D.D. Yu et al.
Bioorganic & Medicinal Chemistry 41 (2021) 116193
triazolinone as an oil (0.87 g), which was purified by flash chromatog-
76.2, 52.3, 49.6, 41.2, 31.1, 24.2, 22.4, 22.3. Anal. Calcd for
raphy (95:5 CH
afford white solid 0.79 g in 91% yield, mp: 77.3 C. H NMR (500 MHz,
CDCl ) δ 10.11 (s, 1H), 6.96 (d, 2H), 6.81 (d, 2H), 6.38 (s, 2H), 4.66 (s,
H), 3.85 (s, 3H), 3.79 (s, 6H), 2.61 (t, 2H), 2.40 (t, 2H), 1.94 (t, 2H),
.60 (s, 6H); 13C NMR (500 MHz, CD
OD) δ 173.9, 153.2, 150.7, 145.3,
32.0, 128.2, 126.1, 120.9, 104.3, 101.6, 101.5, 76.5, 57.9, 53.4, 53.3,
1.6, 30.9, 24.3, 22.3, 22.0. Anal. Calcd for C25 O: C, 57.57;
⋅2H
2
Cl
2
/MeOH) to give an oil, and solidified by pet ether to
24 29 3 5
C H N O : C, 65.59; H, 6.65; N, 9.56. Found: C, 65.57; H, 6.70; N,
◦
1
9.56.
3
2
1
1
4
4.2.17. 2-(4-{3-[4-Benzyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-
propyl}-phenoxy)-2-methyl-propionic acid methyl ester (5c-i)
3
To a solution of 2-(4-{3-[4-benzyl-5-oxo-4,5-dihydro-1H-[1,2,4]tri-
azol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid (5c) (0.70 g, 1.8
mmol) in methanol (30 mL) was added concentrated sulfuric acid (0.3
mL) and the reaction mixture stirred at ambient temperature overnight.
After concentration to small volume, the solution was diluted with
H
31
3
N O
7
2
H, 5.99; N, 8.05. Found: C, 57.40; H, 6.11; N, 7.94.
4
.2.14. 2-(4-{3-[4-(2-Chloro-benzyl)-5-oxo-4, 5-dihydro-1H-[1,2,4]tria-
zol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid (5g)
EtOAc (40 mL), washed with water (25 mL), saturated aqueous NaHCO
3
To a solution of tert-Butyl 2-(4-(4-(2-((2-chlorobenzyl) carbamoyl)
hydrazineyl)-4-oxo-butyl)phenoxy)-2-methyl-propanoate (4g) (1.85 g,
(2 × 25 mL), and brine (25 mL). The organic layer was dried over
Na
SO
2 4
, and concentrated to give the methyl ester as an oil 0.75 g. So-
◦
3
.7 mmol) in methanol (40 mL) was added solid potassium hydroxide
lidified by pet. ether gave white solid 0.64 g in 86% yield, mp: 89.1 C.
1
(
(
(
3.14 g, 56 mmol) and the reaction mixture heated at reflux for 32 h
TLC). After cooling to RT, the reaction mixture was diluted with water
20 mL) and EtOAc (35 mL), and then acidified to pH 2 with 5 N HCl.
H NMR (500 MHz, CDCl
6.95 (d, 2H), 6.75 (d, 2H), 4.75 (s, 2H), 3.77 (s, 3H), 2.56 (t, 2H), 2.36 (t,
2H), 1.88 (t, 2H), 1.57 (s, 6H); 13C NMR (125 MHz, CDCl
) δ 172.0,
152.9, 150.7, 145.3, 132.8, 131.9, 126.2, 126.1, 125.2, 124.3, 116.5,
76.2, 49.6, 41.4, 31.1, 24.2, 22.4, 22.3. Anal. Calcd for C23 : C,
67.46; H, 6.65; N, 10.26. Found: C, 63.37; H, 6.38; N, 10.04.
