T. Yukawa et al. / Bioorg. Med. Chem. 24 (2016) 3207–3217
3213
poured into water, extracted with EtOAc, washed with water and
5.1.18. N-(((6S,7R)-7-(3,4-Dichlorophenyl)-1,4-oxazepan-6-yl)
brine, dried over MgSO4 and concentrated in vacuo. The residue
was purified by column chromatography (silica gel, EtOAc/MeOH)
to give 26b (7.18 g, 95%) as a colorless oil. 1H NMR (300 MHz,
CDCl3) d 1.51 (9H, s), 1.83–2.12 (1H, m), 2.44–2.68 (2H, m), 3.24–
3.46 (1H, m), 3.47–4.24 (6H, m), 7.04 (1H, d, J = 7.5 Hz), 7.15 (1H,
d, J = 9.8 Hz), 7.31–7.43 (1H, m). MS m/z: 359.2 [M+H]+.
methyl)benzamide hydrochloride (4)
Typical procedure B, 94%, colorless solid. 1H NMR (300 MHz,
DMSO-d6) d 2.68–2.86 (1H, m), 3.00–3.31 (5H, m), 3.34 (1H, s),
3.71–3.91 (1H, m), 3.98 (1H, br s), 4.48 (1H, d, J = 9.8 Hz),7.38–
7.57 (4H, m), 7.66 (1H, d, J = 8.3 Hz), 7.75–7.91 (3H, m), 8.69 (1H,
s), 9.01–9.82 (2H, m). MS m/z: 379.0 [M+H]+.
5.1.13. (6R,7R)-tert-Butyl 7-(3,4-dichlorophenyl)-6-(propiona-
midomethyl)-1,4-oxazepane-4-carboxylate
To a solution of 26b (150 mg, 0.40 mmol) in THF (3 mL) was
added Et3N (84 lL, 0.60 mmol) and propionyl chloride (52 lL,
5.1.19. (6R,7R)-tert-Butyl 7-(3,4-dichlorophenyl)-6-((2-methoxy-
acetamido)methyl)-1,4-oxazepane-4-carboxylate
96%, colorless powder. 1H NMR (300 MHz, CDCl3) d 1.50 (11H,
s), 2.20–2.40 (1H, m), 2.91–3.09 (1H, m), 3.12–3.96 (9H, m), 4.03
(1H, d, J = 9.1 Hz), 4.07–4.17 (1H, m), 7.23 (1H, d, J = 8.3 Hz),
7.37–7.59 (3H, m).
0.60 mmol) and stirred at room temperature overnight. The mix-
ture was poured into water, extracted with EtOAc, washed with
water and brine, dried over MgSO4 and concentrated in vacuo.
The residue was purified by column chromatography (silica gel,
hexane/EtOAc) to give (6R,7R)-tert-butyl 7-(3,4-dichlorophenyl)-
6-(propionamidomethyl)-1,4-oxazepane-4-carboxylate (116 mg,
67%) as a colorless oil. 1H NMR (300 MHz, CDCl3) d 1.15 (3H, t,
J = 7.6 Hz), 1.51 (9H, s), 2.11–2.32 (3H, m), 2.92–3.09 (1H, m),
3.09–3.24 (1H, m), 3.24–3.42 (2H, m), 3.46–3.61 (1H, m), 3.92–
4.19 (4H, m), 7.12 (1H, br s), 7.24 (1H, d, J = 1.9 Hz), 7.42 (1H, d,
J = 8.3 Hz), 7.52 (1H, s). MS m/z: 431.0 [M+HꢀBoc]+.
5.1.20. N-(((6S,7R)-7-(3,4-Dichlorophenyl)-1,4-oxazepan-6-yl)
methyl)-2-methoxyacetamide hydrochloride (5)
Typical procedure A, 56%, colorless solid. 1H NMR (300 MHz,
DMSO-d6) d 2.61 (1H, d, J = 8.7 Hz), 2.85 (1H, dt, J = 14.0, 4.7 Hz),
2.95–3.30 (7H, m), 3.71–3.88 (4H, m), 3.91–4.05 (1H, m), 4.39
(1H, d, J = 9.8 Hz), 7.45 (1H, dd, J = 8.3, 1.9 Hz), 7.63–7.71 (1H, m),
7.76 (1H, d, J = 2.3 Hz), 8.06 (1H, t, J = 6.0 Hz), 9.20 (2H, br s). MS
m/z: 347.3 [M+H]+.
