Three-point variation of a gefinitib quinazoline core

Article abstract of DOI:10.1016/j.tetlet.2009.01.099

A versatile four-step process describing the controlled systematic variation of a key quinazoline core from one intermediate is highlighted.

Full text of DOI:10.1016/j.tetlet.2009.01.099

Tetrahedron Letters 50 (2009) 1600–1602
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Three-point variation of a gefinitib quinazoline core
*
Craig S. Harris , Laurent F. Hennequin, Olivier Willerval
AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A versatile four-step process describing the controlled systematic variation of a key quinazoline core from
one intermediate is highlighted.
Received 26 November 2008
Revised 12 January 2009
Accepted 20 January 2009
Available online 23 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Gefinitib
Quinazoline
Mitsunobu alkylation
As an ATP-binding mimic, the quinazoline family has been of
major interest to the pharmaceutical industry offering a relatively
simple scaffold to probe and develop quickly a strong understand-
ing of structure-activity relationships culminating in many candi-
date drug nominations.1 Perhaps quinazolines substituted at C-4,
C-6 and C-7 have emerged as one of the most important classes
of quinazoline-based kinase inhibitors with gefitinib2 and erlotinib3
having already been approved for the treatment of non-small cell
lung cancer refractory to chemotherapy4 and AZD6474,5
AZD2171 and KRN951 showing promising results in the clinic6
(Fig. 1).
Despite numerous synthetic achievements in this domain and
the intensive research carried out during the past decade up to
the present day,7 the synthesis of analogues in the C-4 substituted
6,7-bis(alkoxy)quinazoline family is rather rigid and this has some-
what been an inhibitory factor to fine-tuning structure-activity
exploration and improving physico-chemical properties. Current
methodology to access ‘heterodialkoxy’ C-4 substituted quinazo-
lines relies upon effecting aryl methyl ether deprotections in order
to reveal the corresponding phenols at C-68or C-79 using, for exam-
ple, pyridinium hydrochloride under melt conditions10 or lithium
iodide in 2,4,6-collidine at elevated temperatures.11 However,
retaining sensitive groups such as aryl ethers at C-4 under these
harsh conditions is not possible.
inhibitors can be performed in a very convenient manner allowing
for an explosion in diversity. (Scheme 1).
The synthesis of 5 was realised from 6-AcO-7-OMe-quinazolone
(1).14 Double deprotection of the methyl ether at C-7 and the acetyl
protecting group at C-6 of 1 was achieved using pyridinium hydro-
chloride under melt conditions. The resulting diol 215 was subse-
quently protected with pivaloyl groups. We found the use of
pivaloyl groups over acetyl protecting groups was essential in aid-
ing purification of the subsequent chloride 3, achieved by carefully
treating the quinazolone precursor with an excess of POCl3 in the
presence of TEA at <50 °C. Deprotection of 3 via ammonolysis affor-
ded the stable diol 4, a useful and completely novel intermediate in
itself for synthesising C-6,7-homodialkoxyquinazoline libraries. Fi-
nally, regioselective protection of 4 was achieved, as described in
our previous Letter,12 using pivaloyl chloride in the presence of
TEA at room temperature to afford a good yield of the key interme-
diate 5 (Scheme 2).
In practise, exploitation of 5 was possible going in both direc-
tions. From the left-hand direction, Mitsunobu alkylation using
DTAD and polymer-supported triphenylphosphine16 afforded 6 in
near quantitative conversions. The subsequent phenols 7 were re-
vealed by ammonolysis of the 6-C-OPiv using methanolic ammonia
at room temperature. The solutions were concentrated to dryness
and the residues were exposed to the second Mitsunobu alkylation
conditions to afford the 4-chloro-6,7-heterodialkoxyquinazolines 8
again with excellent conversions. The resin was removed and the
filtrate was concentrated, dissolved in DMF and in the case of ani-
line substitutions, a catalytic quantity of dry HCl was added and
the reaction mixtures were heated at 80 °C with the desired aniline
for 2 h; in the case of phenols and thiophenols substitution, 3 equiv
of potassium carbonate was added and the reaction mixtures were
heated at 80 °C with the desired phenol or thiophenol for 2 h; and
in the case of aliphatic amines, 3 equiv of the desired amine was
In a recent Letter,12 we described a novel route to differentially
alkylate at C-7-OH then at C-6-OH using Mitsunobu alkylation con-
ditions.13 This route allowed us to access a large library of novel
6,7-heterodialkyl-oxyanilinoquinazolines. Herein, we take the
chemistry back to yet another level and prove that systematic var-
iation of all three-key points of this important family of kinase
* Corresponding author. Tel.: +33 03 26 61 5912; fax: +33 03 26 61 6842.
E-mail address: craig.harris2@astrazeneca.com (C.S. Harris).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.099

