A concise synthesis of quinazolinone TGF-β RI inhibitor through one-pot three-component Suzuki-Miyaura/etherification and imidate-amide rearrangement reactions

Article abstract of DOI:10.1016/j.tet.2007.08.069

A simple and efficient synthesis of dihydropyrrolopyrazole boronic acid intermediate (5) has been developed. Utilization of a three-component Suzuki-Miyaura/etherification with microwave heating led to advanced compound 11 in high yield and with easy purification. Reaction of compound 11 with methanesulfonyl chloride at room temperature furnished the 1,3 O-N rearranged product (12), which is postulated to proceed via an intramolecular mechanism. The outlined synthesis provides a highly efficient and high-yielding route that is amenable to rapid analog synthesis.

Full text of DOI:10.1016/j.tet.2007.08.069

Tetrahedron 63 (2007) 11763–11770
A concise synthesis of quinazolinone TGF-b RI inhibitor through
one-pot three-component Suzuki–Miyaura/etherification
and imidate–amide rearrangement reactions
a
a
a
a
Hong-yu Li,a, Yan Wang, William T. McMillen, Arindam Chatterjee, John E. Toth,
*
Sreenivasa R. Mundla,b,y Matthew Voss,b Robert D. Boyera and J. Scott Sawyera
aDiscovery Chemistry Research and Technology, Lilly Research Laboratory, A Division of Eli Lilly and Company,
Lilly Corporate Center, Indianapolis, IN 46285, USA
bProcess Chemistry Research, Lilly Research Laboratory, A Division of Eli Lilly and Company,
Lilly Corporate Center, Indianapolis, IN 46285, USA
Received 12 June 2007; revised 21 August 2007; accepted 22 August 2007
Available online 26 August 2007
This paper is dedicated to Professor Yoshito Kishi on the occasion of his 70th birthday
Abstract—A simple and efficient synthesis of dihydropyrrolopyrazole boronic acid intermediate (5) has been developed. Utilization of
a three-component Suzuki–Miyaura/etherification with microwave heating led to advanced compound 11 in high yield and with easy puri-
fication. Reaction of compound 11 with methanesulfonyl chloride at room temperature furnished the 1,3 O–N rearranged product (12), which
is postulated to proceed via an intramolecular mechanism. The outlined synthesis provides a highly efficient and high-yielding route that is
amenable to rapid analog synthesis.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
replacements for quinoline (Fig. 1). Our efforts led to
the preparation of structure 3 in a highly concise manner
through a set of one-pot, three-component Suzuki/etherifica-
tion and imidate ester–amide rearrangement reactions.
The serine/threonine kinase TGF-b RI is a member of a large
family of growth-factors involved in the regulation of a di-
verse array of angiogenesis processes. It has been postulated
that the TGF-b RI kinase may play an important role in can-
cer.1 A number of TGF-b RI kinase inhibitors are known,
and some have demonstrated anti-tumor activity in tumor
and fibrosis animal models.2 As a result, the search for po-
tent, selective TGF-b RI inhibitors to be used for the clinical
management of cancer and fibrosis remains an active area of
research.
2. Results and discussion
Previously we have reported a synthesis of dihydropyrrolo-
pyrazole TGF-b kinase inhibitors where lepidine was
reacted with an appropriate picolinic ester followed by con-
densation of the resulting ketone with 1-amino-2-pyrrolidi-
none.2e However, this route was neither synthetically
flexible nor durable enough for some of the envisioned ana-
logs, including quinazoline and quinazolinone derivatives.
Our search for novel TGF-b RI inhibitors has been aided by
the availability of high-resolution X-ray crystal structure
data showing that a hydrogen bond forms between the quino-
line nitrogen of compound 1 (LY364947, Fig. 1) and a
hinge-region proton (N–H, His-283), and well as a hydrogen
bond interaction of the pyridine nitrogen with a water
molecule.2b,3 Using this information, we became interested
in quinazoline and quinazolinone rings as heterocyclic
As shown in the retrosynthetic analysis (Fig. 2), we envi-
sioned access to the flexible boronic acid intermediate (5)
as deriving from the corresponding bromide. The bromide
is readily derived from the carboxylic acid, which is avail-
able via 6-methyl-pyridine-2-carboxylic acid methyl ester
and ethyl acetate.