5.1.14. N-(((6S,7R)-7-(3,4-Dichlorophenyl)-1,4-oxazepan-6-yl)
methyl)propionamide hydrochloride (2)
5.1.21. (6R,7R)-tert-Butyl 7-(4-chloro-3-fluorophenyl)-6-((2-
methoxyacetamido)methyl)-1,4-oxazepane-4-carboxylate
71%, colorless oil. 1H NMR (300 MHz, CDCl3) d 1.50 (9H, s), 2.21–
2.37 (1H, m), 2.94–3.97 (12H, m), 4.01–4.18 (2H, m), 6.49–7.56
(4H, m). MS m/z: 431.2 [M+H]+.
4 M HCl–EtOAc (4 mL, 16.0 mmol) was added to (6R,7R)-tert-
butyl 7-(3,4-dichlorophenyl)-6-(propionamidomethyl)-1,4-oxaze-
pane-4-carboxylate (116 mg, 0.27 mmol) and stirred at room
temperature for 1 h. The mixture was concentrated in vacuo and
the residue was washed with Et2O to give 2 (38.0 mg, 38%) as
amorphous solid. 1H NMR (300 MHz, DMSO-d6) d 0.96 (3H, t,
J = 7.6 Hz), 1.96–2.12 (2H, m), 2.57 (1H, dd, J = 9.8, 6.4 Hz), 2.87
(2H, t, J = 5.9 Hz), 2.99–3.33 (4H, m), 3.71–3.90 (1H, m), 3.99 (1H,
dt, J = 13.7, 4.5 Hz), 4.39 (1H, d, J = 10.2 Hz), 7.45 (1H, dd, J = 8.3,
1.9 Hz), 7.67 (1H, d, J = 8.3 Hz), 7.76 (1H, d, J = 1.9 Hz), 8.01
(1H, t, J = 5.7 Hz), 9.17 (1H, br s), 9.65 (1H, br s). MS m/z: 331.3
[M+H]+.
5.1.22. N-(((6S,7R)-7-(4-Chloro-3-fluorophenyl)-1,4-oxazepan-
6-yl)methyl)-2-methoxyacetamide hydrochloride (6)
Typical procedure A, 76%, colorless crystal. 1H NMR (300 MHz,
DMSO-d6) d 2.55–2.69 (1H, m), 2.80–2.90 (1H, m), 2.95–3.31 (8H,
m), 3.72–3.85 (3H, m), 3.92–4.01 (1H, m), 4.39 (1H, d,
J = 10.2 Hz), 7.33 (1H, dd, J = 8.3, 1.5 Hz), 7.55 (1H, dd, J = 10.6,
1.5 Hz), 7.58–7.66 (1H, m), 8.00–8.14 (1H, m), 8.92–9.58 (2H, m).
MS m/z: 331.1 [M+H]+. Mp: 178.0–178.7 °C. Anal. Calcd for C15H21
-
Compounds 3–6 were prepared in same manner using 26a or
26b.
Cl2N2O3F: C, 49.06; H, 5.76; N, 7.63. Found: C, 49.30; H, 5.60; N,
25
7.44. [
a
]
D
+5.2 (c 0.25, MeOH).
5.1.15. (6R,7R)-tert-Butyl 6-(butyramidomethyl)-7-(3,4-dichloro-
phenyl)-1,4-oxazepane-4-carboxylate
5.1.23. (6R,7R)-tert-Butyl 7-(4-chloro-3-fluorophenyl)-6-((3-
methoxypropanamido)methyl)-1,4-oxazepane-4-carboxylate
To a mixture of 26b (100 mg, 0.28 mmol), 3-methoxypropionic
72%, colorless oil. 1H NMR (300 MHz, CDCl3) d 0.90–1.03 (3H,
m), 1.45–1.56 (9H, m), 1.60–1.67 (2H, m), 2.09–2.21 (2H, m),
2.21–2.33 (1H, m), 2.81–3.21 (2H, m), 3.21–3.41 (2H, m), 3.43–
3.60 (1H, m), 3.91–4.21 (4H, m), 7.04–7.19 (1H, m), 7.21–7.27
(1H, m), 7.42 (1H, d, J = 8.3 Hz), 7.51 (1H, s). MS m/z: 445.1 [M+H]+.
