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Synthesis and Biological Evaluation of Some New2-propyl- 4(3H)-Quinazolinone Derivatives as Anti-bacteria
Synthesis and Biological Evaluation of Some New2-propyl- 4(3H)-Quinazolinone Derivatives as Anti-bacteria
Journal of the Korean Chemical Society. 2008. Jun, 52(3): 328-337
Copyright © 2008, The Korean Chemical Society
  • Received : February 08, 2008
  • Published : June 20, 2008
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About the Authors
A. M. F. Eissa
A. M. El-metwally
National Organization for Drug Control And Research, Egypt
M. A. El-hashash
Faculty of science, Ain Shams University, Egypt
A. M. F. El-gohary
National Organization for Drug Control And Research, Egypt

Abstract
Keywords
INTRODUCTION
Quinazolin-4-one is a frequently encountered unit in nature products such as L-vasicinone(1), 1 Chrysongine(2), 2 and drugs 3 such as methaqualone(3), 4 Nolatrexed(4), 5 Chloroqualone(5), 5 Diproqualone 5 (6). This molecules which based on the quinazolin-4-one ring were reported as interesting pharmacological activities, 6 including anticonvulsant, antibacterial, anti tumor, 7 analgesic, 8 antiinflammatory, 9 and anti-diabetic activity. 10 , 11 The most common synthetic method to quinazolin-4-one is based on acylation of anthranilic acid and ring closure with acetic anhydride to afford corresponding benzoxazinone 12 which was treated with hydrazine hydrate to give a new 3-aminoquinazolin-4-one derivatives. The current study also involves in vitro antimicrobial screening (neutriet agar) of synthesized quinazolinone derivatives by filter paper disc method. 13
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RESULT AND DISCUSSION
The key starting material 2-propyl-4H- 3,1-benzoxazin-4-one (2) has been synthesized via the interaction of butyroyl chloride with anthranilic acid in the presence of pyridine which yielded the corresponding anthranil 1. Treatment of anthranil 1 with acetic anhydride afforded the benzoxazinone 2. The structure of anthranil 1 was proved from its microanalytical data and its IR spectra (cm -1 ) which showed strong absorption bands at 1672, 1693, 3286 and 3422 attributable to υ max of two carbonyl groups, υNH and υOH respectively. IR spectrum of the benzoxazinone 2 exhibits strong absorption bands at 1614, 1764 (cm -1 ) due to υ max .of C=N and C=O and lack of any band for NH and / or OH such IR data agreed well with the proposed structure.
The 3-amino-2- propylquinazolin-4(3H)-one (3) resulted via treatment of the Benzoxazinone 2 with hydrazine hydrate in boiling ethanol. The structure of compound 3 was confirmed based on its elemental and spectral analyses, thus IR spectrum of compound 3 reveals strong absorption band at 1596, 1673, 3309 and 3212 attributable to υ max for C=N, C=O and NH 2 . EIMS of compound 3 exhibits an ion peak at m/z (M + ,203). 1 HNMR spectrum of compound 3 exhibits δ(ppm) in CDCl 3 1 (t,3H,CH 3 ), 1.8(m, 2H,CH 2 Me), 2.8(t, 2H, CH 2 Q), 7.2-8 (m, 4H, aromatic), 9.3(s, 2H, NH 2 ).
Stirring of 3-amino-2- propylquinazolin-4(3H)-one (3) with aromalic aldehydes namely, 3,4-dimethoxy benzaldehyde, 4-N,N-dimethylaminobenzaldehyde and 3,4-methylenedioxy benzaldehyde in ethanol at room temperature afforded 3-(arylidenamino)-2-propylquinazolin-4(3H)-ones (4a-c). The structure of compound 4 were confirmed on the basis of their elemental analyses. Thus IR spectra of compounds (4a-c) revealed strong absorption bands at 1600-1612, 1669-1676; attributable to υC=N and υC=O respectively, and lacked of any band due to NH 2 . On treatment of compounds 4a-c with aromatic aldehyde namely, 3,4-dimethoxy benzaldehyde, 4-N,N-dimethylaminobenzaldehyde and 3,4-methylenedioxy benzaldehyde in refluxing glacial acetic acid the 3-(arylideneamino)-2-(1-phenylbut-1-en-2-yl)quinazolin-4(3H)-ones (5a-d) were obtained. The structure of compounds 5 were inferred from their IR spectra which exhibit strong absorption bands at the region 1600-1605 and 1670-1676 attributable to υ max C=N and C=O respectively. EIMS of compound 5b exhibited an ion peak at m/z (465; M + ).
