A facile synthesis of 6H-[1,3,5]triazino[2,1-b]quinazolin-6-ones

Article abstract of DOI:10.1055/s-0030-1260047

Triazinoquinazolinone derivatives are synthesized by cyclization of aminobenzamide-substituted triazine compounds in the presence of a proton source such as trifluoroacetic acid or hydrochloric acid. The reaction is mild, general, and gives high yield (>90%) of the cyclized product. This procedure allows, for the first time, access to triazinoquinazolinone compounds bearing different functionalities on the benzene and triazine moieties that are not available by other routes. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260047

PAPER
1733
A Facile Synthesis of 6H-[1,3,5]Triazino[2,1-b]quinazolin-6-ones
Synthesis of
6
h
H
-[1,3,5]Tria
a
zino[2,1-
b
u
]
quinazolin-6
n
-one
s
Abbott, Josée Cloutier, Karine Houde, Christopher Penney, Boulos Zacharie*
ProMetic BioSciences Inc., 500 boulevard Cartier Ouest, Bureau 150, Laval, QC, H7V 5B7, Canada
Fax +1(450)7811403; E-mail: b.zacharie@prometic.com
Received 7 January 2011; revised 9 March 2011
not general, and is limited to substrates with substituents
on the phenyl and triazine rings that tolerate the harsh re-
action conditions. The reaction required high temperature,
did not proceed to completion, and required the use of
Abstract: Triazinoquinazolinone derivatives are synthesized by
cyclization of aminobenzamide-substituted triazine compounds in
the presence of a proton source such as trifluoroacetic acid or hydro-
chloric acid. The reaction is mild, general, and gives high yield
(>90%) of the cyclized product. This procedure allows, for the first acetic acid as solvent, which was difficult to remove from
time, access to triazinoquinazolinone compounds bearing different
the final product. Furthermore, a disadvantage of this pro-
functionalities on the benzene and triazine moieties that are not
available by other routes.
cedure was the concomitant hydrolysis of the dimethyl
amine and decarboxylation of the starting material 3 under
the reaction conditions. Herein, we report a mild, simple,
efficient, and high-yielding general procedure for the syn-
Key words: amides, heterocycles, cyclization, carboxylic acids, es-
ters
thesis of 6H-[1,3,5]triazino[2,1-b]quinazolin-6-ones and
their derivatives as exemplified by the general structure 2,
where R2 and R3 represent primary amines, and R = H,
CH3, F, NO2, NH2, or OMe. This reaction thus provides
access to triazinoquinazolinone derivatives with a range
of different functionalities.
As part of our effort to prepare new fused s-triazino het-
erocycles, the synthesis of a triazinoquinazolinone 1 was
explored with the aim of producing rigid analogues with
potentially improved oral bioavailability (Figure 1). Both
triazine1 and quinazoline2 scaffolds provide the basis for
the design of biologically relevant molecules with wide-
spread application as therapeutics, and so a fused hetero-
cycle containing both moieties was of interest. Recently
published biological results suggest that a triazino-
quinazolinone nucleus could be a promising new scaffold
for the development of potential anticancer agents.3 Two
methods for the preparation of 6H-[1,3,5]triazino[2,1-
b]quinazolin-6-one derivatives 2 appear in the literature.
The first strategy is a multi-step procedure that requires
stepwise construction of the triazinoquinazolinone ring.4,5
This process requires the use of high temperatures, and
proceeds in moderate to low yield, which limits its use.
Furthermore, no analytical data or assessment of purity of
the final product was reported.
Our study started with the selection of a triazine derivative
as a model compound for the cyclization reaction. In order
to avoid complications arising from regioselectivity, and
1
to provide a clear H NMR fingerprint, the bis(isobutyl-
amino) amide 5 and ester 7 were chosen as key molecules
for this study; their preparation is summarized in
Scheme 1. Dichloro compounds 4 or 6 were treated with
excess isobutylamine in tetrahydrofuran to give the final
product in high yield (>75%). A number of cyclization tri-
als were carried out starting with compounds 5 or 7 in or-
der to produce triazinoquinazolinone derivative 26. For
amide 5, quantitative conversion was achieved at ambient
temperature in the presence of a proton source, such as
20% trifluoroacetic acid in dichloromethane, 0.8 M HCl
in dioxane–dichloromethane (1:4), or 20% 1 M aqueous
HCl in acetonitrile. No reaction was observed when the
cyclization was undertaken in the presence of either Lewis
acid (aluminum chloride/dichloromethane), or base such
as diisopropylethylamine or aqueous sodium hydroxide.
For substituted amides, the yield was dependent on the
bulk of the alkyl groups. For example, the N,N-dimethyl
amide 11, cyclized readily to give quantitative conversion
into 26, whereas amide 10 gave only low yield of cyclic
triazine 26 (<10%) under acidic conditions (1 M HCl).
Use of benzyl amine 14 gave no cyclized material; both
ester 7 and acid 8 failed to give any cyclized product 26
using the same procedure. All the above results indicate
the importance of the amide group for the formation of cy-
clic triazine 26 under these mild conditions. Cyclization
also proceeded smoothly with a variety of substituents on
the benzamide ring, such as methyl 27, nitro 28, amino 29,
fluoro 30 or methoxy 31. We then investigated the role of
the substituents on the triazine in the cyclization. Replace-
The second approach6,7 requires the use of a substituted
triazine, such as 3, as a starting material for the formation
of the triazinoquinazolinone derivative. This method is
O
O
R2
N
N
N
N
R
Me
N
Me
N
N
N
N
2
N
R3
N
1
N
H
N
N
H
O
OMe
MeO
O
3
Figure 1
SYNTHESIS 2011, No. 11, pp 1733–1740
x
x.
x
x
.
