ijprsonline vol2 15

Int. J. Pharm. Res. Sci., 2014, 02(1), 89-97. www.ijprsonline.com ISSN: 2348 –0882============================================================================

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Preparation of 2H-3(o,p-dinitrophenyl)-3,4-dihydro-Methoxy1,3-benzoxazinePC-Model Studies and Biological Activity

Dilesh Indorkar*1, Aruna Parteti1,OP Chourasia1 and SN Limaye1

1Department of Chemistry, Dr. H. S. Gour University (PG CWA& GDC Sausar)Sagar (M.P.)-470003

E-mail: dileshindorkar@yahoo.in---------------------------------------------------------------------------------------------------------------------------------------Abstract

The compounds of the invention are solidcrystallines stable to the light and heat. They showan interesting activity in preventing the depressionfrom reserpine at doses which do not cause anyuntoward side efiects of the parameters considered.The study of the examined products shows a slightcalming action. The first symptoms of toxicity areobserved at about 1000-12000 rug/kg. by oral route.At the tested doses, the compounds are withoutanticonvulsive and antitremorin activity. At higherdoses they potentiate barbituric hypnosis. Thefollowing table illustrates the antidepressing activityof 4H-3-carboxamidomethyl-l,3-benzoxazine-2-oneto reserpine in comparison with the antidepressingactivity of imipramine. 1.4H-3-carboxamidomethyl-1,3-benzoxazine- 2-one 37.9 grams of ethylglyciuate hydrochloride were dissolved in 400 cc. ofethanol and 33.5 g. of salicylic aldehyde wereadded. It is refluxed for half an hour and cooled. 38cc. of triethylamine and g. of Raney nickel are thenadded whereafter hydrogenation is carried out atroom temperature and under atmospheric pressure.After hydrogen adsorption was complete, themixture was filtered and the alcohol evaporated 01f.The residue was taken up with acidified water,extracted with ether to eliminate part of thebyproducts, consisting mainly of o.cresol, thenmade alkaline with ammonia and extracted withethyl acetate. The solvent was removed in vacuoand the residue crystallized from ether/ petroleum

ether. 36.7 g. of o-hydroxybenzyl-aminoacetic acidethyl ester melting at 47 C. are obtained.Keyword;- l,3-benzoxazine ,Reserpine, chloro-benzoxazine.IntroductionIn the present work benzoxazine, methoxybenzoxazine and chloro-benzoxazine groups wereselected for the study. A brief history on syntheticmethods, physical and chemical properties of theselected heterocycles have been dealt in this chapter[1].Benzoxazine is an oxazine ring with an oxygenatom next to the nitrogen. These are unsaturatedaromatic heterocyclic compounds that contain a ringwith four carbon atoms, one oxygen atom and onenitrogen atom [2]. Benzoxazine are found in somenatural products such as ibotenic acid. They alsoform the basis for a number of drugs, including theCOX-2 inhibitor valdecoxib (bextra) [3]. Not onlyamong heterocyclic compounds in general but alsoamong related oxazine. This is because benzoxazineproduct the typical properties of the aromatic system,which are in fact, more pronounced in thesederivatives, together with high liability of the ringunder certain conditions, particularly at the nitrogen-oxygen bond [4].Heterocyclic compounds are thosecyclic compounds in which one or more of the ringcarbons are replaced by another atom [5]. The non-carbon atom in such rings are referred to as heteroatom. The most common hetero atom are Nitrogen,Oxygen and Sulphur, [6] but the other atoms such


90

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.

OH

O

OMe

+

NH2

X

C2H5OH

Step-I

OH

N

OMe

X

Step-II NaBH4

X

Step-III NH

OH

OMe

HCHO

N

OOMe

XX1 =09 = o-chloro- group, 10 = m-nitro- group, 11=p-nitro-group, 12, 0-nitro-group, 13=m-nitro- group,14=P-nitro-group, 15= 2, 4-dinitro- group, 16= 4-bromo- group.Step-I. Preparation of 2-(aryliminomethoxy)-methylphenol

A mixture of 2-Hydroxy 3-methoxybenzaldehyde 2.44 gm (0.02mole) and appropriatearomatic amine (0.02mole) in ethanol (20ml) wasrefluxed on water bath for 30 min. crystalline residuewas obtained on cooling the reaction mixture. Theproduct was dried and crystallized from chloroform-petroleum ether (1:4v/v] to furnish 2-(arylimino)methyl phenol. The amines taken for (Mbenz.09), 0-chloro-aniline, (Mbenz.10), m-chloro-aniline,(Mbenz.11), p-chloro-aniline, (Mbenz.12) 0-nitro-aniline, (Mbenz.13), m-nitro-aniline, (Mbenz.14) p-nitro aniline, (Mbenz.15) o.p.-dinitro-aniline,(Mbenz.16), p-bromo-aniline.