3
) δ 9.34 (s, 1H), 7.34 (m, 2H), 7.13 (t, 2H),
3
The aqueous layer was extracted with ETOAc (2 × 25 mL). The com-
bined organic extracts were washed with water (35 mL), brine (35 mL),
27 3 4
H N O
dried over Na
SO
2 4
, and concentrated to give the desired triazolinone as
Cl /MeOH)
H NMR (500
) δ 9.80 (s, 1H), 7.40 (d, 1H), 7.22 (m, 2H), 7.06 (d, 1H),
.96 (d, 2H), 6.82 (d, 2H), 4.90 (s, 2H), 2.59 (t, 2H), 2.39 (t, 2H), 1.91 (t,
H), 1.60 (s, 6H); 13C NMR (125 MHz, CDCl
) δ 173.7, 153.2, 150.1,
45.4, 132.3, 130.0, 129.6, 126.9, 126.5, 126.2, 125.3, 124.6, 117.2,
3 4
6.7, 38.6, 31.0, 24.1, 22.3, 22.2, 18.1. Anal. Calcd for C22 24ClN O :
oil, which was purified by flash chromatography (95:5 CH
2
2
◦
1
afforded 5g (1.35 g, 84%) as a white solid. mp: 45.1
MHz, CDCl
C
4.2.18. 2-(4-{3-[4-(4-Fluoro-benzyl)-5-oxo-4, 5-dihydro-1H-[1,2,4]tria-
zol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid methyl ester (5d-i)
To a solution of crude 2-(4-{3-[4-(4-fluoro-benzyl)-5-oxo-4, 5-dihy-
dro-1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid
(5d) (0.43 g, 1.0 mmol) in methanol (15 mL) was added concentrated
sulfuric acid (0.3 mL) and the reaction mixture stirred at ambient tem-
perature overnight. After concentration to 20% of original volume, the
solution was diluted with ETOAc (25 mL), washed with water (15 mL),
3
6
2
1
7
3
H
C, 61.46; H, 5.63; Cl, 8.25; N, 9.77. Found: C, 61.12; H, 5.71; Cl, 8.55; N,
9
.87.
General esterification procedure to make intermediates 5a-i to 5 g-i:
saturated aqueous NaHCO
layer was dried over Na SO
as an oil 0.43 g. Solidification by ether gave white solid 0.36 g in 84%
3
(2 x15 mL), and brine (15 mL). The organic
2
4
, and concentrated to give the methyl ester
4
.2.15. 2-(4-{3-[4-(4-Methoxy-benzyl)-5-oxo-4, 5-dihydro-1H-[1,2,4]tri-
◦
1
azol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid methyl ester (5a-i)
yield, mp: 119.3 C. H NMR (500 MHz, CDCl
2H), 7.01 (m, 4H), 6.75 (d, 2H), 4.69 (s, 2H), 3.76 (s, 3H), 2.58 (t, 2H),
2.35 (t, 2H), 1.89 (t, 2H), 1.57 (s, 6H); 13C NMR (125 MHz, CDCl
) δ
3
) δ 9.65 (s, 1H), 7.14 (t,
To a solution of 2-(4-{3-[4-(4-Methoxy-benzyl)-5-oxo-4, 5-dihydro-
1
H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid (5a)
3
(
4.15 g, 10 mmol) in methanol (200 mL) was added concentrated sul-
171.9, 160.5, 158.5, 152.8, 150.7, 145.1, 131.7, 128.6, 126.3, 126.2,
furic acid (2 mL) and the reaction mixture stirred at ambient tempera-
ture overnight. After concentration to 20% of original volume, the
solution was diluted with ETOAc (100 mL), washed with water (100
126.1, 116.4, 113.1, 112.9, 76.2, 49.5, 40.7, 31.0, 24.1, 22.4, 22.2.
3 4
Anal. Calcd for C23H26FN O : C, 64.62; H, 6.13; N, 9.83; F, 4.44. Found:
C, 64.92; H, 6.37; N, 9.75; F, 4.26.
