Synthesis of substituted quinazolines: Application to the synthesis of verubulin

Article abstract of DOI:10.1080/00397911.2010.529730

Through newly adapted methodology, 2-methyl-3H-quinazolin-4-one was activated using a number of methods followed by displacement to afford 4-aminoquinazolines. The most useful of these processes utilize the p-toluenesulfonate ester or I₂/PPh₃ activation. Using this methodology, the anticancer vascular targeting clinical candidate verubulin (1) was synthesized in a highly efficient manner. Copyright Taylor & Francis Group, LLC.

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Synthesis of Substituted Quinazolines:
Application to the Synthesis of Verubulin
Jeffrey W. Lockman a , Yevgeniya Klimova a , Mark B. Anderson a & J.
Adam Willardsen a
a Department of Medicinal Chemistry, Myrexis, Inc., Salt Lake City,
Utah, USA
Available online: 08 Dec 2011
To cite this article: Jeffrey W. Lockman, Yevgeniya Klimova, Mark B. Anderson & J. Adam Willardsen
(2012): Synthesis of Substituted Quinazolines: Application to the Synthesis of Verubulin, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:12, 1715-1723
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Synthetic Communications1, 42: 1715–1723, 2012
Copyright # Myrexis, Inc.
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.529730
SYNTHESIS OF SUBSTITUTED QUINAZOLINES:
APPLICATION TO THE SYNTHESIS OF VERUBULIN
Jeffrey W. Lockman, Yevgeniya Klimova, Mark B. Anderson,
and J. Adam Willardsen
Department of Medicinal Chemistry, Myrexis, Inc., Salt Lake City,
Utah, USA
GRAPHICAL ABSTRACT
Abstract Through newly adapted methodology, 2-methyl-3H-quinazolin-4-one was
activated using a number of methods followed by displacement to afford 4-aminoquinazo-
lines. The most useful of these processes utilize the p-toluenesulfonate ester or I2/PPh3
activation. Using this methodology, the anticancer vascular targeting clinical candidate
verubulin (1) was synthesized in a highly efficient manner.
Keywords 4-Aminoquinazoline; I2 PPh3; quinazolin-4-one; p-toluenesulfonate ester
INTRODUCTION
4-Aminoquinazolines are ubiquitous structures in medicinal chemistry. In
addition to their use as antirheumatic cytokine-suppressing agents,[1] adenosine A3
receptor ligands,[2] and vanilloid 1 receptor antagonists,[3] they provide a scaffold
for the presentation of hydrogen bond donors and acceptors suitable for kinase
inhibition. U.S. Food and Drug Administration–approved non–small cell lung cancer
therapeutics gefitinib and erlotinib are 4-aminoquinazoline inhibitors of epidermal
growth factor receptor (EGFR).[4] Similar compounds have been described as inhi-
bitors of platelet derived growth factors phosphorylation[5] and c-Src.[6]
As part of our efforts to identify new cancer treatments, we examined the
synthesis of 4-amino substituted quinazoline compounds such as verubulin (Azixa,
MPC-6827, 1).[7] As published previously, 1 is a very potent inhibitor of b-tubulin
that interacts at or near the cholchicine binding site.[8] Compound 1 has also been
shown to act as a vascular targeting agent that is highly efficacious against a number
Received August 30, 2010.
Address correspondence to Jeffrey W. Lockman, Discovery Research, Purdue Pharma L.P.,
6 Cedarbrook Dr., Cranbury, NJ 08512, USA. E-mail: jeffrey.lockman@pharma.com
1715

