Novel synthesis of differentially substituted 5,7-dialkoxyquinazolin-4-ones

Article abstract of DOI:10.1080/00397910802219247

The preparation of 7-ethoxy-5-fluoroquinazolin-4-one, starting from 3,5-difluorophenol, is described. Further reaction with alkoxide then gives differentially substituted 5,7-dialkoxyquinazolin-4-ones. Copyright Taylor & Francis Group, LLC.

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Novel Synthesis of
Differentially Substituted 5,7-
Dialkoxyquinazolin-4-ones
Kevin M. Foote a & Glenn Hatter a
a Cancer and Infection Research , AstraZeneca
Research and Developement , Alderley Park, U.K.
Published online: 09 Sep 2008.
To cite this article: Kevin M. Foote & Glenn Hatter (2008) Novel Synthesis of
Differentially Substituted 5,7-Dialkoxyquinazolin-4-ones, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
38:15, 2575-2583, DOI: 10.1080/00397910802219247
To link to this article: http://dx.doi.org/10.1080/00397910802219247
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Synthetic Communications1, 38: 2575–2583, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802219247
Novel Synthesis of Differentially Substituted
5,7-Dialkoxyquinazolin-4-ones
Kevin M. Foote and Glenn Hatter
Cancer and Infection Research, AstraZeneca Research and Developement,
Alderley Park, U.K.
Abstract: The preparation of 7-ethoxy-5-fluoroquinazolin-4-one, starting from
3,5-difluorophenol, is described. Further reaction with alkoxide then gives differ-
entially substituted 5,7-dialkoxyquinazolin-4-ones.
Keywords: Anthranilic acid, 2-aminobenzonitrile, 5,7-dialkoxyquinazolin-4-ones,
5,7-difluoroquinazolin-4-one
Pharmaceutical interest in 4-anilinoquinazolines has increased consider-
ably over the past decade, due mainly to the discovery that these com-
pounds are potent and selective inhibitors of many protein kinases
implicated in proliferative diseases.[1] Much of the earlier work focused
on variation of the solubilizing side chain at C-6 and=or C-7 of the qui-
nazoline core and resulted in the discovery and subsequent regulatory
approval of the EGF receptor tyrosine kinase inhibitors gefitinib[2] and
erlotinib[1] (Fig. 1) for the treatment of non-small cell lung cancer.
As part of our more recent work on inhibitors of the EGFR[3] and
c-Src[4] family of kinases, we have investigated switching the quinazo-
line C-6 substituent to the C-5 position. In this article, we describe a
regioselective and highly versatile route to differentially substituted 5,7-
dialkoxyquinazolin-4-ones as precursors to the desired 4-anilino-5,7-
dialkoxyquinazolines.
Quinazolinones 1 with identical C-5 and C-7 alkoxy substituents
are readily prepared from symmetrically disubstituted anilines via the
Received in the U.K. September 18, 2007
Address correspondence to Kevin M. Foote, Cancer and Infection Research,
AstraZeneca Research and Development, Alderley Park, Cheshire, U.K. E-mail:
kevin.foote@astrazeneca.com
2575

2576
K. M. Foote and G. Hatter
Figure 1.
corresponding isatins and anthranilic acids as outlined in Scheme 1.[5] The
C-5 alkoxy group can be selectively deprotected by treatment with magne-
sium bromide or pyridine hydrochloride in pyridine to give 2, which, after
POM protection of the quinazolinone N-3, can be further elaborated by
Mitsunobu or direct alkylation. Additionally, homologation at C-7 can then
be achieved by deprotection of the C-7 benzyl group in 3 followed by alky-
lation of the resulting 7-hydroxyquinazolinone, thereby enabling sequential
functionalization of the C-5 and C-7 positions.
The use of 5,7-difluoroquinazolin-4-one 5 also allows differing func-
tionalities to be introduced, this time through selective SNAr displacements
of the reactive fluorine leaving groups (Scheme 2).[5] Here the 5-fluorine is
much more reactive than the 7-fluorine and can be displaced selectively by
alkoxides at room temperature in a few minutes. However, because of the
differing reactivities of the two fluorines, the C-5 substituent again has to be
introduced before the C-7. A further limitation of this approach is that the
more forcing conditions required for the second displacement reaction[6]
can lead to displacement of the first introduced alkoxide group (parti-
cularly when this group is methoxide) in competition with displacement
of the 7-fluorine, resulting in scrambling of the two groups.
Scheme 1.