when compound 3 was allowed to react with carbon disulfide and dimethylsulfate in the presence of sodium hydroxide it yielded methyl-4-oxo-2-propylquinazolin-3(4H)-ylcarbamodithioate (6), The structure of compounds 6 was inferred from elemental analyses, its IR spectrum revealed strong absorption bands at 1450 and 1673 attributable to υ max C=S and C=O respectively and devoid the band of NH 2 . The refluxing of compound 6 with secondary amine namely, piperidine, morpholine and piprazine in methanol yielded the corresponding carbothioamide 7a-c. IR spectra of compounds 7a-c exhibit absorption bands in the regions 1450-1470 and 1658-1670 cm -1 attributable to υ max of C=S and C=O respectively, EIMS of compound 7c gave molecular ion peak at M + (332).
Bromination of compound 3 by treatment with bromine in glacial acetic acid in the presence of sodium acetate yielded 1-(3-amino-4-oxo-3,4-dihydroquinazolin-2yl)propyl acetate (8). Formation of compound 8 takes place via bromination of methylene group at position 2 followed by nucleophilic substitution by acetate ion. The structure of compound (8) was proved from its IR spectrum (cm -1 ) which showed a strong absorption bands at 1612, 1645, 1725, 3214 and 3324 due to υ max of C=N, C=O (amide), C=O (ester) and NH 2 respectively. EIMS of 8 exhibited a molecular ion peak at (M + , 260). The reaction of ester 8 with phenylhydrazine involves nucleophilic substitution, with a subsequent oxidation process analogous to the formation of osazones 14 to afford 2-(1-phenylhydrazonopropyl)-3-amino-4(3H)-quinazolinone (9). IR Spectrum of compound (9) exhibits strong absorption bands at 1610, 1673 and 3200, 3300 and 3360 attributable to υ max for C=N, C=O, NH and NH 2 respectively. On treatment of compound 9 with phosphoric acid under fisher indol synthesis condition yielded 3-amino-2-(-3-methylindolin-2-yl)quinazolin-4(3H)-one (10). IR spectrum of compound 10 revealed absorption bands at 1612, 1676, abroad band 3240-3400 due to υ max for C=N, C=O, and NH, NH 2 respectively. When compound 10 was allowed to react with aromatic aldehydes namely, 3,4-dimethoxy benzaldehyde, 4-N,N-dimethylaminobenzaldehyde and 3,4-methylenedioxy benzaldehyde afforded schiffs bases 3-(arylideneamino)-2-(3-methylinolin-2-yl)quinazolin-4(H)-one (11a-c). the structure of compounds 11 were proved from their IR spectra which showed absorption at regions 1600-1612, 1665-1675 attributable to υ max for C=N and C=O and lack the band of NH 2 . EIMS of 11b exhibited a molecular ion peak (M + , 438).
Compound (3) was converted to 3-(cyclopentylidine/hexylidineamino)-2-propylquinazolino-4(3H)-one(12a,b) by the reaction with cyclopentanone and cyclohexanone in ethanol, the structure of compound(12a,b)were proved from their IR spectra (cm -1 ) which showed absorption bands at υ max 1675, 1610 attributable to C=O and C=N and devoid any band for NH 2 . EI.MS of 12a and 12b showed molecular ion peak at m/z (M + 269) and m/z (M + 283) respectively. When Compounds (12a,b) were submitted to react with thioglycolic acid gave spirocomponds (13a,b). IR spectra of compounds (13a,b) revealed strong absorption bands at υ max 16141687. 1675 and attributable to C=N and two carbonyl group respectively. EI. MS of 13b exhibited a molecular ion peak m/z (M + 357).
