Abstract The compounds of the invention are solid crystallines stable to the light and heat. They show an interesting activity in preventing the depression from reserpine at doses which do not cause any untoward side efiects of the parameters considered. The study of the examined products shows a slight calming action. The first symptoms of toxicity are observed at about 1000-12000 rug/kg. by oral route. At the tested doses, the compounds are without anticonvulsive and antitremorin activity. At higher doses they potentiate barbituric hypnosis. The following table illustrates the antidepressing activity of 4H-3-carboxamidomethyl-l,3-benzoxazine-2-one to reserpine in comparison with the antidepressing activity of imipramine. 1.4H-3-carboxamidomethyl-1,3-benzoxazine- 2-one 37.9 grams of ethyl glyciuate hydrochloride were dissolved in 400 cc. of ethanol and 33.5 g. of salicylic aldehyde were added. It is refluxed for half an hour and cooled. 38 cc. of triethylamine and g. of Raney nickel are then added whereafter hydrogenation is carried out at room temperature and under atmospheric pressure. After hydrogen adsorption was complete, the mixture was filtered and the alcohol evaporated 01f. The residue was taken up with acidified water, extracted with ether to eliminate part of the byproducts, consisting mainly of o.cresol, then made alkaline with ammonia and extracted with ethyl acetate. The solvent was removed in vacuo and the residue crystallized from ether/ petroleum ether. 36.7 g. of o-hydroxybenzyl-aminoacetic acid ethyl ester melting at 47 C. are obtained.

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Preparation of 2H-3(o,p-dinitrophenyl)-3,4-dihydro-Methoxy1,3-benzoxazine
PC-Model Studies and Biological Activity
Dilesh Indorkar*1, Aruna Parteti1,OP Chourasia1 and SN Limaye1
1
Department of Chemistry, Dr. H. S. Gour University (PG CWA& GDC Sausar)
Sagar (M.P.)-470003
E-mail: dileshindorkar@yahoo.in
--------------------------------------------------------------------------------------------------------------------------------------ether. 36.7 g. of o-hydroxybenzyl-aminoacetic acid
Abstract
The compounds of the invention are solid
ethyl ester melting at 47 C. are obtained.
crystallines stable to the light and heat. They show
Keyword;- l,3-benzoxazine ,Reserpine, chloroan interesting activity in preventing the depression
benzoxazine.
from reserpine at doses which do not cause any
Introduction
untoward side efiects of the parameters considered.
In the present work benzoxazine, methoxy
The study of the examined products shows a slight
benzoxazine and chloro-benzoxazine groups were
calming action. The first symptoms of toxicity are
selected for the study. A brief history on synthetic
observed at about 1000-12000 rug/kg. by oral route.
methods, physical and chemical properties of the
At the tested doses, the compounds are without
selected heterocycles have been dealt in this chapter
anticonvulsive and antitremorin activity. At higher
[1].Benzoxazine is an oxazine ring with an oxygen
doses they potentiate barbituric hypnosis. The
atom next to the nitrogen. These are unsaturated
following table illustrates the antidepressing activity
aromatic heterocyclic compounds that contain a ring
of 4H-3-carboxamidomethyl-l,3-benzoxazine-2-one
with four carbon atoms, one oxygen atom and one
to reserpine in comparison with the antidepressing
nitrogen atom [2]. Benzoxazine are found in some
activity of imipramine. 1.4H-3-carboxamidomethylnatural products such as ibotenic acid. They also
1,3-benzoxazine- 2-one 37.9 grams of ethyl
form the basis for a number of drugs, including the
glyciuate hydrochloride were dissolved in 400 cc. of
COX-2 inhibitor valdecoxib (bextra) [3]. Not only
ethanol and 33.5 g. of salicylic aldehyde were
among heterocyclic compounds in general but also
added. It is refluxed for half an hour and cooled. 38
among related oxazine. This is because benzoxazine
cc. of triethylamine and g. of Raney nickel are then
product the typical properties of the aromatic system,
added whereafter hydrogenation is carried out at
which are in fact, more pronounced in these
room temperature and under atmospheric pressure.
derivatives, together with high liability of the ring
After hydrogen adsorption was complete, the
under certain conditions, particularly at the nitrogenmixture was filtered and the alcohol evaporated 01f.
oxygen bond [4].Heterocyclic compounds are those
The residue was taken up with acidified water,
cyclic compounds in which one or more of the ring
extracted with ether to eliminate part of the
carbons are replaced by another atom [5]. The nonbyproducts, consisting mainly of o.cresol, then
carbon atom in such rings are referred to as hetero
made alkaline with ammonia and extracted with
atom. The most common hetero atom are Nitrogen,
ethyl acetate. The solvent was removed in vacuo
Oxygen and Sulphur, [6] but the other atoms such
and the residue crystallized from ether/ petroleum
89