Synthesis of 5,7-dialkoxyquinazolin-4-ones
2577
Scheme 2. Reagents and conditions: (a) 4-hydroxytetrahydropyran, NaH, DMF,
20 ꢀC, 30 min.; (b) 2-piperazin-1-ylethanol, t-BuOK, THF, reflux, 15 h.
Although these methodologies allow introduction of a range of C-7
substituents subsequent to functionalization of C-5, we also sought a
route that would enable variation of the C-5 substituent at a later stage
of the synthesis. An ideal intermediate for carrying out such a variation
would be a 5-fluoro-7-alkoxyquinazolinone 6 (Fig. 2) in which the C-7
substituent has been introduced first.
Such compounds are not described in the literature and for reasons
described previously cannot be synthesized from 5,7-difluoroquinazolin-
4-one. We envisaged an alternative approach involving synthesis of the
quinazolinone ring with the required fluoro and alkoxy substituents
already in place. Historically, quinazolinones have been prepared by
the Neimentowski reaction of anthranilic acids[7] (Scheme 1), and we were
aware of one attempt to prepare the required fluoro-methoxyanthranilic
acid starting from 3-fluoro-5-methoxyaniline. However, Friedel–Crafts
acylation of this compound with oxalyl chloride gives only the undesired
regioisomeric isatin (Scheme 3).[8]
As reported by Roth and Tai,[9] it is also possible to form quinazoli-
none rings from 2-aminobenzonitriles by reaction with formic acid, and a
suitably substituted aminobenzonitrile should thus give access to our
desired fluoroalkoxyquinazolinone 6. As shown in Scheme 4, we discov-
ered we could access such an aminobenzonitrile starting from 3,5-
difluorophenol. 3,5-Difluorophenol was first converted to benzonitrile 7
using standard functional group manipulations. Reaction with ammonia
at high temperature gives aminobenzonitrile 8,[10] which cyclizes in formic
acid to give the desired 7-ethoxy-5-fluoroquinazolin-4-one 9 in good yield.
Displacement of the 5-fluorine with alkoxide then takes place cleanly and
under mild conditions to give a 5,7-disubstituted quinazolinone 10 in
Figure 2.

2578
K. M. Foote and G. Hatter
Scheme 3. Reagents: (a) oxalyl chloride.
which the 7-substituent has been introduced first. As illustrated in Table 1,
quinazolinone 9 can thus be used to introduce a range of C-5 substituents
in high yield while keeping the C-7 substituent constant.
Scheme 4. Regants and conditions: (a) Et2SO4, K2CO3, DMF, 80ꢀC; (b) n-BuLi,
THF, CO2; (c) (COCl)2, DCM; (d) NH3(aq.), THF; (e) Cl3CCOCl, Et3N, DCM; (f)
NH3(EtOH), 150 ꢀC; (g) HCO2H, c.H2SO4 (cat.), 100 ꢀC; (h) ROH, NaH, DMF, 60ꢀC.
Table 1. Reaction of fluoroquinazolinone 9 with alkoxides derived from alcohol
ROH and sodium hydride in DMF
Entry
Alcohol ROH
Yield (%)
a
b
c
77
90
73
79
d
e
76

