A novel synthesis of EGFR-tyrosine-kinase inhibitors with 4-(indol-3-yl)quinazoline structure

Article abstract of DOI:10.1002/jhet.5570450311

(Chemical Equation Presented) The epidermal growth factor (EGF) family of membrane receptors has been identified as a key element in the complex signaling network that is utilized by various classes of cell-surface receptors. A new synthetic pathway of 4-(indol-3-yl)quinazolines 15 and 16 is described using cross coupling reactions with quinazoline- and indole moieties. The synthesized compound 15 is a new dual and high potent EGFR- and HER-2-tyrosine kinase inhibitor with excellent cytotoxic properties at different cell lines. Furthermore this substance class shows remarkably strong fluorescence.

Full text of DOI:10.1002/jhet.5570450311

May-Jun 2008
703
A Novel Synthesis of EGFR-Tyrosine-kinase Inhibitors
with 4-(Indol-3-yl)quinazoline Structure
Anja Lüth * and Werner Löwe
Freie Universität Berlin, Institut für Pharmazie, Königin-Luise-Str. 2+4, 14195 Berlin, Germany
anja.lueth@fu-berlin.de
Received April 13, 2007
R1
N
R2
H3CO
HO
H3CO
O
N
H3CO
O
N
Mg
I
O
N
N
R1
R2
O
Cl
N
N
O
O
N
H
The epidermal growth factor (EGF) family of membrane receptors has been identified as a key element
in the complex signaling network that is utilized by various classes of cell-surface receptors. A new
synthetic pathway of 4-(indol-3-yl)quinazolines 15 and 16 is described using cross coupling reactions with
quinazoline- and indole moieties. The synthesized compound 15 is a new dual and high potent EGFR- and
HER-2-tyrosine kinase inhibitor with excellent cytotoxic properties at different cell lines. Furthermore this
substance class shows remarkably strong fluorescence.
J. Heterocyclic Chem., 45, 703 (2008).
INTRODUCTION
O
O
N
Growth of malignant tumors is mostly caused by a
deregulation of the balance between proliferation, survival
and death pathways like apoptosis and necrosis.
N
HN
Cl
F
N
The Epidermal Growth Factor Receptor (EGFR) is a
transmembrane glycoprotein with an extracellular ligand-
binding domain and an intracellular domain with tyrosine
kinase activity for signal transduction [1]. The receptor is
expressed on healthy cells (40-100 EGFR/cell) as well as on
malignant tissues (more than 1 000 000 EGFR/cell) [2].
Overexpression of EGFR has been demonstrated in a wide
variety of malignant cells, and this increase in receptor levels
has been associated with a poor clinical prognosis [3,4].
Thus, therapeutic strategies to inhibit EGFR and EGFR-
related pathways have been pursued, including the
development of ATP-competitive small molecule
inhibitors of the intracellular tyrosine kinase domain of
the receptor or inhibitors of downstream effectors of
EGFR signalling pathways, like Gefitinib 1 (Iressa®, IC50
33 nM) and Erlotinib 2 (Tarceva®, IC50 2 nM) shown in
Figure 1 [4,5]. The 4-anilinoquinazoline derivatives are
both selective and effective inhibitors of the EGFR
kinase. Like Gefitinib and Erlotinib most of the EGFR
tyrosine kinase inhibitors have the same 4-anilino-
quinazoline skeleton, only the substituents and the side-
chains are variable.
O
1
O
O
O
O
N
N
HN
2
The 4-anilinoquinazolines Gefitinib 1 and Erlotinib 2.
Figure 1
could favour specific conformations, which could improve
the inhibitory activities of the resulting derivatives.
Therefore, the 4-(indole-3-yl)quinazolines were
developed as an active and unique new class of EGFR
tyrosine kinase inhibitors [6]. But the previously
described synthesis didn´t work very well, due to lower
overall yield of the total synthesis. We now present a new
synthetic route to the desired 4-(indole-3-yl)quinazolines.
