Synthesis of novel benzoxazinone compounds as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors

Article abstract of DOI:10.1080/00397911.2011.573169

(Chemical Equation Presented) Two benzoxazinone compounds as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were synthesized and characterized by NMR and high-resolution mass spectrometry (HRMS). An efficient chlorination method was introduced in the synthesis of 4-chloro-2-oxo-2H- benzoxazinone-6-yl acetate. The inhibition activities of the target compounds and the important intermediates for EGFR tyrosine kinase activity in vitro were determined. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.573169

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Synthesis of Novel Benzoxazinone
Compounds as Epidermal Growth
Factor Receptor (EGFR) Tyrosine Kinase
Inhibitors
Shaopeng Chen a , Xuemin Li a , Shengbiao Wan a & Tao Jiang a
a Key Laboratory of Marine Drugs, Chinese Ministry of Education,
Shandong Provincial Key Laboratory of Glycoscience and
Glycotechnology, School of Medicine and Pharmacy, Ocean University
of China, Qingdao, China
Accepted author version posted online: 02 Jan 2012.Published
online: 29 May 2012.
To cite this article: Shaopeng Chen , Xuemin Li , Shengbiao Wan & Tao Jiang (2012) Synthesis of Novel
Benzoxazinone Compounds as Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:19, 2937-2946, DOI: 10.1080/00397911.2011.573169
To link to this article: http://dx.doi.org/10.1080/00397911.2011.573169
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Synthetic Communications1, 42: 2937–2946, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.573169
SYNTHESIS OF NOVEL BENZOXAZINONE
COMPOUNDS AS EPIDERMAL GROWTH FACTOR
RECEPTOR (EGFR) TYROSINE KINASE INHIBITORS
Shaopeng Chen, Xuemin Li, Shengbiao Wan, and Tao Jiang
Key Laboratory of Marine Drugs, Chinese Ministry of Education, Shandong
Provincial Key Laboratory of Glycoscience and Glycotechnology, School of
Medicine and Pharmacy, Ocean University of China, Qingdao, China
GRAPHICAL ABSTRACT
Abstract Two benzoxazinone compounds as epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitors were synthesized and characterized by NMR and high-resolution
mass spectrometry (HRMS). An efficient chlorination method was introduced in the
synthesis of 4-chloro-2-oxo-2H-benzoxazinone-6-yl acetate. The inhibition activities of
the target compounds and the important intermediates for EGFR tyrosine kinase activity
in vitro were determined.
Keywords Benzoxazinone; EGFR; inhibitor; synthesis
INTRODUCTION
It is well known that epidermal growth factor receptor (EGFR) tyrosine kinase
plays an important role in a wide range of cancers.[1,2] Compounds that inhibit the
kinase activity of EGFR are of potential interest as new therapeutic antitumor
Received December 30, 2010.
Address correspondence to Tao Jiang, Key Laboratory of Marine Drugs, Chinese Ministry of
Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of
Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China. E-mail:
jiangtao@ouc.edu.cn
2937

2938
S. CHEN ET AL.
Figure 1. Structures of gefitinib, lapatinib, and the target compounds.
agents.[3,4] A well-studied class of these inhibitors is represented by 4-anilinoquina-
zolines.[5] Further development in this class led to the discovery of several drugs,
such as gefitinib and lapatinib (Fig. 1), which have been used for the treatment of
non-small-cell lung cancer and breast cancer.[6,7]
The main modifications of 4-anilinoquinazoline focused on introducing differ-
ent substituents on the C-6 or C-7 positions and a variety of anilines on the C-4 pos-
ition of the quinazoline ring.[8] Structure–activity and molecular modeling studies
demonstrated that the N-1 and N-3 atoms could interact with the kinase domain
by hydrogen bonds.[9] Benzoxazinone compounds with potential anticancer activity
have some similarities with the quinazoline ring.[10,11] In this study, two analogs of
gefitinib and lapatinib were designed by replacing the quinazoline ring with a 3,
4-dihydro-2H-benzoxazinone-2-one scaffold using the strategy of bioisosterism to
develop new EGFR tyrosine kinase inhibitors (Fig. 1).[12]
RESULTS AND DISCUSSION
The synthetic route of the target compounds is outlined in Scheme 1. 2,5-Dihy-
droxybenzoic acid was refluxed in methanol catalyzed by H2SO4 to give methyl
2,5-dihydroxybenzoate, which was then treated with concentrated ammonia liquor
(28%) to give 2,5-dihydroxybenzamide. 2,5-Dihydroxybenzamide was subsequently
reacted with ethyl chloroformate at 122 ꢀC and treated with hydrochloric acid to give
compound 6 following a reported procedure.[13] After acetylation of the hydroxyl
group, compound 7 was obtained in 72% yield.