mL), saturated aqueous NaHCO
organic layer was dried over Na
methyl ester as a white solid 4.07 g, Crystallization by EtOAc gave white
3
(2 × 50 mL), and brine (50 mL). The
2
SO , and concentrated to give the
4
4.2.19. 2-(4-{3-[4-(4-Methyl-benzyl)-5-oxo-4, 5-dihydro-1H-[1,2,4]tria-
zol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid methyl ester (5e-i)
To a solution of 2-(4-{3-[4-(4-methyl-benzyl)-5-oxo-4, 5-dihydro-
1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid (5e)
(0.79 g, 2 mmol) in methanol (30 mL) was added concentrated sulfuric
acid (0.3 mL) and the reaction mixture stirred at ambient temperature
overnight. After concentration to 20% of original volume, the solution
was diluted with ETOAc (50 mL), washed with water (30 mL), saturated
◦
1
crystals 3.86 g in 88% yield, mp: 130.4 C. H NMR (500 MHz, CDCl
.95 (s, 1H), 7.10 (d, 2H), 6.96 (d, 2H), 6.85 (d, 2H), 6.75 (d, 2H), 4.67
s, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 2.57 (t, 2H), 2.36 (t, 2H), 1.88 (t, 2H),
3
) δ
8
(
1
1
5
6
.57 (s, 6H); 13C NMR (125 MHz, CDCl
45.4, 131.9, 126.2, 125.9, 125.8, 124.9, 116.5, 111.4, 111.1, 76.2,
3
) δ 172.0, 156.5, 152.7, 150.7,
2.4, 49.6, 40.9, 31.1, 24.2, 22.4, 22.3. Anal. Calcd for C24
5.59; H, 6.65; N, 9.56. Found: C, 65.86; H, 6.80; N, 9.47.
29 3 5
H N O : C,
aqueous NaHCO
dried over Na SO
0.84 g. Solidification by ether gave white solid 0.71 g in 84% yield, mp:
3
(2 × 30 mL), and brine (30 mL). The organic layer was
2
4
, and concentrated to give the methyl ester as an oil
4
.2.16. 2-(4-{3-[4-(3-Methoxy-benzyl)-5-oxo-4, 5-dihydro-1H-[1,2,4]tri-
◦
1
azol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid methyl ester (5b-i)
122.8 C. H NMR (500 MHz, CDCl ) δ 9.58 (s, 1H), 7.13 (d, 2H), 7.07
3
To a solution of 2-(4-{3-[4-(3-Methoxy-benzyl)-5-oxo-4, 5-dihydro-
(d, 2H), 6.96 (d, 2H), 6.75 (d, 2H), 4.71 (s, 2H), 3.77 (s, 3H), 2.56 (t,
2H), 2.36 (t, 2H), 2.33 (s, 3H), 1.87 (t, 2H), 1.57 (s, 6H); 13C NMR (125
1
H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid (5b)
(
1.30 g, 3.1 mmol) in methanol (40 mL) was added concentrated sulfuric
MHz, CDCl
126.2, 124.3, 116.5, 76.2, 49.6, 41.2, 31.1, 24.2, 22.4, 22.3, 18.2. Anal.
Calcd for C24 : C, 68.06; H, 6.90; N, 9.92. Found: C, 67.90; H,
6.98; N, 9.55.
3
) δ 172.0, 153.0, 150.7, 145.3, 134.9, 132.0, 129.8, 126.7,
acid (0.5 mL) and the reaction mixture stirred at ambient temperature
overnight. After concentration to 20% of original volume, the solution
was diluted with EtOAc (50 mL), washed with water (20 mL), saturated
29 3 4
H N O
aqueous NaHCO
dried over Na SO
Solidified by ether gave white solid 1.16 g in 88% yield, mp: 88.6 C. H
NMR (500 MHz, CDCl ) δ 10.82 (s, 1H), 7.22 (t, 1H), 6.94 (d, 2H), 6.80
d, 1H), 6.71 (d, 4H), 4.71 (s, 2H), 3.75 (s, 6H), 2.54 (t, 2H), 2.35 (t, 2H),
3
(2 × 20 mL), and brine (20 mL). The organic layer was
2
4
, and concentrated to give the methyl ester as oil.
4.2.20. 2-(4-{3-[4-(3,4,5-Trimethoxy-benzyl)-5-oxo-4, 5-dihydro-1H-
[1,2,4]triazol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid methyl ester
(5f-i)
◦
1
3
(
To a solution of 2-(4-{3-[4-(3,4,5-methoxy-benzyl)-5-oxo-4, 5-dihy-
dro-1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid
(5f) (0.87 g, 1.8 mmol) in methanol (30 mL) was added concentrated
1
1
.85 (t, 2H), 1.55 (s, 6H); 13C NMR (125 MHz, CDCl
53.4, 150.6, 145.0, 134.4, 132.0, 127.1, 116.5, 116.4, 110.5, 109.9,
3
) δ 172.0, 157.0,
1
5