Medicinal Chemistry Research (2021) 30:459–472
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7.29–7.25 (m, 1H), 7.24–7.19 (m, 1H), 7.19–7.10 (m, 1H),
7.06–6.93 (m, 3H), 4.82–4.76 (m, 2H), 4.60–4.54 (m, 2H),
3.73–3.63 (m, 2H), 2.70–2.60 (m, 2H); Calculated for
C18H16ClF2N3O2, 379.1; observed (M + H)+ 380.5.
3,4-difluorobenzylamine (0.264 mmol), EDC·HCl (51 mg,
0.264 mmol), triethylamine, and HOBt·H2O (40 mg,
0.264 mmol), and then continued the same procedure to
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afford 25 (8.0 mg, 8%). H NMR (300 MHz, CDCl3): δ
(ppm) 7.49–7.44 (m, 1H), 7.21–7.13 (m, 2H), 7.13–7.00
(m, 3H), 4.83 (s, 2H), 4.56 (s, 2H), 3.70 (t, J = 6.6 Hz, 2H),
2.68 (t, J = 6.6 Hz, 2H); Calculated for C18H15ClF3N3O2,
397.1; observed (M + H)+ 398.5.
N-(3-chloro-4-fluorophenyl)-3-(4-fluorophenethyl)-4-
oxotetrahydropyrimidine-1(2H)-carboxamide (22)
According to the procedure for preparation of compound 21,
Boc-beta-Ala-OH (50 mg, 0.264 mmol) was treated with
N-(3-chloro-4-fluorophenyl)-3-(2,5-difluorobenzyl)-4-
oxotetrahydropyrimidine-1(2H)-carboxamide (26)
2-(4-fluorophenyl)ethanamine
(0.264 mmol),
EDC·HCl
(51 mg, 0.264 mmol), triethylamine, and HOBt·H2O (40 mg,
0.264 mmol), and then continued the same procedure to afford
22 (3.2 mg, 3%). 1H NMR (300 MHz, CDCl3): δ (ppm)
7.53–7.46 (m, 1H), 7.23–7.16 (m, 1H), 7.16–7.08 (m, 2H),
7.08–6.98 (m, 1H), 6.98–6.87 (m, 1H), 4.71 (s, 2H), 3.64–3.50
(m, 4H), 2.83 (t, J = 7.2 Hz, 2H), 2.54–2.49 (m, 2H); Calcu-
lated for C19H18ClF2N3O2, 393.1; observed (M + H)+ 394.5.
According to the procedure for preparation of compound
21, Boc-beta-Ala-OH (50 mg, 0.264 mmol) was treated
with 2,5-difluorobenzylamine (0.264 mmol), EDC·HCl
(51 mg, 0.264 mmol), triethylamine, and HOBt·H2O
(40 mg, 0.264 mmol), and then continued the same proce-
1
dure to afford 26 (13.7 mg, 13%). H NMR (300 MHz,
CDCl3): δ (ppm) 7.48–7.40 (m, 1H), 7.21–7.12 (m, 1H),
7.04–6.84 (m, 4H), 4.85 (s, 2H), 2.59 (s, 2H), 3.72–3.60 (m,
2H), 2.65–2.54 (m, 2H); Calculated for C18H15ClF3N3O2,
397.1; observed (M + H)+ 398.5.
N-(3-chloro-4-fluorophenyl)-3-(3-fluorophenethyl)-4-
oxotetrahydropyrimidine-1(2H)-carboxamide (23)
According to the procedure for preparation of compound 21,
Boc-beta-Ala-OH (50 mg, 0.264 mmol) was treated with
N-(3-chloro-4-fluorophenyl)-3-(2,4-difluorobenzyl)-4-
oxotetrahydropyrimidine-1(2H)-carboxamide (27, 58031)
2-(3-fluorophenyl)ethanamine
(0.264 mmol),
EDC·HCl
(51 mg, 0.264 mmol), triethylamine, and HOBt·H2O (40 mg,
0.264 mmol), and then continued the same procedure to afford
23 (3.7 mg, 4%). 1H NMR (300 MHz, CDCl3): δ (ppm)
7.52–7.44 (m, 1H), 7.24–7.14 (m, 2H), 7.06–7.00 (m, 1H),
7.00–6.91 (m, 1H), 6.91–6.78 (m, 2H), 4.69 (s, 2H), 3.65–3.50
(m, 4H), 2.90–2.83 (m, 2H), 2.58–2.48 (m, 2H); Calculated for
C19H18ClF2N3O2, 393.1; observed (M + H)+ 394.5.