No reaction happened when compound 7 was refluxed in SOCl2 or POCl3 fol-
lowing the conventional procedures.[14,15] To accomplish this reaction, compound 7
was treated with PCl5 at 165 ꢀC under a nitrogen atmosphere, and then compound 8
was obtained as a yellow solid, which was used for the next step without further puri-
fication. With a similar procedure as reported,[11] amination of compound 8 by
3-chloro-4-fluoroaniline or 3-chloro-4-(3-fluorobenzyloxy) aniline in CH3CN using
N-ethyl-N-isopropylpropan-2-amine (DIPEA) as an acid scavenger afforded 9a
and 9b respectively.

NOVEL BENZOXAZINONE COMPOUNDS
2939
Scheme 1. Reagents and conditions: (a) H2SO4, MeOH, reflux, 48 h, 92%%; (b) concentrated ammonia
liquor, 50 ꢀC, 13 h, 70%; (c) ethyl chloroformate, 5 to 122 ꢀC, 1 h, 85%; (d) pyridine/Ac2O, rt to 100 ꢀC,
3 h, 72%; (e) PCl5, 165 ꢀC, 20 min; and (f) 3-chloro-4-fluoroaniline or 3-chloro-4-(3-fluorobenzyloxy)-
aniline, CH3CN, DIPEA, rt, 12 h, 19–34%.
As shown in Scheme 2, compounds 9a and 9b could be deacetylated by concen-
trated ammonia liquor (28%) in methanol to obtain 12a and 12b. However, when 12a
and 12b were treated with 4-(3-chloropropyl)morpholine, the hydroxy group and the
imine group in the N-3 position both might be alkylated simultaneously. Thus,
methylation was carried out through the reaction of compounds 9a and 9b with
CH3I in dimethylformamide (DMF) to afford 10a and 10b respectively before depro-
tection of the acetyl groups.
After deacetylation of 10a and 10b with concentrated ammonia liquor (28%) in
methanol, compounds 11a and 11b were obtained in 93% and 96% yields. Finally,
11a and 11b were reacted with 4-(3-chloropropyl)morpholine in DMF to provide
the target compounds 1 and 2 respectively in 65% and 74% yields. The structures
of the target compounds and the new intermediates were characterized by 1H
NMR, 13C NMR, and high-resoultion mass spectrometry (HRMS).
The inhibition activity of the target compounds and the important intermedi-
ates toward EGFR tyrosine kinase activity in vitro was determined by an
enzyme-linked-immunosorbent assay (ELISA).[16] Preliminary evaluation demon-
strated that most synthesized benzoxazinone compounds showed low or moderate
inhibition effect against EGFR in vitro at the concentration of 10.0 mM. Among
the synthesized compounds, 1 and 11a showed relatively great inhibition effect
against the isolated EGFR enzyme (49.3% and 44.6%). The inhibition rates of target
compounds 1 and 2 against EGFR in vitro are 49.3% and 38.0% at the concentration
of 10.0 mM (Table 1). Comparing with lapatinib, the two analogs exhibited lower
EGFR inhibition activity.
In conclusion, two target benzoxazinone compounds and eight novel inter-
mediates were synthesized and characterized by NMR and HRMS spectrometry.

2940
S. CHEN ET AL.
Scheme 2. Reagents and conditions: (a) CH3I, K2CO3, DMF, 70 ꢀC, 3 h, 69–78%; (b) concentrated
ammonia liquor=MeOH, 91–96%; and (c) 4-(3-chloropropyl)morpholine, DMF, 80 ꢀC, 3 h, 65–74%.
