Synthesis of novel KDR kinase inhibitors through catalytic reductive cyclization of o-nitrobenzylcarbonyl compounds

Article abstract of DOI:10.1021/jo048843m

An efficient synthesis of o-nitrobenzylcarbonyl compounds is demonstrated through the Swern-type oxidation of readily accessible phenethanol analogues. Reductive cyclization of o-nitrobenzylcarbonyl 3 using catalytic Raney nickel gives 1H-indol-2-yl-1H-qu

Full text of DOI:10.1021/jo048843m

H2/Pd,7 H2/RaNi,8 SnCl2,9 Fe/AcOH,10 Zn/AcOH,11 TiCl3/
NH4OAc,12 and Na2S2O4.13 However, the availability of
starting materials has severely limited the utility of this
approach. While recent advances by Buchwald,12a Rawal,12b
RajanBabu,14 and others15 have given ready access to
o-nitrobenzylcarbonyl compounds, there is still a need for
methods which provide highly functionalized o-nitroben-
zylcarbonyl compounds and their subsequent conversion
to indoles. It was envisioned that nitroketone 3 could be
derived by oxidation of nitrocompound 9 which may be
prepared by employing chemistry previously reported
from these laboratories.16
Syn th esis of Novel KDR Kin a se In h ibitor s
th r ou gh Ca ta lytic Red u ctive Cycliza tion of
o-Nitr oben zylca r bon yl Com p ou n d s
Audrey Wong,* J effrey T. Kuethe, Ian W. Davies, and
David L. Hughes
Department of Process Research, Merck & Co., Inc.,
P.O. Box 2000, Rahway, New J ersey 07065
audrey_wong@merck.com
Received J uly 8, 2004
The synthesis of 9 began with 4-nitrobenzyl bromide
4 (Scheme 2). Reaction of 4 with 1-methanesulfonylpip-
erazine 517 in the presence of Na2CO3 in DMF afforded
nitropiperazine derivative 6 in 99% yield after direct
crystallization of the product from the crude reaction
mixture. Addition of trimethylsilylmethylmagnesium
chloride to 6 in THF at -15 °C followed by oxidation of
the intermediate nitronate with aqueous iodine gave
silyl-nitro compound 7 in 85% yield.16 Condensation of 7
with formylquinoline 818 in the presence of a catalytic
amount of TBAF (25 mol %) provided alcohol 9 as a
colorless foam in 89% isolated yield.19
Abstr a ct: An efficient synthesis of o-nitrobenzylcarbonyl
compounds is demonstrated through the Swern-type oxida-
tion of readily accessible phenethanol analogues. Reductive
cyclization of o-nitrobenzylcarbonyl 3 using catalytic Raney
nickel gives 1H-indol-2-yl-1H-quinoline 2 in 95% yield.
Hydrolysis of 2 affords the KDR kinase inhibitor 1 in
quantitative yield. The examination of the reductive cycliza-
tion reaction and optimization of conditions is described.
Vascular endothelial growth factor (VEGF) is a family
of proteins implicated in angiogenic activity, which is key
to normal tissue repair. However, at elevated levels,
VEGF can also add to the progression of several diseases
including solid tumors, which require new blood vessels
for growth.1 The mitogenic cell surface receptor for VEGF
is the tyrosine kinase KDR (kinase insert domain-
containing receptor), which upon activation through
ligand binding initiates the formation and in-growth of
new blood vessels.2 Tumor growth inhibition has been
demonstrated through blockade of endothelial cell growth
signaling by antibodies against the ligand VEGF and the
receptor KDR, as well as small molecule inhibitors of
KDR kinase activity.3,4a Recently, the potent and selective
KDR inhibitor 1 was identified as a clinical candidate
for use in the treatment of cancer.4 The novel 1H-indol-
2-yl-1H-quinolin-2-one ring system of 1,5 which is the key
pharmacophore, was envisioned as arising from reductive
cyclization of the highly functionalized nitroketone 3
(Scheme 1). In this paper, we present the synthesis of 3
and related nitroketones and optimized conditions for
their conversion to 2-substituted indoles of type 2.