Step-II. Preparation of 2-(arylamino)-methylphenolSodium borohydride (0.3gm) was added to a

solution of 2-(aryl amino) methyl phenol

(0.05mole) in methanol and the mixture was stirredfor 30 minute at room temperature. The mixturewas then poured in to ice cold water. The compoundseparated, was filtered off and crystallized fromethanol to yield (2-arylamino)-methyl phenol.Step-III. Preparation of 2H-3-(aryl)-3, 4-dihydro-1, 3-benzoxazine

3, 2-(aryl amino) methyl phenol (0.05mole)and formalin 37% (1ml) were refluxed in ethanol(20ml) for 6 hrs. The product separated out afterpouring the reaction mixture in to ice cold waterand then filtered and crystallized from ethanol toyield methoxy 2H-3–(aryl)-3, 4 –dihydro-1, 3–benzoxazines


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Table 1: Physical data of compounds.Name 2H-3(o,p-dinitrophenyl)-3,4-dihydro-Methoxy1,3-benzoxazineMol.Wt. 331

N

OOMe

NO2

NO2

M.P.°C 120Yield (%) 78

Mol.For. C15H13N3O6

ElementalAnalysis

C % H % N %Found Calcu. Found Calcu. Found Calcu.54.38 54.39 3.96 3.92 12.64 12.69

Table 2: IR Characterization of compounds.Group type Vibration mode Frequency (cm-1)

Oxazine ring

-CH (str.) in–OCH2 2910.55-CH (str.) in –NCH2 2845.12-C-N (str.) in –NCH2 1233.49

C-O(str.) in –OCH2 1059.79-CH (bend.) in–OCH2 1509.23-CH (bend.) in –NCH2 1356.48

Aromatic ring

-CH (str.) 3039.55,3011.15

C=C (str.) 1602.77

-CH (bend.) 1018.44

Ar-OCH3

C-H(str.) in-OCH3 2880.46

C-O (str.) in Ar-OCH3 166.55

Ar-NO2

C-N(str.) in Ar-NO2 519.46

N-O (str.) in-NO2 1356.57

Table 3: 1HNMR Characterization compounds.

SignalNo.

Chemical shift(in δ ppm) Multiplicity

Relativeno. of

protonsInference

1. 7.16-7.70 Multiplet 6 Ar-H2. 4.56 Singlet 2 -OCH2 of Benzoxazine ring3. 3.51 Singlet 2 -NCH2 of Benzoxazine ring4. 3.78 Singlet 3 -OCH3 of Ar-OCH3


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Table-4: PC-Model Studies of Methoxy benzoxazine derivatives.

CompoundCode

Posi-tion

Substi-tuent

B.L. C-N

B.A N-C.

Dihedral Angle C-N-C

Mol.Volu.

VDW

Dip.Mom.

Mebenz.9 12 2 – Cl 1.460 120.67 162.37 276 8.03 4.197Mebenz.10 13 3 – Cl 1.463 121.02 165.39 276 2.11 26.18Mebenz.11

14 4 – Cl 1.463 121.02 166.70 27610.3

02.479

Mebenz.1212 2-NO2 1.462 120.13 178.47 286

517.4

2.312

Mebenz.1313 3-NO2 1.463 121.05 173.00 286

11.36

1.895

Mebenz.1414 4-NO2 1.463 120.85 165.95 286

29.96

1.736

Mebenz.1512,14 2,4-diNO2 1.458 120.63 167.10 331

10.51

1.512

Mebenz.1614 4 – Br 1.461 121.16 167.76 323

10.74

1.089

The overall variations in the dipole moment andmaximum minimization energy values are in goodagreement with the IR spectral frequencies for thesecompounds. This perfect co-relation between thetheoretical data and the experimentalcharacterization supports the steric justificationsextended for various substituents.