An efficient chlorination method was introduced to synthesize compound 8 using
PCl5 at melting temperature and we hope it will be useful for the synthesis of other
similar compounds. Preliminary evaluation demonstrated that compounds 1 and 11b
showed moderate inhibition effect against EGFR in vitro. The reason for moderate
inhibition activity of the target compounds toward EGFR may be the existence of
Table 1. Inhibition effect of compounds 9a–12b and the target compounds
toward EGFR in vitro
Compounds
Concentration (mM)
Inhibition (%)
9a
9b
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
23.8
38.5
31.2
24.0
29.5
44.6
3.85
19.3
49.3
38.0
76.1
10a
10b
11a
11b
12a
12b
1
2
Lapatinib

NOVEL BENZOXAZINONE COMPOUNDS
2941
the methyl in the N-3 position, which could block the interaction between N-3 atom
and the kinase domain. Further modification and bioactivity investigation of this
kind of benzoxazinone compounds are in progress.
EXPERIMENTAL
All reagents used in the experiments were obtained from commercial sources
and purified in a conventional manner. Thin-layer chromatography (TLC) was per-
formed on Merck silica-gel 60 F254 plates. Flash column chromatography was per-
formed on silica gel (200–300 mesh, Qingdao, China). Melting points were
1
measured on a WRX-1S melting-point apparatus and were uncorrected. H NMR
and 13C NMR spectra were taken on Jnm-Ecp-600 spectrometer (Jeol Ltd. Tokyo,
Japan) with tetramethylsilane (Me4Si) as the internal standard. Mass spectra were
recorded on a Q-TOF Global mass spectrometer (Waters Co., Milford, MA, USA).
Compounds 4–6
Literature procedures were used for preparation of compounds 4 to 6.[12,17,18]
Methyl 2,5-dihydroxybenzoate (4). White powder; yield 92%; mp: 85–86 ꢀC
(lit.[19] 84–86 ꢀC).
2,5-Dihydroxybenzamide (5). Yellow needles; yield 70%; mp: 216–219 ꢀC
(lit.[12] 218–220 ꢀC).
6-Hydroxy-1,3-benzoxazine-2,4(3H)-dione (6). White solid; yield 85%; mp:
301–303 ꢀC (lit.[18] 303–305 ꢀC).
2,4-Dioxo-3,4-dihydro-1,3-benzoxazine-6-yl Acetate (7)
A suspension of 6-hydroxy-1,3-benzoxazine-2,4(3H)-dione 6 (7.0 g, 39.1 mmol)
in acetic anhydride (60 mL) and pyridine (18 mL) was stirred and heated to 100 ꢀC
under a N2 atmosphere for 3 h. The solvent was removed under reduced pressure.
Crushed ice=water solution (100 mL) was added to the reaction mixture, and the
resulting white deposit was filtered, washed with water, and dried under reduced
1
pressure to afford 7 (0.22 g, 91% yield) as a white powder. Mp: 204–206 ꢀC; H
NMR (DMSO-d6, 600 MHz): d 12.14 (br, s, 1H, NH), 7.68–7.67 (d, J ¼ 2.8 Hz,
1H, ArH), 7.57–7.55 (dd, J ¼ 8.8, 2.7 Hz, 1H, ArH), 7.47-7.45 (d, J ¼ 8.8 Hz, 1H,
ArH), 2.30 (s, 3H, -OAc); 13C NMR (DMSO-d6 150 MHz): d 169.8, 161.5, 151.7,
147.8, 147.4, 130.4, 120.0, 118.5, 115.9, 21.4; ESI-MS 244.2 (M þNa)þ; HRMS
þ
(ESI): calcd. for C10H8NO5 222.0402; found 222.0411.
4-Chloro-2-oxo-1,3-benzoxazine-6-yl Acetate (8)
A mixture of 2,4-dioxo-3,4-dihydro-1,3-benzoxazine-6-yl acetate 7 and PCl5
was stirred and heated to the melting temperature under N2 atmosphere. The reac-
tion mixture was stirred for a further 20 min. After completion, the solvent was

2942
S. CHEN ET AL.
removed under reduced pressure to give product 8 as a yellow solid which was used
for the next step without further purification.
