1. INTRODUCTION:

The azomethines are prepared by condensation of (-NH₂) group with (C=O) group [1]. They are versatile precursors in prepare of industrial compounds via ring closure, and they exhibit a wide range of pharmacological applications [2-4]. The reaction of 4-fluorobenzaldehyde with 1-benzylpiperidin-4-amine in presence of per chloric acid gives efficiently an imine product [5]. (Scheme 1)

Scheme 1. Using HClO₄as a catalyst to prepare the azomethine compound

The reaction of nicotinohydrazide with 2-chloroquinoline-3-carbaldehyde lead to a good yield of the azomethine compound [6]. (Scheme 2)

Scheme 2. Using lemon juice as a catalyst to prepare the azomethine compound

1,3-Oxazepine is unsaturated seven-membered heterocyclic consist of oxygen atom in location 1 and nitrogen atom in location 3 beside five carbon atoms [7]. Oxazepines are used as antibiotics and enzyme inhibitors. There are many studies on oxazepine in pharmacological applications [8,9]. Oxazepines have been prepared mainly by dipolar cycloaddition reaction of azomethine compoundswith five atoms cyclic anhydride [10-13], such as phthalic, succinic, maleic, and pyromellitic [14-17]. The reaction of phthalic anhydride with N-(4-(dimethylamino) benzylidene) thiophen-2-amine in dry benzene gives an 1,3-oxazepinederivatives [18]. (Scheme 3)

Scheme 3. Prepared 1,3-oxazepinecompound with dry benzene as solvent

The product of the reaction between pyromellitic anhydride and derivative is showed in (Scheme 4) [16].

Scheme 4. Prepared 1,3-oxazepine derivatives with double rings

This work aims to prepare azomethine compounds from the reaction between aromatic aldehyde and aromatic primary amines to produced azomethine compounds, azomethine compounds reacted with anhydride compound, this reaction produced hetero atom compounds, these derivatives are very important in the pharmaceutical and medical fields.

2. EXPERIMENTAL PART:

2. 1. Prepare of hetero atom compounds Ra₁-Ra₅

A mixture of amine (0.01mol) and aldehyde (0.02mol) with trace of glacial acetic acid dissolved in 10mL absolute ethanol was placed in a 50-mL round-bottom. The reactions are refluxing for 4 hours, the purity of the compounds were proved with Thin Lear Chromatography. The solid products were recrystallized from ethanol [19,20], after that a mixture of (0.004mol) of prepared azomethine compounds with (0.008mol) of anhydride compounds in 15mL of benzene, was refluxed for 3h, the purity of the compounds were proved with Thin Lear Chromatography. The solid products were recrystallized from ethanol. Table 1 showed the properties of the Ra₁-Ra₅[21,22].

2.2. Antibacterial activity of prepared hetero atom compounds Ra₁-Ra₅

Antibacterial activity of the chemicals prepared hetero atom compounds Ra₁-Ra₅ against E. coli and S. aureus.6 µg well^-1 of hetero atom compounds. To measure the inhibition diameter a plate method was used [23].

3. DISCUSSION AND RESULTS:

Physical properties of all prepared Ra₁-Ra₅ showed in 1 table. The higher m. p. of the prepared hetero atom compounds was for (Ra₁). The higher yield of hetero atom compounds was for Ra₄(91%).

Table 2. IR of prepared hetero atom compounds Ra₁-Ra₅

IR, n(cm^-1)
Others	C-H Aliph.			C-H Arom.	C=C Arom.	C=O Lacton	C=O Lactam	C-O	C-N	Comp.
Others	Sym.	Asym.		C-H Arom.	C=C Arom.	C=O Lacton	C=O Lactam	C-O	C-N	Comp.
NO₂:1357, 1541 N-H: 3275	2825	---	2231	3095	1602	1745	1703	1274	1145	Ra₁
NO₂:1377, 1527	2879	2975	---	3055	1568	1718	1614	1298	1149	Ra₂
C-S: 700 NO₂:1381, 1584 O-H:3500b	2991	---	---	3045	1587	1730	1614	1282	1153	Ra₃
C-S: 688 NO₂:1355, 1560	2989	---	2223	3062	1579	1730	1620	1278	1168	Ra₄
O-H:3355b	2939	2981	---	3064	1593	1728	1650	1240	1172	Ra₅

Table 3. The ¹H-NMR Spectrum of prepared hetero atom compounds (Ra₁-Ra₅) in Di Methyl Sulphoxide (DMSO )

Compound	Chemical Shift δ ppm
Ra₁	Singlet in location 4.40ppmfor NH, singlet in location 10.10 ppm for 2CH, multiplet in location 7.85-8.40 ppm for aromatic protons (14H).
Ra₂	Singlet in location 4.04 ppm for 2CH₂, singlet in location8.40 ppm for 2N-CH, multiplet in location7.10-7.30 ppm for aromatic protons (20H).
Ra₃	Singlet in location 8.63 ppm for2N-CH, singlet in location 13.22 ppm for (2OH), multiplet in location 6.69-7.22 ppm for aromatic protons (22H).
Ra₄	Singlet in location 10.10 ppm for 2N-CH, multiplet in location 6.69-8.51 ppm for aromatic protons (22H).
Ra₅	Singlet in location1.33 ppm for meta of 2O-CH₃, singlet in location2.67 ppm for para of O-CH₃, singlet in location 3.54 ppm for CH₂-Ph, doublet in location3.82 ppm for 2CH₂-C=O, triplet in 4.02 ppm for 2CH-C=O, singlet in location 7.90 ppm for 2N-CH, singlet in location9.90 ppm for 2OH, multiplet in location 6.33-7.40 ppm for aromatic protons and 1H of pyrimidinering (20H).