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as Boron, Phosphorous, or Silicon can also be
members of heterocyclic rings.
Preparation of Comp.-3 Sub.-o,m,p Cl/NO2 derivatives of methoxy 1,3-benzoxazine.
OMe
OMe
NH2
OH
OH
C2H5OH
O +
N
Step-I
X
X
Step-II
OMe
NaBH4
OMe
O
HCHO
N
Step-III
OH
NH
X
X
X1 =
09 = o-chloro- group, 10 = m-nitro- group, 11=p-nitro-group, 12, 0-nitro-group, 13=m-nitro- group,14=P-nitrogroup, 15= 2, 4-dinitro- group, 16= 4-bromo- group.
(0.05mole) in methanol and the mixture was stirred
Step-I. Preparation of 2-(aryliminomethoxy)for 30 minute at room temperature. The mixture
methylphenol
A mixture of 2-Hydroxy 3-methoxy
was then poured in to ice cold water. The compound
benzaldehyde 2.44 gm (0.02mole) and appropriate
separated, was filtered off and crystallized from
aromatic amine (0.02mole) in ethanol (20ml) was
ethanol to yield (2-arylamino)-methyl phenol.
refluxed on water bath for 30 min. crystalline residue
Step-III.
Preparation of 2H-3-(aryl)-3, 4was obtained on cooling the reaction mixture. The
dihydro-1, 3-benzoxazine
product was dried and crystallized from chloroform3, 2-(aryl amino) methyl phenol (0.05mole)
petroleum ether (1:4v/v] to furnish 2-(arylimino)
and formalin 37% (1ml) were refluxed in ethanol
methyl phenol. The amines taken for (Mbenz.09), 0(20ml) for 6 hrs. The product separated out after
chloro-aniline,
(Mbenz.10),
m-chloro-aniline,
pouring the reaction mixture in to ice cold water
(Mbenz.11), p-chloro-aniline, (Mbenz.12) 0-nitroand then filtered and crystallized from ethanol to
aniline, (Mbenz.13), m-nitro-aniline, (Mbenz.14) pyield methoxy 2H-3–(aryl)-3, 4 –dihydro-1, 3–
nitro aniline, (Mbenz.15) o.p.-dinitro-aniline,
benzoxazines
(Mbenz.16), p-bromo-aniline.
Step-II. Preparation of 2-(arylamino)-methylphenol
Sodium borohydride (0.3gm) was added to a
solution of 2-(aryl amino) methyl phenol
90

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Table 1: Physical data of compounds.
Name
2H-3(o,p-dinitrophenyl)-3,4-dihydro-Methoxy1,3-benzoxazine
Mol.Wt.
331
OMe
M.P.°C
120
NO2
O
Yield (%)
78
Mol.For.
N
C15H13N3O6
C%
Found
Calcu.
54.38
54.39
Elemental
Analysis
NO2
H%
Found
3.96
N%
Calcu.
3.92
Table 2: IR Characterization of compounds.
Group type
Vibration mode
-CH (str.) in–OCH2
-CH (str.) in –NCH2
-C-N (str.) in –NCH2
Oxazine ring
C-O(str.) in –OCH2
-CH (bend.) in–OCH2
-CH (bend.) in –NCH2
-CH (str.)
C=C (str.)
Aromatic ring
-CH (bend.)
C-H(str.) in-OCH3
Ar-OCH3
C-O (str.) in Ar-OCH3
Found
12.64
Frequency (cm-1)
2910.55
2845.12
1233.49
1059.79
1509.23
1356.48
3039.55,3011.15
1602.77
1018.44
2880.46
166.55
C-N(str.) in Ar-NO2
Ar-NO2
Calcu.
12.69
519.46
N-O (str.) in-NO2
1356.57
Table 3: 1HNMR Characterization compounds.
Signal
No.
Chemical shift
(in δ ppm)
1.
2.
3.
4.
7.16-7.70
4.56
3.51
3.78
Multiplicity
Multiplet
Singlet
Singlet
Singlet
Relative
no. of
protons
6
2
2
3
Inference
Ar-H
-OCH2 of Benzoxazine ring
-NCH2 of Benzoxazine ring
-OCH3 of Ar-OCH3
91