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Characterization and physical data of synthesized compounds
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Characterization and physical data of synthesized compounds
13C-NMR of some synthesized compounds
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13C-NMR of some synthesized compounds
Interaction of 3-amino-2-propylquinazolin-4(3H)-one (3) with chloroacetyl chloride in pyridine yielded 2-chloro-N-(4-oxo-2-propylquinazolin-3(4H)-yl)acetamide (14), IR spectrum of compound 14 was revealed strong absorption bands at 1614, 1672, 1710 and 3120 attributable to υ max C=N , tow carbonyl groups and NH. Treatment of compound 14 with ammonium acetate in oil bath yielded 6-propyl-2H-[1,2,4]triazino[2,3-c]quinazolin-3(4H)-one(15). IR spectrum of 15 revealed strong absorption bands at υ max 1615, 1680 and 3200 attributable to υ max C=N,C=O, and NH respectively.
BIOLOGICAL PART
All the synthesized compound were screened for anti-bacteria activity using the following method. The neutrient agar was used as media and filter paper disc (0.7 mm diameter). The qunazolinone derivatives were prepared in ethanol at 3 X concentrations (200 μg/ml,100 μg/ml and 50 μg/ml) Two bacteria isolates (E.coli and Staph. Aureus) were used as a test organisms The compounds 3, 4a, 4b, 5a, 5b, 14 and 15 were highly active against (E. Coli and B.Sublet), whereas 1, 4c, 5c, 7b, 7c, 8, 9, 12a, 12b, 13a and 13b showed moderate activity this microorganism. No significant inhibitory activity of other synthesized derivatives was seen by any against (E. Coli and B.Sublet).
EXPERMINTAL PART
All melting point are uncorrected and determined by the open capillary method using Gallen Kamp melting point apparatus. Microanalysis were carried out by the Micro Analytical Unit at Cairo University. IR spectra (KBr disk) were recorded on FT/IR-300E Jasco spectrophotometer. HNMR spectra were recorded in CDCl 3 or DMSO-d 6 solution on a Varian EM 390-90 MHz. 15 , 16 Mass spectrometry were recorded were recorded Shomadzu, GCMS (QP-1000EX).
Inhibition zones in mm for the synthesized compound at deferent concentration
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(-) Represent no inhibition of growth
- 2-butyramidobenzoic acid (1)
A stirred solution of 2-aminobenzoic acid 13.7 g (0.1 mol) in dry pyridine (150 ml) was treated drop wise with n-butyroyl chloride 10.5 g (0.11 mol) during 10 min. the mixture was stirred at room temperature (3 hours) and poured into a mixture of ice and hydrochloric acid gave crude 2-butyramidobenzoic acid crystallize from the proper solvent. IR(KBr)cm -1 : 3422 (OH), 3286(NH), 3055 (CH aromatic), 2957, 2927, 2869 (CH aliphatic), 1693 (C=O, Acid), 1672 (C=O, amide)
- 2-propyl-4H- 3,1-benzoxazin-4-one(2)
A suspension of 2-butyramidobenzoic acid 2.07 g (0.01 mol) in 50 ml acetic anhydride was heated under reflux (3hours) and then concentrated. The solid was obtained crystallized from petroleum ether 40-60 ℃, giving 2-propyl-4H-3,1-benzoxazin-4-one as a colorless crystals melting point(59 ℃). IR(KBr) cm -1 : 3055 (CH aromatic), 2965, 2935, 2875 (CH aliphatic),1764(C=O), 1614(C=N),1161(C-O).
- 3-amino-2- propylquinazolin-4(3H)-one (3)
Compound (2) (1.89 g- 10 mmol) and 5 ml hydrazine hydrate were heated on water bath for 1/2 hour and then added 50 ml ethanol the mixture was refluxed 3hours, then concentrated and poured on cooled water, the precipitate formed was collected by filtration, dried and crystallization from petroleum ether 60- 80 ℃ to give (1.5g) 3-amino-2-propylquinazolin-4(3H)-one IR(KBr) cm -1 : 3309, 3212 (NH 2 ),3055 (CH aromatic), 2965, 2935, 2875 (CH aliphatic),1673(C=O), 1596(C=N); MS: m/z 203[M + ], 188, 174, 158, 145, 132, 104, 77; 1 HNMR (CDCl 3 ) : δ7.2-8 (m, 4H, aromatic),12 (s, 2H, NH 2 ). 1(t, 3H, CH 3 ), 1.8 (sextet,2H, CH 2 Me), 2.8 (t,2H, CH 2 Q).