Synthesis of 5,7-dialkoxyquinazolin-4-ones
2579
In summary, we have introduced a new intermediate that allows the
preparation of differentially substituted 5,7-dialkoxyquinazolinones and
provides an alternative sequence to previously used methods. This
methodology complements existing strategies and increases the synthetic
scope of the anilinoquinazoline class of receptor tyrosine kinase inhibitors.
EXPERIMENTAL
1H NMR spectra were recorded at 400 MHz on a Bruker DPX-400 spec-
trometer. LCMS were performed using a Waters 2890=ZMD micromass
system. HRMS were recorded on a Thermo LTQ FT or a Waters GCT
Premier system. All solvents (anhydr. where appropriate) and reagents
were used as received.
1-Ethoxy-3,5-difluorobenzene
Diethyl sulfate (13.1 ml, 0.10 mol) was added to a stirred mixture of 3,5-
difluorophenol (13.0 g, 0.10mol) and potassium carbonate (20.9 g,
0.15 mol) in DMF (200 ml). The mixture was heated at 80 ꢀC for 1.5 h. before
adding further diethyl sulfate (3.3 ml, 25mmol) and potassium carbonate
(5.2 g, 37.5 mmol). After heating for a further 2 h, the mixture was cooled
to room temperature, poured into water, and extracted twice with diethyl
ether. The combined extracts were washed with water, dried over magnes-
ium sulfate, and evaporated to a pale yellow oil (13.6 g, 86% yield).
1H NMR (400.132 MHz, DMSO) 6.77–6.65 (m, 3H, ArH), 4.06 (q,
J ¼ 7.0 Hz, 2H, OCH2), 1.32 (t, J ¼ 7.0 Hz, 3H, CH3). MS (þve EI):
158 (Mþ ).
4-Ethoxy-2,6-difluorobenzoic acid
n-Butyl lithium (13.5 ml of a 1.6 M solution in hexanes, 21.6 mmol) was
added dropwise to a stirred solution of 1-ethoxy-3,5-difluorobenzene
(3.42 g, 21.6 mmol) in THF (30 ml) at ꢁ78 ꢀC under an atmosphere of
nitrogen. The mixture was stirred at ꢁ78 ꢀC for 2 h. before adding excess
carbon dioxide (solid, as pellets), then allowed to warm slowly to room
temperature. The resulting solution was poured into water, made basic
by the addition of aqueous sodium hydroxide, and extracted with diethyl
ether. The aqueous layer was separated, acidified with dilute hydrochloric
acid, and extracted twice with diethyl ether. The combined extracts were
washed with water, dried over magnesium sulfate, and evaporated to a
colorless solid (3.87 g, 89% yield).

2580
K. M. Foote and G. Hatter
1H NMR (400.132 MHz, DMSO) 13.36 (br s, 1H, CO2H), 6.79 (d,
J ¼ 10.4 Hz, 2H, ArH), 4.11 (q, J ¼ 7.0 Hz, 2H, OCH2), 1.33 (t,
J ¼ 7.0 Hz, 3H, CH3). MS (þve CI): 203 (M þ H)þ.
4-Ethoxy-2,6-difluorobenzamide
Oxalyl chloride (3.17 ml, 36.4 mmol) was added dropwise to a stirred sus-
pension of 4-ethoxy-2,6-difluorobenzoic acid (3.5 g, 17.3 mmol) and
DMF (5 drops) in dichloromethane (50 ml). The resulting solution was
stirred at room temperature for 4 h, then evaporated. The residue was
dissolved in THF (20 ml) and added dropwise to a vigorously stirred
35% aqueous solution of ammonia (60 ml). After cooling the reaction
in icewater for 1.5 h, the resulting colorless solid was filtered, washed with
ice-cold water, and dried under vacuum (3.23 g, 93% yield).
1H NMR (400.132 MHz, DMSO) 7.91 (s) and 7.65 (s, 2H, CONH2),
6.74 (d, J ¼ 9.9 Hz, 2H, ArH), 4.08 (q, J ¼ 7.0 Hz, 2H, OCH2), 1.32 (t,
J ¼ 7.0 Hz, 3H, CH3). MS (þve EI): 201 (Mþ).
4-Ethoxy-2,6-difluorobenzonitrile (7)
Trichloroacetyl chloride (1.94 ml, 17.4 mmol) was added dropwise at 0–
5 ꢀC to a stirred suspension of 4-ethoxy-2,6-difluorobenzamide (3.18 g,
15.8 mmol) and triethylamine (4.44 ml, 31.6 mmol) in dichloromethane
(25 ml). The mixture was stirred at 0–5 ꢀC for 5 min, then washed succes-
sively with water, dilute hydrochloric acid, dilute sodium hydroxide,
dilute hydrochloric acid, and water. It was then dried over magnesium
sulfate and evaporated to a pale yellow solid (2.56 g, 89% yield).
1H NMR (400.132 MHz, DMSO) 7.05 (d, J ¼ 10.2 Hz, 2H, ArH),
4.17 (q, J ¼ 7.0 Hz, 2H, OCH2), 1.34 (t, J ¼ 7.0 Hz, 3H, CH3). LCMS
(þve CI): 184 (M þ H)þ. HRMS (EI) calcd. for C9H7F2NO 183.0496;
found 183.0481.
2-Amino-4-ethoxy-6-fluorobenzonitrile (8)
A solution of 4-ethoxy-2,6-difluorobenzonitrile (8.0 g, 44 mmol) in a satu-
rated solution of ammonia in ethanol (270 ml) was heated at 150 ꢀC in an
autoclave for 16 h. The resulting solution was evaporated, and the residue
was taken up in dichloromethane and washed with water. The organic
solution was separated, dried over magnesium sulfate, concentrated,
and purified by chromatography on silica using dichloromethane as elu-
ent to give a colorless solid (6.07 g, 77% yield).
1H NMR (400.132 MHz, DMSO) 6.32 (s, 2H, NH2), 6.14–6.11 (m,
2H, ArH), 3.99 (q, J ¼ 7.0 Hz, 2H, OCH2), 1.30 (t, J ¼ 7.0 Hz, 3H,