4-(3-Chloro-4-fluorophenylamino)-2-oxo-1,3-benzoxazine-6-yl
Acetate (9a)
4-Chloro-2-oxo-1,3-benzoxazine-6-yl acetate
8 (2.62 g, 11.0 mmol) and
3-chloro-4-fluoroaniline (1.6 g, 11.0 mmol) were dissolved in CH3CN (100 mL). To
this solution, N,N-Diisopropylethylamine (3.5 mL) was added dropwise until the sol-
ution became alkaline and stirred for a further 12 hours. The progress of the reaction
was monitored by thin-layer chromatography (TLC). After completion of the reac-
tion, the solvent was evaporated under reduced pressure, and the residue was puri-
fied through column chromatography on silica gel (eluent, dichloromethane) to give
1
9a (1.0 g, 19.2% yield) as a yellow powder. Mp: 213–217 ꢀC; H-NMR (DMSO-d6,
600 MHz): d 10.43 (br, s, 1H, NH), 8.19–8.18 (d, J ¼ 1.9 Hz, 1H, ArH), 8.10–8.09
(dd, J ¼ 6.9, 2.3 Hz, 1H, ArH), 7.76–7.75 (m, 1H, ArH), 7.62–7.60 (dd, J ¼ 9.2,
2.8 Hz, 1H, ArH), 7.53–7.51 (t, J ¼ 9.2 Hz, 1H, ArH), 7.45–7.43 (d, J ¼ 8.7 Hz, 1H,
ArH), 2.35 (s, 3H, -OAc); 13C NMR (DMSO-d6 150 MHz): d 169.9, 161.0, 156.1,
154.5, 154.0, 151.9, 146.4, 134.9, 130.4, 126.3, 124.9, 118.5, 117.5, 117.3, 110.8,
21.2; ESI-MS 349.0 (M þ H)þ. HRMS (ESI): calcd. for C16H11N2O4FClþ
349.0391; found 349.0374.
4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)-
2-oxo-1,3-benzoxazine-6-yl Acetate (9b)
Following the procedure used for the preparation of 9a, but with 3-chloro-4-
(3-fluorobenzyloxy)aniline as starting material, product 9b was obtained as a yellow
powder (34% yield). Mp 101–103 ꢀC. 1H-NMR (DMSO-d6, 600 MHz): d 10.34 (br, s,
1H, NH), 8.19–8.18 (d, J ¼ 2.3 Hz, 1H, ArH), 7.95–7.94 (d, J ¼ 2.8 Hz, 1H, ArH),
7.68–7.66 (dd, J ¼ 8.7, 2.7 Hz, 1H, ArH), 7.60–7.58 (dd, J ¼ 9.2, 2.8 Hz, 1H, ArH),
7.50–7.48 (m, 1H, ArH), 7.44–7.42 (d, J ¼ 9.2 Hz, 1H, ArH), 7.34–7.32 (dd,
J ¼ 8.8, 2.8 Hz, 2H, ArH), 7.31 (s, 1H, ArH), 7.20–7.18 (t, J ¼ 8.8 Hz, 1H, ArH),
5.28 (s, 2H), 2.35 (s, 3H, -OAc); 13C NMR (DMSO-d6 150 MHz): d 169.9, 163.6,
162.0, 160.7, 153.9, 152.0, 151.7, 146.3, 140.0, 131.4, 131.3, 130.0, 126.1, 124.4,
123.9, 120.9, 118.5, 117.5, 115.4, 114.7, 110.9, 69.9, 21.2; ESI-MS 455.0 (M þ H)þ.
HRMS (ESI): calcd. for C23H17N2O5FClþ 455.0810; found 455.0830.
