Improved synthesis of gefitinib and erlotinib hydrochloride- anticancer agents

Article abstract of DOI:10.1080/00397910701483761

A highly efficient and commercially viable process for the synthesis of 6,7-dihydroxy-4-anilinoquinazoline derivatives gefitinib (1) and erlotinib hydrochloride (2), used for the treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer, is reported. This new process has improved yields and avoids the unstable 4-chloroquinazoline intermediate. The intermediates and final products were characterized by 1H and 13C nuclear magnetic resonance (NMR), mass spectra (MS), and elemental analysis, and purities of final products were determined by high performance liquid chromatogram (HPLC) and potentiometric titration methods. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701483761

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Improved Synthesis of Gefitinib and Erlotinib
Hydrochloride‐ Anticancer Agents
a
a
Venkateshappa Chandregowda , Gudapati Venkateswara Rao
&
a
Goukanapalli Chandrasekara Reddy
a
Vittal Mallya Scientific Research Foundation, Bangalore, India
Published online: 05 Oct 2007.
To cite this article: Venkateshappa Chandregowda , Gudapati Venkateswara Rao & Goukanapalli
Chandrasekara Reddy (2007): Improved Synthesis of Gefitinib and Erlotinib Hydrochloride‐ Anticancer Agents,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
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w
Synthetic Communications , 37: 3409–3415, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701483761
Improved Synthesis of Gefitinib and
Erlotinib Hydrochloride- Anticancer Agents
Venkateshappa Chandregowda, Gudapati Venkateswara Rao,
and Goukanapalli Chandrasekara Reddy
Vittal Mallya Scientific Research Foundation, Bangalore, India
Abstract: A highly efficient and commercially viable process for the synthesis of 6,7-
dihydroxy-4-anilinoquinazoline derivatives gefitinib (1) and erlotinib hydrochloride
(
2), used for the treatment of non-small cell lung cancer (NSCLC) and pancreatic
cancer, is reported. This new process has improved yields and avoids the unstable
-chloroquinazoline intermediate. The intermediates and final products were character-
4
1
13
ized by H and C nuclear magnetic resonance (NMR), mass spectra (MS), and
elemental analysis, and purities of final products were determined by high performance
liquid chromatogram (HPLC) and potentiometric titration methods.
Keywords: erlotinib, gefitinib, methylthio quinazolines, nonsmall cell lung cancer,
tyrosine kinase inhibitors (TKIs)
INTRODUCTION
Growth-factor signaling pathways governed by protein kinases have been a
main focus of research for novel targeted anticancer agents because of their
fundamental role in regulating key cellular functions including cell proliferation,
differentiation, metastasis, and survival. An important mediator of growth-factor
signaling pathways are the epidermal growth factor receptor (EGFR), a 170 kDa
[
1]
glycoprotein that is highly expressed in most human tissues and plays a key
[2]
role in cancer development and progression. The use of small molecules
that target EGFR and its signal-transduction pathway in cancer therapy was
Received in India February 5, 2007
Address correspondence to G. Chandrasekara Reddy, Vittal Mallya Scientific
Research Foundation, P. O. Box 406, K. R. Road, Bangalore 560004, India. E-mail:
gcreddy@vmsrf.org
3
409

3410
V. Chandregowda, G. V. Rao, and G. C. Reddy
Figure 1. Structures of gefitinib and erlotinib hydrochloride.
proposed 15 years ago. At present there are numerous EGFR-tyrosine kinase
w [3]
inhibitors in development, and a few of them such as gefitinib (1, Iressa )
w
[4]
and erlotinib hydrochloride (2, Tarceva ) (Fig. 1) have been approved by
the U.S. FDA for the treatment of non-small cell lung cancer (NSCLC) and
are marketed in more than 30 countries. In contrast, recently a secondary
mutation has been observed in gefitinib and erlotinib-responsive advanced
NSCLC patients of certain human races. This mutation resulted in a threonine
to methionine change at position 790 in the kinase domain of erbB1 (T790M)
[5]
and is reported to have resistance to gefitinib and erlotinib treatment.
However, treatment with erlotinib is approved by USFDA in parallel or as a
second-line defense with other chemotherapeutic agents in patients with
[
6]
NSCLC and pancreatic cancer. In addition, recent clinical studies suggest
that gefitinib can be still used based on the careful patient selection criteria
[7,8]
such as well-characterized and validated predictive markers.
Recently we have reported a one-pot procedure for making quinazolin-
(3H)-ones from corresponding orthonitrobenzonitriles, leading to synthesis of
4
gefitinib (1) and erlotinib hydrochloride (2) from our laboratory.
[9]
In
continuation of our interest in developing new strategies toward the synthesis of
substituted quinazolines with better yields, here we report an improved method
for synthesis of gefitinib (1) and erlotinib hydrochloride (2). In this method, the
substituted 4-chloroquinazoline derivatives as intermediates were avoided,
therebyeliminatingtheusageofcorrosive thionylchloride or phosphorylchloride.
RESULTS AND DISCUSSION
The synthesis of gefitinib (1) (Scheme 1) has been started from key intermedi-
ate 3. This in turn was prepared from isovanillin in a highly efficient way using
[
9]
our published procedure. In our earlier experiments, we found that the
compound 4-chloro-7-methoxy-6-[3-(4-morpholinyl) propoxy]-quinazoline
[10]
obtained by reacting 3 with thionyl chloride or phosphoryl chloride
was unstable and decomposed in prolonged storage. Now we have
overcome this by making a relatively stable 4-(methylthio)-7-methoxy-6-[3-
(
4-morpholinyl)propoxy]-quinazoline intermediate with good yields.