Figure 1. IR spectrum of Ra₂

Figure 2. IR spectrum of Ra₅

¹H-NMR spectrum appeared DMSOthe chemical shiftsof Ra₁: Singlet in (4.40, 1H) of NH, singlet in (10.10, 2H) of (2CH), multiplet in (7.85-8.40,14H of aromatic protons)[30-34].¹H-NMR of Ra₁-Ra₅showed in table 3. See figure3 and figure4.

Figure3. The¹H-NMR spectrum ofRa₄

Figure 4. The¹H-NMR spectrum ofRa₅

The resonance spectra of ¹³C-NMR was taken for three derivatives (Ra₃-Ra₅), Ra₃ showed the signals: 147 indicated to presence 2 groups of N-CH, 160 indicated to presence 2 lactam groups of N-C=O, 163 indicated to presence 2 lactone groups of O-C=O, 116-133 indicated to presence aromatic carbons [35-41]. See table 4, figure5 and figure 6.

Table 4. The ¹³C-NMR Spectra of 1,3-oxazepin-5(1H)-one derivatives (Ra₃-Ra₅) in Di Methyl Sulphoxide (DMSO)

Compound	Chemical Shift δ ppm
Ra₃	147ppmindicated to presence 2 lactone groups of N-CH, 160 ppm indicated to presence 2 lactone groups of N-C=O, 163 ppm indicated to presence 2 lactone groups of O-C=O, 116-133 ppm for aromatic carbons.
Ra₄	150 ppm indicated to presence 2 lactone groups of N-CH, 156 ppm indicated to presence 2 lactone groups of N-C=O, 157 ppm indicated to presence 2 lactone groups of O-C=O, 190 ppm indicated to presence 2 lactone groups of cyanide CN, 114-136 ppm for aromatic carbons.
Ra₅	14 ppm for two meta (O-CH₃) group, 38 ppm for one para (O-CH₃)group, 56 ppm indicated to presence 2 lactone groups of CH₂-Ph, 61 ppm for (CH₂-C=O), 172 ppm indicated to presence 2 lactone groups of CH-C=O, 173 ppm indicated to presence 2 lactone groups of 2N-CH), 176 ppm indicated to presence 2 lactone groups of N-C=O, 178 ppm indicated to presence 2 lactone groups of O-C=O, 117-153 ppm for aromatic carbons pyrimidine ring carbons.

Figure5.¹³C-NMR spectrum ofRa₄

Figure6.¹³C-NMR spectrum of Ra₅

The reaction included many transition state formed from the bond of O-C=O of the anhydride with the C=N of Azomethine [27-30]. See (Scheme 7)

3.2. The biological activityof prepared hetero atom compoundsRa₁-Ra₅

Tables 5 and 6 appeared the comparison between the drug in table 5 and the prepared hetero atom compounds in table 6.

Table 8 appeared that the best result of inhibition was 20mm for (45%) concentration, 25mm (50%), 28mm (75%) concentration and 32mm (100%) concentration against S. aureus by Ra₅compounds.Maybe the composite of the prepared hetero atom compounds destroyed the wall of microbes [41,42].

Table 5. The zoneinhibition of the drug and Di Methyl Sulphoxide (DMSO)

Type of bacteria	Inhibition (mm)
Type of bacteria	The drug (Gentamycin) 50 µg/well	DMSO 50 µg/well
*E. coli*	24	0
*S. aureus*	28	0

Table 6. Biological activity (mm) of the prepared hetero atom compounds Ra₁-Ra₅

Compound

Isolated

10%

15%

20%

25%

30%

35%

40%

45%

50%

75%

100%

Ra₁

E. coli

-ve

Ra₁

S.aureus

-ve

5mm

8mm

10mm

11mm

12mm

Ra₂

E. coli

-ve

Ra₂

S.aureus

-ve

Ra₃

E. coli

-ve

Ra₃

S.aureus

-ve

7mm

8mm

10mm

Ra₄

E. coli

-ve

Ra₄

S.aureus

-ve

Ra₅

E. coli

-ve

7mm

9mm

11mm

13mm

Ra₅

S.aureus

-ve

7mm

10mm

13mm

15mm

17mm

20mm

25mm

28mm

32mm

4. CONCLUSIONS:

DerivativeRa₅showed the best zone of inhibition against S. aureus, this result helpful the other researchers to applied the concentration of the active prepared hetero atom compounds against pathogenic bacteria in vivo such a rats or rabbits.

5. ACKNOWLEDGEMENTS:

Thankful to the College of Applied Sciences –Hit, College of Sciences and College of Pharmacy/ University of Anbar for their kind support to carry out this project.

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Received on 13.01.2020 Modified on 18.03.2020

Research J. Pharm. and Tech. 2021; 14(1):79-84.

DOI: 10.5958/0974-360X.2021.00015.9

Comp.	Structural formula	Yield%	m.p. °C	Color
Ra₁		83	280-282	Red
Ra₂		81	210-212	Dark Yellow
Ra₃		77	205-207	Off White
Ra₄		91	170-171	Light Yellow
Ra₅		89	80-82	Orange