According to the procedure for preparation of compound
21, Boc-beta-Ala-OH (200 mg, 1.057 mmol) was treated
with 2,4-difluorobenzylamine (0.14 mL, 1.163 mmol),
DCC (240 mg, 1.163 mmol), and HOBt·H2O (178 mg,
1.163 mmol), and then continued the same procedure to
1
afford 27 (58031) (159.4 mg, 38%). H NMR (300 MHz,
CDCl3): δ (ppm) 7.49–7.43 (m, 1H), 7.41–7.31 (m, 1H),
7.18–7.11 (m, 1H), 7.10–7.01 (m, 1H), 6.89–6.76 (m, 2H),
6.50 (s, 1H, NH), 4.91 (s, 2H), 4.63 (s, 2H), 3.70 (t, J =
6.6 Hz, 2H), 2.68 (t, J = 6.6 Hz, 2H); 13C NMR (100 MHz)
showed a conformer mixture: δ (ppm) 169.8, 162.8 (dd, J =
249, 12 Hz), 161.1 (dd, J = 247, 12 Hz), 159.0 (d, J =
41 Hz), 154.9 (d, J = 245 Hz), 154.0, 134.4 (d, J = 3 Hz),
132.0 (dd, J = 10.0, 5.4 Hz), 123.1, 121.1 (d, J = 18 Hz),
120.5 (d, J = 8 Hz), 118.7 (dd, J = 16.4 Hz), 116.6 (d, J =
23 Hz), 111.9 (dd, J = 22, 4 Hz), 104.1 (t, J = 26 Hz), 58.2,
58.1, 42.7, 42.7, 41.0, 31.3; HRMS, Calculated for
C18H15ClF3N3NaO2, 420.0697; observed (M + Na)+
420.0687.
N-(3-chloro-4-fluorophenyl)-3-(2-morpholinoethyl)-4-
oxotetrahydropyrimidine-1(2H)-carboxamide (24)
According to the procedure for preparation of compound
21, Boc-beta-Ala-OH (100 mg, 0.529 mmol) was treated
with 2-morpholinoethanamine (76 μL, 0.581), DCC
(120 mg,
0.581 mmol),
and
HOBt·H2O
(89 mg,
0.581 mmol), and then continued the same procedure to
1
afford 24 (1.7 mg, 2%). H NMR (300 MHz, CD3OD): δ
(ppm) 7.72–7.66 (m, 1H), 7.28–7.20 (m, 1H), 7.20–7.10
(m, 1H), 4.56 (s, 2H), 4.13–3.95 (m, 2H), 3.95–3.70 (m,
4H), 3.70–3.35 (m, 4H), 3.28–3.04 (m, 4H), 2.68–2.58 (m,
1H), 2.45–2.35 (m, 1H); Calculated for C12H22ClFN4O3,
384.1; observed (M + H)+ 385.5.
N-(3-chloro-4-fluorophenyl)-3-(2,4-dimethoxybenzyl)-4-
oxotetrahydropyrimidine-1(2H)-carboxamide (28)
N-(3-chloro-4-fluorophenyl)-3-(3,4-difluorobenzyl)-4-
oxotetrahydropyrimidine-1(2H)-carboxamide (25)
According to the procedure for preparation of compound
21, Boc-beta-Ala-OH (100 mg, 0.529 mmol) was treated
with 2,4-dimethoxybenzylamine (76 μL, 0.581 mmol), DCC
(120 mg, 0.581 mmol), and HOBt·H2O (89 mg, 0.581 mmol),
According to the procedure for preparation of compound
21, Boc-beta-Ala-OH (50 mg, 0.264 mmol) was treated with