(5) (a) Fraley, M. E.; Hoffman, W. F.; Arrington, K. L.; Hungate, R.
W.; Hartman, G. D.; McFall, R. C.; Coll, K. E.; Rickert, K.; Thomas,
K. A.; McGaughey, G. B. Curr. Med. Chem. 2004, 11, 707. (b) Fraley,
M. E.; Arrington, K. L., Buser, C. A.; Ciecko, P. A.; Coll, K. E.;
Fernandes, C.; Hartman, G. D.; Hoffman, W. F.; Lynch, J . J .; McFall,
R. C.; Rickert, K.; Singh, R.; Smith, S.; Thomas, K. A.; Wong, B. K.
Bioorg. Med. Chem. Lett. 2004, 14, 351.
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S. A.; Rawal, V. H. Org. Lett. 1999, 1, 673. (c) Moody, C. J .; Rahimtoola,
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Lobachevsky, P. Aust. J . Chem. 1998, 51, 243. (b) Finger, G. C.;
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One of the oldest effective methods for the construction
of indoles and indolinones is reductive cyclization of
o-nitrobenzylcarbonyl compounds.6 The transformation
has been carried out with a variety of reagents including
(1) Thomas, K. J . Biol. Chem. 1996, 271, 603.
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(17) J acob, R. M. German Patent DE828695, 1950.
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(4) (a) Fraley, M. E.; Arrington, K. L.; Bilodeau, M. T.; Hartman,
G. A.; Hoffman, W. F.; Kin, Y.; Hungate, R. W. US Patent 6,306,874
B1, 2001. (b) Fraley, M. E. Presented at the 29th National Medicinal
Chemistry Symposium, Madison, WI, J une 2004; Abstract 14.
10.1021/jo048843m CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/02/2004
J . Org. Chem. 2004, 69, 7761-7764
7761

SCHEME 1. Retr osyn th etic Ap p r oa ch to 1
SCHEME 2
SCHEME 4
SCHEME 3
the initially formed ketone 3 with NEt3 followed by
reaction with excess activated DMSO. By switching the
competing electrophile generated from DMSO/oxalyl
chloride to DMSO/acetic anhydride,22 the expected ni-
troketone 3 was obtained in 78% yield, through direct
chromatography of the reaction mixture. In addition to
3, sulfide 11 (10%) and acetate 12 (3%)23 were also
observed in the crude reaction mixture. The optimal
conditions for the oxidation of 9 to 3 involved heating an
isopropyl acetate solution of 9 to 80 °C containing DMSO
(12 equiv) followed by the addition of Ac2O (6 equiv).
With nitroketone 3 in hand, our attention turned to
the key reductive cyclization of 3 and the formation of
indole 2 (Scheme 4). A variety of conditions were exam-
ined for the conversion of 3 to 2 (Table 1). While the
reduction of 3 with Fe/AcOH (29%), TiCl3 (70%), or
sodium hydrosulfite (38%) provided the desired product
2, these reactions were plagued with significant levels
of unidentified byproducts which were difficult to remove.
Interestingly, reduction with either Pd/H2 (1 mol %, 5%
Pd/C, 65 °C) or Pt/C (10 mol %, 5% Pt/C, rt) gave hydroxy
With the desired alcohol 9 in hand, efforts turned to
the oxidation of 9 to ketone 3. Reaction of 9 under
standard Swern oxidation conditions (oxalyl chloride/
DMSO)20 afforded R-chloroketone 10 as the sole identifi-
able product in 47% isolated yield (Scheme 3). The
formation of 10 was unanticipated but not unprec-
edented21 and most likely arises from deprotonation of
(22) (a) Albright, J . D.; Goldman, L. J . Am. Chem. Soc. 1965, 18,
4214. (b) Albright, J . D.; Goldman, L. J . Am. Chem. Soc. 1967, 89,
2416.
(23) The formation of acetate 12 was confirmed through independent
synthesis by reaction of alcohol 6 with Ac2O, which yielded 12 in 65%
yield. See the Supporting Information.
(19) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Todesco, P. E. J . Org. Chem.
1986, 51, 3694.
(20) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(21) For the chlorination of ketones under Swern oxidation condi-
tions, see: Tidwell, T. T. Synthesis 1990, 857 and references therein.
