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Vol. 57, No. 11
matographed on silica gel. Eluate of ethyl acetate–n-hexane (1 : 6, v/v) was
evaporated and the residue was recrystallized from ethyl acetate–n-hexane to
give 4c (116 mg, 51%) as colorless needles. mp 82—84 °C (lit.18) 82—
83 °C). 1H-NMR (CDCl3) d: 1.01 (3H, t, Jꢄ7.4 Hz, –CH3), 1.84 (2H, quint,
Jꢄ7.4 Hz, –CH2CH3), 3.98 (2H, t, Jꢄ7.4 Hz, –NCH2CH2–), 7.46—7.82
Contrary to the case of 3, we observed that this reaction did
not proceed at room temperature, as judged by TLC analysis.
Introduction of the methyl moiety at C-2, therefore, prohib-
ited the reaction from taking place. When the reaction solu-
tion was heated to 60 °C, the product 9 was obtained in 20% (3H, m, H-6, 7, and 8), 8.04 (1H, s, H-2), 8.32 (1H, dd, Jꢄ7.8, 1.4 Hz, H-5).
IR (nujol) cmꢀ1: 1677 (CO). FAB-MS m/z: 189 (MHꢂ). Anal. Calcd for
C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C, 69.94; H, 6.27; N, 15.01.
3-(2-Hydroxyethyl)quinazolin-4(3H)-one (4d) Reaction time was 6 h
in DMF (20 ml) at 90 °C. The residue was recrystallized from ethyl acetate
yield. This rather low yield was due to side products which
were indicated by TLC. Finally, we reacted 8 with hydroxyl-
amine. The reaction did not proceed; however, the cyano
to give 4d (122 mg, 53%) as colorless needles. mp 152—153 °C (lit.19)
150—152 °C). 1H-NMR (CDCl3) d: 3.28 (1H, br s, D2O exchangeable, OH),
4.01 (2H, t, Jꢄ4.9 Hz, CH2OH), 4.16 (2H, t, Jꢄ4.9 Hz, NCH2), 7.43 (1H, td,
Jꢄ7.6, 1.5 Hz, H-6), 7.59 (1H, dd, Jꢄ7.6, 1.5 Hz, H-8), 7.72 (1H, td, Jꢄ7.6,
1.4 Hz, H-7), 8.07 (1H, s, H-2), 8.15 (1H, dd, Jꢄ7.8, 1.4 Hz, H-5). IR
(nujol) cmꢀ1: 3255 (OH), 1675 (CO). FAB-MS m/z: 191 (MHꢂ). Anal.
group at the C-2ꢁ position simply hydroxylaminolyzed to an
amide oxime to give 10 in 60% yield. We are currently ex-
ploring their structure–activity relationships of the reaction
products for further potential pharmaceutics.
Experimental
All melting points were determined on a Yanagimoto micro-melting point Calcd for C10H10N2O2: C, 63.15; H, 5.30; N, 14.73. Found: C, 63.06; H,
apparatus, and are uncorrected. Elemental analyses were performed on a
Yanagimoto MT-5 CHN Corder elemental analyzer. The FAB-mass spectra
5.26; N, 14.82.
3-(3-Hydroxypropyl)quinazolin-4(3H)-one (4e) Reaction time was 2 d
were obtained on a VG 70 mass spectrometer and m-nitrobenzyl alcohol was in DMF (20 ml) at 60 °C. The residue was recrystallized from ethyl
used as the matrix. The IR spectra were recorded on a Japan Spectroscopic acetate–n-hexane to give 4e (156 mg, 63%) as colorless needles. mp 102—
1
FT/IR-200 spectrophotometer with nujol and frequencies are expressed in 103 °C. H-NMR (CDCl3) d: 1.97—2.12 (2H, m, CH2CH2CH2), 3.02 (1H,
cmꢀ1. The 1H-NMR spectra were recorded on a Varian VXR-200 instrument br s, D2O exchangeable, OH), 3.64 (2H, t, Jꢄ6.2 Hz, CH2OH), 4.22 (2H, t,
operating at 200 MHz with tetramethylsilane as an internal standard. Chemi-
Jꢄ6.2 Hz, NCH2), 7.49—7.85 (3H, m, H-6, 7, and 8), 8.10 (1H, s, H-2),
cal shifts are given in ppm (d) and J values in Hz, and the signals are desig- 8.32 (1H, dd, Jꢄ7.5, 1.4 Hz, H-5). IR (nujol) cmꢀ1: 3280 (OH), 1670 (CO).