- 3-(3,4-dimethoxybenzylideneamino)-2-propylquinazolin-4(3H)-one (4a), 3-(4-(dimethylamino)-benzylideneamino)-2-propylquinazolin-4(3H)-one(4b) and 3-(benzo[d][1,3]dioxol-5-ylmethyleneamino)-2-propylquinazolin-4(3H)-one (4c)
a mixture of vetraldehyde (1.66 g., 10 mmol) or 4-N,N-dimethylaminobenz aldehyde (1.49 g., 10 mmol) or piperonal (1.5 g., 10 mmol) and compound 3 (2.03 g., 10 mmol) in 50 ml ethanol was stirred for 3 hr. the obtained solid was filtered off and recrystalization from the proper solvent to give 4a, 4b or 4c.
- 3-(3,4-dimethoxybenzylideneamino)-2-propylquinazolin-4(3H)-one (4a).
IR(KBr) cm -1 : 3076 (CH aromatic), 2962, 2919, 2870 (CH aliphatic), 1673(C=O), 1605(C=N); MS: m/z 351[M + ], 320, 289, 192, 179, 97; 1 HNMR(CDCl 3 ) : δ7.7-8.4 (m, 7H, aromatic), 6 (s, H, N= CH ), 3.4 (s, 6H, 2O CH 3 ), 1(t, 3H, CH 3 ), 1.5 (sextet,2H, CH 2 Me ), 1.3 (t,2H, CH 2 Q).
- 3-(4-(dimethylamino)benzylideneamino)-2-propylquinazolin-4(3H)-one (4b).
IR(KBr) cm -1 : 3059 (CH aromatic), 2975, 2925, 2875 (CH aliphatic), 1675(C=O), 1600(C=N); MS: m/z 330[M + ], 315, 300, 286, 273, 259, 244, 216, 188, 174; 1 HNMR (CDCl 3 ) : δ7.7-8.3 (m, 8H, aromatic), 6 (s, H, N= CH ), 3.3 (s, 6H, N( CH 3 ) 2 ), 1(t, 3H, CH 3 ), 1.9 (sextet, 2H, CH 2 Me ), 2.9 (t, 2H, CH 2 Q).
- 3-(benzo[d][1,3]dioxol-5-ylmethyleneamino)-2-propylquinazolin-4(3H)-one (4c).
IR(KBr) cm -1 : 3076 (CH aromatic), 2962, 2919, 2870 (CH aliphatic), 1671(C=O), 1601(C=N), 1255(C-O-C); MS: m/z 235[M + ], 320, 289, 274, 259, 254, 145; 1 HNMR (CDCl 3 ) : δ7.2-8.1 (m, 7H, aromatic), 6.1 (s, 2H, O- CH2 -O), 6 (s, H, N= CH ) 1(t, 3H, CH 3 ), 1.8 (sextet, 2H, CH 2 Me ), 2.8 (t, 2H, CH 2 Q).
- 3,4-dimethoxybenzylideneamino)-2-(3,4-dimethoxyphenyl)but-1-en-2-yl) quinazolin-4(3H)-one(5a)
- 4-(dimethylamino)benzylideneamino)-2-(4-dimethylamino)phenyl)but-1-en-2-yl) quinazolin-4(3H)-one (5b)
- 1-(benzo[d][1,3]dioxol-5-yl)but-1-en-2-yl)-3-(benzo[d][1,3]dioxol-5-ylmethylene amino)quinazolin-4(3H)-one (5c).
A solution of compound 4a (3.51 g 10mmol) or 4b (3.3 g., 10mmol) or 4c (3.35 g., 10 mmol) and vetraldehyde (1.66 g., 10 mmol) or 4-N,N-dimethylaminobenz aldehyde (1.49 g., 10mmol) or piperonal (1.5 g., 10 mmol) respectively in 10 ml glacial acetic acid and the mixtures were refluxed for 12 hours and then allowed to cool and the obtained solids were filtered and recrystallization from proper solvent yielded (5a-c).
- 3,4-dimethoxybenzylideneamino)-2-(3,4-dimethoxyphenyl)but-1-en-2-yl)quinazolin-4(3H)-one(5a).
IR(KBr) cm -1 : 3076 (CH aromatic), 2962, 2919, 2870 (CH aliphatic), 1673(C=O), 1605(C=N); MS: m/z 499[M + ], 468, 437, 406, 375, 300, 225; 1 HNMR (DMSO-d 6 ) : δ7.7-8.4 (m, 7H, aromatic), 6 (s, H, N= CH ), 5.5 (s, 1H, C= CH ) 3.4 (s, 12H, 2OCH 3 ), 1(t, 3H, CH 3 ), 2.2 (q,2H, CH 2 Me).