4-(3-Chloro-4-fluorophenylimino)-3-methyl-
2-oxo-3,4-dihydro-1,3-benzoxazine-6-yl Acetate (10a)
A suspension of 9a (450 mg, 1.29 mmol) and anhydrous potassium carbonate
(330 mg, 2.39 mmol) in dry DMF (30 mL) was stirred at 40 ꢀC for 20 min, then
CH3I (2.39 mmol) was added, and the mixture was stirred at 70 ꢀC for 8 h under a
N2 atmosphere. After completion, the solvent was removed under reduced pressure
and then purified by chromatography on silica gel (eluent, ethyl acetate=petroleum
ether 2=5) to give 10a (364 mg, 69% yield) as a yellow powder. Mp: 149–152 ꢀC;
1H-NMR (DMSO-d6, 600 MHz): d 7.43–7.39 (m, 3H, ArH), 7.10–7.09 (d, J ¼ 4.4 Hz,

NOVEL BENZOXAZINONE COMPOUNDS
2943
1H, ArH), 6.90–6.88 (m, 1H, ArH), 6.70 (br, s, 1H, ArH), 3.30 (s, 3H), 2.16 (s, 3H, -
OAc); 13C NMR (DMSO-d6 150 MHz): d 169.3, 154.9, 153.3, 149.1, 148.2, 146.1,
146.0, 128.2, 121.2, 120.5, 120.1, 120.0, 118.9, 118.4, 118.3, 56.6, 21.2; ESI-MS
363.1 (M þ H)þ. HRMS (ESI): calcd. for C17H13N2O4FClþ 363.0548; found
363.0551.
4-(3-Chloro-4-(3-fluorobenzyloxy)phenylimino)-3-methyl-2-oxo-
3,4-dihydro-1,3-benzoxazine-6-yl Acetate (10b)
Following the procedure used for the preparation of 10a, but with 9b as start-
ing material, product 10b was obtained as a yellow powder (78% yield). Mp
1
145–147 ꢀC; H NMR (DMSO-d6, 600 MHz): d 7.48–7.45 (t, J ¼ 6.0 Hz, 1H, ArH),
7.40–7.39 (t, J ¼ 2.8 Hz, 2H, ArH), 7.33–7.30 (m, 2H, ArH), 7.23–7.21 (d, J ¼ 8.8 Hz,
1H, ArH), 7.20-7.17 (dt, J ¼ 8.2, 2.2 Hz, 1H, ArH), 7.01 (s, 1H, ArH), 6.83–6.82 (d,
J ¼ 8.3 Hz, 1H, ArH), 6.66 (s, 1H, ArH), 5.22 (s, 2H), 3.34 (s, 3H), 2.19 (s, 3H,
-OAc); 13C NMR (DMSO-d6 150 MHz): d 169.3, 163.6, 161.9, 150.0, 149.1, 143.0,
140.3, 140.2, 131.1, 131.0, 128.2, 123.8, 121.1, 120.5, 119.2, 118.9, 116.5, 115.3,
115.2, 114.5, 114.4, 70.3, 56.6, 21.1; ESI-MS 469.1 (M þ H)þ. HRMS (ESI): calcd.
for C24H19N2O5FClþ 469.0967; found 469.0985.
4-(3-Chloro-4-fluorophenylimino)-6-hydroxy-
3-methyl-3,4-dihydro-1,3-benzoxazine-2-one (11a)
Compound 10a (314 mg, 0.87 mmol) was dissolved in methanol (30 mL), and
then concentrated ammonia liquor (28%, 0.5 mL) was added. The reaction mixture
was stirred at room temperature for 3 h. After completion of the reaction, the solvent
was evaporated under reduced pressure. The yellow precipitate formed was filtered
and washed with diethylether (50 mL) to give 11a (259 mg, 93% yield) as a yellow
powder. Mp: 176–178 ꢀC; 1H-NMR (DMSO-d6, 600 MHz): d 9.78 (br, s, 1H, ArOH),
7.41–7.38 (t, J ¼ 9.4 Hz, 1H, ArH), 7.20–7.18 (d, J ¼ 8.8 Hz, 1H, ArH), 7.08–7.06 (m,
1H, ArH), 7.00–6.98 (dd, J ¼ 8.8, 2.8 Hz, 1H, ArH), 6.85–6.83 (m, 1H, ArH), 6.43
(br, s, 1H, ArH), 3.35 (s, 3H); 13C NMR (DMSO-d6 150 MHz): d 154.8, 153.7,
153.2, 148.4, 146.4, 145.1, 144.4, 122.2, 120.9, 119.8, 118.7, 118.5, 118.3, 130.0,
56.6; ESI-MS 321.0 (M þ H)þ; HRMS (ESI): calcd. for C15H11N2O3FClþ
321.0442; found 321.0433.
