Synthesis of 6- and 7-propargyloxy derivatives of 4-(3-fluoroanilino)- quinazoline

Article abstract of DOI:10.1016/j.tetlet.2010.11.107

The preparation of the novel isomeric 6- and 7-propargyloxy derivatives of 4-(3-fluoroanilino)-quinazoline was achieved using a six-step process. An alternate method to the 7-propargyloxy derivative and analogous 7-propargyloxy containing compounds is als

Full text of DOI:10.1016/j.tetlet.2010.11.107

Tetrahedron Letters 52 (2011) 1053–1056
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 6- and 7-propargyloxy derivatives of 4-(3-fluoroanilino)-
quinazoline
Helen Trinh Pham a, Robert N. Hanson a, , Sandra L. Olmsted b, Anton Kozhushnyan a, Adam Visentin a,
⇑
Paul J. Weglinsky a, Chris Massero a, Kristen Bailey a
a Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, United States
b Department of Chemistry, Augsburg College, 2211 Riverside Drive, Minneapolis, MN 55454, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2010
Revised 16 November 2010
Accepted 18 November 2010
Available online 10 December 2010
The preparation of the novel isomeric 6- and 7-propargyloxy derivatives of 4-(3-fluoroanilino)-quinazo-
line was achieved using a six-step process. An alternate method to the 7-propargyloxy derivative and
analogous 7-propargyloxy containing compounds is also described.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Anilinoquinazoline
Tyrosine kinase inhibitors
Bifunctional derivatives
1. Introduction
cule therapeutics with multiple activities would incorporate a sim-
ilar 4-anilinoquinazoline structure, it would be necessary, based on
Growth factor receptor tyrosine kinase inhibitors (TKI) have been
the subject of significant pharmaceutical research in recent years.1
From this work, several agents in the 4-anilinoquinazoline subclass
have been approved and/or evaluated for the treatment of patients
with various forms of cancer, including ovarian and breast cancer
(Fig. 1).2 Of particular interest to our research group were recent
studies demonstrating synergistic effects between the kinase inhib-
itor activity of these drugs and anti-hormonal agents such as ICI
182,780 (Faslodex) in anti-hormone resistant tumor cells.3
Recent studies by Jean-Claude with combi-targeted anilinoqui-
nazoline TKI indicated that bi-functional derivatives retained most
of their individual properties while exerting complementary effects
on target cells.4 Although our strategy in developing single mole-
the binding characteristics of the second molecular target (e.g.,
estrogen receptor) to incorporate a significantly longer and more
modified linker. Because a linear approach to the ultimate target
compounds would also be unwieldy, we chose a convergent
approach in which the two components could be ligated using a
‘click chemistry’ methodology such as the alkyne-azide Huisgen
[3+2] cycloaddition reaction.5 Therefore our choice of targets, based
on the structure–activity relationships of the anilinoquinazolines, is
shown in Figure 2, where the propargyloxy group (selected as one
coupling partner) could reside at either the 6- or 7-positions, sites
known to tolerate significant substituent diversity.6
Numerous syntheses of 4-anilinoquinazolines have been pub-
lished, however, only one example incorporated a propargyloxy
Figure 1. Representative 4-anilinoquinazoline TKI approved or in clinical trials and Fulvestrant.
⇑
Corresponding author. Tel.: +1 617 373 3313; fax: +1 617 373 8795.
E-mail address: r.hanson@neu.edu (R.N. Hanson).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.107