Gefitinib and Erlotinib Hydrochloride
3411
Scheme 1. Reagents and conditions: a ¼ P
2
S
5
, pyridine, reflux; b ¼ aq. MeOH,
NaOH, CH I, 208C; c ¼ 3-chloro-4-flouroaniline/3-chloro-4-flouroaniline hydrochlo-
3
ride, isopropyl alcohol, reflux.
Compound 3 was reacted with phosphorous pentasulfide in pyridine to get
, which was further treated with NaOH and methyl iodide to get compound 5;
4
these compounds 4 and 5 are very stable. The target molecule gefitinib (1) was
obtained by refluxing compound 5 and 3-chloro-4-flouroaniline/3-chloro-4-
flouroaniline hydrochloride in isopropyl alcohol. Gefitinib (1) was obtained
after recrystallization in 99% purity with 64% yield from 3. The synthesis
of erlotinib hydrochloride (2) (Scheme 2) has been started from key intermedi-
[9]
ate 6, which was prepared in an efficient way using our modified procedure.
Scheme 2. Reagents and conditions: a ¼ P
NaOH, CH
I, 208C; c ¼ 3-ethynyl aniline/3-ethynyl aniline hydrochloride, isopropyl
alcohol, reflux.
2
S
5
, pyridine, reflux; b ¼ aq. MeOH,
3

3412
V. Chandregowda, G. V. Rao, and G. C. Reddy
Compound 6 was reacted with phosphorous pentasulfide in pyridine to get 7,
which on treatment with NaOH/MeI gave compound 8. This was reacted with
3-ethynyl aniline/3-ethynyl aniline hydrochloride in isopropyl alcohol, and
the resulting solid was filtered to get erlotinib hydrochloride 2 of about 99%
purity straight away without titrating with external hydrochloric acid and
with 73% overall yield from 6.
In conclusion, we have developed commercially viable alternative
economic processes for making gefitinib (1) and erlotinib HCl (2). Instead
of unstable 4-chloroquinazoline intermediates, we have for the first time
made 4-methyl thioquinazolines, which are easy to handle and scalable.
Using these intermediates, we have prepared compounds 1 and 2 with 85%
and 90% yields respectively.
EXPERIMENTAL
All the starting materials and reagents were obtained from commercial sources
and were used without further purification. IR spectra were recorded using
1
a Nicolet Avatar 320 FT-IR spectrometer. H and C NMR spectra were
13
recorded in CDCl /DMSO-d at 200 MHz on a Bruker A G spectrometer.
3
6
All the chemical shift values are reported in d units downfield from TMS
as internal standard. Mass spectra were recorded using a GC MS-QP2010S
(
direct probe) on a Q-TOF micro TM APS MAX 0/6A system. HPLC
analysis was done using a Shimadzu Class VP using these column conditions:
ODS-3V 4.6 ꢀ 250 mm, particle size 5 m, l ¼ 254 nm, flow rate 1 ml/min,
and mobile phase (40 : 60) buffer–acetonitrile (buffer 1% ammonium
acetate). Melting points were recorded using a melting-point apparatus from
Acro Steel Pvt. Ltd.
Experimental Procedure for 4-(Methylthio)-7-methoxy-6-[3-(4-
morpholinyl) propoxy]-quinazoline (5)
To a stirred solution of 3 (10 g, 0.031 mol) and pyridine (100 mL), phosphor-
ous pentasulfide (11.9 g, 0.062 mol) was added. The reaction mixture was
refluxed for about 24 h. Pyridine was concentrated to get 6-methoxy-7-[3-
(
4-morpholinyl) propoxy]-quinazolin-4(3H)-thione (4). Mp 193–1988C; IR
21 1
KBr) g: 868, 1153, 1271, 1361, 1396, 1486, 1595, 2948, 3419 cm ; H
(
NMR (DMSO-d , 200 MHz): d ¼ 2.04 (m, 2H), 2.62 (m, 6H), 3.65
6
(
(
m, 4H), 3.96 (s, 3H), 4.14–4.20 (m, 2H), 7.17 (s, 1H), 7.94 (s, 1H), 8.08
1
3
s, 1H), 13.65 (brs, 1H); C NMR (DMSO-d , 200 MHz): d ¼ 25.38,
6
5
1
4
3.28, 54.92, 56.61, 65.96, 67.07, 108.28, 109.14, 123.71, 141.38, 142.80,
49.57, 156.38, 182.53; MS (m/z): 335 (M ), 304, 128, 100. To the residue
þ
, methanol (25 mL) was added and cooled to 158C. Sodium hydroxide 5%
aq., (50 mL) was added, the temperature of the reaction mixture was kept