- 4-(dimethylamino)benzylideneamino)-2-(4-dimethylamino)phenyl)but-1-en-2-yl) quinazolin-4(3H)-one (5b).
IR(KBr) cm -1 : 3059 (CH aromatic), 2975, 2925, 2875 (CH aliphatic), 1675(C=O), 1600(C=N); MS: m/z 465[M + ], 421, 377, 315, 303, 228; 1 HNMR(DMSO-d 6 ) : δ7.7-8.3 (m, 8H, aromatic), 6 (s, H, N= CH ), 5.8 (s, 1H, C= CH ), 3.3 (s, 12H, N( CH 3 ) 2 ), 1(t, 3H, CH 3 ), 2.2 (q, 2H, CH 2 Me).
- 1-(benzo[d][1,3]dioxol-5-yl)but-1-en-2-yl)-3-(benzo[d][1,3]dioxol-5-ylmethylene amino)quinazolin-4(3H)-one (5c).
IR(KBr) cm -1 : 3076 (CH aromatic), 2962, 2919, 2870 (CH aliphatic), 1671(C=O), 1601(C=N), 1255(C-O-C); MS: m/z 467[M + ], 421, 375, 300, 225,210, 196; 1 HNMR (DMSO-d 6 ) : δ7.2 -8.1 (m, 7H, aromatic), 6 (s, H, N= CH ), 5.8 (s, 1H, C= CH ),4 (s, 4H, 2O- CH 2 -O), 1(t, 3H, CH 3 ), 2.2 (q, 2H, CH 2 Me).
- methyl 4-oxo-2-propylquinazolin-3(4H)-ylcarbamodithioate(6)
A solution of 3-aminoquinazolinone 3 (4.06 g., 0.02 mol) in dimethyl sulphoxide (10 ml) was stirred vigorously. then added carbon disulphide (1.6 ml) and aqueous sodium hydroxide 1.2 ml (20 mol solution) dropwise during 30 min with stirring . Dimethyl sulphate (0.02 mol) was added gradually keeping the reaction mixture stirring in freezing mixture for 2 hr. The solid obtained was filtered, washed with water, dried and recrystallized from proper solvent gave (6). IR(KBr) cm -1 : 3250 (NH), 3066 (CH aromatic), 2979, 2906, 2867 (CH aliphatic), 1673(C=O), 1600(C=N), 1450 (C=S); MS: m/z 293[M + ], 278, 246, 214, 202, 187, 172, 152, 142; 1 HNMR (CDCl 3 ) : δ 11 (s, 1H, NH), 7.4-8 (m, 4H, aromatic), 2.6 (s, 3H, S CH 3 ), 1(t, 3H, CH 3 ), 1.9(sextet, 2H, CH 2 Me), 2.8 (t, 2H, CH 2 Q).
- N-(4-oxo-2-propylquinazolin-3(4H)-yl)piperidine-4-carbothioamide (7a)
- N-(4-oxo-2-propylquinazolin-3(4H)-yl)morpholine-4-carbothioamide (7b)
- N-(4-oxo-2-propylquinazolin-3(4H)-yl)piperazine-4-carbothioamide (7c)
A mixture of (2.93 g, 0.01 mol) and of piperidine or morpholine or piperazine (10 ml) was refluxed for 3 hr. the produced mixture was cooled triturated with methanol and the solid obtained was filtered off and re crystallization from proper solvent yielded (7a-c).
- N-(4-oxo-2-propylquinazolin-3(4H)-yl)piperidine-4-carbothioamide (7a)
IR(KBr) cm -1 : 3225 (NH), 3045 (CH aromatic), 2963, 2900, 2862 (CH aliphatic), 2270 (C=S), 1645(C=O), 1600(C=N); MS: m/z 331 [M + ], 330, 252, 220, 208, 193, 162, 120; 1 HNMR (DMSO-d 6 ) : δ 10.8 (s, 1H, NH ), 7.2-87.7 (m, 4H, aromatic), 3.2 (s, 4H, N( CH 3 ) 2 piperidine), 1.8 (pentet, 6H, piperidine), 1(t, 3H, CH 3 ), 1.8 (sextet, 2H, CH 2 Me), 2.8 (t, 2H, CH 2 Q).