On the other hand, the replacement of the aniline
structure by an indole nucleus could rigidify the resulting
structure through only one single bonding between the
indole and the quinazoline nucleus and supposed hydrogen
bonding between the indole-NH and the peptide backbone
RESULTS AND DISCUSSION
The 4-(indole-3-yl)quinazolines 15 and 16 were
synthesized by cross coupling reactions of appropriately

704
A. Lüth and W. Löwe
Vol 45
substituted quinazolines and indoles.
compound 4 in quantitative yield. Interestingly in this
case the nitro group of the benzene ring is introduced
ortho to the ester group. The nitro compound 4 was
reduced by palladium/charcoal in the presence of
cyclohexene to give the anthranilic acid ester 5. The
following cyclization with formamidine acetate led to
the desired quinazoline-4-one derivative 6 [10-12].
After that chlorination of compound 6 takes place in
position 4 with thionyl chloride in the presence of
dimethyl formamide [13]. The only reaction product
An improved process for the preparation of Gefitinib
(Iressa®) by Natco Pharma Limited starts with 3-
hydroxy-4-methoxybenzene carbaldehyde and needs 8
steps to give the desired quinazoline unit 7 [7].
Another 7-step synthetic route described by Wang et.
al. starts with the same educt [8]. The quinazoline 7
was received by our new synthetic pathway affording
5
steps
starting
with
ethyl
(3-hydroxy-4-
methoxy)benzoate (Scheme 1) [9]. After introduction
Scheme 1
N
Cl
O
H3CO
O
H3CO
HO
H3CO
O
NO2
HNO3 68 %
K2CO3, 18-crown-6
O
O
O
O
O
O
N
N
4
3
O
O
Pd/C 5 %
NH2
Cl
H3CO
O
N
H3CO
O
N
O
O
S
H3CO
O
NH2
, DMF
N
Cl
NH2+
N
NH
O
Cl
O
N
N
7
6
5
O
O
O
of the morpholinopropoxy side chain in the presence
of potassium carbonate and 18-crown-6 the resulting
compound 3 was nitrated by 68 % nitric acid to give
observed was the corresponding 4-chloro compound 7.
The synthesis of the indole moiety is outlined in
Scheme 2 [14,15]. The experimental conditions of the
Scheme 2
F
N+
O
F
N+
O
-N
N
O
-N
N
O
NaN3
Br
Cl
CHO
O
Cl
9
O
8
H
N
H
N
H
N
F
F
F
O
O
O
OH
Cl
Cl
Cl
NaOH/EtOH
O
12a
+
11a
+
10a
+
F
F
F
Cl
Cl
Cl
HN
HN
HN
O
O
HO
O
12b
11b
10b
Synthesis of 5-chloro-6-fluoroindole 13a

May-Jun 2008
A Novel Synthesis of EGFR-Tyrosine-Kinase Inhibitors
with 4-(Indole-3-yl)quinazoline Structure
705
indole synthesis have been changed in details compared to
the description of Boes and are outlined in the the
experimental part [14]. The target 5-chloro-6-fluoro-
indole 12a was synthesized using the Hemetsberger-
Knittel reaction [16]. Starting with methylbromoacetate
and sodium azide the resulting azido ester 8 was
subsequently condensed with 3-chloro-4-fluorobenzalde-
hyde to give the corresponding azidocinnamate 9. This
intermediate was cyclized by heating with p-xylene to
afford a mixture of indole-2-carboxylates 10a and 10b,
which were hydrolized in the presence of sodium
better inhibition activity then the Tyrphostin-standard. On
the other side remarkable results were observed at a 60
cancer cell lines test performed by the National Cancer
Institute (Table 4). Here outstanding activities were
obtained against different non-small lung cancer-, CNS
cancer-, ovarian cancer-, renal cancer-, colon cancer- and
prostate cancer cell lines. It seems to be that the outstanding
activity against cancer cell lines are not very well correlated
to the results of EGFR/HER-2 tyrosine kinase inhibition
tests. Furthermore, the synthesized 4-(indol-3-yl)-
quinazolines 15 and 16 show remarkable strong
-
!