2
0
1
1
Advanced online publication: 13.05.2011
DOI: 10.1055/s-0030-1260047; Art ID: M10211SS
© Georg Thieme Verlag Stuttgart · New York

1734
S. Abbott et al.
PAPER
HN
N
N
N
HOOC
HN
N
H
8
hydrolysis of 7
R2NH2
and/or
R3NH2
R2
Cl
N
O
N
HN
N
N
N
N
R1
HN
R1
HN
N
R3
N
N
THF
N
dioxane
Cl
R
N
H
R
R
4; R1 = CONH2; R = H
5; R1 = CONH2; R = H;
R2 = R3 = NH-i-Bu
26; R = H
6; R1 = COOMe; R = H
9; R1 = CONH-s-Bu;
R = H
27; R = Me
28; R = NO2
29; R = NH2
30; R = F
7; R1 = COOMe; R = H;
R2 = R3 = NH-i-Bu
12; R1 = CH2NHBoc;
R = H
10; R1 = CONH-s-Bu;
R = H; R2 = R3 = NH-i-Bu
11; R1 = CONMe2; R = H;
R2 = R3 = NH-i-Bu
31; R = OMe
15; R1 = CONH2; R = Me
17; R1 = CONH2; R = NO2
20; R1 = CONH2; R = F
13; R1 = CH2NHBoc; R = H;
R2 = R3 = NH-i-Bu
14; R1 = CH2NH2; R = H;
R2 = R3 = NH-i-Bu
16; R1 = CONH2; R = Me;
R2 = R3 = NH-i-Bu
18; R1 = CONH2; R = NO2;
R2 = R3 = NH-i-Bu
19; R1 = CONH2; R = NH3;
R2 = R3 = NH-i-Bu
21; R1 = CONH2; R = F;
R2 = R3 = NH-i-Bu
22; R1 = CONH2; R = OMe;
R2 = R3 = NH-i-Bu
23; R1 = CONH2; R = H;
R2 = R3 = OMe
24; R1 = CONH2; R = H;
R2 = OMe;
R3 = NEt2
25; R1 = CONH2; R = H;
R2 = R3 = NMe2
Scheme 1
ment of the primary amine groups (R2 and/or R3) of 5 with the two isobutylamino groups in 26, as compared to 5.
13
dichloro 4, dimethoxy 23, dimethylamino 25, or methoxy Analysis of the C NMR spectra reveals a large shift in
and diethylamino 24 resulted in compounds that did not the carbonyl signal from d = 171.82 ppm in 5 to d =
cyclize under these conditions. Based on these results, the 162.35 ppm in 26. The HMBC spectrum of 26 was not
NH group of the alkylamine appears to be essential for the helpful because of the lack of proton substitution in the
cyclization.
heterocyclic portion of the ring system. A 1H NMR exper-
iment was therefore performed to follow the cyclization of
5 with CF3CO2D in CD2Cl2; under these conditions, an
immediate change in the spectrum was observed upon ad-
dition of CF3CO2D, presumably due to a protonation
event, followed by conversion of the new species into 26
over the course of several hours (complete conversion
within 6.5 h). A similar experiment conducted with the
methyl benzoate compound 7 also showed an immediate
change in peak shifts upon addition of CF3CO2D, but no
subsequent reaction was observed.
Limited reports of similar cyclizations of 2-(heterocycle-
amino)-substituted benzamides have appeared in the liter-
ature. For example, 2-(pyridin-2-ylamino)benzamide8 32
and the substituted 2-(pyrrolo[2,3-d]pyrimidin-4-
yl)aminobenzamide9 34 were cyclized to the correspond-
ing quinazolinone derivatives 33 and 35 in the presence of
an acid at 80 °C (Scheme 2). However, ester cyclizations
of similar compounds required harsh conditions, namely
very high temperature (>160 °C), and gave low yields.10
Cyclization of 5 to 26 is characterized by a loss of 17 mass
units (NH3) in the mass spectrum, and can be readily fol-
lowed by 1H NMR analysis due to the non-equivalency of
Additional support for the structure of 26 was provided by
observing the reaction with nucleophiles. For example, re-
action of 26 with dimethylamine yielded the N,N-dimeth-
Synthesis 2011, No. 11, 1733–1740 © Thieme Stuttgart · New York

PAPER
Synthesis of 6H-[1,3,5]Triazino[2,1-b]quinazolin-6-ones
1735
O
N
H+
N
N
80 °C
H
N
NO2
O
NH2
32
NO2
33
Cl
O
N
Cl
N
N
N
N
H+
O
O
S
N
N
S
TFE
80 °C
N
H
O
O
O
NH2
34
35
Scheme 2
ylbenzamide 11; incubation of 26 in MeOH at 21 °C, gave compound 39. The latter has been found to possess anti-
59% conversion into the corresponding methyl benzoate 7 microbial activity against Gram-positive bacteria.11 Thus,
after 13 days.
treatment of triazine 40 with HCl in dioxane at room tem-
perature for three hours induced both cyclization and con-
comitant removal of the Boc protecting group, to give the
two isomers, 41 and 42 (1:1), in high yield (81%).
The general synthetic procedure for 6H-[1,3,5]triazi-
no[2,1-b]quinazolin-6-one derivatives is outlined in
Scheme 3. The cyclization proceeded quantitatively at
room temperature overnight in HCl/dioxane, and was gen- In summary, we report for the first time a mild, general
eral for a variety of substituents on the phenyl and triazine and efficient route for the preparation of triazino-
rings. As expected, when R2 and R3 differed, two isomers quinazolinones 2 bearing different substituents on the
37 and 38 were formed in a 1:1 ratio.
benzene and triazine moieties. This procedure is practical
and amenable to scale-up. The potential utility of this
route is exemplified by the preparation of cyclic com-
pounds 41 and 42, which are not easily available by other
methods.
The potential utility of this approach was illustrated by the
facile synthesis of triazinoquinazolinones 41 and 42
(Scheme 4). These two compounds are rigid analogues of
O
NHR2
R1
Melting points were obtained with an Electrothermal MEL-TEMP®
melting point apparatus. NMR spectra were recorded at 400 MHz
for 1H NMR, 101 MHz for 13C NMR, and 377 MHz for 19F NMR.
All HPLC and mass spectra were recorded with an HP 1100 LC-MS
Agilent instrument, using a diode array detector, monitoring at 230
and 254 nm, and an analytical C18 column (75 × 4.6 mm, 5 mm);
MeCN–H2O (15–99%) containing 0.05% TFA; flow rate: 2 mL/min
(temperature 30 °C).
N
N
N
NHR2
N
37
NHR3
R1
N
N
N
HCl
+
NHR3
25 °C
quantitative
N
O
NHR3
H
R1
O
NH2
N
N
N
36
N
38
NHR2
Preparation of Monosubstituted Dichloro[1,3,5]triazines 4, 6, 9,
12, 15, 17 and 20; General Procedures
Procedure A
Scheme 3
A mixture of substituted aniline (1 equiv) and cyanuric chloride (1
O
N
HN
N
NH2
F
OH
N
N
R2
N
H
HN
N
H
41
F
OH
HCl
N
N
+
dioxane
OH
N
N
N
H
H
R1
39; R1 = R2 = H
40; R1 = CONH2, R2 = Boc
O
HN
N
F
N
N
N
N
NH2
H
42
Scheme 4
Synthesis 2011, No. 11, 1733–1740 © Thieme Stuttgart · New York

1736
S. Abbott et al.
PAPER
Yield: 484 mg (97%); off-white solid; HPLC: tR = 3.6 min.