* Corresponding author. Tel.: +1 317 433 3349; fax: +1 317 276 7600;
e-mail: li_hong-yu@lilly.com
Present address: Sreeni Labs Private Limited, Flat No. 504, Vijayasree
Apartments, Behind Chermas, Ameerpet, Hyderabad 500 073, A.P., India.
e-mail: sreeni@sreenilabs.com
The synthesis of boronic acid 5 is outlined in Scheme 1. Pi-
colinate 64 and 1-aminopyrrolidin-2-one hydrochloride5
were synthesized according to the reported literature proce-
dures.2h–j A Claisen condensation of ester 6 with ethyl
y
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.069

11764
H.-yu Li et al. / Tetrahedron 63 (2007) 11763–11770
N N
N
N N
H
N
N
N
N
O
O
N
N
N
N
N
N
N
1 (LY 364947)
3
2
Figure 1.
acetate under refluxing conditions gave b-keto ester 7. The
purity of compound 7 after a simple extraction was 86%
based on HPLC analysis. Without further purification, b-
keto ester 7 was condensed with 1-amino-2-pyrrolidinone
hydrochloride in pyridine to provide the corresponding
acyl hydrazone 8. On reaction with NaOEt, the crude hydra-
zone 8 underwent cyclization and hydrolysis to give carbox-
ylic acid 9, which was purified by slurring in MTBE. The
overall yield of 9 from 6 was 65%. The conversion of acid
9 to bromide 9a was accomplished in 94% yield by treatment
with NBS at room temperature.6 The boronic acid was then
prepared by lithium–bromide exchange and in situ quench
with triisopropyl borate.7 At this stage, purification by silica
gel chromatography gave compound 5 in 73% yield.2h–j
Our initial exploration of the Suzuki–Miyaura reaction of
boronic acid 5 with quinazoline 10 under several standard re-
action conditions8 was not very encouraging. Besides anunde-
sired Suzuki reaction (10–20%) that occurred at the 2-chloro
of the quinazoline, we observed a 10–40% reduction of the bo-
ronic acid as well (among the catalysts, Pd(PPh3)4 gave the
least reduction of compound 5, while in contrast, PdCl2(dppf)
gave the most). Also separation of the desired product from
multiple undesired products was not synthetically practical
and resulted in impure product. Using ethylene glycol as a
solvent with microwave heating, we discovered that we could
react ethylene glycol to the 2-chloro-position under the
Suzuki–Miyaura reaction conditions and prevent side reac-
tions at the same time.9 As shown in Scheme 2, the three-
component Suzuki–Miyaura/etherification reaction occurs in
one-pot to produce advanced compound 11. Although unde-
sired products from dimerization and boronic acid reduction
were still identified, purification of polar alcohol 11 was
straightforward and the overall yield was good (72%).
O
O
EtOAc, NaOEt,
Toluene
N
N
MeO
Refluxed
O
OEt
6
7
O
O
N
N
N
NH2.HCl
N
Pyridine, rt
O
N
OEt
8
The structure of compound 11 was confirmed by HMBC
(Table 1).10 The clear HMBC cross-peaks between C-9 (dC
112.6) of the pyrazole and H-60 (dH 8.30) and H80 (dH 7.90)
of the quinazoline determined that the Suzuki–Miyaura
reaction occurred at the 70-position of the quinazoline ring.
Furthermore, the clear HMBC cross-peak between C-40 (dC
165.7) of the quinazoline and H2-110 (dH 4.55) of the side
chain confirmed that alkylation occurred at the 4-position
of quinazoline.
N
1) NaOEt, Toluene, 80 °C
N
Overall yield for 9 from 6, 65%
2) N-Bromosuccinimide,
NaHCO3, DMF, 94% for
bromide 9a
R
9: R = COOH
9a: R = Br
N
N
To understand what reagents/factors are necessary for affect-
ing the C–O bond formation, quinazoline 10 was subjected
to the reaction conditions which were used for the Suzuki–
Miyaura/etherification one-pot reaction (Scheme 3, Method
1), as well as similar conditions except without palladium
catalyst and ligand (Scheme 3, Method 2), and further
N
n-BuLi, B(OiPr)3, 73%
B
HO
OH
5
Scheme 1.
N
N
N
N
N
MeOOC
N
N
O
B
R
HO
OH
N
N
6
5
4
Figure 2. Retrosynthetic analysis.

H.-yu Li et al. / Tetrahedron 63 (2007) 11763–11770
11765
13
6'
I
N N
7
N
N N
B
Cl
5
N
10
3
N
N
4'
O
HO
OH
3 % PdCl2(dppf)
HO
11'
N
N
1'
6 % (o-biphenyl)P(t-Bu)2
K2CO3, HO(CH2)2OH/dioxane, MW
120 °C, 20 min, 72 %
5
11
MsCl/pyr/rt, 1 h,
89 %
N N
N
N N
O
MsO
N
N
N
O
11a
Proposed unisolated intermediate
N
N
Cl
12
Scheme 2.