R1
R1
Mg, (I2), CH3I
N
H
N
R2
R2
Mg
I
12a
13
Activation of position 3 of the indole with help of Grignard compounds
Figure 2
H3CO
O
N
R1
R2
H3CO
O
N
+
N
N
N
R1
R2
Mg
I
Cl
N
N
7
O
O
N
H
15: R1=Cl, R2=F
16: R1=Br, R2=H
13: R1=Cl, R2=F
14: R1=Br, R2=H
Hetarylation reaction between chlorinated quinazoline and activated indole
Figure 3
hydroxide to give the indole-2-carboxylic acids 11a and
11b. Then the free acid functions were converted to the
final indoles 12a and 12b by decarboxylation in
diphenylether at 260°C. At this stage the separation of
12a and 12b was performed by column chromatography.
Subsequently the obtained indole 12a was used in the
synthesis leading to the desired 4-(indole-3-yl)-
quinazolines 15 and 16.
fluorescences in the ultraviolet light, comparable with that
of quinine-sulphate (Figure 4, 5 and Table 1, 2) [18].
intensity
10000
350 nm
8000
The 4-(indole-3-yl)quinazolines 15 and 16 were now
synthesized by cross coupling reaction of appropriately
substituted indoles, which were converted to the
metallated intermediates by use of Grignard compounds
and the 4-chlorinated quinazoline 7 (Figure 2 and 3) [17].
The structures of compounds 3-16 were confirmed by
1H-NMR, IR, mass spectra and elemental analysis.
Compound 16 was subjected to EGFR- and 15 was
subjected to EGFR- and HER-2-tyrosine kinase inhibition
activity tests as well as in vitro anticancer testing. The
pharmacological results outlined in Table 3 show that
compound 16 and 17 exhibit a weaker activity against
EGFR and HER-2 then Gefitinib and Erlotinib, but have a
6000
300 nm
4000
260 nm
2000
0
400
500
wave length [nm]
fluorescence spectrum of compound 15 at a concentration of 5 µM
Figure 4

706
A. Lüth and W. Löwe
Vol 45
Table 1
Table 4
excitation [nm]
emission [nm]
intensity
4258
cell line
GI50 (mol) of
260
300
350
413,8
413,8
413,6
compound 15
4268
7948
non-small lung cancer
EKVX
HOP-92
8.97x10-8
5.04x10-7
3.80x10-8
data of fluorescence spectrum of compound 15
NCI-H322M
CNS cancer
SNB-75
intensity
10000
4.93x10-8
ovarian cancer
IGR-OV-1
SK-OV-3
1.08x10-7
5.92x10-7
8000
6000
4000
2000
0
250 nm
renal cancer
A498
ACHN
2.90x10-6
2.15x10-7
9.76x10-8
TK-10
345 nm
319 nm
colon cancer
HT29
3.76x10-6
4.90x10-7
prostate cancer
PC-3
225 nm
Results of growth inhibition (GI) testing of compound 15 at
different cell lines
400
500
600
wave length [nm]
acetonitrile was heated under reflux for 4 hours. After filtration
the solvent was evaporated and the crude product was washed
with n-hexane. There was obtained 1.60 g (97.7 %) of a white
solid. mp: 56-59 °C; 1H-NMR (DMSO-d6): δ 7.60 (dd, 1H,
fluorescence spectrum of comparison quinine sulphate at a concentration
of 5 µM
Figure 5
Table 2
4
3J=8.48 Hz, J=1.88 Hz, H6), 7.45 (d, 1H, 4J=1.81 Hz, H2), 7.07
3
(d, 1H, J=8.50 Hz, H5), 4.28 (q, 2H, J=7.12 Hz, CH2), 4.03 (t,
2H, J=6.57 Hz, H1´´), 3.83 (s, 3H, OCH3), 3.58 (m, 4H, J=7.23
Hz, H2´, H6´), 2.42 (t, 2H, J=7.01 Hz, H3´´), 2.38 (m, 4H,
J=7.14 Hz, H3´, H5´), 1.88 (m, 2H, J=6.99 Hz, H2´´), 1.30 (t,
3H, J=7.10 Hz, CH3); MS: m/z 322.9 (M+.). Anal. Calcd. for
C17H25NO5: C: 63.14; H: 7.79; N: 4.33. Found: C: 63.20; H:
7.77; N: 4.21.