nated as follows: s, singlet; d, doublet; dd, double doublet; t, triplet; q, quar- FAB-MS m/z: 205 (MHꢂ). Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92;
tet; quint, quintet; br, broad; m, multiplet. Solvent systems are as follows: N, 13.72. Found: C, 64.64; H, 6.19; N, 13.54.
methylamine as a 40% methanol solution, ethyl amine as a 70% aqueous so-
lution, and other amines as neat. Column chromatography was performed on
3-Aminoquinazolin-4(3H)-one (4f) To
1.21 mmol) in DMF (20 ml) and methanol (2 ml) was added hydrazine dihy-
a solution of 3 (300 mg,
silica gel (IR-60-63-210-W, Daiso). TLC was carried out on Kieselgel drochloride (1.27 g, 12.1 mmol) and triethylamine (1.23 g, 12.2 mmol) then
60F254 (Merck).
the solution was stirred at 80 °C for 1.5 d. After evaporation of solvent
The structure on X-ray analysis was solved by direct methods with (about 10 ml), water (50 ml) was added, and then allowed to stand in refrig-
MITHRIL13) and DIRDIF14) and refined by the full-matrix least squares erator overnight. The precipitate was filtered and the solid was recrystallized
method by using TEXSAN.15) H atoms were found by difference synthesis from ethyl acetate to give 4f (150 mg, 77%) as dark yellow needles. mp
1
and refined isotropically. The displacement ellipsoids were drawn with the 203—204 °C (lit.20) 209—212 °C). H-NMR (DMSO-d6) d: 5.89 (2H, br s,
aid of ORTEP II.16) Most of the calculations were performed on a VAX 3100 D2O exchangeable, NH2), 7.40—8.32 (4H, m, Ar-H), 8.38 (1H, s, H-2). IR
computer using TEXSAN at the X-ray Laboratory of Okayama University.
3-(2-Cyanophenyl)quinazolin-4(3H)-one (3) 2-Aminobenzonitrile Calcd for C8H7N3O: C, 59.62; H, 4.38; N, 26.07. Found: C, 59.59; H, 4.46;
(nujol) cmꢀ1: 3290, 3160 (NH), 1685 (CO). FAB-MS m/z: 162 (MHꢂ). Anal.
(3.00 g, 25.4 mmol) was added to formic acid (50 ml) and the solution was
stirred at 80 °C for 15 h. After cooled to room temperature, water (50 ml)
N, 26.37.
N-(2-(Nꢀ-Hydroxycarbamimidoyl)phenyl)-2-(Nꢀ-hydroxyformimi-
was added, and then allowed to stand for 3 h. The precipitate was filtered and damido)benzamide (5) To a solution of 3 (1.70 g, 6.88 mmol) in DMF
the solid was recrystallized from DMF-methanol to give 3 (1.80 g, 57%) as
(20 ml) was added hydroxylamine hydrochloride (2.39 g, 34.4 mmol) and tri-
1
colorless prisms. mp 192—193 °C (lit.4) 196—197 °C). H-NMR (DMSO- ethylamine (3.06 g, 30.2 mmol) then the mixture was stirred at room temper-
d6) d: 7.61—8.28 (8H, m, Ar-H), 8.46 (1H, s, H-2). IR (nujol) cmꢀ1: 2238 ature for 15 h. Water (50 ml) was added and then allowed to stand for 1 h.
(CN), 1685 (CO). FAB-MS m/z: 248 (MHꢂ). Anal. Calcd for C15H9N3O: C,
72.87; H, 3.67; N, 16.99. Found: C, 73.16; H, 3.74; N, 16.99.
The precipitate was filtered and the solid was recrystallized from ethyl ac-
etate to give 5 (1.34 g, 62%) as colorless prisms. mp 160—164 °C (dec.).
1H-NMR (DMSO-d6) d: 6.28 (2H, br s, D2O exchangeable, NH2), 7.00—
7.10 (1H, m, Ar-H), 7.19 (1H, br t, Jꢄ7.5 Hz, Ar-H), 7.37—7.57 (3H, m,
General Procedure for the Reaction of 3 with Primary Amines To a
solution of 3 (300 mg, 1.21 mmol) was added primary amine (12.1 mmol)
and the solution was stirred for the appropriate time. Water (50 ml) was Ar-H), 7.51—7.84 (2H, m, Ar-H), 7.77 (1H, d, changed to s after addition of
added and extracted with ethyl acetate (50 mlꢃ3). The combined organic D2O, Jꢄ10.5 Hz, CHꢄNOH), 8.56 (1H, br d, Jꢄ7.8 Hz, Ar-H), 10.17 (1H,
layer was washed with brine, dried over Na2SO4, and then evaporated in s, D2O exchangeable, NH or OH), 10.18 (1H, s, D2O exchangeable, NH or
vacuo. The residue was purified by column chromatography and/or recrys- OH), 10.75 (1H, br d, Jꢄ10.5 Hz, D2O exchangeable, NH–CHꢄNOH),
tallization.