- N-(4-oxo-2-propylquinazolin-3(4H)-yl)morpholine-4-carbothioamide (7b)
IR(KBr) cm -1 : 3225 (NH), 3045 (CH aromatic), 2963, 2900, 2862 (CH aliphatic), 2270 (C=S), 1645(C=O), 1600(C=N), 1110 (c-o-c); MS: m/z 331 [M + ], 330, 303, 205, 186, 162, 145, 120, 90. 77; 1 HNMR (DMSO-d 6 ) : δ 11 (s, 1H, NH ), 7.2-7.7 (m, 4H, aromatic), 3.8 (t,4H,O (CH2)2 morphiline), 3.2 (t, 4H, N(CH 2 ) 2 morpholine), 1(t, 3H, CH 3 ), 1.9(sextet, 2H, CH 2 Me), 2.8 (t, 2H, CH 2 Q).
- N-(4-oxo-2-propylquinazolin-3(4H)-yl)piperazine-4-carbothioamide (7c)
IR(KBr) cm -1 : 3225 (NH), 3045 (CH aromatic), 2963, 2900, 2862 (CH aliphatic), 2270 (C=S), 1645(C=O), 1600(C=N); MS: m/z 331 [M + ], 330, 303, 205, 186, 162, 145, 120, 90. 77.
- 1-(3-amino-4-oxo-3,4-dihydroquinazolin-2-yl)-propyl acetate (8)
A mixture of 3 (2.03 g, 10 mmol) and sodium acetate (10 mmol) in glacial acetic acid (20 ml) was added bromine (10 mmol) in glacial acetic acid (10 ml) drop wise at 40-50 ℃ the reaction mixture was stirred for 3 hr, and it was then left to stand in refrigerator overnight the crystals were filtered off, washed with water and recrystallization from proper solvent to give (8). IR(KBr) cm -1 : 3324, 3249 (NH 2 ), 3025 (CH aromatic), 2963, 2923, 2849 (CH aliphatic), 1725 (C=O ester), 1645(C=O quinazolinone), 1612(C=N), 1265 (C-O); MS: m/z 260 [M + ], 259, 244, 200, 184, 169, 155, 141; 1 HNMR (DMSO-d 6 ) : δ 12 (s, 2H, NH 2 ), 7.9 (s, 3H, CO CH 3 ), 7.2-7.7 (m, 4H, aromatic), 5.5 (t, 1H, CH OCOMe), 1.2(t, 3H, CH 3 ), 2.2 (p, 2H, CH 2 Me).
- 2-(1-phenylhydrazonopropyl)-3-amino-4(3H)-quinazolinone (9)
To a solution of 8 (2.6 g, 0.01 mol) in ethanol (5 ml) was added phenyl hydrazine 1.81 ml, 2 g, 0.02 mol) the reaction mixture was refluxed for 4 hr. after cooling of mixture, the crystallized product was filtered off, washed with cooled ethanol, dried and recrystallization from proper solvent produced (9). IR(KBr) cm -1 : 3360, 3300 (NH 2 ), 3200 (NH) 3025 (CH aromatic), 2963, 2923, 2849 (CH aliphatic), 1673 (C=O), 1610 (C=N); MS: m/z 307 [M + ], 306, 292, 278, 201, 187, 170, 77; 1 HNMR (DMSO-d 6 ) : δ 11.3 (s, 2H, NH 2 ), 7.2-7.7 (m, 9H, aromatic), 4.5 (s, 1H, NH ), 2.1(q, 2H, CH 2 Me), 1.2(t, 2H, CH 3 ).
- 3-amino-2-(3-methylindolin-2-yl)quinazolin-4(3H)-one (10)
Compound 9 (3.07 g 0.1 mol)was added to 85% phosphoric acid (25 ml) at 180 ℃. the reaction mixture was heated for 30 min then cooled and diluted with water 100 ml the solid was filtered and recrystallization from the proper solvent gave (10). IR(KBr) cm -1 : 3400-3324 (abroad NH 2 and NH), 3060 (CH aromatic), 2940 (CH aliphatic), 1676 (C=O), 1612(C=N); MS: m/z 289 [M + ], 288, 274, 258, 144, 114; 1 HNMR (DMSO-d 6 ) : δ 11.2 (s, 2H, NH 2 ), 7.2-7.7 (m, 9H, aromaticand indole NH), 2.8 (s,3H, CH 3 ).
