5.30 Hz,
2 H), 5.13 (d, J = 10.29 Hz, 1 H), 5.19 (dd, J = 17.31, 1.72
Hz, 1 H), 5.31 (s, 2 H), 5.33 (dd, J = 10.45, 1.40 Hz, 1 H),
5.46 (dd, J = 17.31, 1.40 Hz, 1 H), 5.89 (m, 1 H), 6.09 (m, 1
H), 7.02 (s, 1 H), 8.13 (s, 1 H), 8.85 (s, 1 H), 8.94 (s, 1 H),
10.59 (s, 1 H) ppm.
Preparation of Compound 19e
A mixture of 17e (2.93 g, 7.06 mmol) and the Grubbs II
catalyst (0.6 g, 0.71 mmol) in CH2Cl2 (3.6 L) was stirred at
r.t. overnight, and then DMSO (10 mL, 141 mmol) was
added. The resulting mixture was further stirred 24 h and
concentrated. The residue was purified by flash
chromatography eluting with 9% EtOAc in CH2Cl2 to
provide the desired product (2.1 g, 77%) as yellow solid; mp
240 °C (dec.; EtOAc). MS (DCI/NH3): m/z = 404.08 [M +
NH4]+. 1H NMR (500 MHz, DMSO-d6): d = 2.71 (q, J = 7.70
Hz, 2 H), 4.58 (d, J = 6.86 Hz, 2 H), 4.65 (t, J = 7.64 Hz, 2
H), 5.17 (s, 2 H), 5.95–6.07 (m, 2 H), 6.64 (s, 1 H), 7.81 (s,
1 H), 7.96 (s, 1 H), 10.10 (s, 1 H), 10.79 (s, 1 H) ppm; DMSO
was used to facilitate the removal of the green color as
previously described in ref. 12.
Compounds 17c and 18 were prepared using a procedure
similar to that described for 17d.
(10) (a) Miller, S. J.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117,
5855. (b) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39,
3012. (c) Martin, W. H. C.; Blechert, S. Curr. Top. Med.
Chem. 2005, 5, 1521.
(11) Typical Procedures for Ring-Closure Metathesis
The Grubbs II catalyst was used to provide the reported
yields of 19a–e.
(12) The green color could be removed by following a recently
reported method: Ahn, Y. M.; Yang, K.; Georg, G. I. Org.
Lett. 2001, 3, 1411.
Preparation of Compound 19a
Compound 17a (60 mg, 0.15 mmol) in CH2Cl2 (66 mL) was
treated with the Grubbs II catalyst (20 mg, 0.024 mmol). The
reaction mixture was stirred at 50 °C overnight. Then, the
solvent was removed under reduced pressure. The residue
was purified by flash chromatography eluting with hexane–
EtOAc (1:1). The title compound was obtained in 76% yield.
MS (DCI/NH3): m/z = 389.09 [M + NH4]+. 1H NMR (500
MHz, DMSO-d6): d = 2.71 (q, J = 7.49 Hz, 2 H), 4.68 (t,
J = 7.05 Hz, 2 H), 4.70 (d, J = 6.86 Hz, 2 H), 6.02 (m, 1 H),
6.09 (m, 1 H), 7.12 (dd, J = 8.89, 2.65 Hz, 1 H), 7.22 (d,
J = 9.04 Hz, 1 H), 7.98 (s, 1 H), 8.12 (d, J = 2.49 Hz, 1 H),
10.35 (s, 1 H), 10.97 (s, 1 H) ppm. HRMS: m/z calcld for
C17H15ClN5O3: 372.0863; found: 372.0871.
(13) Typical Procedure for the Hydrogenation – Preparation
of Compound 20d
A mixture of 19d (2 g, 3.86 mmol) and 10% Pd/C (160 mg,
0.151 mmol) in THF was stirred under H2 atmosphere for 3
h, and the insoluble material was filtered off. The filtrate was
concentrated, and the residue was purified by flash
chromatography eluting with 9% of EtOAc in CH2Cl2. The
desired product (1.83 g, 91%) was obtained as colorless
solid; mp 203–204 °C (EtOAc). MS (DCI/NH3): m/z =
537.20 [M + NH4]+. 1H NMR (500 MHz, DMSO-d6): d =
0.00 (s, 9 H), 0.90–0.94 (m, 2 H), 1.59–1.65 (m, 2 H), 1.83–
1.87 (m, 2 H), 1.94–2.01 (m, 2 H), 3.77–3.80 (m, 2 H), 4.19–
4.21 (m, 2 H), 4.60–4.63 (m, 2 H), 5.35 (s, 2 H), 7.05 (s, 1
H), 8.00 (s, 1 H), 8.17 (s, 1 H), 9.84 (s, 1 H), 10.90 (s, 1 H).
(14) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 17, 1973.
Compounds 19b,c,d were prepared using a procedure
similar to that described for 19a.
Compound 19d: mp 170–171 °C (EtOAc). MS (DCI/NH3):
m/z = 535.14 [M + NH4]+. 1H NMR (400 MHz, DMSO-d6):
d = 0.00 (s, 9 H), 0.90–0.94 (m, 2 H), 2.73 (q, J = 7.36 Hz, 2
H), 3.76–3.80 (m, 2 H), 4.66–4.73 (m, 4 H), 5.36 (s, 2 H),
5.99–6.14 (m, 2 H), 7.13 (s, 1 H), 7.99 (s, 1 H), 8.07 (s, 1 H),
10.24 (s, 1 H), 10.93 (s, 1 H) ppm.
(15) Johnson, R. A.; Sharpless, K. B. Comprehensive Organic
Synthesis, Vol. 7; Trost, B. M.; Fleming, I., Eds.; Pergamon:
Oxford, 1991, 389.
(16) Bloch, R.; Abecassis, J.; Hassan, D. J. Org. Chem. 1985, 50,
1544.
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