RCHH HARM
A P
Arch. Pharm. Chem. Life Sci. 2016, 349, 363–372
Y. M. Loksha et al.
Archiv der Pharmazie
4-(2,6-Difluorobenzyl)-6-methoxy-N,N,5-trimethylpyrimidin-
2-amine 11c
bromosuccinimide (130 mg, 0.73 mmol) in ethanol (10 mL)
at room temperature. The reaction mixture was stirred for
1 h. During this time, it changed from a yellow suspension to
clear a yellow solution and then to a colorless suspension. The
crystallized product from ethanol was filtered off, washed
with ethanol (2 mL), and dried to afford 165 mg (70% yield)
of compound 13 as a white solid.
Yield 14%; as a white solid; m.p. 75–77°C; 1H NMR (DMSO-d6)
d [ppm]: 2.07 (s, 3H, CH3), 2.95 [s, 6H, (CH3)2N], 3.88 (s, 3H,
OCH3), 3.94 (s, 2H, CH2Ar), 6.84 (t, 2H, J ¼ 7.8 Hz, Harom), 7.09–
7.19 (s, 1H, Harom); 13C NMR (DMSO-d6) d [ppm]: 9.31 (CH3),
27.34 (CH2Ar), 36.35 [(CH3)2N], 53.05 (OCH3), 101.02 (C5),
110.37–110.72 (m, Carom), 115.24 (t, J ¼ 20.2 Hz, Carom) 127.49
(t, J ¼ 10.2 Hz, Carom), 159.92 (C4), 161.84 (dd, J ¼ 8.9, 246.7 Hz,
M.p. 194–196°C; 1H NMR (DMSO-d6) d [ppm]: 1.95 (s, 3H,
CH3–C5), 2.93 [s, 6H, (CH3)2N], 6.43 (s, 1H, CH), 7.12 (t, 2H,
J ¼ 8.9 Hz, Harom), 7.41–7.51 (m, 1H, Harom), 11.13 (bs, 1H, NH);
13C NMR (DMSO-d6) d [ppm]: 9.62 (CH3–C5), 36.53 [(CH3)2N],
38.60 (CH), 105.19 (C5), 111.52–111.86 (m, Carom), 114.70
(t, J ¼ 15.5 Hz, Carom), 130.96 (t, J ¼ 10.9 Hz, Carom), 157.50 (C4),
160.19 (dd, J ¼ 6.7, 250.9 Hz, Carom), 162.63 (C2), 164.71 (C6);
EI-MS: m/z ¼ 257 [Mþ, 79Br] (82%), 258 [Mþþ1, 79Br] (14%), 359
[Mþ, 81Br] (77%), 278 (100%). Anal. calcd. for C14H14BrF2N3O
(358.18): C, 46.95; H, 3.94; N, 11.73. Found: C, 46.95; H, 3.78;
N, 11.48.
C
arom), 163.76 (C2), 168.03 (C6); HRMS-MALDI: m/z ¼ 294.1413
(C15H18F2N3O [MHþ]), requires 294.1403. Anal. calcd. for
15H17F2N3O (293.31): C, 61.42; H, 5.84; N, 14.33. Found: C,
C
60.30; H, 5.78; N, 13.70.
6-Aroyl (and/or arylmethyl)-2-(dimethylamino)-5-
methylpyrimidin-4(3H)-ones 12a–c
Each of compound 11a–c (0.5 mmol) was refluxed in 4 M
hydrochloric acid (10 mL) for 16 h, the reaction mixture was
cooled and the solvent was evaporated under reduced
pressure. The residual material was dissolved in water
(10 mL) and neutralized with 10% aq. sodium bicarbonate.
The solid product formed was filtered off, washed with water,
and dried to afford 12a–c.
4,6-Dichloro-N-(4-iodobenzyl)-N,5-dimethylpyrimidin-2-
amine 15
Sodium hydride (0.26 g, 6 mmol, 55% susp. in paraffin oil) was
added portionwise to a stirred solution of compound 14
(0.77 g, 4 mmol) and 4-iodobenzyl bromide (1.2 g, 4 mmol) in
dry N,N-dimethylformamide (15 mL) at room temperature.
The reaction mixture was stirred for 1 h then poured on
ice-cold water (100 mL) and the solid product formed was
filtered off, washed with water, and dried to afford 1.6 g
(98% yield) of compound 15 as a white solid.