4-(3-Chloro-4-(3-fluorobenzyloxy)phenylimino)-6-hydroxy-3-methyl-
3,4-dihydro-1,3-benzoxazine-2-one (11b)
Following the procedure used for the preparation of 11a, but with 10b as start-
ing material, product 11b was obtained as a yellow powder (96% yield). Mp:
1
199–201 ꢀC; H-NMR (DMSO-d6, 600 MHz): d 10.05 (br, s, 1H, ArOH), 7.48–7.45
(t, J ¼ 7.7 Hz, 1H, ArH), 7.35–7.32 (t, J ¼ 11.0 Hz, 2H, ArH), 7.22–7.15 (m, 3H,
ArH), 6.99–6.97 (dd, J ¼ 8.8, 2.2 Hz, 2H, ArH), 6.79–6.77 (dd, J ¼ 8.8, 2.7 Hz, 1H,
ArH), 6.46 (s, 1H, ArH), 5.22 (s, 2H), 3.34 (s, 3H); 13C NMR (DMSO-d6
150 MHz): d 163.6, 162.0, 154.1, 149.8, 148.6, 144.1, 143.3, 140.3, 131.1, 123.9,
123.1, 122.0, 120.9, 119.0, 118.5, 116.2, 115.3, 115.2, 114.6, 114.5, 70.1, 56.6; ESI-MS

2944
S. CHEN ET AL.
427.1 (M þ H)þ; HRMS (ESI): calcd. for C22H17N2O4FClþ 427.0861; found
427.0847.
4-(3-Chloro-4-fluorophenylamino)-2-oxo-1,3-benzoxazine-6-yl
Acetate (12a)
Following the procedure used for the preparation of 11a, but with 9a as start-
ing material, product 12a was obtained as a yellow powder (91% yield). Mp
1
221–223 ꢀC; H NMR (DMSOd6, 600 MHz): d 10.35 (br, s, 1H, ArH), 9.97 (s, 1H,
NH), 8.12–8.11 (t, J ¼ 2.7 Hz, 1H, ArH), 7.78–7.77 (m, 1H, ArH), 7.74–7.73 (d,
J ¼ 2.3 Hz, 1H, ArH), 7.52–7.49 (t, J ¼ 9.2 Hz, 1H, ArH), 7.27–7.25 (dd, J ¼ 9.1,
2.3 Hz, 1H, ArH), 7.24–7.22 (d, J ¼ 9.2 Hz, 1H, ArH); 13C NMR (DMSO-d6
150 MHz): d 161.6, 154.1, 152.5, 149.5, 133.1, 126.4, 125.1, 124.4, 119.6, 118.1,
117.3, 117.2, 1þ10.7, 109.2; ESI-MS 307.0 (M þ H)þ; HRMS (ESI): calcd. for
C14H9ClFN2O3 307.0286; found 307.0284.
4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)-
6-hydroxy-1,3-benzoxazine-2-one (12b)
Following the procedure used for the preparation of 11a, but with 9b as
starting material, product 12b was obtained as a yellow powder (93% yield). Mp
1
250–252 ꢀC; H NMR (DMSO-d6, 600 MHz): d 10.23 (br, s, 1H, ArOH), 9.91 (br,
s, 1H, NH), 7.95–7.94 (d, J ¼ 2.3 Hz, 1H, ArH), 7.71–7.70 (d, J ¼ 2.3 Hz, 1H,
ArH), 7.68–7.67 (dd, J ¼ 9.1, 2.3 Hz, 1H, ArH), 7.50–7.47 (q, J ¼ 8.8 Hz, 1H,
ArH), 7.34–7.29 (q, J ¼ 9.1 Hz, 3H, ArH), 7.24–7.19 (m, 3H, ArH), 5.28 (s, 2H);
13C NMR (DMSO-d6 150 MHz): d 163.6, 162.0, 161.3, 154.0, 152.6, 151.6, 149.5,
140.1, 131.2, 131.1, 126.2, 124.5, 124.2, 123.9, 121.5, 118.1, 115.2, 114.5, 110.8,
109.2, 69.9; ESI-MS 413.1 (M þ H)þ. HRMS (ESI): calcd. for C21H15N2O4FClþ
413.0704; found 413.0715.
