Selective alkylation of a 6,7-dihydroxyquinazoline

Article abstract of DOI:10.1016/j.tetlet.2005.09.038

A convenient 3-step multi-parallel process for the preparation of 4-(3-chloro-2-fluoroanilino)-6,7-bisalkoxyquinazolines is highlighted.

Full text of DOI:10.1016/j.tetlet.2005.09.038

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7715–7719
Selective alkylation of a 6,7-dihydroxyquinazoline
Craig S. Harris,a,* Laurent F. Hennequin,a Jason G. Kettleb and Olivier A. Willervala
aAstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France
bAstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
Received 9 August 2005; accepted 7 September 2005
Available online 26 September 2005
Abstract—A convenient 3-step multi-parallel process for the preparation of 4-(3-chloro-2-fluoroanilino)-6,7-bisalkoxyquinazolines
is highlighted.
Ó 2005 Elsevier Ltd. All rights reserved.
In recent years, inhibition of receptor tyrosine kinases
(RTKs) has been the focus of much research in the
pharmaceutical industry.1 4-Anilinoquinazolines have
emerged as an important class of potent and selective
inhibitors of RTKs and numerous compounds are
currently in clinical development for the treatment of
cancer (Fig. 1). The small molecule tyrosine kinase
inhibitors gefitinib2 and erlotinib1 have been approved
for the treatment of non-small cell lung cancer refrac-
tory to chemotherapy.3
In our recent efforts to explore variation at positions
C-6 and C-7 of the ring nucleus to further investigate
the structure–activity relationships, we became inter-
ested in preparing a library of quinazolines containing
extended ether side chains at both positions. Herein,
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
ZD6474
F
O
F
O
S
H
HN
Cl
O
N
HN
Cl
O
HN
O
N
O
N
N
N
N
O
C1-1033
GW-572016
Figure 1. Examples of anilinoquinazolines in clinical development.
Keywords: Selective; Mitsunobu; Quinazoline.
*
Corresponding author. Tel.: +33 (0)3 26 61 5912; fax: +33 (0)3 26 61 6842; e-mail: craig.harris2@astrazeneca.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.038

7716
C. S. Harris et al. / Tetrahedron Letters 46 (2005) 7715–7719
O
N
We hypothesised that differentiating between the two
O
phenols should be achievable due to the large difference
in acidity between the C-7-phenol (pKa = 7.6), whose
delocalisation base can be stabilised by conjugation into
the quinazoline ring, and the C-6-phenol (pKa = 10.02)
which cannot be stabilised by the quinazoline.6 How-
ever, initial attempts to apply standard Mitsunobu chem-
istry7 failed. No sign of any selective alkylation was
observed despite attempts looking at both the mode of
addition and solvent choice. We eventually chose to
selectively esterify 4 with a view to preparing an interme-
diate, which could be utilised in a 3-step approach to
prepare a differentially alkylated 6,7-bis-alkoxyquinazo-
line library. Selective acylation at C-6 was achieved
using acetic anhydride in the presence of one equivalent
of sodium hydroxide (Scheme 2).
O
O
HO
O
NH
(ii)
(i)
NH
(iii)
N
1
2
O
Cl
N
HN
Cl
O
O
F
HO
HO
(iv)
(v)
N
N
N
3
4
Scheme 1. Synthesis of 4-(3-chloro-2-fluoroanilino)-6,7-dihydroxyquin-
azoline. Conditions: (i) methionine, MeSO3H, 100 °C, 3 h, 45%; (ii)
Ac2O, pyridine, 100 °C, 100%; (iii) SOCl2, reflux, 16 h, 70%; (iv) 3-
chloro-2-fluoroaniline, i-PrOH, reflux, 98%; (v) pyridinium hydrochlo-
ride, 150 °C, 3 h, 67%.
We postulate that the excellent degree of regioselectivity
can be explained by the Curtin-Hammet principle.8
While based upon the differences in pKa, the phenoxide
at C-7 must be dominant, the rate of acylation of C-6-
OÀ is much greater than that of C-7-OÀ thus driving
the equilibrium towards the C-6-OAc (Scheme 2).
Although the yield of 6-AcO-7-OH-quinazoline was
acceptable, the resulting precursor proved to be some-
what unstable to the Mitsunobu alkylation conditions
employed (di-tert-butylazadicarboxylate, triphenylphos-
phine, alcohol, DCM, 0 °C to rt). A signification quan-
tity of bis-phenol 4 was observed, presumably through
attack of the acylhydrazide anion generated by reaction
of triphenylphosphine with the azadicarboxylate. How-
ever, the C-6-OAc derivative 5 did allow us to isolate
our first examples of bis-alkylated products in accept-
able overall yields.9 In order to eliminate the observed
in situ deprotection at C-6, we turned to the increase ste-
ric bulk offered by a pivalate protecting group, which
also served to increase solubility in the reaction solvent
(Scheme 2).10
we communicate the facile and parallel chemistry em-
ployed to achieve this important class of kinase inhibi-
tors from the corresponding bis-phenol precursor 4
(Scheme 1).
The synthesis of 4 was realised from 6,7-dimethoxyquin-
azolone 1.4 Deprotection of the methyl ether at C-6
was achieved using methionine in the presence of
methanesulfonic acid.5 The resulting C-6-phenol 2 was
subsequently acetylated and chlorinated to afford the
corresponding 4-chloroquinazoline 3. Substitution of 3
with 3-chloro-2-fluoroaniline was achieved in excellent
yield in i-PrOH at reflux. Cleavage of the second methyl
ether at C-7, with simultaneous unmasking of the C-6-
phenol to afford the requisite bis-phenol 4 was achieved
in good yield using pyridium hydrochloride under melt
conditions (Scheme 1).
Cl
Cl
Cl
F
F
F
HN
HN
HN
-
O
HO
HO
HO
N
N
N
HO
N
O
-
N
N
4
Ac2O, NaOH, THF
or
slow
F
fast
F
Piv-Cl, TEA, THF,
0˚C to r.t.
Cl
Cl
R
O
HN
HN
O
HO
O
N
N
HO
N
N
R
R = CH3 (5, 45%), t-Bu (6, 56%)
O
Scheme 2. Possible mechanistic explanation of the excellent regioselective acylation at C-6.