The validity of the PC Model simulated datahas been examined separately by comparing these

values with the electrical polarizability valuesobtained from the theoretical values as described byHansch for various substituents at various positionfor the present set of synthesized compounds. Thefollowing table (Table 4.12) records the electricalpolarizability for the said substituents of series IIalong with their dipole moment values.

N

O

O M e1

2

34

5

6

78

9

10

11

12 13

14

1516

R 1

2H-3-(4’-Chlorophenyl)-3,4-dihydro-7-methoxy 1,3- Benzoxazine


93

Table 5: Characterization and Chemical Shift of 13C NMR data

Compound codeBenzx.7, diNO2 –ph

InferenceRelative no.of carbon (δppm)

Stru.

N

O NO2

NO2

119.6

138.8

128.6145.7

148.7

133.9

55.9122.2129.0

120.9

128.1

114.1 157.6 89.5

(O-C-N)(C-NO2)(N-C)

(C),89.5,(C), 138.2,133.2(C), 55.9

NO2-Ar

Benzene Ring

(C), 119.6,128.1,116.4, 145.7,

(C), 114.1, 128.1,120.09,129.0,122.0, ,157.6

6 Compound code Mebenz. – PC Model valuesMMX Energy 4.747

0.959Structure: Str

N

OOMe

NO2

Bnd 3.64Str Bnd 0.097

11.47111.365

TorVDWQQ 2.784DM 1.895HF 31.59SE 20.2


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Table 7 : Z-Matrix Parameters for Compounds of as obtained from PC ModelPrecise gnorm=0.01Mebenz.141 C 0.000000 0 0.000000 0 0.000000 0 0 0 02 C 1.400825 1 0.000000 0 0.000000 0 1 0 03 C 1.399224 1 120.008621 1 0.000000 0 2 1 04 C 1.400653 1 119.988075 1 0.000000 1 3 2 15 C 1.399192 1 120.020966 1 0.000000 1 4 3 26 C 1.400848 1 119.984863 1 0.000000 1 5 4 37 C 1.103118 1 120.012062 1 -180.000000 1 5 4 38 O 1.103109 1 119.992279 1 180.000000 1 6 5 49 N 1.256616 1 117.430649 1 -180.000000 1 7 5 410 C 1.315407 1 123.193153 1 0.000000 1 8 6 511 C 2.958652 1 178.238083 1 -180.000000 1 9 7 512 C 1.400824 1 179.198380 1 0.000000 1 11 9 713 C 1.399223 1 59.189919 1 0.000000 1 11 9 714 C 1.400648 1 119.988480 1 180.000000 1 13 11 915 C 1.399192 1 120.020782 1 0.000000 1 14 13 1116 C 1.400847 1 119.984947 1 0.000000 1 15 14 1317 N 1.100001 1 119.948837 1 180.000000 1 15 14 1318 O 1.103110 1 119.999214 1 -180.000000 1 1 2 319 C 1.154034 1 174.933609 1 -180.000000 1 18 1 220 H 1.100002 1 119.938850 1 -180.000000 1 2 3 121 H 1.099999 1 119.955444 1 180.000000 1 3 2 122 H 1.099998 1 120.041443 1 -180.000000 1 4 3 223 H 1.110107 1 105.007965 1 55.221603 1 7 5 424 H 1.110109 1 105.007980 1 -55.221447 1 7 5 425 H 1.110108 1 111.363655 1 -121.582985 1 10 8 626 H 1.110109 1 111.363625 1 121.583176 1 10 8 627 H 1.109933 1 109.999001 1 -180.000000 1 19 18 128 H 1.109878 1 110.000053 1 59.998360 1 19 18 129 H 1.109879 1 110.000046 1 -59.998112 1 19 18 130 H 1.100001 1 120.059509 1 180.000000 1 12 11 931 H 1.100001 1 119.955246 1 0.000000 1 13 11 932 H 1.100000 1 120.041367 1 -180.000000 1 14 13 1133 H 2.918083 1 126.647446 1 -85.301239 1 16 15 1434 O 4.072706 1 88.442802 1 104.511551 1 17 15 1435 O 1.514127 1 128.087860 1 26.447401 1 17 15 14


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Table: 8 Antibacterial activityof Methoxy Benzoxazine-derivativesantibacterial activity zones of inhibition (mm)

Compound codeE. coli Bacillus subtalis

Pseudomonasalcaligens

Salmonella sp.