7762 J . Org. Chem., Vol. 69, No. 22, 2004

TABLE 1. Su m m a r y of Red u ctive Cycliza tion on 3
SCHEME 5
timea H2
2f 13 14
entry
catalyst
Fe/AcOH
TiCl3
Na2S2O4
solvent
(h) (psi) (%) (%) (%)
1
2
3
4
5
6
MeOH/H2O
MeOH
MeOH/THF
THF
6
0.5
4
0
0
0
29
70
38
1
3
0
0
0
0
0
b
10 mol % 5% Pt/Cb
1 mol % 5% Pd/Cc
30% Raney Ni
2800 (H2O)
20
12
15
40
40
0
THF
THF
40 6.6 76
0
40
60
80
40
20
30
40
40
40
93
0
4.7
7
8
30% Raney Ni
2800 (H2O)
30% Raney Ni
2800 (H2O)
40% Raney Ni
2800 (H2O)
60% Raney Ni
2800 (H2O)
60% Raney Ni
2800 (H2O)
60% Raney Ni
2800 (H2O)
THF
THF
THF
THF
THF
THF
THF
THF
6
6
88 2.8 5.8
81 5.2 5.2
9
7.5
6
95
89
91
95
0
2
0
0
1.3
4.3
3.8
1
10
11
12
13
14
6
6
than 40 wt % catalyst led to incomplete reactions and
higher levels of impurities such as amino alcohol 14. The
formation of 14 arises from competitive reduction of the
carbonyl group prior to reduction of the nitro group. It
was hypothesized that the formation of 14 may be due
to the enolization of ketone 3 under the basic reaction
conditions induced by the pH >9 slurry of Ra/Ni (H2O).
However, adjusting the pH between 5 and 7, using Ra/
Ni in EtOH, or washing the catalyst in THF or water to
reduce the basicity did not correspondingly decrease the
observed amount of aniline alcohol 14. Efforts to elimi-
nate the formation of 14 by the addition of competitively
reducible ketones (acetone or cyclohexanone) did not
significantly improve the reaction profile. Solvent choice
was also critical to the success of the reaction. For
example, the use of alcoholic solvents such as IPA or
MeOH gave 2 (65%) and varying amounts of 13 and 14,
and solvents such as toluene and isopropyl acetate led
to increased levels of other unidentified impurities and
lower yields of 2. The optimal reaction conditions were
40 wt % Ra/Ni 2800 (55 wt % in H2O), 40 psi H2, 65 °C,
in THF for 7.5 h and gave 2 in 95% yield. Detectable
impurities present in the crude reaction mixture were
identified as 14 (1.3%), 15 (0.7%), and methyl derivative
16 (0.6%). The isolation of 2 was simply a matter of
filtering the catalyst, concentrating the solution, and
adding MeOH which precipitated the product in analyti-
cally pure form in an unoptimized 90% isolated yield.
The presence of impurities 14, 15, and 16 was unam-
biguously established by independent synthesis, which
also serves to address the scope of the reaction conditions
(Scheme 5). For example, reduction of nitro alcohols 9
and 17 with Ra/Ni afforded 14 and 15 in 86% and 58%
yields, respectively. Alternatively, oxidation of 17 fol-
lowed by reductive cyclization under the optimized reac-
tion conditions afforded 16 in 52% overall yield. An
additional example which highlights the methodology is
the reductive cyclization of nitroketone 18 to give 19 in
83% yield.
50% Raney
6
94 0.5
95
2
2400 (H2O)d
60% Raney
9
0
1.2
3100 (H2O)e
a
Reactions were performed at 65 °C unless otherwise noted.
b Reaction at room temperature. c J ohnson Matthey, type A503023-
d
5. Chromium-promoted nickel. e Molybdenum-promoted nickel.
f Yield determined by HPLC.
indole 13 as the major product24 with small amounts of
2 (<7%) formed. Ketone 3 was subjected to lead-promoted
reductive cyclization conditions25 for forming hydroxy
indoles to give 13 as the sole product in 92% yield.