Table 1. 13C (125 MHz) and 1H (500 MHz) NMR spectral data for compounds 11, 12, and 3 in DMSO-d6
No.
dC 11
dH 11 (J in Hz)
dC 12
dH 12 (J in Hz)
dC
3
dH 3 (J in Hz)
2
3
4
5
6
7
156.6
121.5
136.6
118.6
152.2
23.4
156.6
121.4
136.5
118.7
152.2
23.4
156.6
121.4
136.5
118.7
152.2
23.4
7.15 (d, 7.6)
7.69 (t, 7.7)
7.56 (d, 7.2)
7.15 (d, 7.6)
7.69 (t, 7.7)
7.53 (d, 7.5)
7.15 (d, 7.6)
7.68 (t, 7.7)
7.53 (d, 7.5)
2.28 (s)
2.31 (s)
2.31 (s)
8
9
10
11
12
150.9
112.6
146.1
22.7
25.3
47.5
153.2
165.7
115.3
121.8
132.9
135.4
125.8
148.7
68.2
150.9
112.4
145.9
22.8
25.4
47.4
147.2
159.9
120.7
124.9
132.6
134.9
126.0
145.6
47.2
150.8
112.5
145.7
22.8
25.3
47.5
147.4
159.8
120.8
125.0
132.3
134.6
125.9
145.6
44.4
3.06 (t, 6.8)
2.64 (m)
4.22 (t, 7.2)
8.72 (s)
3.05 (t, 6.8)
2.63 (m)
4.21 (t, 7.2)
8.33 (s)
3.04 (t, 6.9)
2.63 (m)
4.20 (t, 7.3)
8.27 (s)
13
20
40
50
60
8.30 (dd, 2.1, 0.5)
8.31 (dd, 2.1, 0.5)
8.29 (dd, 2.1, 0.5)
70
80
7.90 (dd, 8.7, 2.1)
7.80 (d, 8.8)
7.81 (dd, 8.5, 2.1)
7.60 (d, 8.4)
7.78 (dd, 8.4, 2.1)
7.57 (d, 8.4)
90
100
110
120
120-OH
140/170
150/160
4.55 (t, 5.0)
3.80 (dd, 10.2, 5.4)
4.94 (t, 5.8)
4.32 (t, 6.0)
3.98 (t, 5.9)
4.07 (t, 6.1)
2.72 (t, 6.1)
58.8
41.9
53.6
53.3
22.9
2.50 (m)
1.65 (m)
I
I
I
Method 1) K2CO3, HO(CH2)2OH/dioxane, MW
120 °C, 20 min, 16, 65 %
+
O
Cl
HO
HO
or Method 2) 3 % PdCl2(dppf)
6 % (o-biphenyl)P(t-Bu)2
K2CO3, HO(CH2)2OH/dioxane, MW
120 °C, 20 min, 16, 61 %
N
N
N
N
N
N
10
16
17
or Method 3) K2CO3,
HO(CH2)2OH/dioxane,
120 °C, 16 hr, 16, 25 %; 17, 31%
Scheme 3.

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H.-yu Li et al. / Tetrahedron 63 (2007) 11763–11770
N N
N
N N
I
N
B
HO
5
OH
3 % PdCl2(dppf)
O
HO
6 % (o-biphenyl)P(t-Bu)2
K2CO3, HO(CH2)2OH/dioxane, MW
120 °C, 20 min, 87 %
O
HO
N
N
N
N
16
11
Scheme 4.
without microwave heating (Scheme 3, Method 3). Although
the conversion of 4-chloroquinazolines to 4-alkoxyquinazo-
line is generally done using a strong base (alkoxide or
hydride), the etherification with a relatively weaker base
K2CO3 proceeded nicely under the first two conditions
(Methods 1 and 2) with microwave heating to give com-
pound 16 with comparable yields of 65% and 61%, respec-
tively. Apparently, the presence of a palladium catalyst did
not show a positive impact on this reaction. However, the
conditions using conventional heating at 120 ꢀC (Method
3) for 16 h afforded two isolated products with similar yields
(w30%). This result indicated that conventional heating with
a weaker base was insufficient for the imidate formation. In-
terestingly, it is likely that microwave heating accelerated
the favored etherification more than hydrolysis, which
resulted in the low selectivity of the reaction.
be distinguished conclusively by the 1H and 13C NMR chem-
ical shifts. The N–CH2 peak (dC 47.2) in compound 12 is
much more upfield compared to the corresponding peak
(dC 68.2) of the O–CH2 in compound 11.
A survey of the literature indicates that aryl, alkyl, or allyl
groups of imidates are known to migrate from oxygen to
nitrogen.13 The uncatalyzed thermal rearrangement of aryl
imidates via a 1,3 O–N shift requires harsh conditions of
over 200 ꢀC for several days.13a,d,e Even if the alkyl 1,3
O–N rearrangement is catalyzed by chloride, the energy
for rearrangement still requires refluxing in an organic sol-
vent for many hours.13c This 1,3 rearrangement has also
been reported with the quinazoline system by refluxing in
MeCN for 24 h.13f Although a closely related alkyl 1,3
O–N rearrangement with a tosylate as the leaving group
was reported to occur (TsCl/triethylamine/CH2Cl2) at prob-
ably low temperature, the detailed information was not dis-
closed.13g In our case, the quantitative 1,3 rearrangement
took place in just 30 min at room temperature, which is
likely consistent with the observation in Ref. 13g. It appears
that mesylate is a better leaving group and speeds up the rate
of rearrangement. Evidently, the complete migration
observed at such a low temperature further ascertains that
the mechanism probably proceeds via intra- rather than in-
termolecular rearrangement of the alkyl group.13d
To test that the one-pot protocol was superior to the two-step
sequence, compound 16 was reacted with boronic acid 5 us-
ing the conditions used for the one-pot reaction (Scheme 4).