C. S. Harris et al. / Tetrahedron Letters 46 (2005) 7715–7719
7717
Cl
Cl
F
F
O
O
HN
HN
DTAD, DCM,
O
O
O
r.t.,100%
N
Ph
P+
N
+
R1
HO
N
NH3/MeOH, r.t.
100%
O
R1
R1-OH
N
Ph
6
7
PPh2
remove by filtration
Cl
Cl
F
F
HN
R2
HN
DTAD, DCM, r.t.,
70-100% conv.
HO
O
O
Ph
P+
N
N
+
R1
R1
N
O
R2
R2-OH
Ph
O
N
8
remove by filtration
9
PPh2
Scheme 3. Double-Mitsunobu transformation of 6 to 6,7-heteroalkylatedanilinoquinazolines 9.
Table 1. Selected examples given in isolated yields after purification by preparative LCMS13
Entry
R1
R2
Conversion (LCMS) (7-,8-,9)
100-,95-,85
Yield (%)
N
1
55
78
53
O
O
O
O
O
2
100-,96-,91
N
3a
100-,96-,94-,93
O
N
O
4a
100-,96-,94-,92
45
N
OH
O
N
O
5
6
80-,70-,65
98-,90-,81
43
44
S
N
N
O
7
8
9
98-,90-,76
98-,90-,70
98-,90-,75
51
59
O
O
O
O
O
O
50
(continued on next page)