Synthesis of 5,7-dialkoxyquinazolin-4-ones
2581
CH3). MS (þve EI): 180 (Mþ). HRMS (ES) calcd. for C9H9FN2O
(M þ H) 181.07717; found 181.07716.
7-Ethoxy-5-fluoroquinazolin-4(3H)-one (9)
2-Amino-4-ethoxy-6-fluorobenzonitrile (2.5 g, 13.9 mmol) was added
portionwise over 20 min to a stirred mixture of formic acid (20 ml) and
conc. sulfuric acid (5 drops) heated at 100 ꢀC. The mixture was heated
at 100 ꢀC for a further 5 h, then cooled to room temperature and
quenched in icewater (80 ml). The resulting colorless solid was filtered,
washed with water followed by diethyl ether, and then dried under vac-
uum (2.02 g, 70% yield).
1H NMR (400.132 MHz, DMSO) 12.06 (br s, 1H, NH), 8.01 (s, 1H,
ArH), 6.91 (d, J ¼ 2.8 Hz, 1H, ArH), 6.87 (dd, J ¼ 12.7, 2.8 Hz, 1H,
ArH), 4.17 (q, J ¼ 7.0 Hz, 2H, OCH2), 1.36 (t, J ¼ 7.0 Hz, 3H, CH3).
LCMS (þve CI): 209 (M þ H)þ. HRMS (ES) calcd. for C10H9FN2O2
(M þ H) 209.07208; found 209.07210.
7-Ethoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4(3H)-one (10a)
Sodium hydride (93 mg of a 60% dispn. in oil, 2.31 mmol) was suspended
in DMF (2 ml), then 4-hydroxytetrahydropyran (117 mg, 1.15 mmol)
was added dropwise over 5 min. The resulting mixture was stirred
20 min before adding 7-ethoxy-5-fluoroquinazolin-4(3H)-one (160 mg,
0.77 mmol). The reaction was stirred at room temperature for 30 min,
then heated to 60 ꢀC for a further 30 min before cooling to room tempera-
ture and quenching in dilute aqueous ammonium chloride solution to
give a pale yellow solid. It was filtered, washed with water followed by
diethyl ether, and then dried (172 mg, 77% yield).
1H NMR (399.902 MHz, DMSO) 11.7 (br s, 1H, NH), 7.90 (s, 1H,
ArH), 6.66 (d, J ¼ 2.0 Hz, 1H, ArH), 6.61 (d, J ¼ 1.9 Hz, 1H, ArH),
4.77–4.70 (m, 1H, OCH), 4.14 (q, J ¼ 6.9 Hz, 2H, ArOCH2), 3.94–3.89
(m, 2H, OCH2), 3.53–3.48 (m, 2H, OCH2), 1.99–1.88 (m, 2H, CH2),
1.73–1.62 (m, 2H, CH2), 1.36 (t, J ¼ 7.0 Hz, 3H, CH3). LCMS (þve
CI): 291 (M þ H)þ . HRMS (ES) calcd. for C15H18N2O4 (M þ H)
291.13393; found 291.13394.
7-Ethoxy-5-(3-morpholin-4-ylpropoxy)quinazolin-4(3H)-one (10b)
Compounds 10b–e were prepared in the same manner as described
previously.