1H NMR (400 MHz, DMSO-d6): d = 12.37 (s, 1 H), 8.23 (s, 1 H),
8.02 (s, 1 H), 7.75 (s, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.07 (dd,
J = 8.0, 1.0 Hz, 1 H), 2.35 (s, 3 H).
equiv) in 1,4-dioxane (5–10 mL per mmol) was treated with DIPEA
(3 equiv), and the mixture was stirred at ambient temperature over-
night. Solvent was evaporated in vacuo and the residue washed with
H2O (20 mL per mmol), then dried to give the dichloro[1,3,5]tria-
zine compound.
MS (ESI): m/z (%) = 298.0/300.0/301.9 (100) [Cl2-pattern, MH+].
Procedure B
2-(4,6-Dichloro[1,3,5]triazin-2-ylamino)-4-nitrobenzamide (17)
2-Amino-4-nitrobenzamide (131 mg, 0.72 mmol) was reacted ac-
cording to general method B to give the title compound.
Cyanuric chloride (1 equiv) in acetone (1 vol) was cooled to 0 °C
and treated with ice (0.2 vol). A suspension of substituted aniline (1
equiv) in either acetone or MeCN (2 vol) was added, followed by a
further portion of ice (0.4 vol). The reaction was stirred at 0 °C for
10 min, and the pH was adjusted from 1 to 7 with 5% NaHCO3. The
reaction was stirred at 0 °C for a further 5 h and then partitioned be-
tween EtOAc and H2O. The organic phase was washed with 1 M
HCl and with saturated aq NaCl, dried (Na2SO4), filtered and evap-
orated in vacuo to give the dichloro[1,3,5]triazine compound.
Yield: 208 mg (80%); pale-yellow solid; HPLC: tR = 3.6 min.
1H NMR (400 MHz, DMSO-d6): d = 12.10 (s, 1 H), 8.98 (d,
J = 2.3 Hz, 1 H), 8.53 (s, 1 H), 8.11 (s, 1 H), 8.09 (dd, J = 8.6,
2.3 Hz, 1 H), 8.01 (d, J = 8.6 Hz, 1 H).
MS (ESI): m/z = 351.0/353.0/354.9 (Cl2-pattern, MNa+).
2-(4,6-Dichloro[1,3,5]triazin-2-ylamino)-4-fluorobenzamide
(20)
2-Amino-4-fluorobenzamide (200 mg, 1.30 mmol) was reacted ac-
cording to general method B, to give the title compound.
2-(4,6-Dichloro-[1,3,5]triazin-2-ylamino)benzamide (4)
2-Aminobenzamide (5.0 g, 36.7 mmol) was reacted according to
general procedure B to give the title compound.
Yield: 8.5 g (81%); off-white solid; HPLC: tR = 3.3 min.
Yield: 356 mg (91%); off-white solid; HPLC: tR = 3.7 min.
1H NMR (400 MHz, DMSO-d6): d = 12.68 (s, 1 H), 8.41 (s, 1 H),
8.32 (s, 1 H), 8.14 (dd, JH–H = 2.6, JH–F = 11.6 Hz, 1 H), 7.95 (dd,
1H NMR (400 MHz, DMSO-d6): d = 12.18 (s, 1 H), 8.29 (s, 1 H),
8.14 (d, J = 7.8 Hz, 1 H), 7.83 (s, 1 H), 7.80 (dd, J = 8.0, 1.4 Hz,
1 H), 7.59 (ddd, J = 7.9, 7.9, 1.4 Hz, 1 H).
JH–H = 8.9, JH–F = 6.4 Hz, 1 H), 7.13 (ddd, JH–H = 8.4, 2.6, JH–F
8.4 Hz, 1 H).
=
MS (ESI): m/z (%) = 283.9/285.9/288.0 (100) [Cl2-pattern, MH+].
19F NMR (377 MHz, DMSO-d6): d = –106.24 to –106.17 (m, 1 F).
MS (ESI): m/z (%) = 302.0/304.0/306.0 (100) [Cl2-pattern, MH+].
Methyl 2-(4,6-Dichloro[1,3,5]triazin-2-ylamino)benzoate (6)
Methyl 2-aminobenzoate (2.1 mL, 16.3 mmol) was reacted accord-
ing to general procedure B to give the title compound.
Preparation of Bis(isobutylamino)-Substituted Triazines 5, 7,
10, 13, 16, 18, 21 and Bis (dimethylamino)-Substituted Triazine
25; General Procedure C
A suspension of dichloro[1,3,5]triazine (1 equiv) in 1,4-dioxane (5–
10 mL per mmol) was treated with isobutylamine (10 equiv) and the
reaction was heated at 80 °C in a sealed tube overnight. The suspen-
sion was treated with MeOH to give a clear solution, and evaporated
onto silica gel. Purification by flash chromatography gave the
bis(isobutylamino) substituted triazine compound.
Yield: 4.75 g (98%); off-white solid; HPLC: tR = 2.6 min.
1H NMR (500 MHz, acetone-d6): d = 11.36 (s, 1 H), 8.51 (d,
J = 8.5 Hz, 1 H), 8.08 (dd, J = 8.0, 1.5 Hz, 1 H), 7.69–7.72 (m,
1 H), 7.26–7.30 (m, 1 H), 3.93 (s, 3 H).
MS (ESI): m/z (%) = 298.0/300.0/301.9 (100) [Cl2-pattern, MH+].
N-(But-2-yl)-2-(4,6-dichloro[1,3,5]triazin-2-ylamino)benz-
amide (9)
2-Amino-N-(but-2-yl)benzamide (282 mg, 1.5 mmol) was reacted
according to general procedure A to give the title compound.
2-[4,6-Bis(isobutylamino)-[1,3,5]triazin-2-ylamino]benzamide
(5)
Yield: 364 mg (73%); pale-yellow crystals; HPLC: tR = 4.5 min.