Gefitinib and Erlotinib Hydrochloride
3413
between 15 and 208C, the mixture was filtered to remove the insolubles, and
the mother liquor was cooled to 208C. Methyl iodide (8.8 g, 0.062 mol) was
added slowly over 30 min, and stirring continued for about 5 h. Water
(
(
50 mL), was added and the product extracted into ethyl acetate
3 ꢀ 50 mL). The organic layer was washed with water (1 ꢀ 50 mL), dried
over anhydrous sodium sulfate, filtered, and evaporated to yield compound
5
1
2
(8.3 g, 76% yield). Mp 127–1318C; IR (KBr) g: 819, 967, 1117, 1347,
1
610, 2959; H NMR (CDCl , 200 MHz): d ¼ 2.05–2.18 (m, 2H), 2.50–
3
.62 (m, 6H), 2.72 (s, 3H), 3.75 (m, 4H), 4.01 (s, 3H), 4.23 (m, 2H), 7.22
1
3
s, 1H), 7.27 (s, 1H), 8.86 (s, 1H); C NMR (CDCl , 200 MHz):
(
3
d ¼ 12.39, 25.91, 53.65, 55.26, 56.13, 66.88, 67.32, 102.48, 107.10, 149.29,
þ
1
52.40, 167.50; MS (m/z): 349 (M ), 128, 100.
Experimental Procedure for 4-(3-Chloro-4-flourophenylamino)-7-
methoxy-6-[3-(4-morpholinyl) propoxy]-quinazoline (1)
To a stirred solution of 5 (10 g, 0.031 mol) and isopropyl alcohol (100 mL),
3
-chloro-4-flouroaniline (13.5 g, 0.093 mol) and 3-chloro-4-flouroaniline
hydrochloride (16.8 g, 0.093 mol) were added. The reaction mixture was
refluxed for about 24 h and then concentrated under vacuum. To the
H
residue, water (100 mL) was added and basified to p ¼ 8 with NaOH. The
product was extracted into ethyl acetate (3 ꢀ 50 mL); the organic layer was
washed with water (50 mL) and dried over anhydrous sodium sulfate. It was
then filtered and evaporated to get crude material, which was recrystallized
from ethyl acetate to get pure compound 1 (9 g, 85% yield) (3-chloro-4-
flouroaniline was recovered from mother liquor), mp 193–1958C; HPLC
1
purity . 99%; H NMR (CDCl , 200 MHz): d ¼ 2.11 (m, 2H), 2.46–2.59
3
(
(
(
m, 6H), 3.74 (dd, J ¼ 4.5 Hz & 4.4 Hz, 4H), 3.98 (s, 3H), 4.17
t, J ¼ 6.5 Hz, 2H), 7.09 (s, 1H), 7.16 (t, J ¼ 8.8 Hz, 1H), 7.26 (s, 1H), 7.34
brs, 1H, exchangeable with D O), 7.50–7.58 (m, 1H), 7.84–7.88 (m, 1H),
2
þ
8
.66 (s, 1H); MS (m/z): 446(M ). Anal. calcd. for C H ClFN O : C,
4 3
2
2
24
5
9.19; H, 5.38; N, 12.55. Found: C, 59.17; H, 5.21; N, 12.33.
Experimental Procedure for 6,7-Bis-(2-methoxyethoxy)-quinazolin-
(3H)-thione (7)
4
To a stirred solution of 6 (10 g, 0.034 mol) and pyridine (100 mL), phosphorous
pentasulfide (15.1 g, 0.068 mol) was added. The reaction mixture was refluxed
for about 24 h. Pyridine was removed under vacuum. Methanol (150 mL) was
added to the residue, heated to 608C, stirred for 30 min, and filtered hot. The
mother liquor was cooled to 10–158C, and the solid was filtered and dried at
5
08C to get compound 7 (10 g, 95% yield). Mp 190–1958C; IR (KBr) g:
69, 1163, 1292, 1362, 1402, 1486, 1592, 2931; H NMR (DMSO-d6,
1
8