- 3-(3,4-dimethoxybenzylideneamino)-2-(3-methylindolin-2-yl)quinazolin-4(3H)-one (11a), 3-(4-(dimethylamino)benzylideneamino)-2-(3-methylindolin-2-yl)quinazolin-4(3H)-one (11b), 3-(benzo-[d][1,3]dioxol-5-ylmethyleneamino)-2-(3-methylindolin-2-yl)quinazolin-4(3H)-one (11c).
To asolution of 10 (2.89 g, 0.01 mol) in DMF (20 ml) and vetraldehyde (1.66 g., 10 mmol) or 4-N,N-dimethylaminobenzaldehyde (1.49 g, 10mmol) or piperonal (1.5 g., 10 mmol) the mixture was stirred at 50 ℃ for 3 hr following pouring the reaction mixture in cooled water and recrystallization the solid produced from the proper solvent yielded (11a-c).
- 3-(3,4-dimethoxybenzylideneamino)-2-(3-methylindolin-2-yl)quinazolin-4(3H)-one (11a).
IR(KBr) cm -1 : 3180 (NH), 3055 (CH aromatic), 2967 (CH aliphatic), 1675 (C=O), 1610(C=N); MS: m/z438 [M + ], 437, 407, 376, 361, 284, 271, 257, 144, 113; 1 HNMR (DMSO-d 6 ) : δ 7.2-7.9 (m, 12H, aromaticand indole NH), 6 (s, H, N= CH ), 3.8(s, 6H, 2OCH 3 ), 2.8 (s, 3H, CH 3 ).
- 3-(4-(dimethylamino)benzylideneamino)-2-(3-methylindolin-2-yl)quinazolin-4(3H)-one (11b).
IR(KBr) cm -1 : 3195 (NH), 3065 (CH aromatic), 2957 (CH aliphatic), 1675 (C=O), 1607(C=N); MS: m/z 421 [M + ], 377, 362, 349, 335, 191, 144, 77; 1 HNMR (DMSO-d 6 ) : δ7.2-7.9 (m, 13H, aromatic and indole NH), 6 (s, H, N= CH ), 3.2(s, 6H, N( CH 3 ) 2 ), 2.8 (s, 3H, CH 3 ).
- 3-(benzo[d][1,3]dioxol-5-ylmethyleneamino)-2-(3-methylindolin-2-yl)quinazolin-4(3H)-one (11c).
IR(KBr) cm -1 : 3193 (NH), 3045 (CH aromatic), 2957 (CH aliphatic), 1675 (C=O), 1603(C=N); MS: m/z 422 [M + ], 407, 377, 361, 286, 273, 259, 144, 115; 1 HNMR (DMSO-d 6 ) : δ8.8 (s, H, N= CH ), 7.2-7.7 (m, 12H, aromaticand indole NH), 6 (s, 2H, OCH2O ), 2.8 (s, 3H, CH 3 ).
- 3-(cyclohexylideneamino)-2-propylquinazolin-4(3H)-one (12a), 3-( cyclopenty lidene amino)-2-propylquinazolin-4(3H)-one (12b).
Cyclohexanone (0.01 mol) or cyclopentanone (0.01 mol) was added to solution of 3 (0.01 mol ) in 50 ml ethanol. The reaction mixture was heated under reflux for 3 hr and then poured in cooled water and stirring the mixture for 5 min. the solid that separated was filtered and washed with water and recrystallized from the proper solvent giving (12a,b).
- 3-(cyclopenty lidene amino)-2-propylquinazolin-4(3H)-one (12a).
IR(KBr) cm -1 : 3035 (CH aromatic), 2967, 2906, 2876, 2789 (CH aliphatic), 1675 (C=O), 1609(C=N); MS: m/z 283 [M + ], 363, 239, 180, 146, 120, 92, 65.
- 3-(cyclohexylideneamino)-2-propylquinazolin-4(3H)-one (12b).
3035 (CH aromatic), 2967, 2906, 2876, 2789 (CH aliphatic), 1675 (C=O), 1609(C=N) ; MS: m/z 269 [M + ], 254, 240, 226, 158, 144, 120, 77.