A mixture of 4 (1.00 g, 3.5 mmol) and isobutylamine (2.9 mL, 28.2
mmol) in THF (10 mL) and MeOH (2 mL) was heated at 130 °C for
10 min in a microwave apparatus. Solvent was evaporated in vacuo,
and the crude material was purified by flash chromatography (SiO2;
EtOAc–hexanes, 10% then THF–hexanes, 20→50%) to give a
white solid (1.3 g). This material was dissolved in a minimum of
EtOAc and added dropwise to hexanes (180 mL). The solid was
collected by filtration, washed with hexanes (2 × 25 mL) and dried
in vacuo to give the title compound.
1H NMR (400 MHz, acetone-d6 + CD3OD): d = 8.27 (dd, J = 8.4,
1.2 Hz, 1 H), 8.18 (d, J = 6.5 Hz, 1 H), 7.70 (dd, J = 7.8, 1.4 Hz,
1 H), 7.49–7.54 (m, 1 H), 7.23 (ddd, J = 7.6, 7.6, 1.0 Hz, 1 H),
3.93–4.02 (m, 1 H), 1.48–1.60 (m, 2 H), 1.16 (d, J = 6.7 Hz, 3 H),
0.90 (t, J = 7.4 Hz, 3 H).
MS (ESI): m/z (%) = 340.0/342.0/344.1 (100) [Cl2-pattern, MH+].
2-[(tert-Butoxycarbonylaminomethyl)phenyl]amino-4,6-dichlo-
ro[1,3,5]triazine (12)
2-(tert-Butoxycarbonylaminomethyl)aniline (898 mg, 4.04 mmol)
was reacted according to general method A to give the title com-
pound.
Yield: 0.8 g (64%); white solid; HPLC: tR = 2.5 min.
1H NMR (400 MHz, CD3OD): d = 8.62–8.78 (m, 1 H), 7.66 (d,
J = 7.4 Hz, 1 H), 7.39–7.43 (m, 1 H), 6.99 (dd, J = 7.6, 7.4 Hz,
1 H), 3.08–3.20 (m, 4 H), 1.85–1.97 (m, 2 H), 0.94 (d, J = 6.5 Hz,
12 H).
Yield: 426 mg (28%); pale-yellow solid; HPLC: tR = 4.4 min.
1H NMR (400 MHz, CDCl3): d = 10.03 (s, 1 H), 7.78 (d, J = 8.0 Hz,
2 H), 7.37 (ddd, J = 8.2, 7.4, 1.9 Hz, 2 H), 7.26 (dd, J = 7.6, 1.9 Hz,
1 H), 7.22 (ddd, J = 7.6, 7.4, 1.0 Hz, 2 H), 5.22 (t, J = 6.5 Hz, 1 H),
4.24 (d, J = 6.5 Hz, 2 H), 1.43 (s, 9 H).
MS (ESI): m/z (%) = 358.3 (100) [MH+].
Methyl 2-[4,6-Bis(isobutylamino)-[1,3,5]triazin-2-ylamino]ben-
zoate (7)
A solution of 6 (53 mg, 0.18 mmol) and isobutylamine (0.09 mL,
0.91 mmol) in THF (5 mL) was heated at 50 °C for 18 h. Solvent
was evaporated in vacuo, and the crude material was purified by
flash chromatography (SiO2; EtOAc–hexanes, 0→100%) to give
the title compound.
MS (ESI): m/z (%) = 370.2/372.2/374.2 [Cl2-pattern, MH+].
2-(4,6-Dichloro[1,3,5]triazin-2-ylamino)-4-methylbenzamide
(15)
2-Amino-4-methylbenzamide (251 mg, 1.67 mmol) was reacted ac-
cording to general method A to give the title compound.
Synthesis 2011, No. 11, 1733–1740 © Thieme Stuttgart · New York

PAPER
Synthesis of 6H-[1,3,5]Triazino[2,1-b]quinazolin-6-ones
1737
Yield: 57 mg (86%); white solid; HPLC: tR = 3.4 min.
1H NMR (400 MHz, CD3OD): d = 9.85–9.97 (m, 1 H), 7.87 (d,
J = 8.6 Hz, 1 H), 7.79 (dd, J = 8.7, 2.1 Hz, 1 H), 3.10–3.35 (m,
4 H), 1.83–1.95 (m, 2 H), 0.95–1.02 (m, 12 H).
1H NMR (400 MHz, acetone-d6): d = 10.39–10.57 (m, 1 H), 9.05–
9.13 (m, 1 H), 7.98–8.03 (m, 1 H), 7.44–7.57 (m, 1 H), 6.96–7.02
(m, 1 H), 6.39–6.45 (m, 1 H), 6.17–6.24 (m, 1 H), 3.92 (s, 3 H),
3.23–3.27 (m, 4 H), 1.85–2.03 (m, 2 H), 0.95 (d, J = 6.8 Hz, 12 H).
MS (ESI): m/z (%) = 403.1 (100) [MH+].
4-Amino-2-{4,6-bis(isobutylamino)-[1,3,5]triazin-2-ylami-
no}benzamide (19)
MS (ESI): m/z (%) = 387.2 (100) [MH+].
A mixture of 17 (44 mg, 0.11 mmol) and ammonium formate (33
mg, 0.52 mmol) in EtOH (3 mL) was treated with 10% Pd/C (11
mg), and the reaction was stirred at ambient temperature for 18 h.
The reaction mixture was filtered through Celite, and evaporated in
vacuo to give the title compound.
2-[4,6-Bis(isobutylamino)-[1,3,5]triazin-2-ylamino]-N,N-di-
methylbenzamide (11)
A suspension of 26 (24 mg, 0.07 mmol) in MeCN (1.5 mL) was
treated with dimethylamine hydrochloride (114 mg, 1.4 mmol) and
aq NaOH (1 M, 1.4 mL), and the heterogeneous reaction mixture
was stirred vigorously at ambient temperature for 5 d. The reaction
was quenched by addition of MeOH (1 mL), and was stirred in
MeOH (10 mL) for 4 d. Purification by flash chromatography
(SiO2; EtOAc–hexanes, 10→100%) gave the title compound 11.
Yield: 41 mg (100%); white solid; HPLC: tR = 3.20 min.
1H NMR (400 MHz, DMSO-d6): d = 11.32 (s, 1 H), 8.07–8.23 (m,
1 H), 7.64 (br s, 1 H), 7.43 (d, J = 8.6 Hz, 1 H), 6.96 (br s, 1 H),
6.82–6.88 (m, 1 H), 6.65–6.72 (m, 1 H), 6.07–6.11 (m, 1 H), 5.41
(s, 2 H), 3.00–3.18 (m, 4 H), 1.76–1.85 (m, 2 H), 0.85 (d,
J = 6.0 Hz, 12 H).