excitation [nm]
emission [nm]
intensity
225
461,4
2416
250
319
345
470,6
468,6
468,6
7089
1542
1556
data of fluorescence spectrum of comparison quinine sulphate
Ethyl 4-methoxy-5-(3-morpholin-4-ylpropoxy)-2-nitro-
benzoate (4). 3 (1.00 g, 3.09 mmol) was added to cooled nitric
acid (65 %, 25 mL) in portions and stirred under cooling for
2.5 hours. The reaction mixture was put into ice water. After that
sodium hydroxide (10 %) was added with a pH > 8. The mixture
was extracted with dichloromethane. After evaporation of the
solvent the crude product was washed with ethyl acetate/n-
Table 3
EGFR-TK-Inhibition
(IC50 or inhibition at a
concentration
HER-2-TK-Inhibition
at a concentration
of 100 nM
compound
of 100 nM)
1
hexane. There was obtained 1.10 g (96.8 %) of a yellow oil. H-
15
16
333 nM (62 %)
131 nM (26 %)
1.1 µM
19 %
NMR (DMSO-d6): δ 7.63 (s, 1H, H6), 7.31 (s, 1H, H3), 4.28 (q,
2H, J=7.12 Hz, CH2), 4.17 (t, 2H, J=6.60 Hz, H1´´), 3.91 (s, 3H,
OCH3), 3.56 (m, 4H, J=7.23 Hz, H2´, H6´), 2.40 (t, 2H, J=6.99
Hz, H3´´), 2.36 (m, 4H, J=7.20 Hz, H3´, H5´), 1.90 (m, 2H,
J=7.00 Hz, H2´´), 1.26 (t, 3H, J=7.08 Hz, CH3); MS: m/z 368.0
(M+.). Anal. Calcd. for C17H24N2O7: C: 55.43; H: 6.57; N: 7.60.
Found: C: 55.49; H: 6.66; N: 7.66.
not tested
5.7 µM
Tyrphostin 47
Gefitinib
Erlotinib
33 nM
> 3.7 µM
134,5 nM
2 nM
EGFR- and HER-TK inhibition of compound 15, 16 the reference
Tyrphostin, Gefitinib and Erlotinib [4-5, 18]
Ethyl 2-amino-4-methoxy-5-(3-morpholin-4-ylpropoxy)-
benzoate (5). 4 (5.50 g, 14.93 mmol), palladium/carbon (5 %,
3.2 g) and cylohexene (57 mL) in ethanol (570 mL) were heated
under reflux for 2 h. After filtration and evaporation of the
solvent the crude product was washed with n-hexane. There was
obtained 4.65 g (92.0 %) of a white solid. mp: 72-74 °C; H-
NMR (DMSO-d6): δ 7.15 (s, 1H, H6), 6.44 (s, 2H, NH2), 6.34 (s,
1H, H3), 4.19 (q, 2H, J=7.09 Hz, CH2), 3.82 (t, 2H, J=6.64 Hz,
EXPERIMENTAL
Ethyl 4-methoxy-3-(3-morpholin-4-ylpropoxy)-benzoate
(3). A mixture of ethyl-3-hydroxy-4-methoxybenzoate (1.00 g,
5.10 mmol), 4-(3-chloropropyl)morpholin (1 mL), potassium
carbonate anhydrous (2.00 g), 18-crown-6 (0.20 g) in
1

May-Jun 2008
A Novel Synthesis of EGFR-Tyrosine-Kinase Inhibitors
with 4-(Indole-3-yl)quinazoline Structure
707
H1´´), 3.74 (s, 3H, OCH3), 3.57 (m, 4H, J=7.21 Hz, H2´, H6´),
2.38 (t, 2H, J=7.02 Hz, H3´´), 2.35 (m, 4H, J=7.19 Hz, H3´,
H5´), 1.80 (m, 2H, J=7.01 Hz, H2´´), 1.28 (t, 3H, J=7.08 Hz,
CH3); MS: m/z 338.1 (M+.). Anal. Calcd. for C17H26N2O5: C:
60.34; H: 7.74; N: 8.28. Found: C: 60.30; H: 7.75; N: 8.33.