C. S. Harris et al. / Tetrahedron Letters 50 (2009) 1600–1602
1601
F
Br
O
HN
4
Cl
HN
HN
6
N
O
O
O
O
N
F
O
O
O
O
N
N
7
N
N
N
Gefitinib
Erlotinib
N
AZD6474
Cl
H
N
H
N
H
N
O
N
O
O
O
N
F
O
O
O
N
N
N
O
N
AZD2171
KRN951
Figure 1. Examples of C4-substituted quinazolines on the market or in late-stage clinical development.
A short selection of simple compounds was made to illustrate
this highly adaptable process which can be seen in Table 1. It is
worth noting that by adapting this process, one can access libraries
of 9 in 5 h as opposed to weeks using existing routes and introduce
sensitive groups at C-4, for example, ethers (entries 7 and 8) which
would not be retained following existing methodology.
O
O
O
N
O
O
HO
HO
NH
(ii)
(i)
NH
(iii)
N
1
2
In conclusion, we have developed new, flexible and tolerant
routes passing through novel and highly versatile quinazoline
intermediates to thoroughly explore quinazoline substitution at
C-4, C-6 and C-7 in a selective and rapid manner compared with
existing methodology.
O
O
Cl
Cl
N
Cl
N
O
O
HO
HO
(iv)
O
(v)
N
N
N
N
HO
3
4
5
O
Scheme 1. Synthesis of 4-chloro-6-OPiv-7-OH-quinazoline. Reagents and condi-
tions: (i) pyridinium hydrochloride, 170 °C, 3 h, 95%; (ii) Piv-Cl, TEA, DMF, rt, 2 h,
71%; (iii) POCl3, TEA, toluene, rt, 40 °C, 3 h, 70%; (iv) NH3/MeOH, rt, 2 h, 100%; (v)
Piv-Cl, TEA, DMF, rt, 2 h, 57%.
Table 1
Selected examples given in isolated yields after purification by preparative LC–MS17
Entry Cpd R1
R2
R3
Conversion (LC–MS) Yield
5–6–7–8–9 (% purity (%)
at 254 nm)
O
R3
N
O
O
Cl
N
HN
N
Cl
N
N
N
1a
2
9a
9a
9b
9c
9d
9e
9f
88-,100-,96-,93
95-,100-,94-,98
93-,98-,100-,94
96-,92-,98-,93
90-,98-,92-,66
90-,98-,92-,81
90-,98-,92-,71
90-,98-,92-,64
49
51
51
60
42
75
58
38
O
O
O
O
O
O
O
(i)
N
O
O
(iv)
N
HN
HN
HN
only under
acid catalysis
O
O
H
H
R1
6
5
10
(ii)
Cl
(i)-(iii)
R3
3b
4b
5
"
R2
NH/O/S
R2
O
Cl
O
O
O
H
(iii)
N
N
(iv)
N
O
N
O
N
O
N
R1
R1
R1
9
O
O
O
O
O
O
8
7
HN
HN
N
Scheme 2. Two routes to access 9. Reagents and conditions: (i) R1-OH, DTAD, TPP,
DCM, rt; (ii) NH3/MeOH, rt, 2 h, 100%; (iii) R2-OH, DTAD, TPP, DCM, rt; (iv) R3-Ar-
NH2, cat. HCl, MeCN or DMF, 80 °C or R3-Ar-OH or R3-Ar-SH, K2CO3, DMF, 70 °C or
excess R3-aliphatic amines, DMF, 80 °C, 38–75%.
N
N
N
N
O
O
O
O
N
6
added and the reaction mixtures were heated at 80 °C for 2 h. The
resulting solution or suspensions were filtered and purified di-
rectly by preparative LC–MS to afford libraires of 9 in good yield
for a four-step process. From the right-hand direction, application
of similar aniline substitution conditions as described above in
MeCN resulted in little or no in situ deprotection of the C-6-OPiv
affording 10. However, it was necessary to purify 10 by preparative
LC–MS in order to carry out the double Mitsunobu alkylation pro-
cess. All attempts to displace the C-4-Cl of 5 under basic conditions
failed, as expected, resulting in deprotection of the C-6-OPiv and
further degradation.
7
O
S
8
9g
a
Final compound prepared going from right hand direction with after purifica-
tion of 10.
b
Final compounds can also be prepared from intermediate 4.