Increased catalyst loading (10 mol % 5% Pd/C) or
increased temperature (65 °C for 10 mol % Pt/C) afforded
only a modest increase in the level of 2 (up to 45%);
however, significant levels of unidentified impurities were
formed, with <2% of ketone 3 and only 6% of hydroxy
indole 13 observed. When Raney catalysts 2700 (cobalt)
and 2724 (chromium promoted cobalt) were employed,
hydroxy indole 13 was observed to be the major product
(82% and 70% yield, respectively). When catalytic Raney
Nickel 2800 (66 wt % of a 55 wt % slurry in water, rt, 20
h) was employed, the desired indole 2 was obtained in
59% yield, with no detectable amount of N-hydroxy indole
13 present in the NMR and HPLC of the crude reaction
mixture. Encouraged by the success of this reaction,
optimal conditions were sought with regard to Raney
nickel catalyst, catalyst loading, and reaction solvent.
Reduction with Raney nickel catalysts 3100 and 2400
resulted in clean conversion to indole 2; however, high
catalyst loadings (60 wt %) were required for the reaction
to approach completion. The optimal catalyst loading was
observed to be 40 wt % of Ra/Ni 2800 (H2O) catalyst. Less
(24) We speculate that hydroxyl indole 13 arises by cyclization on
a hydroxylamine intermediate 20 onto the adjacent ketone.
Deprotection of the masked quinolinone 2 was achieved
by hydrolysis of 2 with concentrated HCl in methanol
and afforded the KDR kinase inhibitor 1 in quantitative
yield.
In summary, a practical and efficient three-step syn-
thesis of highly functionalized 2-nitrobenzyl alcohol
compounds from 4-nitrobenzene derivatives has been
demonstrated. The alcohols are easily oxidized to the
(25) Wong, A.; Kuethe, J . T.; Davies, I. W. J . Org. Chem. 2003, 68,
9865.
J . Org. Chem, Vol. 69, No. 22, 2004 7763

over Celite and the solution concentrated under reduced pres-
sure. The indole was crystallized by addition of MeOH to the
concentrated solution to yield 4.23 g (90%) of a light yellow
solid: mp 197-198 °C; 1H NMR (CDCl3, 400 MHz) δ 2.61 (m,
4H), 2.78 (s, 3H), 3.27 (m, 4H), 3.66 (s, 2H), 4.31 (s, 3H), 7.07 (s,
1H), 7.18 (dd, 1H, J ) 1.4, 8.3 Hz), 7.44 (m, 2H), 7.57 (s, 1H),
7.64 (t, 1H, J ) 8.4 Hz), 7.81 (d, 1H, J ) 8.1 Hz), 7.88 (d, 1H, J
) 8.4 Hz), 8.48 (s, 1H), 9.68 (br s, 1H); 13C NMR (CDCl3, 100
MHz) δ 34.0, 46.0, 52.3, 54.1, 63.3, 101.5, 111.3, 116.8, 121.1,
124.2, 124.8, 125.5, 127.0, 127.6, 128.3, 129.0, 129.6, 134.0, 135.2,
136.0, 145.3, 158.3. Anal. Calcd for C24H26N4O3S: C, 63.98; H,
5.82; N, 12.44. Found: C, 64.28; H, 5.68; N, 12.05.
corresponding ketones with DMSO/Ac2O, at which point
intramolecular Ra/Ni-catalyzed reductive cyclization
smoothly furnishes the desired 1H-indol-2-yl-1H-quino-
line ring system in 95% yield (90% isolated yield). The
quinolinone functionality of the potent KDR kinase
inhibitor is then easily revealed through hydrolysis.
Alternate approaches to the 1H-indol-2-yl-1H-quinoline
are currently being explored in this laboratory.