7-Methoxy-6-(3-morpholin-4-ylpropoxy)-3H-quinazoline-
4-one (6). 5 (1.90 g, 5.61 mmol) and formamidine acetate
(3.19 g, 30.64 mmol) in 2-methoxyethanol (37 mL) were heated
under reflux for 8 h. After evaporation of the solvent, liquid
ammonia was added and the resulted crystals were isolated.
There was obtained 1.24 g (69.2 %) of an ivory-colored solid.
and 10b as white crystals which was used in the next step
1
without further purification. H-NMR: (DMSO-d6) δ 12.37 (s,
1H, NH, 10b), 12.22 (s, 1H, NH, 10a), 7.91 (d, JH-F=7.47 Hz,
1H, H4, 10a), 7.67 (m, 1H, H4, 10b), 7.35 (d, JH-F=9.87 Hz, 1H,
3
H7, 10a), 7.29 (s, 1H, H3, 10b), 7.17 (t, J=9.20 Hz, 1H, H5,
10b), 7.15 (s, 1H, H3, 10a), 3.89 (s, 3H, OCH3), 3.88 (s, 3H,
OCH3); MS: m/z 227.0 (M+.).
5-Chloro-6-fluoroindole-2-carboxylic acid (11a) and 7-
Chloro-6-fluoroindole-2-carboxylic acid (11b). A suspension
of an almost 1:1 mixture of 10a and 10b (2.04 g, 8.96 mmol) in
ethanol (90 mL) and sodium hydroxide solution (2 N, 45 mL)
was stirred at ambient temperature for 2 h. The alcohol was
evaporated and the residue was treated with hydrochloric acid
(2 N). The crystals were isolated, washed with water and dried.
There were obtained 1.8 g (94.1 %) of an almost 1:1 mixture of
11a and 11b as white solid. 1H-NMR: (DMSO-d6): δ 13.10 (s,
2H, COOH, 11a, 11b) 12.18 (s, 1H, NH, 11b), 12.02 (s, 1H,
NH, 11a), 7.88 (d, JH-F=7.48 Hz, 1H, H4, 11a), 7.65 (m, 1H, H4,
11b), 7.33 (d, JH-F=9.94 Hz, 1H, H7, 11a), 7.21 (s, 1H, H3, 11b),
1
mp: 233-236 °C; H-NMR (DMSO-d6): δ 12.08 (s, 1H, NH),
8.00 (s, 1H, H2), 7.45 (s, 1H, H5), 7.15 (s, 1H, H8), 4.14 (t, 2H,
J=6.66 Hz, H1´´), 3.92 (s, 3H, OCH3), 3.58 (m, 4H, J=7.22 Hz,
H2´, H6´), 2.45 (t, 2H, J=7.00 Hz, H3´´), 2.38 (m, 4H, J=7.20
Hz, H3´, H5´), 1.94 (m, 2H, J=7.01 Hz, H2´´) ; MS: m/z 319.0
(M+.). Anal. Calcd. for C16H21N3O4: C: 60.17; H: 6.63; N: 13.16.
Found: C: 60.11; H: 6.37; 13.35.
4-Chloro-7-methoxy-6-(3-morpholin-4-ylpropoxy)-quina-
zoline (7). A stirred mixture of 6 (1.00 g, 3.13 mmol), thionyl
chloride (25 mL) and N,N-dimethylformamide (0.5 mL) was
heated at reflux for 4 h. The liquid layer was evaporated. The
residue was washed with diethyl ether and dried and give 1.05 g
3
7.13 (t, J=9.07 Hz, 1H, H5, 11b), 7.08 (s, 1H, H3, 11a); MS:
m/z 212.9 (M+.).