4-(3-Chloro-4-fluorophenylimino)-3-methyl-
6-(3-morpholinopropoxy)-3,4-dihydro-1,3-benzoxazine-2-one (1)
A suspension of 11a (150 mg, 0.47 mmol) and anhydrous potassium carbonate
(70 mg, 0.51 mmol) in dry DMF (35 mL) was stirred at 40 ꢀC for 20 min,
4-(3-chloropropyl)morpholine (82 mg, 0.50 mmol) was added, and the reaction mix-
ture was stirred at 80 ꢀC for 8 h under a N2 atmosphere. After completion of the reac-
tion, the solvent was removed under reduced pressure and then purified by
chromatography on silica gel (eluent, ethyl acetate=petroleum ether 2=1) to give pro-
duct 1 (135 mg, 65% yield) as a yellow solid. Mp: 122–125 ꢀC; 1H-NMR (DMSO-d6,
600 MHz): d 7.52–7.49 (t, J ¼ 8.8 Hz, 1H, ArH), 7.36–7.35 (d, J ¼ 8.8 Hz, 1H, ArH),
7.25–7.23 (dd, J ¼ 8.8, 2.8 Hz, 1H, ArH), 7.20–7.18 (dd, J ¼ 6.6, 2.2 Hz, 1H, ArH),
6.98–6.96 (m, 1H, ArH), 6.51 (br, s, 1H, ArH), 3.63–3.58 (m, 6H), 3.43 (br, s,
3H), 2.36–2.31 (m, 6H), 1.74–1.72 (t, J ¼ 6.6 Hz, 2H); 13C NMR (DMSO-d6,
150 MHz): d 154.7, 154.4, 153.1, 148.3, 146.6, 145.6, 122.7, 121.2, 120.2, 120.1,
119.0, 118.4, 118.3, 111.2, 66.8, 66.7, 66.6, 55.0, 54.9, 53.9, 53.8, 25.9; ESI-MS

NOVEL BENZOXAZINONE COMPOUNDS
2945
448.2 (M þ H)þ; HRMS (ESI): calcd. for C22H24N3O4FClþ 448.1439; found
448.1434.
4-(3-Chloro-4-(3-fluorobenzyloxy)phenylimino)-3-methyl-6-
(3-morpholinopropoxy)-3,4-dihydro-1,3-benzoxazine-2-one (2)
Following the procedure used for the preparation of 1, but with 11b as starting
material, product 2 was obtained as a yellow solid (74% yield). Mp: 97–101 ꢀC;
1H-NMR (DMSO-d6, 600 MHz): d 7.48–7.47 (q, J ¼ 6.1 Hz, 1H, ArH), 7.34–7.31
(t, J ¼ 7.7 Hz, 2H, ArH), 7.28 (s, 1H, ArH), 7.27 (s, 1H, ArH), 7.21–7.17 (dd,
J ¼ 7.8, 2.8 Hz, 1H, ArH), 7.16–7.14 (dd, J ¼ 8.8, 2.8 Hz, 1H, ArH), 7.04–7.03 (d,
J ¼ 2.8 Hz, 1H, ArH), 6.86–6.84 (dd, J ¼ 8.8, 2.2 Hz, 1H, ArH), 6.49 (s, 1H, ArH),
5.22 (s, 2H), 3.50–3.43 (m, 6H), 3.34 (s, 3H), 2.2 (br, s, 6H), 1.64–1.60 (m, 2H);
13C NMR (DMSO-d6, 150 MHz): d 163.6, 162.0, 150.0, 148.4, 145.5, 143.6, 140.2,
131.1, 123.6, 123.5, 122.5, 121.1, 119.3, 118.9, 116.3, 115.3, 115.2, 114.4, 114.3,
111.3, 70.1, 66.7, 66.6, 66.4, 56.6, 54.9, 53.8, 53.7, 25.9; ESI-MS 554.2 (M þ H)þ.
HRMS (ESI): calcd. for C29H30N3O5FClþ 554.1858; found 554.185.
ACKNOWLEDGMENTS
We are grateful for the financial support of the Key International S&T
Cooperation Projects (No. 2008DFA31040 and No. 2009DFA32080) of the Ministry
of Science and Technology of the People’s Republic of China. We are also grateful to
Meiyu Geng from Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, for the biological assay.
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