3414
V. Chandregowda, G. V. Rao, and G. C. Reddy
2
7
00 MHz): d ¼ 3.35 (s, 6H), 3.74 (m, 4H), 4.21–4.33 (m, 4H), 7.15 (s, 1H),
1
.95 (s, 1H), 8.10 (s, 1H), 13.64 (brs, 1H); C NMR (DMSO-d , 200 MHz):
3
6
d ¼ 58.70, 68.63, 68.84, 70.40, 109.20, 109.68, 123.68, 141.37, 142.92,
þ
1
49.60, 155.68, 182.53; MS (m/z): 310 (M ), 279, 221, 207, 194, 59.
Experimental Procedure 4-(Methylthio)-6,7-bis-(2-methoxyethoxy)-
quinazoline (8)
To a solution of 7 (10 g, 0.032 mol) in methanol (50 mL), 5% aq. sodium
hydroxide solution (100 mL) was added, keeping the temperature of the
reaction mixture at 208C. The mixture was stirred for about 30 min. Methyl
iodide (6.84 g, 0.048 mol) was added slowly over 30 min, and stirring
continued for about 5 h at 258C. Water (100 mL) was added to the reaction
mass, and the product was extracted into ethyl acetate (3 ꢀ 50 mL). The
organic layer was washed with water (50 mL) and dried over anhydrous
sodium sulfate. The solids were filtered and the organic layer evaporated to
get compound 8 (9 g, 86% yield), mp 86–908C; IR (KBr) g: 864, 1170,
1
1
232, 1416, 1509, 1612, 2925; H NMR (CDCl , 200 MHz): d ¼ 2.71
3
(
s, 3H), 3.48 (s, 3H), 3.50 (s, 3H), 3.87 (m, 4H), 4.28 (m, 4H), 7.27 (s, 2H),
1
3
8
7
1
.86 (s, 1H); C NMR (CDCl , 200 MHz): d ¼ 12.40, 59.24, 68.39, 68.73,
3
0.35, 70.59, 103.44, 108.09, 118.92, 145.13, 148.92, 152.47, 155.00,
67.56; MS (m/z): 324 (M ), 279, 221, 208, 59.
þ
Experimental Procedure for [6,7-Bis-(2-methoxyethoxy)-
quinazolin-4-yl]-(3-ethynylphenyl) amine Hydrochloride (2)
To a stirred solution of 8 (9 g, 0.028 mol) and isopropyl alcohol (100 mL),
3
0
-ethynylaniline (3.9 g, 0.033 mol) and 3-ethynylaniline hydrochloride (5 g,
.033 mol) were added. The reaction mixture was refluxed for about 15 h,
cooled to 108C, filtered, and dried at 508C to get compound 2 (10.7 g, 90%
1
yield), mp 228–2308C. Purity by HPLC .99%; H NMR (DMSO-d6,
2
00 MHz): d ¼ 3.36 (s, 6H), 3.77 (m, 4H), 4.29 (s, 1H), 4.32–4.38
(m, 4H), 7.38–7.55 (m, 3H), 7.78 (d, J ¼ 8.0 Hz, 1H), 7.88 (s, 1H), 8.38
(
s, 1H), 8.86 (s, 1H), 11.42 (s, 1H). Anal. calcd. for C H N O Cl: C,
2
2 24 3 4
61.32; H, 5.85; N, 9.75. Found: C, 61.45; H, 5.62; N, 9.60. Chloride assay
by potentiometric method 98.82%.
ACKNOWLEDGMENT
Our sincere thanks are due to Anil Kush, CEO, Vittal Mallya Scientific
Research Foundation, for his keen interest and support in this work.

Gefitinib and Erlotinib Hydrochloride
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