Exp er im en ta l Section
P r ep a r a tion of3-[5-[[4-(Meth a n esu lfon yl)-1-p ip er a zin yl]-
m eth yl]-1H-in d ol-2-yl]qu in olin -2(1H)on e Hyd r och lor id e
(1). To a slurry of 174 mg (0.386 mmol) of 2 in 3 mL of MeOH
was added 0.48 mL of concentrated HCl. The slurry was heated
at reflux for 8 h and stirred overnight at rt. The resulting solid
was filtered to provide 180 mg (98%) of 1 as a mono-HCl salt:
P r ep a r a tion of 1-(2-Meth oxyqu in olin -3-yl)-2-[5-[[4-(m e-
th ylsu lfon yl)p ip er a zin -1-yl]m eth yl]-2-n itr op h en yl]eth a n -
on e (3). To a heated (80 °C) solution of 19.7 g (39.4 mmol) of
alcohol 9 in 79 mL of isopropyl acetate and 36.9 g (473 mmol) of
DMSO was added 24.1 g (236 mmol) of acetic anhydride. The
reaction was heated at 80 °C for 2 h. After being cooled to rt,
the reaction was neutralized with (175 mL) satd NaHCO3 to a
final pH of 8.0. The layers were separated, and the organic layer
was washed with water (250 mL). The solvent was removed
under reduced pressure. The residual oil was chromatographed
over silica gel, eluting with 70% EtOAc/hexanes to yield 15.3 g
(78%) of ketone 3 as an off-white solid. An analytical sample
was obtained by recrystallization from THF/MeOH: mp 122-
124 °C; 1H NMR (CDCl3, 400 MHz) δ 2.58 (m, 4H), 2.80 (s, 3H),
3.27 (m, 4H), 3.63 (s, 2H), 4.22 (s, 3H), 4.80 (s, 2H), 7.36 (s, 1H),
7.43 (ddd, 2H, J ) 1.2, 8.0, 9.2 Hz), 7.73 (ddd, 1H, J ) 1.6, 6.8,
8.4 Hz), 7.87 (d, 1H, J ) 14.7 Hz), 7.85 (d, 1H, J ) 15.6), 8.12
(d, 1H, J ) 9.1 Hz), 8.59 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ
34.3, 45.8, 48.8, 52.3, 53.9, 61.5, 122.9, 124.4, 124.9, 125.4, 127.0,
128.4, 129.2, 131.2, 131.9, 132.9, 133.9, 141.8, 144.2, 147.9, 159.1,
195.9. Anal. Calcd for C24H26N4O6S: C, 57.82; H, 5.26; N, 11.24.
Found: C, 57.71; H, 5.20; N, 10.96.
1
yellow solid; mp 250 °C; H NMR (DMSO-d6, 500 MHz) δ 2.98
(s, 3H), 3.12 (m, 2H), 3.33 (t, 2H, J ) 12.6 Hz), 3.39 (m, 2H),
3.70 (d, 2H, J ) 12.6 Hz), 4.42 (m, 2H), 7.25 (m, 1H), 7.39 (m,
2H), 7.41 (d, 1H, J ) 8.2 Hz), 7.52 (ddd, 1H, J ) 1.2, 7.2, 8.2
Hz), 7.60 (d, 1H, J ) 8.4 Hz), 7.73 (d, 1H, J ) 7.7 Hz), 7.82 (s,
1H), 8.63 (s, 1H), 11.45 (br s, 1H), 11.86 (s, 1H), 12.21 (s, 1H);
13C NMR (DMSO-d6, 126 MHz) δ 35.2, 42.2, 49.7, 53.4, 102.2,
112.0, 115.0, 119.3, 119.9, 122.1, 122.3, 123.7, 124.9, 127.8, 130.3,
134.6, 134.8, 136.8, 137.7, 160.5. Anal. Calcd. For C23H24N4O3S‚
HCl: C, 58.40; H, 5.33; N, 11.85. Found: C, 58.38; H, 5.26; N,
11.71.
Ack n ow led gm en t. We thank Dr. Robert A. Reamer
for help with NMR analysis and Mr. J ess Sager for
experimental assistance.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
2-Meth oxy-3-[5-[[4-(m eth ysu lfon yl)-1-piper azin yl]m eth yl]-
1H-in d ol-2-yl]qu in olin e (2). To a solution of 5.22 g (10.5 mmol)
of ketone 3 in 60 mL of THF was added 2.10 g of Raney Nickel
2800 (H2O). The reaction slurry was then heated to 65 °C for
7.5 h under 40 psi H2. The cooled reaction mixture was filtered
J O048843M
7764 J . Org. Chem., Vol. 69, No. 22, 2004