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H. T. Pham et al. / Tetrahedron Letters 52 (2011) 1053–1056
Figure 2. Example of combi-targeted 4-anilinoquinazoline4 and our proposed convergent ligation approach.
tBoc
N
tBoc
N
tBoc
N
N
N
N
N
N
N
Subsequent
Transformations
Multiple
Steps
Propargyl
Bromide
K2CO3
R6
R7
H2-Pd/C
R6
R7
R6
R7
N
N
N
R6 = OH R7 = OMe
R6 = OMe R7 = OH
R
6 = OPropargyl R7 = OMe
R6 = OBn R7 = OMe
R6 = OMe R7 = OBn
R6 = OMe R7 = OPropargyl
Scheme 1. Approach used to prepare 6-/7-O-propargyl derivatives.7
group at either the 6- or 7-positions.7 In that study, the O-propar-
gyl derivatives were only one part of a larger series of compounds
prepared and evaluated. The synthetic method used in this study
(Scheme 1) did not focus on its preparation and there it did not ap-
pear optimal for our purposes in which the alkynyl group was cen-
tral to our goals. In this study alternate approaches were
considered in which one could establish the 6,7-dimethoxy-qui-
nazolone or 4-anilinoquinazoline scaffold first and then selectively
demethylate the 6-position6 or prepare the 6/7-benzyloxy quinaz-
oline and then debenzylate to provide the appropriate precursor
for propargylation.8 In our hands, the demethylation of the dime-
thoxy quinazolone was not sufficiently reproducible to meet our
needs and the benzylation/debenzylation sequence would conceiv-
ably add an additional step. Therefore we elected to introduce the
propargyl group at the initial step of the process, although we real-
ized that the presence of this substituent would affect virtually all
subsequent reactions because of its sensitivity to acidic and reduc-
tive reagents.
2. Results and discussion
The synthesis of the two target compounds 13 and 14 was
undertaken in parallel (Scheme 2). Alkylation of the phenolic group
of the starting materials 1 and 2 proceeded in essentially quantita-
tive yield.8 The resultant propargyl ethers 3 and 4 were nitrated
using stannic chloride and fuming nitric acid in dichloromethane
to give the desired nitrated intermediates 5 and 6.9 Use of concen-
trated nitric acid in acetic acid at temperatures up to 120 °C, con-
ditions used for nitration of the corresponding benzyl ethers,
gave hydration of the propargyl group. Because catalytic hydroge-
nation of the nitro-group was precluded by the propargyl moiety,
we evaluated several other reductive methods, including stannous
chloride,10 dithionite,11 Raney nickel-hydrazine,12 zinc dust13, and
sodium borohydride-nickel chloride.14 Although all methods
worked well on small scale (1–3 mmol), only dithionite and so-
dium borohydride-nickel chloride were reasonably successful on
larger scale (10–20 mmol) reductions to give the anilines 7 and
O
O
O
O
O
CH3
O
O
CH3
O
O
CH3
b
a
R1
R2
O
R1
R2
O
R1
R2
O
NO2
3 R1 = CH3; R2 = Propargyl
4 R1 = Propargyl; R2 = CH3
1. R1= CH3; R2 = H
5 R1 = CH3; R2 =Propargyl
6 R1 = Propargyl; R2 = CH3
2
R1 = H; R2 = CH3
O
O
O
O
CH3
O
R1
R2
O
R1
R2
NH
e
d
c
NH2
O
N
7 R1 =CH3; R2 =Propargyl
8 R1 = Propargyl; R2 =CH3
9
R1 = CH3; R2 = Propargyl
10 R1 = Propargyl; R2 =CH3
R1=R2= CH3 Dimethoxyquinazolinone
Cl
N
HN
N
F
O
O
O
O
R1
R2
N
R1
R2
N
f
11 R1 =CH3; R2 = Propargyl
12 R1 = Propargyl; R2 =CH3
13 R1 = CH3; R2 = Propargyl
14 R1 = Propargyl; R2 =CH3
Scheme 2. Preparation of Isomeric 6- and 7-propargyloxy-4-(3-fluoroanilino)quinazolines 13 and 14. Reagents and condition: (a) Propargyl bromide, K2CO3, acetone, reflux,
16 h; (b) fuming nitric acid, SnCl4, CH2Cl2; (c) Na2S2O4, CH3OH; (d) formamide, ammonium formate, 150 °C, 6 h; (e) CCl4, (C6H5)3P, C2H4Cl2, 50 °C, 2 h; (f) 3-fluoroaniline,
isopropanol, reflux, 6 h.