Yield: 1.6 mg (6%); colorless glass; HPLC: tR = 3.4 min.
1H NMR (400 MHz, CD3OD): d = 8.12–8.32 (m, 1 H), 7.39 (dd,
J = 7.8, 7.6 Hz, 1 H), 7.28 (d, J = 7.6 Hz, 1 H), 7.12 (dd, J = 7.6,
7.4 Hz, 1 H), 3.31 (s, 3 H), 3.03–3.20 (m, 4 H), 2.95 (s, 3 H), 1.83–
1.93 (m, 2 H), 0.93 (d, J = 6.8 Hz, 12 H).
MS (ESI): m/z (%) = 373.4 (100) [MH+].
2-{4,6-Bis(isobutylamino)-[1,3,5]triazin-2-ylamino}-4-fluoro-
benzamide (21)
Compound 20 (100 mg, 0.33 mmol) was reacted according to gen-
eral procedure C to give the title compound.
MS (ESI): m/z (%) = 386.2 (100) [MH+].
2-[4,6-Bis(isobutylamino)-[1,3,5]triazin-2-ylamino]-N-[but-2-
yl]benzamide (10)
Yield: 48 mg (39%); white solid; HPLC: tR = 2.9 min.
Compound 9 (170 mg, 0.50 mmol) was reacted according to general
procedure C to give the title compound 10.
1H NMR (400 MHz, CD3OD): d = 9.70–9.81 (m, 1 H), 7.73 (dd,
JH–H = 8.2, JH–F = 6.7 Hz, 1 H), 6.65–6.72 (m, 1 H), 3.08–3.22 (m,
4 H), 1.84–1.97 (m, 2 H), 0.95–1.02 (m, 12 H).
Yield: 172 mg (83%); white solid; HPLC: tR = 3.1 min.
1H NMR (400 MHz, CD3OD): d = 8.30–8.62 (m, 1 H), 7.55 (d,
J = 7.0 Hz, 1 H), 7.38–7.42 (m, 1 H), 7.23 (ddd, J = 7.6, 7.6,
1.0 Hz, 1 H), 3.97–4.04 (m, 1 H), 3.08–3.19 (m, 4 H), 1.82–1.93
(m, 2 H), 1.51–1.61 (m, 2 H), 1.18–1.23 (m, 3 H), 0.88–0.98 (m,
15 H).
19F NMR (377 MHz, CD3OD): d = –108.52 to –108.26 (m, 1 F).
MS (ESI): m/z = 376.1 [MH+].
2-{4,6-Bis(isobutylamino)-[1,3,5]triazin-2-ylamino}-4-meth-
oxybenzamide (22)
Reaction of 2-amino-4-methoxybenzamide (339 mg, 2.04 mmol)
according to general method A gave a mixture of mono- and di-
addition products. This crude mixture was reacted according to gen-
eral method C to give the title compound.
MS (ESI): m/z (%) = 414.2 (100) [MH+].
2-{[2-(tert-Butoxycarbonylaminomethyl)phenyl]amino}-4,6-
bis(isobutylamino)[1,3,5]triazine (13)
Compound 12 (200 mg, 0.54 mmol) was reacted according to gen-
eral procedure C to give the title compound.
Yield: 51 mg (6.5%); white solid; HPLC: tR = 3.7 min.
1H NMR (400 MHz, DMSO-d6): d = 11.30 (s, 1 H), 8.50–8.54 (m,
1 H), 7.98 (s, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.35 (s, 1 H), 7.06–
7.15 (m, 1 H), 6.77–6.97 (m, 1 H), 6.45–6.52 (m, 1 H), 3.79 (s,
3 H), 3.00–3.20 (m, 4 H), 1.75–1.87 (m, 2 H), 0.85 (d, J = 6.6 Hz,
12 H).
Yield: 223 mg (92%); pale-yellow solid; HPLC: tR = 3.2 min.
1H NMR (400 MHz, CDCl3): d = 7.48–7.85 (m, 2 H), 7.20–7.31 (m,
2 H), 7.01–7.12 (m, 1 H), 5.00–5.32 (m, 3 H), 4.20–4.32 (m, 2 H),
3.08–3.35 (m, 4 H), 1.74–1.83 (m, 2 H), 1.43 (s, 9 H), 0.89 (d,
J = 6.3 Hz, 12 H).
MS (ESI): m/z (%) = 388.4 (100) [MH+].
MS (ESI): m/z (%) = 444.3 (100) [MH+].
2-{4,6-Dimethoxy[1,3,5]triazin-2-ylamino}benzamide (23)
A mixture of compound 4 (203 mg, 0.71 mmol) and Et3N (0.30 mL,
2.2 mmol) in MeOH (2.5 mL) was heated at 120 °C for 30 min in a
microwave apparatus. The complex mixture of products was puri-
fied by flash chromatography (SiO2; EtOAc–hexanes, 10–100%) to
give the title compound.
2-[4,6-Bis(isobutylamino)-[1,3,5]triazin-2-ylamino]-4-methyl-
benzamide (16)
Compound 15 (149 mg, 0.50 mmol) was reacted according to gen-
eral procedure C to give the title compound.
Yield: 142 mg (77%); white solid; HPLC: tR = 2.7 min.
Yield: 11 mg (5.5%); white solid; HPLC: tR = 2.6 min.
1H NMR (400 MHz, CD3OD): d = 8.43–8.68 (m, 1 H), 7.57 (d,
J = 7.8 Hz, 1 H), 6.82 (d, J = 7.8 Hz, 1 H), 3.10–3.23 (m, 4 H), 2.38
(s, 3 H), 1.82–1.97 (m, 2 H), 0.92–1.00 (s, 12 H).
1H NMR (400 MHz, DMSO-d6): d = 11.60 (s, 1 H), 8.56 (d,
J = 8.4 Hz, 1 H), 8.29 (s, 1 H), 7.78 (d, J = 7.6 Hz, 1 H), 7.74 (s,
1 H), 7.51 (dd, J = 8.0, 7.6 Hz, 1 H), 7.09 (dd, J = 7.6, 7.2 Hz, 1 H),
3.89 (s, 6 H).
MS (ESI): m/z (%) = 372.1 (100) [MH+].
