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N3-Alkyl-Thienopyrimidin-4-Ones as mGluR1 Antagonists
KOREAN CHEMICAL SOCIETY
133.8, 130.2, 128.7, 128.3, 127.9, 124.8, 53.2, 33.0, 25.9,
25.3; LC/MS (ESI+): m/z: calcd for C18H18N2OS: 310.42,
[M + H]+; found: 311.10
0.6H), 8.19 (s, 0.4H), 7.82–7.79 (m, 3H), 7.48–7.44 (m,
2H), 7.39–7.35 (m, 1H), 4.90–4.79 (m, 1H), 2.07–1.62 (m,
8H), 1.51–1.43 (m, 1H), 1.33–1.16 (m, 2H), 0.95–0.90 (m,
3H); 13C NMR (75 MHz, CDCl3) δ 157.4, 153.6, 145.1,
144.9, 137.8, 133.8, 130.2, 128.7, 128.3, 128.3, 128.0,
124.9, 124.8, 53.8, 53.4, 38.5, 33.5, 32.7, 31.9, 29.3, 29.0,
27.2, 23.7, 12.3, 11.6; LC/MS (ESI+): m/z: calcd for
C20H22N2OS: 338.47, [M + H]+; found: 339.10.
7-Phenyl-3-(4-propylcyclohexyl)thieno[3,2-d]pyrimidin-
4(3H)-one (4–12). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-phenylthio-
phene-2-carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL),
4-propylcyclohexylamine (0.148 mL, 0.90 mmol), and AcOH
(0.1 mL) gave the title compound 4–12 (106 mg, 0.30 mmol,
70% yield, dr = 1:1): 1H NMR (400 MHz, CDCl3) δ 8.22 (s,
0.5H), 8.18 (s, 0.5H), 7.80–7.78 (m, 3H), 7.49–7.43 (m,
2H), 7.38–7.34 (m, 1H), 4.88–4.78 (m, 1H), 2.05–1.14 (m,
13H), 0.94–0.87 (m, 3H); 13C NMR (75 MHz, CDCl3) δ
157.3, 153.5, 145.1, 144.9, 137.8, 137.8, 133.8, 130.2,
130.2, 128.7, 128.6, 128.3, 128.3, 128.0, 124.9, 124.8,
53.8, 53.4, 38.9, 36.5, 33.2, 32.7, 32.3, 31.3, 29.3, 27.3,
20.8, 20.1, 14.4, 14.3; LC/MS (ESI+): m/z: calcd for
C21H24N2OS: 352.50, [M + H]+; found: 353.10
3-(2-Methylcyclohexyl)-7-phenylthieno[3,2-d]pyrimi-
din-4(3H)-one (4–8). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-phenylthio-
phene-2-carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL),
2-methylcyclohexylamine (0.120 mL, 0.90 mmol), and
AcOH (0.1 mL) gave the title compound 4–8 (66 mg, 0.20
1
mmol, 47% yield, dr = 1:2): H NMR (400 MHz, CDCl3) δ
8.14 (m, 1H), 7.83–7.81 (m, 3H), 7.49–7.45 (m, 2H),
7.40–7.36 (m, 1H), 5.00 (dt, J = 3.8, 13.2 Hz, 0.3H), 4.67 (s,
0.7H), 2.49–1.23 (m, 9H), 0.88 (d, J = 7.2 Hz, 1H), 0.83 (d,
J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 157.7,
153.4, 145.5, 137.9, 133.8, 130.3, 128.7, 128.3, 128.0,
56.5, 34.8, 31.9, 31.0, 26.6, 26.0, 25.7, 25.4, 19.6, 18.2,
11.4; LC/MS (ESI+): m/z: calcd for C19H20N2OS: 324.45,
[M + H]+; found: 325.05
3-(3-Methylcyclohexyl)-7-phenylthieno[3,2-d]pyrimi-
din-4(3H)-one (4–9). Following the same procedure with
compound 4–1, the reaction of methyl 3-amino-4-phenylthio-
phene-2-carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL),
3-methylcyclohexylamine (0.120 mL, 0.90 mmol), and
AcOH (0.1 mL) gave the title compound 4–9 (98 mg, 0.30
3-(4-Isopropylcyclohexyl)-7-phenylthieno[3,2-d]pyrimi-
din-4(3H)-one (4–13). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-phenylthio-
phene-2-carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL),
4-isopropylcyclohexylamine (0.148 mL, 0.90 mmol), and
AcOH (0.1 mL) gave the title compound 4–13 (89 mg, 0.25
1
mmol, 71% yield, dr = 1:2): H NMR (400 MHz, CDCl3) δ
8.23 (s, 0.3H), 8.20 (s, 0.7H), 7.83–7.80 (m, 3H), 7.49–7.46
(m, 2H), 7.41–7.35 (m, 1H), 5.19–5.11 (m, 0.3H),