5-Chloro-6-fluoroindole (12a) and 7-Chloro-6-fluoroindole
(12b). A suspension of 1.92 g (8.99 mmol) of an almost 1:1
mixture of 11a and 11b in diphenyl ether (45 mL) was stirred at
260 °C for 4 h. The reaction mixture was chromatographed over
silica gel with n-hexane and n-hexane/toluene (3:1). There were
obtained 0.70 g (45.9 %) of 12a as white and 0.40 g (26.3 %) of
12b as lightbrown crystals. 12a: mp: 83 °C [Lit. 14: 88-90°C,
1
(99.3 %) of a beige solid. mp: 180-181 °C; H-NMR (DMSO-
d6): δ 8.93 (s, 1H, H2), 7.49 (s, 1H, H5), 7.45 (s, 1H, H8), 4.33
(t, 2H, J=6.65 Hz, H1´´), 4.03 (s, 3H, OCH3), 3.81 (m, 4H,
J=7.20 Hz, H2´, H6´), 3.30 (t, 2H, J=6.99 Hz, H3´´), 3.10 (m,
4H, J=7.19 Hz, H3´, H5´), 2.30 (m, 2H, J=7.05 Hz, H2´´) ; MS:
m/z 337.0 (M+.). Anal. Calcd. for C16H23Cl2N3O3: C: 48.99; H:
5.91; N: 10.71. Found: C: 48.82; H: 5.68; N: 10.60.
1
light brown crystals]; H-NMR (DMSO-d6): δ 11.32 (s, 1H,
NH), 7.70 (d, JH-F=7.40 Hz, 1H, H4), 7.41 (t, J=5.70 Hz, 1H,
H2), 7.38 (d, JH-F=10.22 Hz, 1H, H7), 6.43 (t, J=5.02 Hz, 1H,
H3); MS: m/z 169.2 (M+.). Anal. Calcd. for C8H5ClFN: C: 56.66;
H: 2.97; N: 8.26. Found: C: 56.67; H: 3.06; N: 8.24. 12b: mp:
Methylazidoacetate (8). Sodium azide (44.00 g,
676.81 mmol) and methylbromoacetate (96.90 g, 687.44 mmol)
were suspended in N,N-dimethylformamide and stirred at
ambient temperature for 16 h. The reaction mixture was given
into icewater and was extracted with diethylether. The organic
layer was washed with water and dried. After evaporation of
N,N-dimethylformamide, the crude product was destillated
1
42 °C [Lit. 14: dark brown oil]; H-NMR (DMSO-d6): δ 11.61
(s, 1H, NH), 7.53 (m, 1H, H4), 7.42 (t, J=5.46 Hz, 1H, H2) 7.04
3
(t, J=8.79 Hz, 1H, H5), 6.54 (t, J=4.94 Hz, 1H, H3); MS: m/z
169.1 (M+.). Anal. Calcd. for C8H5ClFN: C: 56.66; H: 2.97; N:
8.26. Found: C: 56.63; H: 3.09; N: 8.17.
1
under vacuo to give 64.20 g (82.4 %) of a colourless oil. H-
NMR (DMSO-d6): δ 3.90 (s, 2H, CH2), 3.81 (s, 3H, OCH3);
MS: m/z 115.1 (M+.).
4-(5-Chloro-6-fluoroindole-3-yl)-7-methoxy-6-(3-morpho-
lin-4-ylpropoxy)quinazoline (15). Under cooling magnesium
Methyl-α-azido-3-chloro-4-fluorocinnamate (9). Under
cooling sodium (1.35 g) was disolved in methanol (30 mL). A
mixture of 3-chloro-4-fluorobenzaldehyde (4.65 g, 29.33 mmol)
and 8 (6.75 g, 58.65 mmol) in methanol (10 mL) was dropwise
given to the sodium methanolate. The mixture was stirred at
(0.25 g) and iodine were stirred with
a mixture from
methyliodide (1.2 mL) and diethyl ether (5 mL) for 15 min.