H. T. Pham et al. / Tetrahedron Letters 52 (2011) 1053–1056
1055
O
HN
N
F
HN
N
F
O
CH3
g
a-f
O
O
H3C
O
h
O
H3C
N
H3C
N
13
HO
HO
1
15
16
HN
N
F
i
HO
O
O
O
O
O
O
O
H3C
N
17
16
O
O
O
O
j
TsO
O
O
O
19
18
Scheme 3. Synthesis of propargyloxy derivatives through a Mitsunobu coupling of 16 with tetraethylene glycol moiety giving 19. Reagents and conditions: (a) Benzyl
bromide, K2CO3, acetone; (b) fuming HNO3, acetic acid; (c) NaBH4–NiCl2–6H2O; (d) formamide ammonium formate; (e) SOCl2–DMF; (f) 3-fluroaniline, isopropanol; (g)
CF3CO2H, dichloromethane; (h) propargyl bromide, K2CO3, acetonitrile; (i) triphenylphosphine, DIAD, dichloromethane; (j) K2CO3, acetonitrile.
8. Cyclization of the anilines to the quinazolin-4-ones 9 and 10 was
achieved using formamide-ammonium formate in reasonable
yields.15 Subsequent efforts to achieve dehydro-chlorination with
thionyl chloride and DMF were unsuccessful due to the sensitivity
of the propargyloxy group to the acidic conditions. The only iden-
tifiable products from that reaction were the depropargylated 4-
quinazolines which appeared as fluorescent materials on TLC.
Use of carbon tetrachloride-triphenylphosphine, which proceeds
under neutral conditions, gave the desired 4-chloroquinazoline
intermediates 11 and 12 in good yields.16 Because the quinazo-
lin-4-one intermediates were isolated as partially hydrated mate-
rials, additional triphenylphosphine was necessary to achieve
complete consumption of the starting materials. Temperature
was also an important factor as temperatures greater than 60 °C
also produced depropargylated materials in addition to the desired
compounds. Subsequent anilination with 3-fluoroaniline in isopro-
panol at reflux gave the final products 13 and 14 as the hydrochlo-
ride salts in 80–90% yields.
such as anti-estrogens, fluorophores, and radiolabels.21 This work
is in progress, and the biological and cellular imaging properties
of those products will be reported in subsequent publications.
Acknowledgments
This work was supported by grants from the Susan G. Komen
Foundation (BCTR0600659), the Department of Energy (ER-
64823), and in part through Summer Research Program of the
Merck Research Laboratories, Boston, MA.
Supplementary data
Supplementary data (synthesis and characterization of the final
compounds and intermediates) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.11.107.
Because of the sensitivity of the propargyl group to many of the
reagents used in the typical anilino-quinazoline synthesis, we also
undertook the preparation of 13 via an alternate route, proceeding
through the 7-O-benzyl intermediate (Scheme 3). Commercially
available methyl 4-hydroxy-3-methoxy-benzoate 1 was converted
in five steps into 4-(3-fluoroanilino)-6-methoxy-7-benzyloxy-qui-
nazoline 15 (35% overall yield).17,18 The only significant modifica-
tion involved an improved workup of the nickel chloride
hexahydrate-sodium borohydride reduction of the nitro intermedi-
ate. Debenzylation with trifluoroacetic acid to give the 7-hydroxy
intermediate 16, followed by alkylation with propargyl bromide
in acetonitrile, gave 13 in a 65% yield for 2 steps. Although this
method involved an additional step, the individual reactions were
more reproducible and the overall yield was greater. In addition,
the final 7-hydroxy intermediate 16 could be used to generate
other products.19 Introduction of the tetraethylene glycol moiety
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