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A.W. Ireland et al. / Bioorg. Med. Chem. 22 (2014) 6490–6502
(d, 2H, J = 8.1 Hz), 5.19 (d, 1H, J = 3.3 Hz), 4.21–3.96 (m, 2H), 3.58 (s,
3H), 3.34–3.06 (m, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, d6-DMSO) d
166.1, 153.5, 152.5, 149.6, 142.7, 139.9, 139.3, 129.0, 127.5, 126.9,
126.7, 102.9, 59.8, 52.3, 51.3, 39.3, 23.3, 15.8; HRMS (ESI) m/z calcd
for C22H23N6O3 [M+H]+ 419.1832, found 419.1862.
16.8 Hz), 2.64 (s, 3H); HRMS (ESI) m/z calcd for C28H25N3O3Na
[M+Na]+ 474.1794, found 474.1801.
A mixture of benzyl 4-([1,10-biphenyl]-4-yl)-1-(2-cyanoethyl)-
6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(0.200 g, 0.443 mmol), 1 M TBAF in THF (0.443 mL, 0.443 mmol),
and TMSN3 (0.240 mL, 1.77 mmol, 4 equiv) was stirred at 90 °C
for 23 h in a sealed vial. The solution was diluted with EtOAc and
H2O. The aqueous layer was extracted with EtOAc (3ꢁ), and the
combined organic layers were washed with H2O (3ꢁ), 1 M NaHSO4
(3ꢁ), dried (Na2SO4), filtered, and concentrated to obtain a crude
residue that was washed with distilled hexanes (3ꢁ), MTBE (3ꢁ),
and recrystallized (EtOAc) to obtain ML282-61 (0.0161 g,
0.0326 mmol, 7%) as a solid: 1H NMR (400 MHz, d6-DMSO) d 8.06
(d, 1H, J = 3.6 Hz), 7.64 (d, 2H, J = 7.2 Hz), 7.54 (d, 2H, J = 8.4 Hz),
7.48 (t, 2H, J = 7.6 Hz), 7.38 (t, 1H, J = 7.2 Hz), 7.29–7.27 (m, 3H),
7.18–7.14 (m, 4H), 5.22 (d, 1H, J = 3.2 Hz), 5.11, 5.06 (ABq, 2H, J
=12.8 Hz), 4.20–4.12 (m, 1H), 4.10–4.00 (m, 1H), 3.40–3.30 (m,
1H), 3.18–3.10 (m, 1H), 2.60 (s, 3H); 13C NMR (100 MHz, d6-DMSO)
d 165.3, 152.3, 150.2, 142.8, 139.9, 139.4, 136.3, 129.0, 128.3,
127.8, 127.7, 127.5, 126.9, 126.8, 123.7, 102.5, 65.3, 52.5, 39.9,
23.3, 15.8; HRMS (ESI) m/z calcd for C28H26N6O3Na [M+Na]+
517.1964, found 517.1974.
4.1.4. Methyl 1-(4-(1H-tetrazol-5-yl)benzyl)-4-([1,10-biphenyl]-
4-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxy-
late (ML282-60)
A suspension of 1-(4-cyanobenzyl)urea (0.250 g, 1.43 mmol) in
THF (4.76 mL) was treated with 4-biphenylcarboxaldehyde (0.650 g,
3.57 mmol, 2.5 equiv) and methyl acetoacetate (0.385 mL, 3.57 mmol,
2.5 equiv). After stirring at rt for 5 min, concd HCl (1 drop) was added,
and the resulting solution was stirred at rt for 45 h, and filtered. The
filtered white solid was re-suspended in THF (4.76 mL), treated with
concd HCl (2 drops), stirred at 50 °C for 1 h, and at rt for an additional
3 h. The solvent was evaporated, and the crude residue was purified by
chromatography on SiO2 (hexanes/EtOAc, 3:2) to yield methyl 4-([1,
10-biphenyl]-4-yl)-1-(4-cyanobenzyl)-6-methyl-2-oxo-1,2,3,4-tet-
rahydropyrimidine-5-carboxylate (0.560 g, 1.28 mmol, 90%) as a
colorless solid: Mp 180–181 °C; 1H NMR (400 MHz, CDCl3) d 7.60–
7.52 (m, 6H), 7.46 (t, 2H, J = 7.6 Hz), 7.37 (t, 1H, J = 7.2 Hz), 7.32 (d,
2H, J = 8.0 Hz), 7.23 (d, 2H, J = 8.0 Hz), 5.69 (d, 1H, J = 2.8 Hz), 5.52
(d, 1H, J = 2.8 Hz), 5.17, 5.01 (ABq, 2H, J = 16.8 Hz), 3.69 (s, 3H),
4.1.6. Benzyl 1-(5-(1H-tetrazol-5-yl)pentyl)-4-(40-fluoro-[1,10-
biphenyl]-4-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylate (LR340-001)
2.42 (s, 3H); HRMS (ESI) m/z calcd for
C
27H24N3O3 [M+H]+
438.1818, found 438.1830.