Afterwards a solution of 12a (0.50 g, 2.99 mmol) in diethyl
ether (15 mL) was given to the reaction mixture and was stirred
for 15 min. Subsequently 7 (0.75 g, 2.22 mmol) was added in
portions. The mixture was heated under reflux for 1 h and then
was added to ice-water. After extraction with ethyl acetate and
diethylether the organic layer was dried over molecular sieve
and the ethyl acetate was evaporated. The crude product was
chromatographed over silica gel with diethylether/ethyl
acetate/methanol (3:1:1) and was recrystallisated from ethyl
acetate/n-hexane. There were obtained 0.10 g (9.6 %) of yellow
crystals. mp: 186-188 °C; 1H-NMR (DMSO-d6): δ 12.10 (s, 1H,
NH), 9.09 (s, 1H, H2), 8.37 (d, J=2.74 Hz, 1H, H2´), 8.33 (d,
1H, JH-F=7.59 Hz, H4´), 7.65 (s, 1H, H5), 7.54 (d, 1H, JH-F=10.00
Hz, H7´), 7.39 (s, 1H, H8), 4.19 (t, 2H, J=6.65 Hz, H1´´´), 4.01
(s, 3H, OCH3), 3.54 (t, 4H, J=7.22 Hz, H2´´, H6´´), 2.43 (t, 2H,
J=7.06 Hz, H3´´´), 2.34 (t, 4H, J=7.21 Hz, H3´´, H5´´), 1.96 (m,
2H, J=7.03 Hz, H2´´´); MS: m/z 470.7 (M+.). Anal. Calcd. for
C24H24ClFN4O3: C: 61.21; H: 5.14; N: 11.90. Found: C: 61.31;
H: 5.28; N: 12.10.
ambient temperature for
3 h. After neutralization with
hydrochloric acid (2 N) the reaction mixture was extracted with
ethyl acetate. The organic layer was washed with water and
dried. After evaporation of ethyl acetate at a temperature less
than 40 °C the resulting residue was chromatographed on silica
gel with ethyl acetate/n-hexane (1:3) to give 4.55 g (60.7 %) of
1
white crystals. mp: 58 °C [Lit. 14: 72-74°C]; H-NMR (DMSO-
d6): δ 8.13 (dd, 4J=2.16 Hz, JH-F= 7.42 Hz, 1H, H2), 7.90 (m, 1H,
3
H6), 7.47 (t, J=9.01 Hz, 1H, H5), 6.93 (s, 1H, CH aliph), 3.86
(s, 3H, OCH3); MS: m/z 255.1 (M+.). Anal. Calcd. for
C10H7ClFN3O2: C: 46.98; H: 2.76; N: 16.44. Found: C: 47.05;
H: 2.99; N: 16.36.
Methyl 5-chloro-6-fluoroindole-2-carboxylate (10a) and
Methyl 7-chloro-6-fluoroindole-2-carboxylate (10b).
A
mixture of 9 (2.38 g, 10.11 mmol) and xylene (180 mL) was
heated under reflux for 45 min. The solvent was removed. There
were obtained 1.00 g (47.8 %) of an almost 1:1 mixture of 10a

708
A. Lüth and W. Löwe
Vol 45
[2] Pedersen, M.; Poulsen, H. S. Science & Medicine 2002, 206.
[3] Schlessinger, J. Cell 2000, 103, 211
[4] Toschi, L.; Cappuzzo, F. Oncologist 2007, 12, 211.
[5] Tibes, R.; Trent, J.; Kurzrock, R. Annu. Rev. Pharmacol.
Toxicol. 2005, 45, 357.
[6] Loewe, W.; Lueth, A. International Patent 1,846,396, 2006;
Chem. Abstr. 2006, 145, 249220.