- 2-(1-(4-oxo-2-propylquinazolin-3(4H)-ylamino)-cyclohexylthio)acetic acid (13a) or 2-(1-(4-oxo-2-propylquinazolin-3(4H)-ylamino)cyclopentylthio)-acetic acid (13b).
A mixture of compound 12a (2.83 g,. 0.01 mol) or 12 b (2.69 g, 0.01 mol) and thioglycolic acid (0.01 mol) in benzene (50 ml) were refluxed for 3 hr and the solvent was evaporated under reduced pressure. The residue was crystallization from the proper solvent gave (13a,b).
- 2-(1-(4-oxo-2-propylquinazolin-3(4H)-ylamino)-cyclopentylthio)acetic acid (13a).
IR(KBr) cm -1 : 3035 (CH aromatic), 2967, 2906, 2876, 2789 (CH aliphatic), 1685 (C=O thiazole), 1675 (C=O Quinazolinone), 1609(C=N); MS: m/z 357 [M + ], 358, 343, 269, 254, 240, 226,144, 120; 1 HNMR (DMSO-d 6 ) : δ7.2-7.7 (m, 9H, aromatic), 5.8 (s, 2H, CH 2 thiazole ring), 2.1 (t, 4H, cyclopentane), 1.8 (pentet, 6H, cyclopentane) 1.8 (sextet, 2H, CH 2 Me ), 2.7 (t, 2H, CH 2 Q), 1(t, 3H, CH 3 ).
- 2-(1-(4-oxo-2-propylquinazolin-3(4H)-ylamino)-cyclohexylthio)acetic acid (13b).
IR(KBr) cm -1 : 3035 (CH aromatic), 2967, 2906, 2876, 2789 (CH aliphatic), 1687 (C=O thiazole), 1675 (C=O Quinazolinone), 1609(C=N); MS: m/z 343 [M + ], 328, 314, 300, 269, 254, 240, 226, 144, 120; 1 HNMR (DMSO-d 6 ) : δ7.2-7.7 (m, 9H, aromatic), 5.8 (2H, CH 2 thiazole ring), 2.1 (t, 4H, cyclopentane), 1.8 (pentet, 4H, cyclopentane) 1.5 (sextet, 2H, CH 2 Me), 2.8 (t, 2H, CH 2 Q), 1(t, 3H, CH 3 ).
- 2-chloro-N-(4-oxo-2-propylquinazolin-3(4H)-yl)acetamide (14).
Compound 3 (2.03 g, 0.01 mol)was dissolved in dry pyridine (25 ml) was stirred at room temperature, chloroacetyl chloride was added drop by drop during 20 min the stirring was continued for 3 hr the produced mixture was poured on ice and HCl, the resulting precipitate was collected and washed with water and recrystallization from the proper solvent gave (14). IR(KBr) cm -1 : 3120 (NH), 3068 (CH aromatic), 2967, 2906, 2876, 2789 (CH aliphatic), 1710 (C=O ), 1672 (C=O Quinazolinone), 1610(C=N); MS: m/z 279 [M + ], 244, 230, 202, 187, 158; 1 HNMR (DMSO-d 6 ) : δ10.9 (s, 1H, NH ), 7.2-7.7 (m, 4H, aromatic), 6.6 (s,2H, CO CH 2 Cl), 1(t, 3H, CH 3 ), 1.8 (sextet, 2H, CH 2 Me), 2.8 (t, 2H, CH 2 Q).
- 6-propyl-2H-[1,2,4]triazino[2,3-c]quinazolin-3-(4H)-one (15)
Compound (14) (2.79, 0.01 mol) and ammonium acetate (5 g) was heated in oil bath for 3 hr. The reaction mixture was allowed to cool and treated with water the obtained solid was filtered off and recrystallized from the proper solvent gave (15). IR(KBr) cm -1 : 3200 (NH), 3068 (CH aromatic), 2967, 2906, 2876, 2789 (CH aliphatic), 1680 (C=O), 1615(C=N); MS: m/z 242 [M + ], 227, 213, 199, 171, 157, 142; 1 HNMR (DMSO-d 6 ) : δ 11.5 (s, 1H, NH ), 7.2-7.7 (m, 4H, aromatic), 5.1 (s, 2H, CO CH 2 ), 1(t, 3H, CH 3 ), 1.8 (sextet, 2H, CH 2 Me), 2.8 (t, 2H, CH 2 Q).
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