1602
C. S. Harris et al. / Tetrahedron Letters 50 (2009) 1600–1602
9. (a) Heron, N. M.; Pasquet, G. R.; Mortlock, A. A.; Jung, F. H. PCT Int. Appl., 2004
Acknowledgements
(WO200494410).; (b) Hennequin, L. F.; Thomas, A. P.; Johnstone, C.; Stokes, E.
S. E.; Ple, P. A.; Lohmann, J.-J. M.; Ogilvie, D. J.; Dukes, M.; Wedge, S. R.;
Curwen, J. O.; Kendrew, J.; Lambert-van der Brempt, C. J. Med. Chem. 1999, 42,
5369–5389.
The author would like to acknowledge Dr. Euan Arnott (Astra-
Zeneca Process Research and Development) for his very helpful
discussions concerning the chlorination process and Dr. David M.
Andrews (AstraZeneca Discovery) for useful comments during
the preparation of this manuscript.
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Supplementary data
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Detailed experimental procedures for the synthesis of all final
compounds, intermediates with supporting 1H NMR and LC–MS
characterisation data are available. Supplementary data associated
with this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.01.099.
16. Free triphenylphosphine can be used for this chemistry12 but for multi-parallel
approaches where the end product is purified by mass-triggered preparative
LC–MS using reverse-phase chromatography, the presence of large quantities
of triphenylphosphine oxide can contaminate the final compounds depending
on their polarity but more importantly ‘drown’ the mass detector resulting in
loss of compound.
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17. Typical procedure: To
a
stirred suspension of polymer-supported
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triphenylphosphine (3 equiv), and the first alcohol (3 equiv) in DCM (5 ml/g
of resin) at 0 °C was added di-tert-butyl azadicarboxylate (DTAD, 3 equiv)
followed by 5. The reaction mixture was slowly agitated for 1 h at room
temperature, filtered, and the filtrate was concentrated. The residue
(containing 6) was dissolved in methanolic ammonia (7 N) and stirred for
5 h, concentrated to dryness, re-dissolved in THF and re-concentrated to
dryness. The phenol 7 was subsequently added to a stirred suspension of
polymer-supported triphenylphosphine (4 equiv) the second alcohol
(4 equiv), and DTAD (4 equiv) at 0 °C. The reaction mixture was slowly
agitated for 1 h at room temperature and concentrated to dryness. The
resulting residue was exposed to the following conditions: (a) for the
introduction of C-4-anilines (e.g., entry 2), the residues were taken up in DMF
and treated with 1.1 equiv of aniline and 0.2 equiv of HCl in dry 1,4-dioxane
at 80 °C for 2 h; (b) for the introduction of C-4-aryl(thio)ethers, the residues
were taken up in DMF and treated with (thio)phenol (3 equiv) and K2CO3
(3.3 equiv) at 80 °C for 2 h (entry 7); (c) for the introduction of C4-aliphatic
amines (entry 6), the residues were taken up in DMF and treated with the
desired amine (3 equiv) at 80 °C for 2 h. The reaction mixtures were cooled to
room temperature, filtered and purified directly by preparative LC–MS to
afford the desired C4-substituted 6,7-bis-alkyoxyquinazolines (9) in
acceptable overall yields.
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7. According to a search carried out using SciFinder (09/01/2009), there are over
5700 references, including 412 chemistry patents containing relevant
preparations, around the C-4-substitued 6,7-bis(alkoxy)quinazoline series. In
addition, over 1600 references including 96 chemistry patents with
preparations have been published since 2007 proving that research just
around this substructure is still very active.
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