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Table-4: PC-Model Studies of Methoxy benzoxazine derivatives.
Compound
Code
Mebenz.9
Mebenz.10
Mebenz.11
Mebenz.12
Mebenz.13
Mebenz.14
Mebenz.15
Mebenz.16
Position
12
13
Substituent
2 – Cl
3 – Cl
B.L. CN
1.460
1.463
B.A NC.
120.67
121.02
14
4 – Cl
1.463
121.02
12
2-NO2
1.462
120.13
13
3-NO2
1.463
121.05
14
4-NO2
1.463
120.85
12,14
2,4-diNO2
1.458
120.63
14
4 – Br
1.461
121.16
The overall variations in the dipole moment and
maximum minimization energy values are in good
agreement with the IR spectral frequencies for these
compounds. This perfect co-relation between the
theoretical
data
and
the
experimental
characterization supports the steric justifications
extended for various substituents.
The validity of the PC Model simulated data
has been examined separately by comparing these
Dihedral Angle
N-C
162.37
165.39
C-
Mol.
Volu.
276
276
VD Dip.Mo
W
m.
8.03
4.197
2.11
26.18
10.3
166.70
276
2.479
0
517.
178.47
286
2.312
4
11.3
173.00
286
1.895
6
29.9
165.95
286
1.736
6
10.5
167.10
331
1.512
1
10.7
167.76
323
1.089
4
values with the electrical polarizability values
obtained from the theoretical values as described by
Hansch for various substituents at various position
for the present set of synthesized compounds. The
following table (Table 4.12) records the electrical
polarizability for the said substituents of series II
along with their dipole moment values.
OMe
1
7
8
O
6
12
2
13
11
9
5
10
4
R1
14
N
3
16
15
2H-3-(4’-Chlorophenyl)-3,4-dihydro-7-methoxy 1,3- Benzoxazine
92

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Table 5: Characterization and Chemical Shift of
13
Compound code
Benzx.7, diNO2 –ph
Inference
157.6
O
89.5
NO2
133.9
128.1
119.6
N
120.9
129.0
6
148.7
NO2
138.8
122.2 55.9
145.7
128.6
Compound code Mebenz. –
Structure:
OMe
NO2
O
N
Relative no.of carbon (δppm)
(O-C-N)
(C-NO2)
(N-C)
NO2-Ar
Stru.
114.1
C NMR data
(C),89.5,
(C), 138.2,133.2
(C), 55.9
(C), 119.6,128.1,116.4, 145.7,
Benzene Ring
(C), 114.1, 128.1,
120.09,129.0,122.0, ,157.6
PC Model values
MMX Energy
Str
Bnd
Str Bnd
Tor
VDW
QQ
DM
HF
SE
4.747
0.959
3.64
0.097
11.471
11.365
2.784
1.895
31.59
20.2
93

