8
M. Cellier et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
6 3
d ), 7.61–7.68
-DMSO) d 10.92 (1H, br s, NH), 8.35 (3H, br s, NH+
5
.10. tert-Butyl N-[(1S)-1-({4-[2-(1,3-Benzothiazol-2-yl)phenoxy-
methyl]phenyl}carbamoyl)ethyl]carbamate (17d)
(3H, m, Ar-H), 7.41 (2H, d, J = 8.7 Hz, Ar-H), 7.02 (1H, d, J = 2.3 Hz,
Ar-H), 6.97 (1H, dd, J = 8.7 Hz, 2.3 Hz, Ar-H), 6.17 (1H, d,
A mixture of 2-(2-hydroxyphenyl)benzothiazole 16d (0.33 g,
J = 0.9 Hz, Ar-H), 5.13 (2H, s, CH
(3H, s, CH ), 1.43 (3H, d, J = 6.9 Hz, CH
-DMSO) d 168.9 (C@O), 161.8 (C@O), 160.7 (Ar-C), 155.2 (Ar-C),
2
), 4.01–4.13 (1H, m, CH), 2.35
1
3
1
(
.47 mmol), compound 15 (0.46 g, 1.47 mmol) and Cs
2
CO
3
3
3
); C NMR (101 MHz,
0.48 g, 1.47 mmol) was stirred (6 h) in dry DMF (20 mL) at 90 °C.
d
6
The mixture was allowed to cool to room temperature and the sol-
vent was evaporated. EtOAc (30 mL) was added to the residue and
the resulting mixture was washed successively with 10% aq
154.0 (Ar-C), 138.8 (Ar-C), 132.2 (Ar-C), 129.3 (2 ꢁ Ar-C), 127.0
(Ar-C), 119.9 (2 ꢁ Ar-C), 113.8 (Ar-C), 113.3 (Ar-C), 111.8 (Ar-C),
2 3 3
102.2 (Ar-C), 70.1 (CH ), 18.7 (CH ), 17.8 (CH ); IR mmax 3600–
+
NaHCO
was dried (MgSO
column chromatography (SiO
98:2)) giving compound 17d as a white powder (0.27 g, 84%),
3
solution (40 mL) and water (40 mL). The organic fraction
) and evaporated. The residue was purified by
, CH Cl changing to CH Cl –MeOH
3
2550 (br, NH and NH ), 1682 (C@O), 1606 (C@O), 1514, 1395,
ꢀ1
+
4
1260, 836 cm ; HRMS calcd for C20
353.1495.
21 2 4
H N O [M] 353.1496; found
2
2
2
2
2
(
1
mp 102 °C; H NMR (400 MHz, d
8
7
6
-DMSO) d 10.04 (1H, s, NH),
.46 (1H, dd, J = 7.8 and 1.8 Hz, Ar-H), 8.12–8.03 (2H, m, Ar-H),
.67 (2H, d, J = 8.7 Hz, Ar-H), 7.57–7.50 (4H, m, Ar-H), 7.44–7.38
5.13. (2S)-2-Amino-N-(4-{[(4-oxo-2-phenyl-4H-chromen-7-yl)
oxy]methyl}phenyl)propanamide Hydrochloride (18b)
(
2H, m, Ar-H), 7.17 (1H, t, J = 7.1 Hz, Ar-H), 7.12 (1H, J = 7.3 Hz,
NH), 5.39 (2H, s, CH ), 4.13 (1H, dt, J = 7.1 Hz, CH), 1.39 (9H, s,
ꢁ CH ), 1.27 (3H, d, J = 6.9 Hz, CH
DMSO) d 172.5 (C@O), 162.7 (C@O), 156.4 (Ar-C), 155.7 (Ar-C),
52.0 (Ar-C), 139.6 (Ar-C), 136.0 (Ar-C), 132.8 (Ar-C), 131.2 (Ar-
C), 129.5 (2 ꢁ Ar-C), 129.4 (Ar-C), 126.8 (Ar-C), 125.4 (Ar-C),