2582
K. M. Foote and G. Hatter
1H NMR (399.902 MHz, DMSO) 11.74 (br s, 1H, NH), 7.96 (s, 1H,
ArH), 6.69 (d, J ¼ 2.3 Hz, 1H, ArH), 6.58 (d, J ¼ 2.3 Hz, 1H, ArH), 4.19
(q, J ¼ 7.0 Hz, 2H, ArOCH2), 4.13 (t, J ¼ 6.1 Hz, 2H, ArOCH2), 3.66 (m,
4H, OCH2), 2.70–2.59 (m, 2H, NCH2), 2.55–2.41 (m, 4H, NCH2), 1.98
(quintet, J ¼ 6.4 Hz, 2H, CH2), 1.41 (t, J ¼ 7.0 Hz, 3H, CH3). LCMS
(þve CI): 334 (M þ H)þ. HRMS (ES) calcd. for C17H23N3O4 (M þ H)
334.17613; found 334.17618.
7-Ethoxy-5-(2-methoxyethoxy)quinazolin-4(3H)-one (10c)
1H NMR (399.902 MHz, DMSO) 11.7 (br s, 1H, NH), 7.90 (s, 1H, ArH),
6.65 (d, J ¼ 2.3 Hz, 1H, ArH), 6.54 (d, J ¼ 2.3 Hz, 1H, ArH), 4.16 (m,
4H, OCH2), 3.71 (m, 2H, OCH2), 3.37 (s, 3H, OCH3), 1.37 (t, J ¼ 6.9 Hz,
Hz, 3H, CH3). LCMS (þve CI): 265 (M þ H)þ. HRMS (ES) calcd. for
C13H16N2O4 (M þ H) 265.11828; found 265.11826.
7-Ethoxy-5-(2-pyrrolidin-1-ylethoxy)quinazolin-4(3H)-one (10d)
1H NMR (399.902 MHz, DMSO) 11.64 (br s, 1H, NH), 7.90 (s, 1H,
ArH), 6.64 (d, J ¼ 2.3 Hz, 1H, ArH), 6.54 (d, J ¼ 2.3 Hz, 1H, ArH),
4.17–4.12 (m, 4H, OCH2), 2.85 (t, J ¼ 6.0 Hz, 2H, NCH2), 2.62–2.56
(m, 4H, NCH2), 1.68 (m, 4H, CH2CH2), 1.37 (t, J ¼ 7.0 Hz, 3H, CH3).
LCMS (þve CI): 304 (M þ H)þ. HRMS (ES) calcd. for C16H22N3O3
(M þ H) 304.16557; found 304.16556.
7-Ethoxy-5-[(1-methylpiperidin-4-yl)oxy]quinazolin-4(3H)-one (10e)
1H NMR (399.902 MHz, DMSO) 11.57 (br s, 1H, NH), 7.89 (s, 1H,
ArH), 6.65 (d, J ¼ 2.4 Hz, 1H, ArH), 6.56 (d, J ¼ 2.3 Hz, 1H, ArH),
4.53–4.47 (m, 1H, OCH), 4.14 (q, J ¼ 7.0 Hz, 2H, ArOCH2), 2.68–2.63
(m, 2H, NCH2), 2.26–2.18 (m, 2H, NCH2), 2.19 (s, 3H, NCH3), 1.93–
1.86 (m, 2H, CH2), 1.77–1.69 (m, 2H, CH2), 1.36 (t, J ¼ 7.0 Hz, 3H,
CH3). LCMS (þve CI): 304 (M þ H)þ. HRMS (ES) calcd. for
C16H22N3O3 (M þ H) 304.16557; found 304.16553.
ACKNOWLEDGMENT
The authors thank Katherine Bogle for technical assistance.

Synthesis of 5,7-dialkoxyquinazolin-4-ones
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