[7] Ramanadham, J., P.; Muddasani, P. R.; Bollepalli, N. R.;
Nannapaeni, V. C. International Patent 0,823,900, 2005; Chem. Abstr.
2005, 143, 194029.
[8] Wang, J.-Q.; Gao, M.; Miller, K. D.; Sledge, G. W.; Zheng,
Q.-H. Bioorg. Med. Chem. Lett. 2006, 16, 4102
[9] Pearl, I. A.; Beyer, D. L. J. Am. Chem. Soc. 1953, 75, 2630.
[10] Stevenson, T. M.; Kazmierczak, F.; Leonard, N. J. J. Org.
Chem. 1986, 51, 616
4-(5-Bromoindole-3-yl)-7-methoxy-6-(3-morpholin-4-yl-
propoxy)quinazoline (16). Under cooling magnesium (0.25 g)
and iodine were stirred with a mixture from methyliodide
(1.2 mL) and diethyl ether (5 mL) for 15 min. Afterwards a
solution of 5-bromoindole (0.50 g, 2.55 mmol) in diethyl ether
(15 mL) was given to the reaction mixture and was stirred for
15 min. Subsequently 7 (0.75 g, 2.22 mmol) was added in
portions. The mixture was heated under reflux for 1 h and then
was added to ice-water. After extraction with ethyl acetate and
diethylether the organic layer was dried over molecular sieve
and the ethyl acetate was evaporated. The crude product was
chromatographed over silica gel with diethylether/ethyl
acetate/methanol (3:1:1) and was recrystallisated from ethyl
acetate/n-hexane. There were obtained 0.11 g (10,0 %) of
yellow crystals. mp: 204-206 °C; 1H-NMR (DMSO-d6): δ 12.14
[11] McNamara, D. J.; Berman, E. M.; Fry, D. W.; Werbel, L. M.
J. Med. Chem. 1990, 33, 2045.
4
(s, 1H, NH), 9.14 (s, 1H, H2), 8.39 (d, J=1.97 Hz, 1H, H4´),
7.71 (s, 1H, H5), 7.57 (d, 1H, J=8.61 Hz, H7´), 7.44 (s, 1H,
3
[12] Wright, S. W.; Carlo, A. A.; Carty, M. D.; Danley, D. E.;
Hageman, D. L.; Karam, G. A.; Levy, C. B.; Mansour, M. N.;
Mathiowetz, A. M.; McClure, L. D.; Nestor, N. B.; McPherson, R. K.;
Pandit, J.; Pustilnik, L. R.; Schulte, G. K.; Soeller, W. C.; Treadway, J.
L.; Wang, I.-K.; Bauer, P. H. J. Med. Chem. 2002, 45, 3865.
[13] Ple, P. A. J. Med. Chem. 2004, 47, 871.
3
4
H8), 7.41 (dd, 1H, J=8.68 Hz, J=1.94 Hz, H6´), 4.23 (t, 2H,
J=6.67 Hz, H1´´´), 4.07 (s, 3H, OCH3), 3.60 (t, 4H, J=7.18 Hz,
H2´´, H6´´), 2.49 (t, 2H, J=7.04 Hz, H3´´´), 2.40 (t, 4H, J=7.19
Hz, H3´´, H5´´), 2.02 (m, 2H, J=6.99 Hz, H2´´´); MS: m/z 496.2
(M+.). Anal. Calcd. for C24H26BrN4O3,5: C: 56.91; H: 5.17; N:
11.06. Found: C: 57.03; H: 5.41; N: 10.78.
[14] Boes, M. European Patent 0,655,440, 1996; Chem. Abstr.
1995, 123, 285766.
[15] Faull, A. W.; Kettle, J. International Patent 1,150,954, 2000;
Chem. Abstr. 2000, 133, 150462.
[16] Kondo, K. Chem. Pharm. Bull. 1999, 47, 1227.
[17] Powers, J. C.; Meyer, W. P.; Parson, T. G. J. Am. Chem. Soc.
1967, 89, 5812.
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