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C. S. Harris et al. / Tetrahedron Letters 46 (2005) 7715–7719
Table 1 (continued)
Entry
R1
R2
Conversion (LCMS) (7-,8-,9)
Yield (%)
67
10
11
12
13
98-,90-,92
98-,90-,86
96-,96-,86
100-,94-,84
N
O
O
62
55
58
N
N
N
14
93-,77-,71
65
O
a The final Mitsunobu steps were carried out, with excellent conversions, using 2-bromoethanol and glycidinol, respectively. The resulting bromide
and epoxide were treated with an excess of N-acetylpiperazine in DMF at 90 °C and in IPA at 90 °C, respectively, before purification.
The introduction of the C-6-OPiv greatly reduced the
problem of in situ deprotection and the desired C-7-
alkoxyquinazolines 7 were isolated in excellent yields.
Subsequent deprotection of the C-6-OPiv was effected
by treatment of the intermediate 7 with 7N methanolic
ammonia in quantitative yield. This permitted the isola-
tion of 8 not only in excellent overall yield but, after
concentration, in a state of sufficient purity to carry
out the final Mitsunobu alkylation. In essence, the
process simply requires two filtrations and concentra-
tions, and was automated to provide a large library of
6,7-bis-alkoxy-(2-chloro-3-fluoroanilino)quinazolines 9
(Scheme 3).
We found that lower loading polymer-supported triphen-
ylphosphines (1–1.2 mmol/g) resulted in excellent con-
versions in both steps and little or no homo-alkylated
product was formed. A small selection of hetero-
bis-alkylated final compounds can be seen in Table 1.
The reaction conditions are indeed tolerant of a wide
variety of functionality, as one would expect of the ver-
satile Mitsunobu alkylation. Alcohols containing basic
functionality (e.g., entries 1 and 10), hindered secondary
alcohols (e.g., entries 12 and 14), alcohols containing
electrophilic sites (e.g., entries 4 and 5) can all be trans-
formed in acceptable to excellent overall yields with this
simple 3-step process.
Although the reaction can be carried out entirely in
solution in a 3-step-one-pot manner with simple con-
centrations between steps,11 we have found the intro-
duction of polymer-supported triphenylphosphine is
beneficial to (a) improve the yield of 9; (b) eliminate
competing N-alkylation through steric hindrance;12 (c)
completely eliminate any in situ deprotection in the first
step and consequential contamination with homo-alkyl-
ated product; and (d) to reduce mass of crude product
charges on the column and thus aid separation. The
author would like to emphasise that the choice of resin
appears critical when adopting this approach where a
large degree of diversity is introduced. High loading
polystyrene-supported triphenylphosphines (ꢀ3 mmol/
g) were generally acceptable for preparing un-hindered
primary ether libraries where all the alcohol reacted
thus was captured on the polymer during the first Mits-
unobu step and none was carried through to the final
Mitsunobu alkylation. However, for ether libraries
where at least one of the side chains was derived from
a secondary alcohol, high loading resins were not effi-
cient in ensuring complete reaction in the initial Mitsun-
obu alkylation, that is, unreacted alcohol ÔleachedÕ
through to the final Mitsunobu step resulting, in certain
cases, in significant quantities of homo-alkylated
product.
Acknowledgements
We would like to acknowledge Dr. Geoff Bird (Astra-
Zeneca) and Dr. Andy Whiting (University of Durham,
UK) for their very helpful discussions during the prepa-
ration of this manuscript.
References and notes
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11. Solution-based alkylation of 6 resulted in a 52% overall
yield of 6,7-heteroalkylated final compound. The main
impurities, as judged by LCMS, were homoalkylated
product (5–10%) and N-alkylation of the desired com-
pound (5%). Both impurities are practically eliminated
using polymer-supported triphenylphosphine suggesting
that access to the reactive sites on the polymer is dictated
by steric hindrance.
5. Gibson, K. H.; Grundy, W.; Godfrey, A.; Woodburn, J.
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6. The pKas of 4 were determined by mutli-wavelength
spectrophotometry on a Sirius GlpKa, sweeping the pH
from 2.5 to 11.5 and returning to 2.5. The analyte was
composed of 2 mg of 4 and was dissolved in 200 ll of
DMSO; 7.5 ll of this solution was diluted with 250 ll of a
buffer solution containing 0.2 g of KH2PO4 dissolved in
100 ml of water.
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13. Typically: To a stirred suspension of polymer-supported
triphenylphosphine (3 equiv), the first alcohol (3 equiv) in
DCM (5 ml/g of resin) at 0 °C, was added di-tert-
azadicarboxylate (DTAD, 3 equiv) followed by 6. The
reaction mixture was slowly agitated for 1 h at room
temperature, filtered and the filtrate was concentrated.
The residue (containing 7) was dissolved in methanolic
ammonia (7 N) and stirred for 5 h, concentrated to
dryness, re-dissolved in THF and re-concentrated to
dryness. Phenol 8 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, concentrated and
purified by preparative LCMS to afford the desired 6,7-
bis-alkylatedquinazolines 9 in acceptable to excellent
overall yields.
7. Mitsunobu, O. Synthesis 1981, 1.
8. Curtin, D. Y. Rec. Chem. Prog. 1954, 15, 111.
9. On average, exposure of 7 to solution-phase Mitsunobu
conditions resulted in formation of 15–20% of bis-phenol
by LCMS. This figure could not be significantly improved
upon by changing the order of addition of Mitsunobu
reagents.
10. The regiochemistry of the 6-OPiv-7-OH intermediate 6
was determined by NMR experiments. In comparison, to
the parent bis-phenol 4, the proton at C-5 shifted 0.5 ppm
downfield (as opposed to C-8 proton which did not move)
and a NOE was observed between the C-5 proton and the
aniline N–H.