1716
J. W. LOCKMAN ET AL.
of cancer cell lines in mouse xenograft studies.[9] Recently completed phase II clinical
trials have shown that 1 is safe and well tolerated when coadministered with carbo-
platin in patients with recurrent=refractory glioblasoma multiforme[10a] and when
coadministered with temozolomide in patients with metastatic melanoma.[10b]
Via more classical synthetic methodology, 1 has been synthesized by activation
of 2-methyl-3H-quinazolin-4-one (2) as chloride 3 by treatment with POCl3
(Scheme 1A).[7] Subsequent reaction of 4-chloroquinazoline 3 with N-methyl-p-
anisidine gave 1. This route has several drawbacks: chloride 3 is quite difficult to
work with, has a very foul odor, and is not stable to prolonged storage. Literature
has shown that similar heterocycles, such as 4-hydroxypyrimidines, can be substi-
tuted through activation as their sulfonate esters.[11] Subsequent displacement of
the sulfonate ester with a variety of nucleophiles gives the desired substitution pro-
ducts in good yield. It was envisioned that this methodology could be expanded to
the synthesis of 1, resulting in good yield and with the added benefit of eliminating
the problematic chloride 3 from the synthetic route.
As outlined in Scheme 1B, treatment of quinazolinone 2 with p-toluenesulfonyl
chloride, triethylamine, and a catalytic amount of dimethylaminopyridine (DMAP)
in CH2Cl2 resulted in activated quinazoline sulfonate ester 4 in 91% yield. The sul-
fonate ester 4 was found to be stable to both silica-gel chromatography and room
temperature storage for several months. Treatment of 4 with N-methyl-p-anisidine
Scheme 1. Reagents: (a) POCl3; (b) N-methyl-p-anisidine, 2-PrOH=CH2Cl2 (c) TsCl, Et3N, DMAP,
CH2Cl2; (d) coupling agent, DIEA, DMF; and (e) I2, PPh3, DIEA, PhCH3.

SYNTHESIS OF SUBSTITUTED QUINAZOLINES
1717
Scheme 2. Reagents: (a) TsCl, Et3N, DMAP, CH2Cl2; (b) N-methyl-p-anisidine, 2-PrOH=CH2Cl2; (c)
coupling agent, DIEA, DMF; and (d) I2, PPh3, DIEA, PhCH3.
in 2-propanol, with CH2Cl2 added for solubility, resulted in displacement of the
sulfonate, yielding 1 in >99% yield.
We next explored the scope of this reaction: sulfonate ester 4 was allowed to
react under conditions analogous to those used for the synthesis of 1. As 4-amino-
quinazolines are a common medicinal chemistry building block, a range of primary
aliphatic and aromatic amines were investigated, as were secondary amines of vary-
ing size and electronics (Table 1, conditions B). With the notable exception of
extremely hindered derivatives, all amines studied reacted in a near-quantitative
fashion when performed on a 0.5 mmol scale and as judged by high-performance
liquid chromatoraphy–mass spectrometry (HPLC-MS) using Ph2O as an internal
standard. Reactions with both diisopropylamine and diphenylamine resulted in
recovery of sulfonate 4 along with hydrolysis product 2 without any evidence of pro-
duct by HPLC-MS. The synthesis of 1 by this method was also performed on a 3.1-g
(10-mmol) scale with 99% isolated yield. This result demonstrates that the synthesis
of 1 via the sulfonate ester route is amenable to multigram synthesis, while benefiting
from both the reduced price of p-toluenesulfonyl chloride ($20–30=kg vs. $60–70=kg
for phosphorus oxychloride) and the stoichiometric vs. solvent quantities.
Other synthetic methods of synthesizing 4-aminoquinazolines were also
examined. The peptide coupling reagent benzotriazol-1-yloxytris(dimethylamino)-
phosphonium hexafluorophosphate (BOP) has been used to synthesize 4-amino-
purines and 4-aminoquinazolines,[12] and consequently we attempted the synthesis
of 1 utilizing a range of peptide coupling conditions (Scheme 1C). Contrary to litera-
ture reports utilizing 4-hydroxyquinazoline,[12] only a small amount (<10%) of pro-
duct was observed by HPLC-MS, and none was isolated with BOP when the
reaction was conducted using N,N-diisopropylethylamine (DIEA) (iPr2NEt) in
dimethylformamide (DMF) at 60 ꢀC (Table 2). The use of AcCN as solvent and