The overall yield from two reactions and two purifications,
including etherification was 56%, in comparison with 72%
yield from one reaction and one purification.
Forthe preparation ofourpotentialtarget compound2 (Fig. 1),
compound 11 was treated with methanesulfonyl chloride in
pyridine at room temperature, which unexpectedly led to
a chlorinated product instead of our desired key intermediate,
mesylate 11a (Scheme 2). The structure of the undesired prod-
uct was determined to be the arranged product 12 by the com-
bination of HMBC, ROESY,11 and HSQC12 spectra.
Consequently, the final products bearing a solublizing group
(3, 13–15) were synthesized by the amination of compound
12 under microwave heating conditions (Scheme 5).
As shown in Figure 3, the HMBC connection from H2-110
(dH 4.32) to C-20 (dC 156.6) and C-40 (dC 136.5) indicates
that the 110-CH2 is attached to a nitrogen atom N-30. The
NOE between H-20 (dH 8.33) and H2-110 (dH 4.32) further
confirmed this conclusion. In addition, the structures of N-
alkylated compound 12 and O-alkylated compound 11 could
3. Conclusion
In summary, by utilizing the synthetic route outlined in
Scheme 1, a dihydropyrrolopyrazole boronic acid intermedi-
ate was synthesized, which should allow rapid preparation of
diverse heterocyclic analogs of the quinazoline group of 2
and 3. Furthermore, the three-component Suzuki–Miyaura/
etherification procedure allows for access to advanced com-
pound 11 and proved to be more facile than the two-step se-
quence. Finally, the 1,3 O–N rearrangement at room
temperature is postulated to proceed via an intramolecular
mechanism and provides a practical approach for the synthe-
sis of substituted quinazolinone analogs. Compounds 3,
13–15 were potent at inhibiting the TGF-b RI kinase domain
with enzymatic IC50 values of 93, 95, 123, and 192 nM,
respectively, and were comparable in activity to a previously
reported TGF-b RI inhibitor having an enzymatic IC50 of
68 nM.2b,g
N N
N
O
4'
N
N
2'
Cl
ROESY: Dashed Line
HMBC: Plain Line
HH
H
12
Figure 3. Selected HMBC and ROESY correlations for compound 12.

H.-yu Li et al. / Tetrahedron 63 (2007) 11763–11770
11767
13
N N
N N
7'
N
7
N
10
6'
3, pyrrolidine, MW, 75%
13, morpholine, MW, 71%
3
5
14, piperidine, MW, 71%
15, azepine, MW, 75%
O
O
9'
N
N
Cl
N
N
1'
R
11'
12
3: R=
N
N
13: R=
O
14: R=
15: R=
N
N
Scheme 5.
4. Experimental section
4.08 (q, J¼7.1 Hz, 2H), 2.53 (s, 3H), 1.13 (t, J¼7.1 Hz,
3H), tautomer-2 (minor w13%) d 12.20 (s, 1H), 7.84
(t, J¼7.7 Hz, 1H), 7.70 (d, J¼7.8 Hz, 1H), 7.41 (d,
J¼7.7 Hz, 1H), 6.22 (s, 1H), 4.22 (q, J¼7.1 Hz, 2H), 4.09
(s, 2H), 2.51 (s, 3H), 1.26 (t, J¼7.1 Hz, 3H).
4.1. General
All reagents and solvents were used without further purifica-
tion or drying. All reagents were purchased from Sigma–
Aldrich, unless otherwise specified. Commercial grade
anhydrous solvents were purchased from EMD chemicals
or Mallinckrodt. All reactions were performed under nitrogen,
unless otherwise specified. Flash column chromatography
was carried out using prepacked silica gel columns from
4.1.2. 3-(6-Methyl-pyridin-2-yl)-3-(2-oxo-pyrrolidin-1-
ylimino)-propionic acid ethyl ester (8). To a mixture of
1-aminopyrrolidin-2-one hydrochloride (99.4 g, 0.73 mol)
and compound 7 (154 g, 0.66 mol) in a 3 L flask equipped
with mechanical stirrer and nitrogen inlet was added pyri-
dine (280 mL). After stirring at rt for 20 h, the resulting mix-
ture was diluted with water (200 mL) and extracted with
toluene (2ꢁ250 mL). The organic layer was combined, fil-
tered, and concentrated in vacuo to yield the title product
1
Isco. H NMR spectra were collected on Varian 400 MHz
or 500 MHz instrument. Mass spectra were obtained on
a Micromass QTOF-II, a Finnigan LCQ Duo Ion Trap or a
PESciex API 150EX mass spectrometer, using electrospray
ionization (ES) or atmospheric pressure chemical ionization
(APCI). Analytical HPLC (system A) was conducted on LC
column of Xterra C18 2.1ꢁ50 mm, 3.5 mM with flow rate of
1 mL/min, using the following gradient: 5–100% MeCN
with 0.2% NH4OH in 7.0 min, then held at 100% MeCN
for 1.0 min. Analytical HPLC (system B) was conducted on
LC column of YMC C18 2.0ꢁ50 mm, 3 mM with flow rate
of 1 mL/min, using the following gradient: 5–100% 1:1
MeCN/H2O with 0.2% ammonium formate in 7.0 min, then
held at 100% 1:1 acetonitrile/water for 1.0 min.