12.33 (1H, br s, D2O exchangeable, NH or OH). IR (nujol) cmꢀ1: 3455,
3-Methylquinazolin-4(3H)-one (4a) Reaction time was 10 h in DMF 3340, 3170 (NH and OH), 1635 (CO). FAB-MS m/z: 314 (MHꢂ). Anal.
(20 ml) at room temperature. The residue was chromatographed on silica Calcd for C15H15N5O3·1/2 H2O: C, 55.90; H, 5.00; N, 21.73. Found: C,
gel. Eluate of ethyl acetate–n-hexane (1 : 5, v/v) was evaporated and the 55.69; H, 4.73; N, 21.87.
residue was recrystallized from ethyl acetate–n-hexane to give 4a (109 mg,
The crystals were grown from an acetonitrile solution by slow evapora-
56%) as colorless needles. mp 103—105 °C (lit.17) 106 °C). 1H-NMR tion. This analytical sample was dried around 100 °C under vacuum.
(CDCl3) d: 3.61 (3H, s, –CH3), 7.47—7.82 (3H, m, H-6, 7, and 8), 8.06 (1H,
Crystal Structure Analysis of 521) Crystal data: C15H15N5O3·0.5C2H3N;
Mrꢄ333.63; monoclinic, space group C2/c (#15), aꢄ11.731(6),
s, H-2), 8.32 (1H, dd, Jꢄ7.4, 1.4 Hz, H-5). IR (nujol) cmꢀ1: 1670 (CO).
FAB-MS m/z: 161 (MHꢂ). Anal. Calcd for C9H8N2O: C, 67.49; H, 5.03; N, bꢄ14.589(8), cꢄ20.04(1) Å, bꢄ104.66(4)°, Vꢄ3319(1) Å3; Zꢄ8; Dcꢄ
17.49. Found: C, 67.28; H, 5.05; N, 17.60.
1.370 g cmꢀ3. A crystal of size 0.430ꢃ0.300ꢃ0.500 mm was examined by
3-Ethylquinazolin-4(3H)-one (4b) Reaction time was 10 h in DMF using graphite-monochromated MoKa radiation (lꢄ0.71073 Å). Cell di-
(20 ml) at room temperature. The residue was chromatographed on silica mensions were obtained from 25 reflections (19.0ꢅ2qꢅ22.0°). In total 4010
gel. Eluate of ethyl acetate–n-hexane (1 : 5, v/v) was evaporated and the reflections were measured by the w–2q scan method, and 3812 of these were
residue was recrystallized from ethyl acetate–n-hexane to give 4b (109 mg,
unique (Rintꢄ0.063). Refinements were carried out including all the hydro-
1
52%) as colorless needles. mp 99—101 °C (lit.18) 76.5—78.5 °C). H-NMR gen atoms except those of the methyl group of the solvent molecule by using
(CDCl3) d: 1.43 (3H, t, Jꢄ7.2 Hz, –CH3), 4.08 (2H, q, Jꢄ7.2 Hz, –CH2–), 2859 reflections with Iꢆ2.00 s (I) within 2qmax of 55°. Rꢄ0.050, Rwꢄ
7.46—7.82 (3H, m, H-6, 7 and 8), 8.06 (1H, s, H-2), 8.32 (1H, dd, Jꢄ7.5, 0.052, Sꢄ1.73. The formular unit was confirmed by the structure analysis.
1.4 Hz, H-5). IR (nujol) cmꢀ1: 1677 (CO). FAB-MS m/z: 175 (MHꢂ). Anal.
Calcd for C10H10N2O: C, 68.95; H, 5.79; N, 16.08. Found: C, 68.94; H, 5.66;
N, 16.11.
The solvent molecule lies on the two-fold axis in the unit cell.
2-Amino-N-(2-cyanophenyl)benzamide (6) To solution of
a
3
(300 mg, 1.21 mmol) in DMF (20 ml) and methanol (2 ml) was added ethyl-
enediamine (730 mg, 12.1 mmol) and the solution was stirred at room tem-
3-n-Propylquinazolin-4(3H)-one (4c) Reaction time was 10 h in DMF
(20 ml) and methanol (2 ml) at room temperature. The residue was chro- perature for 1.5 d. Water (50 ml) was added and then allowed to stand for 1 h.