1718
J. W. LOCKMAN ET AL.
Table 1. Scope of amine displacement reactions
Conditions (% conversiona)
Compound
Amine
B
D1
D2
1
5
N-Methyl-p-anisidine
4-OMePh
4-MePh
99þ
99þ
99þ
99þ
99þ
99þ
99þ
86
64
2
99þ
87
6
26
22
99þ
40
99þ
99þ
50
0
36
30
7
3-MePh
2-MePh
8
82
45
9
Ph
4-ClPh
4-NO2Ph
10
11
12
13
14
15
16
17
18
99þ
99þ
79
4-Aminopyridine
MeNH2-HCl
Me2NH-HCl
Morpholine
n-BuNH2
i-Pr2NH
75b
99þ
99þ
99þ
99þ
0
5c
c
0
99þ
99þ
0
99þ
0
0
0
Ph2NH
0
0
0
Notes. Conditions B: 4, R1 R2NH (1.2 equiv.), 10:1 IPA=CH2Cl2, rt, 1 h. Conditions D1: 2, R1R2NH
(1.2 equiv.), I2 (1.2 equiv.), PPh3 (1.2 equiv.), DIEA (2 equiv.), PhCH3, 60 ꢀC, 19 h. Conditions D2:
R1R2NH (5 equiv.), I2 (3.6 equiv.), PPh3 (3.8 equiv.), DIEA (5.8 equiv.), CH2Cl2, rt, 19 h.
aConversion determined by HPLC using Ph2O as an internal standard (Ref. 12c).
bConversion complete at 4 h. by HPLC.
c11.6 equiv. DIEA used.
1,3-diazabicyclo[5.4.0]undec-7-ene (DBU) as base improved the conversion, but only
when the reaction was run at reflux. Much better results were obtained with
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP),
O-(7-azabenzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium
hexafluorophosphate
(HATU), O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium hexafluoropho-
sphate (HBTU), O-(6-chlorobenzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium
hexafluorophosphate (HCTU), and O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyl-
uronium tetrafluoroborate (TBTU) (Table 2, entries 2–6). The major by-product of
each reaction was the dimethylamine adduct that was clearly observed by HPLC-MS.
This likely resulted from the decomposition of DMF under the reaction conditions as
reported by others.[11c] As seen previously,[12] an analog of hydroxybenzotriazole was
required for the reaction to proceed as the use of bromotripyrrolidinophosphonium
hexafluorophosphate (PyBrop) yielded no product. In many cases, it was difficult to
chromatographically separate 1 from coupling reagent by-products, and the isolated
yields were significantly lower than the >80% conversion observed by HPLC-MS for
entries 4–8.
Carbodiimide reagents N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide
hydrochloride (EDCI) and dicyclohexylcarbodiimide (DIC), in the presence or
absence of 1-hydroxybenzotriazole hydrate (HOBt), bis(2-oxo-3-oxazolidinyl)-
phosphinic chloride (BOP-Cl), 1,1-carbonyldiimidazole (CDI), and tetraethyl pyro-
phosphate (TEPP) gave no evidence of product formation by HPLC-MS even after
7 days at 60 ꢀC (Table 2, entries 8–14). The formation of an activated adduct was not
seen when HOBt was added in the cases utilizing carbodiimides, suggesting that a