1
(201 g, 94%) as dark oil. MS ES+ m/z 290 (M+1)+. H
NMR (500 MHz, DMSO-d6) d 7.89 (t, J¼7.5 Hz, 1H),
7.79 (t, J¼7.5 Hz, 1H), 7.55 (d, J¼7.5 Hz, 1H), 4.10
(s, 2H), 4.05 (q, J¼7.0 Hz, 2H), 2.53 (s, 3H), 1.14
(t, J¼7.0 Hz, 3H). 13C NMR (125 MHz, CD2Cl2) d 195.1,
168.4, 158.2, 151.6, 138.3, 128.1, 119.3, 60.9, 44.9, 24.3,
14.4.
4.1.3. 2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyr-
rolo[1,2-b]pyrazole-3-carboxylic acid (9). To a solution
of sodium ethoxide (657 g, 9.26 mol) and toluene (12 L) in
a 22 L flask equipped with a mechanical stirrer, nitrogen in-
let, and a reflux condenser was added compound 8 (1.24 kg,
4.63 mol). The resulting mixture was heated at 100 ꢀC for
24 h and then cooled to rt. After the content was diluted
with water (6 L) and the pH adjusted to 4 with concentrated
hydrochloric acid, compound was extracted with 10% iso-
propyl alcohol in chloroform (3ꢁ8.5 L) and washed with
water. The organic fraction was combined and dried with so-
dium sulfate, filtered, and concentrated in vacuo, reslurried
in MTBE (1.2 L), filtered and dried to yield the title product
(743 g, 86% yield) as a light yellow solid in 98% purity by
HPLC analysis. MS ES+ m/z 244.11 (M+1)+, MS ESꢂ m/z
4.1.1. 3-(6-Methyl-pyridin-2-yl)-3-oxo-propionic acid
ethyl ester (7). To a mixture of sodium ethoxide (90 g,
1.32 mol) and toluene (0.5 L) in a 2 L flask equipped with
reflux condenser, mechanical stirrer, and nitrogen inlet was
added ethyl acetate (0.2 L, 1.98 mol). After stirring for
1 h, was added 6-methyl-pyridine-2-carboxylic acid methyl
ester (6, 100 g, 0.66 mol). Upon heating the mixture at reflux
(92 ꢀC) for 20 h, the mixture was cooled to rt and acidified
with glacial acetic acid to pH 6. The mixture was then di-
luted with water (0.5 L) and extracted with toluene (0.5 L).
The organic layer was dried with sodium sulfate, filtered,
and concentrated in vacuo to yield the title product (154 g,
96%) as dark oil in 86% purity by HPLC analysis. MS
ES+ m/z 208 (M+1)+. 1H NMR (300 MHz, toluene-d8) tauto-
mer-1 (major w87%) d 7.90 (7.90, J¼7.7 Hz, 1H), 7.78
(d, J¼7.8 Hz, 1H), 7.53 (d, J¼7.7 Hz, 1H), 4.09 (s, 2H),
1
242.19 (Mꢂ1)ꢂ. H NMR (500 MHz, DMSO-d6) d 8.03
(d, J¼7.0 Hz, 1H), 7.99 (t, J¼7.5 Hz, 1H), 7.10 (d,
J¼7.5 Hz, 1H), 4.21 (t, J¼7.5 Hz, 2H), 3.08 (t, J¼7.0 Hz,
2H), 2.59 (m, 2H), 2.56 (s, 3H). 13C NMR (125 MHz,

11768
H.-yu Li et al. / Tetrahedron 63 (2007) 11763–11770
CD2Cl2) d 163.5, 155.5, 154.9, 149.9, 149.1, 140.8, 124.5,
118.6, 108.9, 48.7, 25.5, 24.9, 22.3.
MeOH/CH2Cl2 to give the desired product (80 mg, 72%).
HRMS (AP+): m/z calcd for C22H21N5O2 388.1773, found
388.1799. HPLC (system A), 98%.
4.1.4. 3-Bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-
4H-pyrrolo[1,2-b]pyrazole (9a). To a solution of com-
pound 9 (1.4 g, 5.8 mmol) in N,N-dimethylformamide
(20 mL) was added N-bromosuccinamide (1 g, 5.6 mmol).