22.9 (Ar-C), 122.4 (Ar-C), 122.0 (Ar-C), 121.7 (Ar-C), 119.6
), 70.7 (CH O), 51.0 (CHCH ),
max 3360–3250 (br, NH), 2982, 1669
Compound 17b (0.24 g, 0.47 mmol) was stirred (1 h) in anhy-
drous EtOAc/HCl (10 mL) at room temperature. The resulting pre-
cipitate was collected and dried giving compound 18b as an
2
13
3
3
3 6
); C NMR (101 MHz, d -
1
orange powder (0.20 g, 95%), mp 98–100 °C; H NMR (400 MHz
6 3
d ), 8.10
-DMSO) d 11.05 (1H, s, NH), 8.45 (3H, d, J = 3.7 Hz, NH+
1
(2H, dd, J = 7.3 and 1.8 Hz, Ar-H), 7.97 (1H, d, J = 8.7 Hz, Ar-H),
7.75 (2H, d, J = 8.7 Hz, Ar-H), 7.63–7.56 (3H, m, Ar-H), 7.51 (2H,
d, J = 8.7 Hz, Ar-H), 7.44 (1H, d, J = 2.3 Hz, Ar-H), 7.14 (1H, dd,
1
(
2
2 ꢁ Ar-C), 114.4 (Ar-C), 78.6 (C(CH
3
)
3
2
3
8.7 (C(CH
3
)
3
), 18.5 (CH
3
); IR
m
J = 8.7 and 2.3 Hz, Ar-H), 6.99 (1H, s, Ar-H), 5.25 (2H, s, CH
2
),
); C NMR
-DMSO) d 176.9 (C@O), 168.9 (C@O), 163.4 (Ar-C),
62.7 (Ar-C), 157.9 (Ar-C), 138.9 (Ar-C), 132.2 (Ar-C), 132.0
ꢀ1
13
(
C@O), 1601 (C@O), 1510, 1499, 1244, 1161, 754 cm ; LRMS calcd
4.17–4.10 (1H, m, CH), 1.50 (3H, d, J = 6.9 Hz, CH
(101 MHz, d
3
+
for C28
H
29
N
3
O
4
SNa [M+Na] 526.60; found 526.13.
6
1
(
Ar-C), 131.7 (Ar-C), 129.63 (2 ꢁ Ar-C), 129.3 (2 ꢁ Ar-C), 126.7
5
.11. tert-Butyl N-[(1S)-1-{[4-({[6-(1,3-Benzothiazol-2-yl)naph-
thalen-2-yl]oxy}methyl)phenyl]carbamoyl}ethyl]carbamate
17e)
(
-CH=), 119.9 (2 ꢁ Ar-C), 117.8 (Ar-C), 115.7 (Ar-C), 107.3 (Ar-C),
1
2
1
C
2 3 3
02.5 (Ar-C), 70.3 (CH ), 49.4 (CHCH ), 17.8 (CH ); IR mmax 3600–
(
+
250 (br, NH
3
NH), 1693 (C@O), 1614 (C@O), 1515, 1450, 1378,
ꢀ
1
246, 1173, 1092, 829, 772, 674 cm
;
HRMS calcd for
A mixture of 16e (0.30 g, 1.08 mmol), compound 15 (0.41 g,
.30 mmol) and Cs CO (0.53 g, 1.62 mmol) was stirred (12 h) in
+
H
25 23
N
2
O
4
[M] 415.1652; found 415.1647.
1
2
3
dry DMF (20 mL) at 90 °C. The mixture was allowed to cool to room
temperature and the solvent was evaporated. EtOAc (60 mL) was
added to the residue and the mixture was washed successively
5
.14. (2S)-2-Amino-N-{4-[2-(1,3-benzoxazol-2-yl)phenoxymethyl]
phenyl}propanamide Hydrochloride (18c)
with 10% aq NaHCO
The organic fraction was dried (MgSO
due was purified by column chromatography (eluent; EtOAc,
3
solution (30 mL) and water (2 ꢁ 20 mL).