2-{4,6-Bis(isobutylamino)-[1,3,5]triazin-2-ylamino}-4-nitro-
benzamide (18)
Compound 17 (100 mg, 0.31 mmol) was reacted according to the
MS (ESI): m/z (%) = 276.1 (100) [MH+].
2-{4-Diethylamino-6-methoxy-[1,3,5]triazin-2-ylamino}benz-
amide (24)
general procedure C to give the title compound.
The title compound was isolated as a side product during the forma-
tion of compound 23.
Yield: 62 mg (51%); pale-yellow solid; HPLC: tR = 3.0 min.
Synthesis 2011, No. 11, 1733–1740 © Thieme Stuttgart · New York

1738
S. Abbott et al.
PAPER
Yield: 8.2 mg; colorless glass; HPLC: tR = 3.3 min.
1 H), 7.95–8.00 (m, 1 H), 7.27 (d, J = 7.8 Hz, 1 H), 3.63–3.70 (m,
1 H), 3.40–3.48 (m, 1 H), 3.16–3.23 (m, 2 H), 2.43 (s, 3 H), 1.96–
2.05 (m, 1 H), 1.83–1.93 (m, 1 H), 0.89–0.95 (m, 6 H).
MS (ESI): m/z (%) = 355.1 (100) [MH+].
1H NMR (400 MHz, DMSO-d6): d = 8.66 (dd, J = 8.5, 0.9 Hz, 1 H),
7.70 (dd, J = 8.0, 1.4 Hz, 1 H), 7.45 (ddd, J = 8.7, 7.3, 1.6 Hz, 1 H),
7.04 (ddd, J = 7.8, 7.2, 1.2 Hz, 1 H), 3.91 (s, 3 H), 3.59–3.64 (m,
4 H), 1.19–1.23 (m, 6 H).
2,4-Bis(isobutylamino)-9-nitro-6H-[1,3,5]triazino[2,1-
b]quinazolin-6-one (28)
MS (ESI): m/z (%) = 317.3 (100) [MH+].
Compound 18 (5.3 mg) was cyclized according to general cycliza-
tion method B (CH2Cl2) to give the title compound.
2-{4,6-Bis(dimethylamino)-[1,3,5]triazin-2-ylamino}benz-
amide (25)
Compound 4 (284 mg, 1.00 mmol) was reacted according to general
procedure C, but replacing isobutylamine with a mixture of dimeth-
ylamine hydrochloride (872 mg, 10.7 mmol) and DIPEA (1.8 mL,
10 mmol) to give the title compound.
Pale-yellow solid; HPLC: tR = 2.9 min.
1H NMR (400 MHz, DMSO-d6): d = 10.18 and 9.97 (2 × t, J = 5.8
and 5.6 Hz, 1 H), 9.34 and 9.25 (2 × t, J = 6.3 and 6.5 Hz, 1 H),
8.30–8.44 (m, 2 H), 6.65–6.83 (m, 2 H), 3.36–3.43 (m, 2 H), 3.17–
3.22 (m, 2 H), 1.98–2.06 (m, 1 H), 1.83–1.93 (m, 1 H), 0.93 (d,
J = 6.6 Hz, 6 H), 0.89 (d, J = 6.8 Hz, 6 H).
Yield: 269 mg (89%); lustrous white solid; HPLC: tR = 2.6 min.
1H NMR (400 MHz, CD3OD): d = 8.27 (dd, J = 8.4, 1.0 Hz, 1 H),
7.77 (dd, J = 7.8, 1.6 Hz, 1 H), 7.56 (ddd, J = 8.4, 7.4, 1.6 Hz, 1 H),
7.25 (ddd, J = 7.8, 7.4, 1.0 Hz, 1 H), 3.23 (s, 12 H).
MS (ESI): m/z (%) = 386.1 (100) [MH+].
9-Amino-2,4-bis(isobutylamino)-6H-[1,3,5]triazino[2,1-
b]quinazolin-6-one (29)
MS (ESI): m/z (%) = 301.8 (100) [MH+].
Cyclization of compound 19 was inefficient under the general meth-
ods due to precipitation of the aryl-ammonium salt upon HCl addi-
tion. As an alternative, a suspension of compound 19 (5.0 mg) in
MeCN (0.5 mL) was treated with 2.4 M aq HCl (0.7 mL), and the
clear solution was stirred at ambient temperature for 5 h. Evapora-
tion of solvents give the pure title compound.
Cyclization; General Procedure
Method A
A solution of the compound in CH2Cl2 (4 vol) was treated with TFA
(1 vol), and the reaction was stirred at ambient temperature over-
night. Solvent and acid were evaporated in vacuo to give the cy-
clized material.
Pale-beige solid; HPLC: tR = 3.7 min.
Method B
1H NMR (400 MHz, DMSO-d6): d = 10.55 and 10.41 (2 × t, J = 5.8
and 5.8 Hz, 1 H), 8.85 and 8.78 (2 × t, J = 6.0 and 6.1 Hz, 1 H),
7.68–8.72 (m, 1 H), 6.56–6.61 (m, 1 H), 6.40 (d, J = 1.6 Hz, 1 H),
6.3–7.8 (very broad, 3 H), 3.30–3.36 (m, 2 H), 3.13–3.18 (m, 2 H),
1.93–2.03 (m, 1 H), 1.81–1.90 (m, 1 H), 0.92 (d, J = 6.5 Hz, 6 H),
0.89 (d, J = 6.68 Hz, 6 H).
A solution (suspension) of the compound in either CH2Cl2 or 1,4-
dioxane (4 vol) was treated with 4 M HCl (1 vol) in 1,4-dioxane,
and the reaction was stirred at ambient temperature overnight. Sol-
vents and acid were evaporated in vacuo to give the cyclized mate-
rial.
MS (ESI): m/z (%) = 356.4 (100) [MH+].
HRMS: m/z [M + Na+] calcd for C18H25N7NaO+: 378.20128; found:
Method C
The compound was treated with 2 M or 4 M HCl in 1,4-dioxane, and
the reaction was stirred at ambient temperature overnight. Solvent
and acid were evaporated in vacuo to give the cyclized material.
378.20153.
2,4-Bis(isobutylamino)-9-fluoro-6H-[1,3,5]triazino[2,1-
b]quinazolin-6-one (30)
Compound 21 (5.1 mg) was cyclized according to general cycliza-
tion method B (CH2Cl2) to give the title compound.