2-(Dimethylamino)-6-(2-fluoro-6-methoxybenzoyl)-5-
methylpyrimidin-4(3H)-one 12a
Yield 80%; as a white solid; m.p. 202–204°C; 1H NMR (DMSO-
d6) d [ppm]: 2.04 (s, 3H, CH3), 2.84 [s, 6H, (CH3)2N], 3.72 (s, 3H,
OCH3), 6.83–6.97 (m, 2H, Harom), 7.40–7.48 (m, 1H, Harom),
11.33 (bs, 1H, NH); 13C NMR (DMSO-d6) d [ppm]: 9.79 (CH3),
36.51 [(CH3)2N], 56.29 (OCH3), 107.42 (d, J ¼ 17.7 Hz, Carom),
107.56 (d, J ¼ 6.5 Hz, Carom), 107.55 (C5), 131.70 (d, J ¼ 10.3 Hz,
M.p. 100–102°C; 1H NMR (CDCl3) d [ppm]: 2.28 (s, 3H,
CH3–C5), 3.07 (s, 3H, CH3–N), 4.75 (s, 2H, CH2–N), 6.99 (d, 2H,
J ¼ 8.1 Hz, Harom), 7.63 (d, 2H, J ¼ 8.1, Harom); 13C NMR (CDCl3)
d [ppm]: 15.05 (CH3–C5), 34.91 (CH3–N), 52.07 (CH2–N), 114.25
(C5), 92.68, 129.61, 137.15, 137.61 (Carom), 161.54 (C2), 165.69
(C4 and C6); HRMS-MALDI: m/z ¼ 407.9526 (C13H13Cl2IN3
[MHþ]), found 407.9534.
C
arom), 157.44 (C4), 157.74 (d, J ¼ 8.0 Hz, Carom), 160.69 (C2),
–
–
165.31 (C6), 193.95 (C O); HRMS-MALDI: m/z ¼ 328.1068
(C15H16FNaN3O3 [MNaþ]), requires 328.1060.
6-(2,6-Dimethoxybenzoyl)-2-(dimethylamino)-5-
methylpyrimidin-4(3H)-one 12b
2-{6-Chloro-2-[(4-iodobenzyl)(methyl) amino]-5-
Yield 83%; as a white solid; m.p. 250–252°C; 1H NMR (DMSO-
d6) d [ppm]: 2.01 (s, 3H, CH3), 2.82 [s, 6H, (CH3)2N], 3.67 (s, 6H,
2OCH3), 6.66 (d, 2H, J ¼ 8.2 Hz, Harom), 7.31 (t, 1H, J ¼ 8.2 Hz,
methylpyrimidin-4-yl}-2-(2,6-difluorophenyl)acetonitrile 16
Sodium hydride (0.38 g, 9 mmol, 55% susp. in paraffin oil) was
added portionwise to a stirred solution of compound 15
(1.42 g, 3.5 mmol) and 2,6-difluorobenzyl cyanide (0.612 g,
4 mmol) in dry N,N-dimethylformamide (15 mL) at room
temperature. The reaction mixture was stirred for 1 h, and
then poured on ice-cold water (100 mL). The solid product
formed was filtered off, washed with water, and dried to
afford 2.08 g (99% yield) of compound 16 as a white solid.
M.p. 108–110°C; 1H NMR (CDCl3) d [ppm]: 2.23 (s, 3H,
CH3–C5), 3.04 (s, 3H, CH3–N), 4.52 (bs, 1H, HCH–N), 4.78 (d, 1H,
J ¼ 15 Hz, HCH–N), 5.54 (s, 2H, CH–CN), 6.90 (bs, 4H, Harom),
7.28–7.33 (m, 1H, Harom), 7.57 (d, 2H, J ¼ 7.8 Hz, Harom);
13C NMR (CDCl3) d [ppm]: 13.31 (CH3–C5), 32.07 (CH–CN), 34.71
(CH3–N), 51.99 (CH2–N), 113.19 (C5), 115.57 (CN), 92.52,
129.65, 137.33, 137.44 (Carom), 109.56 (t, J ¼ 16.5 Hz, Carom),
111.63–111.96 (m, Carom), 131.02 (t, J ¼ 10.5 Hz, Carom), 160.65
(dd, J ¼ 6.6, 252.1 Hz, Carom), 159.25 (C2), 159.83 (C4), 162.67
H
arom), 11.23 (bs, 1H, NH); 13C NMR (DMSO-d6) d [ppm]: 9.81
(CH3), 36.44 [(CH3)2N], 55.77 (2ꢃOCH3), 104.09, 130.60, 157.01,
119.17 (Carom), 104.13 (C5), 157.02 (C4þ), 162.23 (C2), 165.64
–
(C6), 196.84 (C O). EI-MS: m/z ¼ 317 [M ] (68%), 286 (100%).
–
Anal. calcd. for C16H19N3O4 ꢄ 0.7H2O (329.96): C, 58.24; H, 6.23;
N, 12.73. Found: C, 58.13; H, 5.69; N, 12.44.
6-(2,6-Difluorobenzyl)-2-(dimethylamino)-5-methylpyrimidin-
4(3H)-one 12c
Yield 84%; as a white solid; m.p. 208–210°C; Lit. [18] 208–210°C.
6-[Bromo(2,6-difluorophenyl)methyl]-2-(dimethylamino)-
5-methylpyrimidin-4(3H)-one 13
Few crystals of benzoyl peroxide were added to a stirred
solution of compound 12c (200 mg, 0.66 mmol) and N-
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