A mixture of methyl 4-([1,10-biphenyl]-4-yl)-1-(4-cyanoben-
zyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(0.200 g, 0.457 mmol), 1 M TBAF in THF (0.457 mL, 0.457 mmol,
1 equiv), and TMSN3 (0.248 mL, 1.83 mmol, 4 equiv) was stirred
at 90 °C for 24 h in a sealed vial. The solution was diluted with
EtOAc and H2O, and the aqueous layer was extracted with EtOAc
(3ꢁ). The combined organic layers were washed with H2O (3ꢁ)
and NaHSO4 (1 M, 3ꢁ), dried (Na2SO4), filtered, and concentrated
to obtain a crude residue that was washed with MTBE (3ꢁ), dis-
tilled hexanes (3ꢁ), and recrystallized (EtOAc) to obtain ML282-
60 (0.153 g, 0.319 mmol, 70%) as a colorless solid: Mp 193–
195 °C; ATR IR (neat) 3208, 3057, 2731, 1700, 1692, 1642, 1501,
1486, 1447, 1430, 1419, 1380, 1366, 1325, 1311, 1204,
To a suspension of 1-(5-cyanopentyl)urea (0.520 g, 3.05 mmol)
and 4-bromobenzaldehyde (0.837 g, 4.52 mmol, 1.5 equiv) in THF
(4.0 mL) were added benzyl acetoacetate (0.81 mL, 4.52 mmol,
1.5 equiv) and concd HCl (0.070 mL, 0.603 mmol). The suspension
was stirred at rt for 18 h, diluted with ether and the precipitate was
collected by filtration and dried under vacuum to give benzyl 4-(4-
bromophenyl)-1-(5-cyanopentyl)-6-methyl-2-oxo-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate (1.03 g, 2.08 mmol, 69%) as a white
solid: Mp 156–157 °C; 1H NMR (400 MHz, CDCl3) d 7.37 (d, 2H,
J = 8.4 Hz), 7.32–7.30 (m, 3H), 7.16–7.13 (m, 2H), 7.03 (d, 2H,
J = 8.4 Hz), 5.35–5.33 (m, 1H), 5.15, 5.01 (ABq, 2H, J = 12.4 Hz),
3.86 (ddd, 1H, J = 14.8, 9.2, 5.6 Hz), 3.62 (ddd, 1H, J = 14.6, 9.2,
5.4 Hz), 2.54 (s, 3H), 2.32 (t, 2H, J = 7.0 Hz), 1.70–1.49 (m, 4H),
1.44–1.36 (m, 2H); 13C NMR (100 MHz, CDCl3) d 165.7, 153.2,
149.6, 142.4, 135.9, 131.9, 128.7, 128.7, 128.4, 121.2, 121.9,
119.6, 103.9, 66.4, 53.6, 42.5, 29.1, 25.9, 25.1, 17.2, 16.4; HRMS
(ESI) m/z calcd for C25H26N3O3BrNa [M+Na]+ 518.1055, found
518.1094.