4.95–4.87 (m, 0.7H), 2.28–1.50 (m, 8H), 1.34–1.24 (m,
1H), 1.16 (d, J = 7.3 Hz, 1H), 1.02–0.92 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 157.3, 153.5, 145.0, 144.9, 137.8,
133.8, 130.3, 128.7, 128.3, 127.9, 124.8, 55.0, 41.3, 38.3,
34.0, 32.6, 32.3, 30.8, 28.5, 25.4, 22.3, 20.6, 17.9; LC/MS
(ESI+): m/z: calcd for C19H20N2OS: 324.45, [M + H]+; found:
325.05
3-(trans-4-Methylcyclohexyl)-7-phenylthieno[3,2-d]pyri-
midin-4(3H)-one (4–10). Following the same procedure as
with compound 4–1, the reaction of methyl 3-amino-4-phe-
nylthiophene-2-carboxylate (76 mg, 0.33 mmol), CH(OEt)3
(1 mL), trans-4-methylcyclohexylamine (0.1 mL, 0.76
mmol), and AcOH (0.1 mL) gave the title compound 4–10
(54 mg, 0.17 mmol, 50% yield): 1H NMR (400 MHz, CDCl3)
δ 8.20 (s, 1H), 7.84–7.79 (m, 3H), 7.49–7.45 (m, 2H),
7.40–7.36 (m, 1H), 4.90–4.82 (m, 1H), 2.05–2.01 (m, 2H),
1.92–1.88 (m, 2H), 1.75–1.64 (m, 2H), 1.55–1.44 (m, 1H),
1.31–1.21 (m, 2H), 0.98 (d, J = 6.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 157.4, 153.5, 144.9, 137.8, 133.8, 130.2,
128.7, 128.3, 127.9, 124.8, 53.1, 34.3, 32.7, 31.9, 22.0; LC/
MS (ESI+): m/z: calcd for C19H20N2OS: 324.45, [M + H]+;
found: 325.05.
1
mmol, 58% yield, dr = 1:1): H NMR (400 MHz, CDCl3) δ
8.22 (s, 0.5H), 8.18 (s, 0.5H), 7.81–7.77 (m, 3H), 7.47–7.43
(m, 2H), 7.38–7.34 (m, 1H), 4.88–4.79 (m, 1H), 2.08–1.12
(m, 10H), 0.93 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 157.4, 157.4, 153.5, 145.2,
144.8, 137.9, 137.8, 133.8, 130.2, 130.2, 128.7, 128.6,
128.3, 127.9, 124.8, 53.7, 53.4, 43.1, 39.2, 32.8, 32.5, 29.0,
27.5, 27.4, 26.1, 21.0, 19.9; LC/MS (ESI+): m/z: calcd for
C21H24N2OS: 352.50, [M + H]+; found: 353.10.
3-(4-(tert-Butyl)cyclohexyl)-7-phenylthieno[3,2-d]pyri-
midin-4(3H)-one (4–14). Following the same procedure as
with compound 4–1, the reaction of methyl 3-amino-4-phe-
nylthiophene-2-carboxylate
(100 mg,
0.43 mmol),
CH(OEt)3 (1 mL), 4-tert-butylcyclohexylamine (0.161 mL,
0.90 mmol), and AcOH (0.1 mL) gave the title compound
1
4–14 (103 mg, 0.28 mmol, 65% yield, dr = 1:1): H NMR
(400 MHz, CDCl3) δ 8.51 (s, 0.5H), 8.20 (s, 0.5H),
7.82–7.80 (m, 3H), 7.50–7.45 (m, 2H), 7.41–7.36 (m, 1H),
5.05–5.01 (m, 0.5H), 4.88–4.80 (m, 0.5H), 2.22–1.10 (m,
9H), 0.90 (d, 9H); 13C NMR (100 MHz, CDCl3) δ 157.8,
157.4, 153.7, 153.5, 145.7, 144.8, 137.9, 133.8, 130.2,
128.7, 128.7, 128.3, 127.9, 53.3, 49.5, 47.2, 46.1, 33.0,
32.8, 32.4, 29.3, 27.6, 27.6, 26.8, 22.7; LC/MS (ESI+): m/z:
calcd for C22H26N2OS: 366.53, [M + H]+; found: 367.10.
3-Cycloheptyl-7-phenylthieno[3,2-d]pyrimidin-4(3H)-
one (4–15). Following the same procedure as with compound
4–1, the reaction of methyl 3-amino-4-phenylthiophene-2-
3-(4-Ethylcyclohexyl)-7-phenylthieno[3,2-d]pyrimidin-
4(3H)-one (4–11). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-phenylthio-
phene-2-carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL),
4-ethylcyclohexylamine (0.133 mL, 0.90 mmol), and AcOH
(0.1 mL) gave the title compound 4–11 (7 mg, 0.02 mmol,
1
5% yield, dr = 3:2): H NMR (400 MHz, CDCl3) δ 8.22 (s,
Bull. Korean Chem. Soc. 2015, Vol. 36, 1439–1451
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim