T. Imaizumi, et al.
Bioorganic&MedicinalChemistry27(2019)115091
analogous to the preparation of 21a. The crude material was purified by
silica gel column chromatography eluted with 10–20% AcOEt in hep-
tane to afford the titled compound (1.31 g, 54%) as a yellow oil. 1H
NMR (400 MHz, CDCl3) δ: 8.20 (d, J = 2.0 Hz, 1H), 8.00 (dd, J = 8.8,
2.0 Hz, 1H), 7.49 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.27 (d,
J = 7.8 Hz, 2H), 5.66 (q, J = 7.2 Hz, 1H), 3.37–3.29 (m, 1H), 3.24–3.15
(m, 1H), 1.70 (d, J = 6.8 Hz, 3H), 1.64–1.43 (m, 2H), 1.33–1.22 (m,
132.1, 131.0, 130.5, 130.5, 128.9(2C), 127.7, 126.9(2C), 123.5, 120.8,
116.1, 108.2, 55.4, 44.4, 42.4, 30.9, 25.6, 19.5, 17.1, 13.6.
m.p.:103–105 °C. LC-MS (ESI) m/z = 510 [M + H]+. Purity: 99.9%.
HR-LC-MS (ESI) m/z [M + H] + calcd, 510.2617; found, 510.2618.
5.1.27. (R)-1-({N-[1-(4-bromophenyl)ethyl]-N-butyl-2-aminobenzo[d]
oxazol-5-yl}methyl)-3-methylurea (26)
2H), 0.88 (t, J = 7.3 Hz, 3H). LC-MS (ESI) m/z = 418 [M + H]+
.
Compound 22 (300 mg, 0.696 mmol) was suspended in toluene
(5 mL). To this suspension was added Et3N (0.291 mL, 2.09 mmol) and
DPPA (0.449 mL, 2.09 mmol). After stirring for 5 h at 110 °C, methy-
lamine (2.0 M THF solution 1.74 mL, 3.48 mmol) was added at 0 °C.
After stirring for 18 h at room temperature, saturated NaHCO3 was
added. The mixture was extracted with CHCl3, dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The crude material
was purified by silica gel column chromatography eluted with 5–10%
MeOH in CHCl3 to afford the titled compound (223 mg, 70%) as a
colorless oil. 1H NMR (400 MHz, CDCl3) δ: 7.45 (d, J = 8.8 Hz, 2H),
7.27 (s, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 7.8 Hz, 1H), 6.90 (d,
J = 7.8 Hz, 1H), 5.64–5.56 (m, 1H), 5.44 (br s, 1H), 5.07 (br s, 1H),
4.33 (d, J = 3.9 Hz, 2H), 3.32–3.08 (m, 2H), 2.71 (d, J = 4.9 Hz, 3H),
1.65 (d, J = 6.8 Hz, 3H), 1.44–1.57 (m, 2H), 1.19–1.29 (m, 2H), 0.86 (t,
5.1.23. (R)-2-{N-[1-(4-bromophenyl)ethyl]-N-butyl-2-aminobenzo[d]
oxazol-5-yl}-acetic acid (22)
Compound 21a (1.32 g, 2.96 mmol) was dissolved in EtOH (15 mL).
To this solution was added 3 M NaOH (5 mL). After stirring for 3 h at
50 °C, 3 M HCl was added at 0 °C. The mixture was extracted with
CHCl3, dried over MgSO4, filtered, and concentrated under reduced
pressure to afford the titled compound (1.16 g, 91%) as a brown solid.
1H NMR (400 MHz, DMSO‑d6) δ: 7.57 (d, J = 8.6 Hz, 2H), 7.41–7.36
(m, 3H), 7.23 (s, 1H), 6.95 (dd, J = 8.4, 1.6 Hz, 1H), 5.55–5.49 (m,
1H), 3.61 (s, 2H), 3.41–3.23 (m, 2H), 1.67 (d, J = 6.8 Hz, 3H),
1.59–1.15 (m, 4H), 0.82 (t, J = 7.2 Hz, 3H). LC-MS (ESI) m/z = 431
[M + H]+
.
J = 7.3 Hz, 3H). LC-MS (ESI) m/z = 459 [M + H]+
.
5.1.24. (R)-2-{N-[1-(4-bromophenyl)ethyl]-N-butyl-2-aminobenzo[d]
oxazol-5-yl}-N-methylacetamide (23)
Compound 22 (512 mg, 1.19 mmol) was dissolved in DMF (10 mL).
To this solution was added methylamine (2.0 M THF solution, 2.97 mL,
5.94 mmol), HOBt・H2O (545 mg, 3.56 mmol) and EDCI·HCl (683 mg,
3.56 mmol). After stirring for 24 h at room temperature, saturated
NH4Cl was added. The mixture was extracted with CHCl3, dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
material was purified by silica gel column chromatography eluted with
5–10% MeOH in CHCl3 to afford the titled compound (491 mg, 93%) as
a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 7.47 (d, J = 8.8 Hz, 2H),
7.31–7.21 (m, 4H), 6.89 (d, J = 8.8 Hz, 1H), 5.67–5.61 (m, 2H), 3.62
(s, 2H), 3.36–3.11 (m, 2H), 2.74 (d, J = 4.9 Hz, 3H), 1.68 (d,
J = 6.8 Hz, 3H), 1.59–1.45 (m, 2H), 1.31–1.21 (m, 2H), 0.87 (t,
5.1.28. (R)-1-({N-butyl-N-[1-(2′-cyano-[1,1′-biphenyl]-4-yl)ethyl]-2-
aminobenzo[d]oxazol-5-yl}methyl)-3-methylurea (27)
The titled compound was synthesized from compound 26 (223 mg,
0.485 mmol) by a process analogous to the preparation of 5b. The crude
material was purified by silica gel column chromatography eluted with
5–10% MeOH in CHCl3 to afford the titled compound (231 mg, 99%) as
a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 7.75 (d, J = 7.8 Hz, 1H),
7.66–7.62 (m, 1H), 7.55–7.41 (m, 6H), 7.31–7.26 (m, 1H), 7.17 (d,
J = 8.8 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 5.76–5.68 (m, 1H), 5.43 (br s,
1H), 5.06 (br s, 1H), 4.35 (d, J = 5.9 Hz, 2H), 3.40–3.32 (m, 1H),
3.25–3.17 (m, 1H), 2.71 (d, J = 4.9 Hz, 3H), 1.73 (d, J = 7.8 Hz, 3H),
1.60–1.48 (m, 2H), 1.31–1.21 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H). LC-MS
J = 7.3 Hz, 3H). LC-MS (ESI) m/z = 444 [M + H]+
.
(ESI) m/z = 482 [M + H]+
.
5.1.25. (R)-2-{N-butyl-N-[1-(2′-cyano-[1,1′-biphenyl]-4-yl)ethyl]-2-
aminobenzo[d]oxazol-5-yl}-N-methylacetamide (24)
5.1.29. (R)-1-[(N-butyl-N-{1-[2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl]
ethyl}-2-aminobenzo[d]oxazol-5-yl)methyl]-3-methylurea (28)
The titled compound was synthesized from compound 23 (490 mg,
1.10 mmol) by a process analogous to the preparation of 5b. The crude
material was purified by silica gel column chromatography eluted with
5–10% MeOH in CHCl3 to afford the titled compound (511 mg, 99%) as
a yellow oil.1H-NMR (300 MHz, CDCl3) δ: 7.75 (dd, J = 7.7, 1.3 Hz,
1H), 7.63 (ddd, J = 7.7, 7.7, 1.3 Hz, 1H), 7.56–7.47 (m, 5H), 7.43 (ddd,
J = 7.7, 7.7, 1.3 Hz, 1H), 7.24–7.21 (m, 2H), 6.87 (dd, J = 8.2, 1.6 Hz,
1H), 5.75 (q, J = 7.1 Hz, 1H), 5.56 (br s, 1H), 3.61 (s, 2H), 3.43–3.16
(m, 2H), 2.72 (d, J = 5.1 Hz, 3H), 1.73 (d, J = 7.3 Hz, 3H), 1.62–1.47
(m, 2H), 1.32–1.20 (m, 2H), 0.86 (t, J = 7.1 Hz, 3H). LC-MS (ESI) m/
The titled compound was synthesized from compound 27 (220 mg,
0.457 mmol) by a process analogous to the preparation of 6b. The crude
material was purified by silica gel column chromatography eluted with
5–10% to afford the titled compound (123 mg, 51%) as a yellow solid.
1H NMR (400 MHz, CDCl3) δ: 7.82 (d, J = 6.8 Hz, 1H), 7.58–7.53 (m,
1H), 7.49–7.40 (m, 2H), 7.16–7.03 (m, 6H), 6.81 (d, J = 8.8 Hz, 1H),
5.57–5.51 (m, 1H), 5.38–5.31 (m, 2H), 4.24–4.09 (m, 2H), 3.43–3.33
(m, 1H), 3.23–3.14 (m, 1H), 2.56 (s, 3H), 1.63–1.52 (m, 5H), 1.32–1.24
(m, 2H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, DMSO‑d6) δ:
162.5, 158.7, 155.1, 147.2, 143.3, 141.1, 140.0, 138.5, 137.0, 131.2,
130.7, 129.5, 129.0(2C), 127.9, 127.0(2C), 123.5, 119.1, 114.4, 108.3,
55.5, 44.4, 43.2, 31.0, 26.5, 19.6, 17.3, 13.7. m.p.:111–113 °C. LC-MS
z = 467 [M + H]+
.
5.1.26. (R)-2-(N-butyl-N-{1-[2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl]
ethyl}-2-aminobenzo[d]oxazol-5-yl)-N-methylacetamide (25)
(ESI) m/z = 525 [M + H]+
.
Purity: 96.9%. HR-LC-MS (ESI) m/z
+
[M + H] calcd, 525.2726; found, 525.2729.
The titled compound was synthesized from compound 24 (500 mg,
1.07 mmol) by a process analogous to the preparation of 6b. The crude
material was purified by silica gel column chromatography eluted with
5–10% MeOH in CHCl3 to afford the titled compound (475 mg, 87%) as
a white solid. 1H NMR (400 MHz, CDCl3) δ: 7.93 (d, J = 7.8 Hz, 1H),
7.61 (dd, J = 7.8, 7.8 Hz, 1H), 7.53 (dd, J = 7.8, 7.8 Hz, 1H), 7.45 (d,
J = 7.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 7.8 Hz, 1H), 7.14
(d, J = 7.8 Hz, 2H), 6.94 (s, 1H), 6.86–6.83 (m, 1H), 5.60 (br s, 1H),
5.45 (q, J = 6.8 Hz, 1H), 3.48 (s, 2H), 3.39–3.31 (m, 1H), 3.20–3.13 (m,
1H), 2.67 (d, J = 4.9 Hz, 3H), 1.65 (d, J = 6.8 Hz, 3H), 1.60–1.48 (m,
2H), 1.32–1.22 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz,
DMSO‑d6) δ: 170.8, 162.3, 157.1, 147.1, 143.2, 141.0, 139.9, 138.4,
5.1.30. (R)-N-[1-(4-bromophenyl)ethyl]-N-butyl-2-aminobenzo[d]
oxazole-5-carboxylic acid (29)
The titled compound (1.54 g, quant., as a brown solid) was syn-
thesized from compound 21b (1.52 g, 3.52 mmol) by a process analo-
gous to the preparation of 22. 1H NMR (400 MHz, DMSO‑d6) δ: 7.80 (d,
J = 2.0 Hz, 1H), 7.68 (dd, J = 7.8, 2.0 Hz, 1H), 7.57 (d, J = 8.4 Hz,
2H), 7.50 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 5.56–5.49 (q,
J = 6.8 Hz, 1H), 3.41–3.23 (m, 2H), 1.67 (d, J = 6.8 Hz, 3H), 1.59–1.36
(m, 2H), 1.29–1.18 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H). LC-MS (ESI) m/
z = 417 [M + H]+
.
9