SYNTHESIS OF SUBSTITUTED QUINAZOLINES
1719
Table 2. Peptide coupling methods
Entry
Coupling methoda
Isolated yield (%)
1
2
BOP
BOPb
0
0
3
BOPc
PyBOP
56d
47
30
51
86
25
0
4
5
HATU
HBTU
6
7
HCTU
TBTU
8
9
PyBrop
BOP-Cl
DIC
10
11
12
13
14
15
16
17
0
0
EDCI
0
DIC=HOBt (1:1)
EDCI=HOBt (1:1)
CDI
TEPPe
I2=PPh3=DIEAf
0
0
0
0
54
aN-Methyl-p-anisidine (1.2 equiv.), coupling reagent (1.2 equiv), DIEA (2 equiv),
DMF, 60 ꢀC.
bN-Methyl-p-anisidine (1.5 equiv.), BOP (3 equiv), DBU (2 equiv), AcCN, 60 ꢀC
(Ref. 12c).
cN-Methyl-p-anisidine (1.5 equiv.), BOP (3 equiv), DBU (2 equiv), AcCN, reflux.
dConversion determined by HPLC using Ph2O as an internal standard (Ref. 12c).
eN-Methyl-p-anisidine (1.2 equiv.), TEPP (1.2 equiv), PhCH3, 110 ꢀC.
fN-Methyl-p-anisidine (1.2 equiv.), I2 (1.2 equiv), PPh3 (1.2 equiv), DIEA (2 equiv),
PhCH3, 60 ꢀC.
more reactive phosphonium or uronium intermediate is required for quinazolinone
addition. No evidence of N3 alkylation was observed in the cases of HATU and
HBTU, as has been reported with quinazolinones unsubstituted at C2 in the presence
of DBU in AcCN.[13]
Lastly, the formation of 1 was attempted utilizing the Appel combination of
triphenylphosphine and I2 to couple quinazolinone 2 with N-methyl-p-anisidine
(Scheme 1D). This method has been described previously for functionalizing hydro-
xypurines, but with the use of a large excess of both incoming amine and I2=PPh3.[14]
The advantages of this reaction are its simplicity and its cost: only one step is
required for the synthesis of 1 from 2 as compared with two steps via the sulfonate;
the cost of PPh3=I2 (<$0.10=g) is trivial compared to coupling reagents such as
PyBOP and HCTU (ꢁ$1.00=g).
Using only a slight excess of incoming amine and I2=PPh3, the reaction pro-
ceeded cleanly and in moderate yield to form 1, 65% conversion by HPLC using
Ph2O as an internal standard and 54% isolated yield on a 0.5-mmol scale. The reac-
tion was performed with the same panel of amines as the sulfonate ester reaction,
and the results are shown in Table 1 (conditions D1). The reaction was much less
predictable than the sulfonate ester displacement, showing widely varying conversion
for the tested anilines with little trend in regards to sterics or electronics. Most
aliphatic amines were completely unreactive under these conditions, as was the steri-
cally congested and electron-poor diphenylamine.

1720
J. W. LOCKMAN ET AL.
An increase in conversion to 1 was observed when the equivalents of all
reagents other than the 2-methyl-4-hydroxyquinazoline were increased to coincide
with those described by Lin and Robins[14] and the solvent changed from toluene
to CH2Cl2 (Table 1, conditions D2). While dramatically greater conversion was
noted in the cases of N-methyl-p-anisidine, p-anisidine, and dimethylamine hydro-
chloride, in most cases the effect was small. These moderate increases in conversion
seen in most cases upon the change from conditions D1 to conditions D2 are miti-
gated by the small amount by total mass of desired product that must be purified
from a mixture of various by-products.
We next attempted to gauge this procedure’s potential on a multigram scale by
repeating it on a 3.2-g (20-mmol) scale. We felt that the increased conversion provided
by the Lin protocol was not enough in the case of 1 to compensate for the difficulty in
purification it would entail on a large scale, and consequently only small excesses of
reagents were used. A workup with 10% aqueous Na2S2O3 was found to be useful in
removing residual base and iodine from the reaction mixture, but once this workup is
done the product was more easily purified by column chromatography, resulting in a
45% isolated yield.
In conclusion, several alternative syntheses of 1 have been identified that
obviate the use of unstable and difficult-to-handle 2-methyl-4-chloroquinazoline
(3). Several peptide coupling reagents affect the transformation, although the pre-
viously reported reagent BOP resulted in very low product yields. Synthesis of 1
via the formation and subsequent amine displacement of toluene sulfonate ester 4
proceeded in good yield on a multigram scale. On similar scale, the one-step forma-
tion of 1 from quinazolinone 2 utilizing I2=PPh3=DIEA also gave a moderate yield.
In most cases, only a small excess of I2=PPh3 was needed for the reaction to proceed
well. Both the sulfonate displacement and I2=PPh3 methods were shown to work
with moderate to good yields on amines with a variety of steric and electronic
requirements, suggesting the use of these procedures as general methods to generate
4-aminoquinazolines.
EXPERIMENTAL
The 1H NMR spectra were recorded at 400 MHz. Chemical shifts are reported
in parts per million (ppm) downfield from tetramethylsilane (TMS, 0.00 ppm), and J
coupling constants are reported in hertz. HPLC-MS were run in the electrospray
ionization (ESI) mode using an Xterra MS C18 (Waters) 4.6 mm ꢂ 50 mm 5 u col-
umn; HPLC purity was performed using a 4.6 mm ꢂ 150 mm Xterra C18 5 u column.
Both HPLC-MS and HPLC were reverse phase with an AcCN=H2O (0.01% v=v
TFA) gradient and a flow rate of 0.5 mL=min. Medium-pressure liquid chromato-
graphy (MPLC) purifications were performed using an Isco RF system utilizing a
hexane=EtOAc gradient. Compounds 1,[7b] 5,[7b] 6–11,[15] 12,[16] 13,[17] 14,[18] and
16[11c] have been previously reported.
Method B
(2-Methylquinazolin-4-yl)4-methylbenzenesulfonate (4). p-Toluenesulfo-
nyl chloride (2 equiv) was added to quinazolinone 2, Et3N (2 equiv), and DMAP (0.01