2% 4% 2% 4% 2% 4% 2% 4%Mebenz.9 10 11 11 14 8 10 12 13Mebenz.10 8 10 12 15 10 13 9 11Mebenz.11 9 12 8 10 11 12 10 12Mebenz.12 12 12 15 18 12 15 14 16Mebenz.13 12 13 10 11 13 15 12 14Mebenz.14 10 12 13 12 11 14 8 10Mebenz.15 11 12 13 14 13 14 9 10Mebenz.16 12 16 16 19 10 13 13 11Standard drug 15 18 16 19 14 16 14 13

02468

101214161820

Conc

entr

atio

n %

stan.drug

Meben.9

Meben.10

Meben.11

Meben.12

Meben.13

Meben.14

Meben.15

Meben.16

Compound Code

Fig.3.2b. Antibacterial activity of methoxy benzoxazine derivatives.(Bacillus subtalis )

2% 4%


96

Table 9: Antifungal activity of Methoxy Benzoxazine derivativesAntifungal activity zones of inhibition (mm)

Compound codePenicillium

citrinumAspergillus flavus

Rhizoctoniabataticola

Aspergillus niger

2% 4% 2% 4% 2% 4% 2% 4%Mebenz.9 11 13 13 15 9 11 12 15Mebenz.10 09 11 10 15 12 16 10 13Mebenz.11 17 20 15 18 17 20 14 17Mebenz.12 10 12 9 13 12 15 12 14Mebenz.13 9 10 14 10 11 12 8 12Mebenz.14 10 11 12 14 10 13 12 15Mebenz.15 9 14 10 10 13 17 10 14Mebenz.16 10 12 10 15 13 14 12 13Standard drug 15 20 16 19 17 22 18 21

0

2

4

6

8

10

12

14

16

18

20

Conc

entr

atio

n %

stan.d

rug

Meben.9

Meben.1

0

Meben.1

1

Meben.1

2

Meben.1

3

Meben.1

4

Meben.1

5

Meben.1

6

Compound code

Fig.3.2a. Antifungal activity of methoxy benzoxazine derivatives ( Penicillium citrinum )

2% 4%


97

ReferencesG.N. Mukhopadhya, “History of IndianMedicines”. Calcutta University, 324, 11,1992 .C.H. Collens, “Microbiological Method”,Butterworth Co., London, 297, 43, 1994.Freeman, “Text Book of Microbiology”, Boba,W.B. Saunders Co., Toronto, 21st Edn, 1979.T. Rosebury and R.J. Dubos “Bacterial andMycotic Infection of Man”, J.B. Lippincott company,Philadelphiya, 3rd ed. 1958.R.K. Bansal, V.K. Jain, N. Gupta and P.G.Jones “Heterocyclic ChemistryTetrahedron.”, 157, 58, 2002.E.S. Goll, P.C. Jurs. “Prediction of the normalboiling points of organic Compounds frommolecular Strutures with a computational neuralnet work model, J Chem. Inf. Comput. Sci.”,974, 39, 1999.S.N. Limaye, D.Sc. thesis, Dr. H.S. GourUniversity, Sagar (M.P). India, 1994.N.T. Carnall P.R. Fields and K.Rajnak. “J.Chem. Phys.,” 4472, 14, 1968.S. Harikrishna, S.P. Shrivastava, S.N.Limayeand J.T.Rao “E.J. Chem.”, 182, 2, 2005.C.Hansch, “J. med. Chem.,” 11,2, 1967.D.K.Indorkar, S.N.Limaye and O.P.chourasia“Asian.J. Chem.”, 1095, 09, 2012.S. Bhosale, S. Kurhade, V. P. Uppuleti, P. Palleand D. Bhuniya, Tetrahedron Letters, 50, Issue27, 3948-3951, 08 July 2009.Jose Leeis Gancia Ruano, Cristina Fajardo andM. Rossrio Maitim, Tetrahedron Letter, 61,4363-4371, 2005.R. Iglesias, J.L. Serrano and T. Sierra, LiquidCrystals, 22, 37, 1997.

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