After the resulting mixture was stirred at rt for 16 h, com-
pound was extracted with ethyl acetate and washed three
times with water, once with brine. The organic layer was
dried with sodium sulfate, filtered, and concentrated in va-
cuo to yield the title compound, (1.5 g, 94%), as light yellow
solid. MS ES+ m/z 278 (M+1)+. HRMS (AP+): m/z calcd for
C12H12B3N3 278.0293, found 278.0283. 1H NMR
(400 MHz, CD2Cl2) d 7.67 (d, J¼8.0 Hz, 1H), 7.62 (t,
J¼7.6 Hz, 1H), 7.10 (d, J¼7.6 Hz, 1H), 4.21 (t, J¼7.6 Hz,
2H), 2.91 (t, J¼6.8 Hz, 2H), 2.62 (m, 2H), 2.58 (s, 3H).
13C NMR (100 MHz, CD2Cl2) d 157.9, 151.5, 151.3,
146.7, 136.3, 121.8, 118.8, 85.4, 49.0, 25.4, 24.2, 22.8.
4.1.7. 3-(2-Chloro-ethyl)-6-[2-(6-methyl-pyridin-2-yl)-
5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-3H-quin-
azolin-4-one (12). To a solution of compound 11 (300 mg,
0.8 mmol) in dry pyridine (5 mL) at ꢂ20 ꢀC was added meth-
anesulfonyl chloride (1 mL, 12.67 mmol). The resulting
mixture was stirred at ꢂ20 ꢀC for 10 min and then at room
temperature for 30 min. After the reaction was quenched
with adding 3:1 CHCl3/i-PrOH, the organic layer was
washed with brine, dried with Na2SO4, filtered, and concen-
trated in vacuo. The residue was subjected to silica gel chro-
matography eluting gradually from CH2Cl2 to 10% MeOH/
CH2Cl2 to give the targeted compound (280 mg, 89%). MS
ES+ m/z 405.1 (M+1)+. HRMS (AP+): m/z calcd for
C22H20ClN5O 406.1435, found 406.1450. For NMR data,
see Table 1.
4.1.5. 2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-
pyrrolo[1,2-b]pyrazole-3-boronic acid (5). To a solution
of compound 9a (1.44 g, 5.18 mmol) in tetrahydrofuran
(28.0 mL) in a 100 mL round-bottom flask equipped with
a temperature probe, a magnetic stirrer, and a septum and
put under a nitrogen atmosphere was added triisopropyl bo-
rate (3.10 mL, 13.5 mmol). Upon cooling the mixture to
ꢂ78 ꢀC using a dry ice/acetone bath, 1.4 M n-butyllithium
in hexanes (8.80 mL, 12.4 mmol) was added dropwise via
a syringe pump over 10 min keeping the temperature below
ꢂ40 ꢀC. After removing the dry ice/acetone bath, the reac-
tion mixture was warmed to room temperature. The satu-
rated aqueous ammonium chloride (10 mL) was added and
extracted with chloroform (2ꢁ100 mL). The organic layers
were combined, dried over solid sodium sulfate, and the sol-
vent was removed under reduced pressure to afford oil. The
oil was purified with normal phase flash chromatography
(120 g Biotage KP-Sil 40L: 100% ethyl acetate in hexanes
for 25 min, 0–10% methanol in ethyl acetate in ramp over
15 min, then 10% methanol in ethyl acetate) to yield the title
compound (910 mg, 73%). MS ES+ m/z 244 (M+1)+. HRMS
(AP+): m/z calcd for C12H14BN3O2 243.1293, found
243.1312. 1H NMR (400 MHz, 10% CDOD3/CD2Cl2)
d 7.95 (d, J¼8.4 Hz, 1H), 7.70 (t, J¼7.2 Hz, 1H), 7.12 (d,
J¼7.2 Hz, 1H), 4.13 (t, J¼7.6 Hz, 2H), 3.01 (t, J¼6.8 Hz,
2H), 2.59 (m, 2H), 2.59 (s, 3H). 13C NMR (100 MHz, 10%
CDOD3/CD2Cl2) d 158.2, 156.3, 156.1, 152.6, 138.1,
122.2, 117.9, 47.6, 25.6, 24.2, 22.7.
4.1.8. 6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyr-
rolo[1,2-b]pyrazol-3-yl]-3-(2-pyrrolidin-1-yl-ethyl)-3H-
quinazolin-4-one (3). Compound 12 (30 mg, 0.07 mmol) in
pyrrolidine (1 mL) was sealed in a pressure tube (10 mL)
and placed in a microwave reactor. After the reaction mix-
ture was irradiated at 140 ꢀC for 1 h, the crude reaction mix-
ture was subjected to silica gel chromatography eluting
gradually from CH2Cl2 to 10% MeOH/CH2Cl2 to give the
targeted compound (25 mg, 75%). MS ES+ m/z 457.5
(M+1)+. HRMS (AP+): m/z calcd for C26H28N6O
441.2403, found 441.2394. For NMR data, see Table 1.