Compound 17c (0.25 g, 0.51 mmol) was stirred (1 h) in anhy-
drous EtOAc/HCl (5 mL) at room temperature. The resulting precip-
itate was collected and dried giving compound 18c as a light
4
) and evaporated. The resi-
1
2
8
00%) giving compound 17e as a pink powder (0.40 g, 67%), mp
1
brown solid (0.18 g, 83%), mp 132 °C, H NMR (400 MHz, d
6
-DMSO)
), 8.00 (1H, dd, J = 7.2 Hz, Ar-
H), 7.63–7.78 (4H, m, Ar-H), 7.50–7.56 (3H, m, Ar-H), 7.35–7.41
2H, m, Ar-H), 7.30 (1H, dd, J = 8.7 Hz, Ar-H), 7.12 (1H, t,
J = 7.3 Hz, Ar-H), 5.25 (2H, s, CH ), 4.04 (1H, m, CH), 1.42 (3H, d,
), C NMR (101 MHz, d -DMSO) d 155.7 (C@O),
50.6 (Ar-C), 141.7 (Ar-C), 139.1 (Ar-C), 133.7 (Ar-C), 132.0 (Ar-
C), 131.6 (Ar-C), 128.1 (Ar-C), 127.5 (Ar-C), 127.2 (2 ꢁ Ar-C),
1
04–205 °C; H NMR (400 MHz, d
6
-DMSO) d 10.04 (1H, br s, NH),
+
d 10.88 (1H, s, NH), 8.36 (3H, br s, NH
3
.63 (1H, d, J = 0.9 Hz, NH), 8.21–8.15 (2H, m, Ar-H), 8.12–8.05
(
2H, m, Ar-H), 7.97 (1H, d, J = 8.7 Hz, Ar-H), 7.67 (2H, d, J = 8.7 Hz,
(
Ar-H), 7.59–7.53 (2H, m, Ar-H), 7.51–7.43 (3H, m, Ar-H), 7.33 (1H,
dd, J = 9.2 and 2.3 Hz, Ar-H), 7.11 (1H, d, J = 7.3 Hz, Ar-H), 5.21 (2H,
2
13
J = 6.9 Hz, CH
3
6
s, CH
d, J = 7.3 Hz, CH
68.1 (C@O), 158.3 (Ar-C), 155.7 (Ar-C), 154.2 (Ar-C), 139.5 (Ar-
C), 136.3 (Ar-C), 135.0 (Ar-C), 131.7 (Ar-C), 131.1 (Ar-C), 129.2
2 ꢁ Ar-C), 128.7 (Ar-C), 128.6 (Ar-C), 128.3 (Ar-C), 127.8 (Ar-C),
27.2 (Ar-C), 125.9 (Ar-C), 125.0 (Ar-C), 123.2 (Ar-C), 122.9 (Ar-
C), 120.6 (Ar-C), 119.6 (2 ꢁ Ar-C), 108.0 (Ar-C), 78.6 (C(CH ),
9.9 (CH ), 51.0 (CHCH ), 28.7 (C(CH ), 18.6 (CH ); IR max 3312
br, NH), 2980, 1688 (C@O), 1663 (C@O), 1603, 1520, 1248, 1161,
2
), 4.13 (1H, dt, J = 7.3 Hz, CH), 1.39 (9H, s, 3 ꢁ CH
3
), 1.27 (3H,
1
1
3
3
); C NMR (101 MHz, d -DMSO) d 172.5 (C@O),
6
1
1
(
(
1
7
3
25.1 (Ar-C), 121.3 (Ar-C), 121.0 (Ar-C), 119.4 (2 ꢁ Ar-C), 119.0
Ar-C), 116.5 (Ar-C), 115.0 (Ar-C), 111.1 (Ar-C), 70.2 (CH ), 50.3
2
(
1
); IR vmax 3300–2025 (br, NH+NH+
CHCH ), 17.7 (CHCH ), 2976,
3
3
3
668 (C@O), 1609, 1515, 1455, 1418, 1310, 1139, 994, 797, 751,
3
)
3
ꢀ1
+
22, 704 cm ; HRMS calcd for C23
H
22
N
3
O
3
[M] 388.1656; found
6
2
3
3
)
3
3
m
88.1653.
(
8
5
ꢀ1
+
12, 757, 674 cm ; LRMS calcd for C32
76.67; found 576.06.
31 3 4
H N O SNa [M+Na]
5
.15.
(2S)-2-Amino-N-{4-[2-(1,3-benzothiazol-2-yl)phenoxy-
methyl]phenyl}propanamide Hydrochloride (18d)
5
.12. (2S)-2-Amino-N-(4-{[(4-methyl-2-oxo-2H-chromen-7-yl)
Compound 17d (0.20 g, 0.40 mmol) was stirred (1 h) in anhy-
drous EtOAc/HCl (10 mL) at room temperature. The resulting
precipitate was collected and dried giving compound 18d as a
oxy]methyl}phenyl)propanamide Hydrochloride (18a)
Compound 17a (0.26 g, 0.57 mmol) was stirred (2 h) in anhy-
1
yellow powder (0.17 g, 97%), mp 136 °C; H NMR (400 MHz,
drous EtOAc/HCl (15 mL) at room temperature. The resulting
precipitate was collected and dried giving compound 18a (0.20 g,
-DMSO) d 11.11 (1H, s, NH), 8.55–8.40 (4H, m, Ar-H, NH+
d
6
3
),
8
.12–8.03 (2H, m, Ar-H), 7.76 (2H, d, J = 8.7 Hz, Ar-H), 7.62–7.51
1
9
0%) as a white powder, mp 202–204 °C; H NMR (400 MHz,
(
4H, m, Ar-H), 7.45–7.38 (2H, m, Ar-H), 7.17 (1H, t, J = 7.6 Hz,