SYNTHESIS OF SUBSTITUTED QUINAZOLINES
1721
equiv) in CH2Cl2, and the solution was stirred at rt overnight. The solution was
washed with saturated NaHCO3, dried with Na2SO4, and concentrated. The resulting
solid was purified by MPLC, isolated as 3:1 mixture of rotamers, and gave 91% yield
as a mixture. 1H NMR (DMSO-d6) d 8.17 (d, J ¼ 7.7 Hz, 0.75 H), 8.14 (d, J ¼ 7.7 Hz,
0.25 H), 7.96 (t, J ¼ 7.7 Hz, 0.75 H), 7.90 (t, J ¼ 7.7 Hz, 0.25 H), 7.69 (d, J ¼ 7.7 Hz,
0.75 H), 7.64 (t, J ¼ 7.7 Hz, 0.75 H), 7.59 (t, J ¼ 7.7 Hz, 0.25 H), 7.55 (d, J ¼ 7.7 Hz,
0.25 H), 7.47 (d, J ¼ 7.7 Hz, 2H), 7.11 (d, J ¼ 7.7 Hz, 2H), 2.80 (s, 3H), 2.29 (s, 3H).
13C NMR (CD3OD) d 170.0, 164.6, 142.1, 141.5, 140.3, 137.1, 135.6, 129.7, 129.2,
128.4, 127.8, 127.7, 127.5, 125.5, 124.6, 22.8, 22.0, 19.9, 18.3. HRMS calculated for
C16H14NsO3S (M þ Hþ) 315.07979; found 315.07967.
4-Aminoquinazoline 1,5–18. A solution of 4 in IPA=CH2Cl2 (approx. 10:1)
was added to the appropriate amine (1.2 equiv.), and the reaction was stirred or
shaken at ambient temperatures while being monitored by HPLC-MS or HPLC.
Upon complete reaction, a portion of the mixture was removed and purified by
MPLC. Compounds 10 and 11 precipitated from solution as TsOH salts and were
isolated by filtration.
Method C
DIEA (2 equiv) was added to quinazolinone 2, aniline (1.2 equiv), and coupling
reagent (1.2 equiv) in DMF, and the solution stirred or shaken at 60 ꢀC for 16–18 h.
The reaction mixture was concentrated and purified by MPLC.
Method D
DIEA (2 equiv) was added to quinazolinone 2, aniline (1.1 equiv), I2 (1.2
equiv), and PPh3 (1.2 equiv), and the was reaction stirred or shaken at 60 ꢀC for
16–18 h. Upon completion of the reaction, a portion of the mixture was removed
and purified by MPLC. On a large scale (10 mmol), the reaction mixture was worked
up by diluting it in EtOAc, washing it with 10% aqueous Na2S2O3, drying it with
Na2SO4, and MPLC purification.
4-(2-Methylquinazolin-4-yl)morpholine (15). 1H NMR (DMSO-d6) d 7.98
(d, J ¼ 8.0 Hz, 1H), 7.81–7.71 (m, 2H), 7.47 (t, J ¼ 8.0 Hz, 1H), 3.79 (t, J ¼ 4.7 Hz,
4H), 3.67 (t, J ¼ 4.7 Hz, 4H), 2.54 (s, 3H). 13C NMR (CD3OD) d 164.6, 162.9,
151.3, 132.7, 126.1, 125.0, 124.8, 114.0, 66.4, 49.9, 24.3. HRMS calculated for
C13H16N3O (M þ Hþ), 230.1288; found 230.1276.
ACKNOWLEDGMENTS
We thank the Myrexis, Inc., analytical chemistry group for their work on
compound characterization and Drs. Kraig M. Yager and Robert Carlson for
support of this work.

1722
J. W. LOCKMAN ET AL.
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