HPLC (system A), >99%; HPLC (system B), >99%.
4.1.9. 6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyr-
rolo[1,2-b] pyrazol-3-yl]-3-(2-morpholin-4-yl-ethyl)-3H-
quinazolin-4-one (13). Prepared using the same procedure
as for 3, but employing morpholine as the amine resource
(25 mg, 75% yield). MS ES+ m/z 457.5 (M+1)+. HRMS
(AP+): m/z calcd for C26H28N6O 457.2347, found
457.2347. 1H NMR (400 MHz, CD2Cl2) d 8.29 (d,
J¼2.0 Hz, 1H), 8.01 (s, 1H), 7.74 (dd, J¼8.0, 2.0 Hz, 1H),
7.57 (t, J¼7.6 Hz, 1H), 7.56 (d, J¼8.4 Hz, 1H), 7.46 (d,
J¼7.6 Hz, 1H), 7.07 (d, J¼8.0 Hz, 1H), 4.25 (t, J¼7.2 Hz,
2H), 4.07 (t, J¼5.6 Hz, 2H), 3.65 (t, J¼4.4 Hz, 4H), 3.10
(t, J¼6.8 Hz, 2H), 2.70 (m, 4H), 2.51 (t, J¼4.4 Hz, 4H),
2.42 (s, 3H). 13C NMR (100 MHz, 10% CDOD3/CD2Cl2)
d 161.5, 155.9, 148.6, 147.3, 146.6, 142.2, 135.1, 135.1,
131.9, 127.7, 125.6, 124.4, 122.1, 121.7, 114.4, 63.9, 55.4,
52.6, 48.5, 41.1, 25.9, 23.1, 21.4. HPLC (system A),
>99%; HPLC (system B), >99%.
4.1.6. 2-[2-(6-Methyl-pyridin-2-yl-5,6-dihydro-4H-pyr-
rolo[1,2-b]pyrazol-3-yl)-quinazolin-4-yloxy]-ethanol
(11). To a solution of compound 5 (70 mg, 0.3 mmol), 4-
chloro-6-iodo-quinazoline (130 mg, 0.45 mmol), and 2 M
potassium carbonate (1 mL) in 2:1 dioxane/ethylene glycol
(6 mL) in a 10 mL glass tube was added Pd(dppf)2Cl2
(7 mg, 3% mol) and (o-biphenyl)P(t-Bu)2 (3 mg, 6% mol).
The tube was then sealed with a septum and placed in a mi-
crowave reactor. After the mixture was irradiated at 120 ꢀC
(100 W) for 20 min, 3:1 CHCl3/i-PrOH was added and
washed with brine. The organic layer was dried, filtered
through Na2SO4, and concentrated in vacuo to give a viscous
mixture. Finally, the mixture was subjected to silica gel flash
chromatography eluting gradually from CH2Cl2 to 10%
4.1.10. 6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-
pyrrolo[1,2-b]pyrazol-3-yl]-3-(2-piperidin-1-yl-ethyl)-
3H-quinazolin-4-one (14). Prepared using the same
procedure as for 3, but employing piperidine as the amine
resource (136 mg, 71% yield). LRMS (ES+) m/z 455.2
1
(M+1)+. H NMR (400 MHz, CD2Cl2) d 8.28 (d, J¼2.4 Hz,
1H), 8.02 (s, 1H), 7.71 (dd, J¼8.4, 2.4 Hz, 1H), 7.56 (t,
J¼7.6 Hz, 1H), 7.55 (d, J¼8.4 Hz, 1H), 7.46 (d, J¼7.6 Hz,
1H), 7.07 (d, J¼7.6 Hz, 1H), 4.25 (t, J¼7.2 Hz, 2H), 4.04 (t,
J¼5.6 Hz, 2H), 3.10 (t, J¼6.8 Hz, 4H), 2.70 (m, 2H), 2.63 (t,
J¼6.4 Hz, 2H), 2.44 (m, 4H), 2.42 (s, 3H), 1.59 (m, 4H), 1.45
(m, 2H). HPLC (system A), >99%; HPLC (system B), >99%.

H.-yu Li et al. / Tetrahedron 63 (2007) 11763–11770
11769
4.1.11. 3-(2-Azepan-1-yl-ethyl)-6-[2-(6-methyl-pyridin-
2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-3H-
quinazolin-4-one (15). Prepared using the same procedure
as for 3, but employing azepane as the amine resource
silica gel flash chromatography eluting gradually from
CH2Cl2 to 10% MeOH/CH2Cl2 to give the desired product
16 (78 mg, 25%) and 17 (85 mg, 31%). Compound 17:
LRMS (ES+) m/z 273.0 (M+1)+. 1H NMR (400 MHz,
DMSO-d6) d 12.4 (s, 1H), 8.35 (d, J¼2.0 Hz, 1H), 8.10 (s,
1H), 8.05 (dd, J¼8.8, 2.0 Hz, 1H), 7.41 (d, J¼8.8 Hz, 1H).