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Table 7 : Z-Matrix Parameters for Compounds of as obtained from PC Model
Precise gnorm=0.01
Mebenz.14
1
C
0.000000
0 0.000000
0 0.000000
0
000
2
C 1.400825
1 0.000000
0 0.000000
0
100
3
C
1.399224
1 120.008621 1 0.000000
0
210
4
C
1.400653
1 119.988075 1 0.000000
1
321
5
C
1.399192
1 120.020966 1 0.000000
1
432
6
C
1.400848
1 119.984863 1 0.000000
1
543
7
C
1.103118
1 120.012062 1 -180.000000
1
543
8
O
1.103109
1 119.992279 1 180.000000
1
654
9
N
1.256616
1 117.430649 1
-180.000000
1
754
10 C
1.315407
1 123.193153 1 0.000000
1
865
11 C
2.958652
1 178.238083 1 -180.000000
1
975
12 C
1.400824
1 179.198380 1 0.000000
1
11 9 7
13 C
1.399223
1 59.189919
1 0.000000
1
11 9 7
14 C
1.400648
1 119.988480 1 180.000000
1
13 11 9
15 C
1.399192
1 120.020782 1 0.000000
1
14 13 11
16 C
1.400847
1 119.984947 1 0.000000
1
15 14 13
17 N
1.100001
1 119.948837 1 180.000000
1
15 14 13
18 O
1.103110
1 119.999214 1 -180.000000
1
123
19 C
1.154034
1 174.933609 1 -180.000000
1
18 1 2
20 H
1.100002
1 119.938850 1 -180.000000
1
231
21 H
1.099999
1 119.955444 1 180.000000
1
321
22 H
1.099998
1 120.041443 1 -180.000000
1
432
23 H
1.110107
1 105.007965 1 55.221603
1
754
24 H
1.110109
1 105.007980 1 -55.221447
1
754
25 H
1.110108
1 111.363655 1 -121.582985
1
10 8 6
26 H
1.110109
1 111.363625 1 121.583176
1
10 8 6
27 H
1.109933
1 109.999001 1 -180.000000
1
19 18 1
28 H
1.109878
1 110.000053 1 59.998360
1
19 18 1
29 H
1.109879
1 110.000046 1 -59.998112
1
19 18 1
30 H
1.100001
1 120.059509 1 180.000000
1
12 11 9
31 H
1.100001
1 119.955246 1 0.000000
1
13 11 9
32 H
1.100000
1 120.041367 1 -180.000000
1
14 13 11
33 H
2.918083
1 126.647446 1 -85.301239
1
16 15 14
34 O
4.072706
1 88.442802
1 104.511551
1
17 15 14
35 O
1.514127
1 128.087860 1 26.447401
1
17 15 14
94

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Table: 8 Antibacterial activityof Methoxy Benzoxazine-derivatives
antibacterial activity zones of inhibition (mm)
E. coli
Compound code
2%
10
8
9
12
12
10
11
12
15
Mebenz.9
Mebenz.10
Mebenz.11
Mebenz.12
Mebenz.13
Mebenz.14
Mebenz.15
Mebenz.16
Standard drug
4%
11
10
12
12
13
12
12
16
18
Bacillus subtalis
2%
11
12
8
15
10
13
13
16
16
4%
14
15
10
18
11
12
14
19
19
Pseudomonas
alcaligens
2%
4%
8
10
10
13
11
12
12
15
13
15
11
14
13
14
10
13
14
16
Salmonella sp.
2%
12
9
10
14
12
8
9
13
14
4%
13
11
12
16
14
10
10
11
13
eb
en
.1
0
M
eb
en
.1
1
M
eb
en
.1
2
M
eb
en
.1
3
M
eb
en
.1
4
M
eb
en
.1
5
M
eb
en
.1
6
M
eb
en
.9
M
n.
dr
ug
20
18
16
14
12
10
8
6
4
2
0
st
a
Concentration %
Fig.3.2b. Antibacterial activity of methoxy benzoxazine derivatives.
(Bacillus subtalis )
Compound Code
2%
4%
95

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Table 9: Antifungal activity of Methoxy Benzoxazine derivatives
Antifungal activity zones of inhibition (mm)
Penicillium
Rhizoctonia
Aspergillus flavus
citrinum
bataticola
Compound code
2%
4%
2%
4%
2%
4%
Mebenz.9
11
13
13
15
9
11
Mebenz.10
09
11
10
15
12
16
Mebenz.11
17
20
15
18
17
20
Mebenz.12
10
12
9
13
12
15
Mebenz.13
9
10
14
10
11
12
Mebenz.14
10
11
12
14
10
13
Mebenz.15
9
14
10
10
13
17
Mebenz.16
10
12
10
15
13
14
Standard drug
15
20
16
19
17
22
Aspergillus niger
2%
12
10
14
12
8
12
10
12
18
4%
15
13
17
14
12
15
14
13
21
Fig.3.2a. Antifungal activity of methoxy benzoxazine derivatives
( Penicillium citrinum )
18
16
14
12
10
8
6
Compound code
eb
en
.1
6
M
eb
en
.1
5
M
eb
en
.1
4
M
eb
en
.1
3
M
eb
en
.1
2
M
eb
en
.1
1
M
eb
en
.1
0
M
eb
en
.9
M
n.
dr
ug
4
2
0
st
a
Concentration %
20
2%
4%
96

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97