; d 8.27 (d, 1H,
1186 cmꢂ1 1H NMR (300 MHz, d6-DMSO)
J = 3.6 Hz), 7.97 (d, 2H, J = 8.1 Hz), 7.63 (dd, 4H, J = 7.8, 3.6 Hz),
7.46 (t, 2H, J = 7.5 Hz), 7.39–7.31 (m, 5H), 5.31 (d, 1H, J = 3.3 Hz),
5.16, 4.97 (ABq, 1H, J = 16.8 Hz), 3.60 (s, 3H), 2.41 (s, 3H); 13C
NMR (75 MHz, d6-DMSO) d 166.1, 155.1, 153.0, 149.7, 142.8,
142.1, 139.8, 139.5, 128.9, 127.5, 127.2, 126.9, 126.7, 122.8,
103.3, 52.1, 51.3, 45.0, 16.2; HRMS (ESI) m/z calcd for C27H25N6O3
[M+H]+ 481.1988, found 481.1949.
To a suspension of benzyl 4-(4-bromophenyl)-1-(5-cyanopen-
tyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(1.00 g, 2.01 mmol) and di-N-butyltin oxide (51.2 mg, 0.201 mmol,
0.1 equiv) in toluene (4 mL) was added TMSN3 (0.56 mL,
4.03 mmol, 2 equiv). The mixture was heated in a sealed vial to
4.1.5. Benzyl 1-(2-(1H-tetrazol-5-yl)ethyl)-4-([1,10-biphenyl]-4-
yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(ML282-61)
110 °C for 24 h. Additional TMSN3 (250 lL, 1.89 mmol) was added
and heating was continued at 110 °C for 18 h. After addition of hex-
anes, the precipitate was collected by filtration, washed several
times with hexanes and recrystallized from a MeOH/H2O solution
to provide benzyl 1-(5-(1H-tetrazol-5-yl)pentyl)-4-(4-bromophe-
nyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(0.650 g, 1.21 mmol, 60%) as a white solid: Mp 174–176 °C; ATR IR
(neat) 3059, 2934, 1705, 1681, 1604, 1420, 1216, 1192, 1128, 1094,
A suspension of 1-(2-cyanoethyl)urea (0.200 g, 1.77 mmol) in
THF (5.89 mL) was treated with 4-biphenylcarboxaldehyde
(0.805 g, 4.42 mmol, 2.5 equiv) and benzyl acetoacetate (0.789 mL,
4.43 mmol, 2.5 equiv) and stirred at rt for 5 min. After addition of
concd HCl (1 drop), the resulting solution was stirred at rt for
48 h, concentrated to remove solvent and subsequently purified
by chromatography on SiO2 (hexanes/EtOAc, 3:2–1:1) to obtain
benzyl 4-([1,10-biphenyl]-4-yl)-1-(2-cyanoethyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (0.365 g, 0.808 mmol,
46%) as a colorless solid: 1H NMR (400 MHz, CDCl3) d 7.57–7.55
(m, 2H), 7.52–7.50 (m, 2H), 7.45 (t, 2H, J = 7.4 Hz), 7.36 (t, 1H,
J = 7.4 Hz), 7.28–7.25 (m, 5H), 7.14–7.12 (m, 2H), 5.44 (d, 1H,
J = 2.4 Hz), 5.38 (br s, 1H), 5.12, 5.06 (ABq, 2H, J = 12.4 Hz), 4.12,
4.02 (t of ABq, 2H, J = 7.0, 14.4 Hz), 2.81, 2.70 (t of ABq, 2H, J = 7.2,
839, 798, 768, 734 cmꢂ1 1H NMR (300 MHz, d6-DMSO) d 7.98 (d,
;
1H, J = 3.6 Hz), 7.48 (d, 2H, J = 8.4 Hz), 7.30–7.23 (m, 3H), 7.17–
7.13 (m, 2H), 7.11 (d, 2H, J = 8.4 Hz), 5.15–5.10 (m, 1H), 5.11,
5.01 (ABq, 2H, J = 12.6 Hz), 3.84–3.74 (m, 1H), 3.50–3.41 (m, 1H),
2.78 (t, 2H, J = 7.4 Hz), 2.49 (s, 3H), 1.67–1.58 (m, 2H), 1.50–1.34
(m, 2H), 1.17–1.20 (m, 2H); 13C NMR (100 MHz, d6-DMSO) d
165.2, 155.8, 152.4, 150.9, 143.2, 136.3, 131.3, 128.4, 128.3,
127.9, 127.7, 120.5, 102.0, 65.2, 51.8, 41.6, 28.8, 26.6, 25.5, 22.6,