2,4-Bis(isobutylamino)-6H-[1,3,5]triazino[2,1-b]quinazolin-6-
one (26)
Compound 5 was cyclized on different scales under different acidic
conditions using methods A–C, to give the title compound.
White solid; HPLC: tR = 2.6 min.
White solid; HPLC: tR = 2.6 min.
1H NMR (400 MHz, DMSO-d6): d = 10.26 and 10.07 (2 × t, J = 6.0
and 5.6 Hz, 1 H), 9.20 and 9.15 (2 × t, J = 6.2 and 6.0 Hz, 1 H),
8.14–8.20 (m, 1 H), 7.24–7.44 (m, 2 H), 3.35–3.40 (m, 2 H), 3.15–
3.20 (m, 2 H), 1.97–2.06 (m, 1 H), 1.83–1.92 (m, 1 H), 0.88–0.94
(m, 12 H).
19F NMR (377 MHz, CD3OD): d = –98.68 to –98.46 (m, 1 F).
MS (ESI): m/z (%) = 359.2 (100) [MH+].
1H NMR (400 MHz, DMSO-d6): d = 10.28 (t, J = 5.5 Hz, 1 H),
10.10 (t, J = 5.5 Hz, 1 H), 9.03–9.12 (m, 1 H), 8.08 (dd, J = 8.6,
8.4 Hz, 1 H), 7.86 (dd, J = 8.4, 8.4 Hz, 1 H), 7.51–7.60 (m, 1 H),
7.38–7.45 (m, 1 H), 3.33–3.40 (m, 2 H), 3.14–3.20 (m, 2 H), 1.95–
2.07 (m, 1 H), 1.83–1.93 (m, 1 H), 0.93 (d, J = 6.7 Hz, 6 H), 0.89 (d,
J = 6.7 Hz, 6 H).
13C NMR (101 MHz, DMSO-d6): d = 162.35, 159.44, 152.97,
150.79, 138.75, 138.19, 128.81, 125.66, 117.41, 115.63, 49.50,
49.00, 28.71, 27.80, 20.76 (2C), 20.59 (2C).
2,4-Bis(isobutylamino)-9-methoxy-6H-[1,3,5]triazino[2,1-
b]quinazolin-6-one (31)
Compound 22 (5.1 mg) was cyclized according to general cycliza-
tion method B (CH2Cl2) to give the title compound.
MS (ESI): m/z (%) = 341.2 (100) [MH+].
HRMS: m/z [MH+] calcd for C18H25N6O+: 341.20844; found:
341.20877.
Off-white solid; HPLC: tR = 3.8 min.
1H NMR (400 MHz, DMSO-d6): d = 13.03 (s, 1 H), 10.36 and 10.19
(2 × t, J = 5.5 and 5.6 Hz, 1 H), 9.03 (t, J = 5.8 Hz, 1 H), 7.98 (d,
J = 8.8 Hz, 1 H), 7.64–7.70 (m, 1 H), 6.91–7.03 (m, 1 H), 3.89 (s,
3 H), 3.30–3.40 (m, 2 H), 3.14–3.19 (m, 2 H), 1.97–2.06 (m, 1 H),
1.83–1.91 (m, 1 H), 0.93 (d, J = 6.6 Hz, 6 H), 0.89 (d, J = 6.6 Hz,
6 H).
2,4-Bis(isobutylamino)-9-methyl-6H-[1,3,5]triazino[2,1-
b]quinazolin-6-one (27)
Compound 16 (20 mg, 0.054 mmol) was cyclized according to gen-
eral cyclization method C (2 M HCl) to give the title compound.
White solid; HPLC: tR = 2.7 min.
1H NMR (400 MHz, DMSO-d6): d = 13.24 (s, 1 H), 13.06 (s, 1 H),
10.31 and 10.14 (2 × t, J = 5.8 and 5.6 Hz, 1 H), 8.98–9.04 (m,
MS (ESI): m/z (%) = 371.2 (100) [MH+].
Synthesis 2011, No. 11, 1733–1740 © Thieme Stuttgart · New York

PAPER
Synthesis of 6H-[1,3,5]Triazino[2,1-b]quinazolin-6-ones
1739
+
HRMS: m/z [MH+] calcd for C19H27N6O2 : 371.21900; found:
371.21968.
0.46 mmol) and the reaction was heated at 140 °C for 20 min in a
microwave apparatus. Solvents were evaporated in vacuo, and the
crude material was purified by flash chromatography (SiO2;
EtOAc–hexanes, 50→100%) to give the title compound.
Cyclization of 2-[4,6-Bis(isobutylamino)-[1,3,5]triazin-2-yl-
amino]-N-[but-2-yl]benzamide (10) to Compound 26
Compound 10 (20 mg, 0.048 mmol) was reacted by general cycliza-
tion method B (1,4-dioxane). LCMS analysis showed an 11:89 mix-
ture of compound 26 and starting material. The mixture was further
reacted by general cyclization method C (2 M HCl) to give a 75:25
mixture (LCMS analysis) of compound 26 and starting material.
Yield: 95 mg (54%); white solid; HPLC: tR = 2.6 min.
1H NMR (400 MHz, CD3OD): d = 8.60–8.70 (m, 1 H), 7.40–7.47
(m, 1 H), 7.15–7.23 (m, 1 H), 7.05 (d, J = 8.4 Hz, 2 H), 6.71 (d,
J = 8.4 Hz, 2 H), 3.46–3.54 (m, 2 H), 3.30–3.41 (m, 2 H), 3.03 (t,
J = 7.0 Hz, 2 H), 2.73–2.79 (m, 2 H), 1.56–1.64 (m, 2 H), 1.50 (tt,
J = 7.2, 7.2 Hz, 2 H), 1.41 (s, 9 H), 1.33–1.43 (m, 2 H).
MS (ESI): m/z (%) = 569.3 (100) [MH+].
Cyclization of 2-[4,6-Bis(isobutylamino)-[1,3,5]triazin-2-yl-
amino]-N,N-dimethylbenzamide (11) to Compound 26
Compound 11 (1.5 mg, 0.0039 mmol) was reacted by general cy-
clization method C. LCMS and 1H NMR analyses showed complete
conversion into compound 26.