acid (31.4
Et3N (97
l
L, 0.33 mmol), HOBtꢂH2O (45.2 mg, 0.33 mmol) and
lL, 0.70 mmol) in THF (1.4 mL) was added WSCꢂHCl
(64.1 mg, 0.33 mmol). The mixture was stirred at room tempera-
ture for 3 h, and then poured into water and extracted with EtOAc.
The organic layer was separated, washed with water and brine,
dried over Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, Hexane/EtOAc) to
give (6R,7R)-tert-butyl 7-(4-chloro-3-fluorophenyl)-6-((3-methox-
5.1.16. N-(((6S,7R)-7-(3,4-Dichlorophenyl)-1,4-oxazepan-6-yl)
methyl)butyramide hydrochloride (3)
Typical procedure B, 77%, colorless solid. 1H NMR (300 MHz,
DMSO-d6) d 0.83 (3H, t, J = 7.4 Hz), 1.47 (2H, sxt, J = 7.4 Hz), 2.01
(2H, t, J = 7.4 Hz), 2.58 (1H, d, J = 2.6 Hz), 2.76–3.01 (2H, m),
3.02–3.36 (4H, m), 3.69–3.91 (1H, m), 4.00 (1H, dt, J = 13.9,
4.2 Hz), 4.39 (1H, d, J = 10.2 Hz), 7.35–7.52 (1H, m), 7.60–7.72
(1H, m), 7.76 (1H, d, J = 1.9 Hz), 8.04 (1H, t, J = 5.9 Hz), 9.22 (1H,
br s), 9.73 (1H, br s). MS m/z: 345.5 [M+H]+.
ypropanamido)methyl)-1,4-oxazepane-4-carboxylate
(81 mg,
65%) as a colorless oil. 1H NMR (300 MHz, CDCl3) d 1.50 (9H, s),
2.20–2.49 (3H, m), 2.94–3.40 (7H, m), 3.47–3.74 (3H, m), 3.91–
4.16 (4H, m), 6.13–7.47 (4H, m). MS m/z: 445.4 [M+H]+.
5.1.24. N-(((6S,7R)-7-(4-Chloro-3-fluorophenyl)-1,4-oxazepan-
6-yl)methyl)-3-methoxypropanamide hydrochloride (7)
Typical procedure B, 81%, colorless solid. 1H NMR (300 MHz,
DMSO-d6) d 2.28 (2H, t, J = 6.4 Hz), 2.53–2.64 (1H, m), 2.81–2.95
(2H, m), 3.05–3.39 (7H, m), 3.49 (2H, t, J = 6.4 Hz), 3.72–3.85 (1H,
m), 3.94–4.06 (1H, m), 4.38 (1H, d, J = 10.2 Hz), 7.33 (1H, d,
J = 8.3 Hz), 7.53 (1H, dd, J = 10.6, 1.5 Hz), 7.59–7.67 (1H, m), 8.01–
8.18 (1H, m), 8.88–9.77 (2H, m). MS m/z: 345.4 [M+H]+.
5.1.17. (6R,7R)-tert-Butyl 6-(benzamidomethyl)-7-(3,4-
dichlorophenyl)-1,4-oxazepane-4-carboxylate
81%, colorless powder. 1H NMR (300 MHz, CDCl3) d 1.49 (9H, s),
2.41 (1H, td, J = 7.7, 4.2 Hz), 3.03–3.26 (2H, m), 3.38 (1H, dd,
J = 14.7, 4.5 Hz), 3.45–3.81 (2H, m), 3.96–4.27 (4H, m), 7.29 (1H,
d, J = 2.3 Hz), 7.37–7.50 (4H, m), 7.50–7.62 (1H, m), 7.88 (2H, d,
J = 7.2 Hz), 8.02 (1H, br s). MS m/z: 479.3 [M+H]+.
Compounds 9–15 were prepared in same manner using 26b.