13C NMR (100 MHz, DMSO-d6) d 159.8, 148.5, 146.6,
143.1, 134.6, 129.8, 124.9, 92.2. HPLC (system A),w86.0%.
1
(136 mg, 71% yield). LRMS (ES+) m/z 469.2 (M+1)+. H
NMR (400 MHz, CD2Cl2) d 8.28 (d, J¼2.0 Hz, 1H), 8.04
(s, 1H), 7.71 (dd, J¼8.4, 2.0 Hz, 1H), 7.56 (t, J¼7.6 Hz,
1H), 7.55 (d, J¼8.4 Hz, 1H), 7.45 (d, J¼7.6 Hz, 1H), 7.06
(d, J¼7.6 Hz, 1H), 4.25 (t, J¼7.2 Hz, 2H), 4.04 (t,
J¼5.6 Hz, 2H), 3.14 (d, J¼6.0 Hz, 2H), 3.10 (t, J¼7.6 Hz,
2H), 2.83 (m, 2H), 2.69 (m, 4H), 2.42 (s, 3H), 1.59 (m,
8H). HPLC (system A), >99%; HPLC (system B), >99%.
Acknowledgements
We would like to thank Drs. J. Yingling and R. M. Campbell
for TGF-b RI enzymatic assays.
4.1.12. 3-(2-Azepan-1-yl-ethyl)-6-[2-(6-methyl-pyridin-
2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-3H-
quinazolin-4-one (16). Method 1. To a solution of 4-chloro-
6-iodo-quinazoline (292 mg, 1.0 mmol) in 2:1 dioxane/
ethylene glycol (6 mL) in a 10 mL glass tube was added
2 M potassium carbonate (1 mL). The tube was then sealed
with a septum and placed in a microwave reactor. After that,
the mixture was irradiated at 120 ꢀC for 20 min and was
monitored by LCMS, which indicated the completion of
reaction. The reaction was then quenched with 3:1 CHCl3/
i-PrOH and washed with brine. The organic layer was dried,
filtered through Na2SO4, and concentrated in vacuo to give
a viscous mixture. Finally, the mixture was subjected to
silica gel flash chromatography eluting gradually from
CH2Cl2 to 10% MeOH/CH2Cl2 to give the desired product
Supplementary data
NMR spectra of compounds 11, 12, and 3. Supplementary
data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2007.08.069.
References and notes
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1
(205 mg, 65%). LRMS (ES+) m/z 317.0 (M+1)+. H NMR
(400 MHz, DMSO-d6) d 8.78 (s, 1H), 8.57 (d, J¼2.4 Hz,
1H), 8.17 (dd, J¼8.8, 2.4 Hz, 1H), 7.66 (d, J¼8.8 Hz, 1H),
4.52 (t, J¼4.8 Hz, 2H), 3.81 (t, J¼5.2 Hz, 2H). 13C
NMR (100 MHz, DMSO-d6) d 165.4, 155.0, 149.9, 142.8,
132.4, 129.8, 117.9, 93.4, 69.6, 59.3. HPLC (system A),
>99%.
Method 2. To a solution of 4-chloro-6-iodo-quinazoline
(292 mg, 1.0 mmol) and 2 M potassium carbonate (1 mL)
in 2:1 dioxane/ethylene glycol (6 mL) in a 10 mL glass
tube were added Pd(dppf)2Cl2 (23 mg, 3% mol) and
(o-biphenyl)P(t-Bu)2 (10 mg, 6% mol). The tube was then
sealed with a septum and placed in a microwave reactor.
After the mixture was irradiated at 120 ꢀC for 20 min, the
reaction was monitored by LCMS, which indicated the com-
pletion of reaction. The reaction was quenched (CHCl3/
i-PrOH) and washed with brine. The organic layer was dried,
filtered through Na2SO4, and concentrated in vacuo to give
a viscous mixture. Finally, the mixture was subjected to sil-
ica gel flash chromatography eluting gradually from CH2Cl2
to 10% MeOH/CH2Cl2 to give the desired product (192 mg,
61%).
Method 3. To a solution of 4-chloro-6-iodo-quinazoline
(292 mg, 1.0 mmol) in 2:1 dioxane/ethylene glycol (6 mL)
in a 10 mL glass tube was added 2 M potassium carbonate
(1 mL). The tube was then sealed with a septum and placed
in a microwave reactor. After that, the mixture was heated at
120 ꢀC and the reaction was monitored by LCMS until the
reaction was completed after 16 h (starting material disap-
peared). The reaction was then quenched with 3:1 CHCl3/
i-PrOH and washed with brine. The organic layer was dried,
filtered through Na2SO4, and concentrated in vacuo to give
a viscous mixture. Finally, the mixture was subjected to
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