4-(5-Aminopentylamino)-8-fluoro-2-(4-hydroxyphenethylami-
no)-6H-[1,3,5]triazino[2,1-b]quinazolin-6-one (41) and 2-(5-
Aminopentylamino)-8-fluoro-4-(4-hydroxyphenethylamino)-
6H-[1,3,5]triazino[2,1-b]quinazolin-6-one (42)
Compound 40 (90 mg, 0.14 mmol) was deprotected and cyclized
according to general cyclization method B (1,4-dioxane; two cy-
cles) to give a 1:1 mixture of the title compounds as a white solid.
The isomers could be separated by reverse-phase HPLC.
2-[2-Aminomethylphenylamino]-4,6-bis(isobutylamino)-
[1,3,5]triazine (14)
Compound 13 (10 mg, 0.023 mmol) was deprotected according to
general cyclization method A (CH2Cl2), followed by conversion
into the free base, to give the title compound.
More polar isomer: HPLC: tR = 3.3 min.
Yield: 6.2 mg (80%); white solid; HPLC: tR = 1.7 min.
1H NMR (400 MHz, DMSO-d6): d = 10.24 and 10.07 (2 × t, J = 5.3
and 5.5 Hz, 1 H), 9.27–9.32 (m, 1 H), 8.93–8.98 (m, 1 H), 7.73–
7.84 (m, 5 H), 7.47–7.50 (m, 1 H), 7.04–7.10 (m, 2 H), 6.69–7.10
(m, 2 H), 3.62–3.73 (m, 2 H), 3.35–3.42 (m, 2 H), 2.73–2.85 (m,
4 H), 1.51–1.62 (m, 4 H), 1.31–1.38 (m, 2 H).
19F NMR (377 MHz, DMSO-d6): d = –116.7 to –116.0 (m, 1 F).
MS (ESI): m/z = 452.2 [MH+].
1H NMR (400 MHz, CDCl3): d = 8.00–8.32 (m, 1 H), 7.23–7.27 (m,
1 H), 7.12–7.19 (m, 1 H), 6.94–6.98 (m, 1 H), 4.95–5.20 (m, 2 H),
3.99 (s, 2 H), 3.17–3.26 (m, 4 H), 1.80–1.93 (m, 2 H), 0.93–0.99
(m, 12 H).
MS (ESI): m/z (%) = 344.3 (100) [MH+].
2-[4,6-Bis(isobutylamino)-[1,3,5]triazin-2-ylamino]benzoic
Acid (8)
Less polar isomer: HPLC: tR = 3.7 min.
A solution of 7 (25 mg, 0.067 mmol) in MeCN (5 mL) and MeOH
(3 drops) was treated with a solution of LiOH (8.3 mg, 0.35 mmol)
in H2O (0.25 mL), and the reaction was stirred at ambient tempera-
ture for 5 d. The mixture was filtered and the filtrate was treated
with 0.5 M aq HCl (10 mL). The white precipitate was extracted
with EtOAc (2 × 10 mL) and the combined extracts were washed
with H2O (10 mL) and sat. aq NaCl (12 mL), then dried (Na2SO4),
filtered and evaporated in vacuo to give the title compound.
1H NMR (400 MHz, DMSO-d6): d = 10.24 and 10.07 (2 × t, J = 5.6
and 5.5 Hz, 1 H), 8.87–8.96 and 9.28–9.35 (2 × m, 1 H), 7.74–7.83
(m, 5 H), 7.45–7.52 (m, 1 H), 7.02–7.05 (m, 2 H), 6.67–7.00 (m,
2 H), 3.42–3.58 (m, 4 H), 2.74–2.81 (m, 4 H), 1.52–1.69 (m, 4 H),
1.35–1.41 (m, 2 H).
19F NMR (377 MHz, DMSO-d6): d = –116.8 to –115.9 (m, 1 F).
MS (ESI): m/z = 452.2 [MH+].
Yield: 24 mg (quant.); white solid; HPLC: tR = 3.6 min.
1H NMR (400 MHz, CD3OD): d = 8.38–8.45 (m, 1 H), 7.93 (dd,
J = 7.6, 7.6 Hz, 1 H), 7.33 (dd, J = 7.6, 7.6 Hz, 1 H), 6.96–7.01 (m,
1 H), 3.13–3.20 (m, 4 H), 1.82–1.91 (m, 2 H), 0.89 (d, J = 6.6 Hz,
12 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
MS (ESI): m/z (%) = 359.2 (100) [MH+].
We thank Ms. L. Marcil for the skillful preparation of this manus-
cript.
2-{4-(5-tert-Butoxycarbonyl-aminopentylamino)-6-(4-hy-
droxyphenethylamino)-[1,3,5]triazin-2-ylamino}-5-fluoro-
benzamide (40)
A suspension of 2-(4,6-dichloro[1,3,5]triazin-2-ylamino)-5-fluo- References
robenzamide (100 mg, 0.33 mmol) and tyramine (46 mg, 0.34
(1) Zacharie, B.; Abbott, S.; Bienvenu, J.-F.; Cameron, A. D.;
mmol) in MeOH (5 mL) and THF (5 mL), was treated with DIPEA
(0.06 mL, 0.34 mmol) and the reaction was stirred at ambient tem-
perature for 140 min. Solvents were evaporated in vacuo, and the
residue was washed with H2O (20 mL), and dried in vacuo to give
2-{4-chloro-6-(4-hydroxyphenethylamino)-[1,3,5]triazin-2-ylami-
no}-5-fluorobenzamide as an off-white solid (124 mg, 93%). A
sample was taken for LCMS analysis {LRMS (ESI): m/z (%) =
403.3/405.2 (100) [Cl isotope pattern, MH+]; HPLC: tR = 3.27
min}, and the remaining material was used immediately in the next
reaction.
Cloutier, J.; Duceppe, J.-S.; Ezzitouni, A.; Fortin, D.;
Houde, K.; Lauzon, C.; Moreau, N.; Perron, V.; Wilb, N.;
Asselin, M.; Doucet, A.; Fafard, M.-E.; Gaudreau, D.;
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A mixture of 2-{4-chloro-6-(4-hydroxyphenethylamino)-[1,3,5]tri-
azin-2-ylamino}-5-fluorobenzamide (124 mg, 0.31 mmol) and 5-
(tert-butoxycarbonylamino)pentylamine (72 mg, 0.36 mmol) in
MeOH (1 mL) and THF (1 mL), was treated with DIPEA (0.08 mL,
Synthesis 2011, No. 11, 1733–1740 © Thieme Stuttgart · New York

1740
S. Abbott et al.
PAPER
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Synthesis 2011, No. 11, 1733–1740 © Thieme Stuttgart · New York