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T. Chen et al. / Bioorg. Med. Chem. 19 (2011) 613–622
DMSO-d6, d): 11.67 (br s, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.45–7.36
(m, 6H), 7.24 (t, J = 7.5 Hz, 1H), 5.46 (s, 1H), 4.11 (s, 2H); 13C NMR
(125 MHz, DMSO-d6, d): 153.1, 148.2, 138.6, 135.5, 130.2, 129.5,
128.9, 128.8, 125.5, 120.9, 87.0, 25.1; HPLC method A (gradient;
ACN/H2O 30:70–80:20, 0–20 min, ACN/H2O 80:20–30:70,
20–40 min; 0.1% TFA): rt = 18.88 min, purity = 96.4%; HPLC method
B (isocratic; MeOH/H2O 70:30, 60 min; 0.1% TFA): rt = 12.98 min,
purity = 96.0%.
4.1.15. 5-((Biphenyl-4-ylthio)methyl)-1H-pyrazol-3(2H)-one
(11)
In analogy to 5, compound 11 was prepared following the general
procedure of ASPII products. Biphenyl-4-thiol (0.50 g, 2.68 mmol)
was treated with ethyl 4-chloroacetoacetate (0.37 mL, 2.68 mmol)
and triethylamine (0.56 mL, 4.02 mmol) to afford ethyl 4-(biphe-
nyl-4-ylthio)-3-oxobutanoate (0.72 g, 2.30 mmol). Immediately
after flash column chromatography ethyl 4-(4-methoxyphenyl-
thio)-3-oxobutanoate (1.78 g, 6.63 mmol) was allowed to react with
hydrazine(2 N in EtOH, 1.15 mL, 2.30 mmol)to give 11 as a white so-
lid (0.36 g, 47%, two steps). 1H NMR (500 MHz, DMSO-d6, d): 11.39
(br s, 1H), 9.52 (br s, 1H), 7.66–7.34 (m, 9H), 5.36 (s, 1H), 4.12 (s,
2H); 13C NMR (125 MHz, DMSO-d6, d): 161.0, 139.4, 137.6, 135.3,
129.0, 128.5, 127.5, 127.2, 126.5, 89.2, 27.8; HPLC method A (gradi-
ent; ACN/H2O 30:70–80:20, 0–20 min, ACN/H2O 80:20–30:70, 20–
40 min; 0.1% TFA): rt = 11.62 min, purity = 95.3%; HPLC method B
(isocratic; MeOH/H2O 60:40, 60 min; 0.1% TFA): rt = 13.55 min,
purity = 98.8%.
4.1.12. 5-((4-tert-Butylphenylthio)methyl)-1H-pyrazol-3(2H)-
one (8)
In analogy to 5, compound 8 was prepared following the gen-
eral procedure of ASPII products. 4-tert-Butylbenzenethiol
(1.04 mL, 6.01 mmol) was treated with ethyl 4-chloroacetoacetate
(0.82 mL, 6.02 mmol) and triethylamine (1.26 mL, 9.01 mmol) to
afford ethyl 4-(4-tert-butylphenylthio)-3-oxobutanoate (1.65 g,
5.60 mmol). Immediately after flash column chromatography,
ethyl 4-(4-tert-butylphenylthio)-3-oxobutanoate (1.09 g, 3.70
mmol) was allowed to react with hydrazine (2 N in EtOH,
1.86 mL, 3.72 mmol) to give 8 as a white solid (0.54 g, 51%, two
steps). 1H NMR (500 MHz, DMSO-d6, d): 11.22 (br s, 1H), 10.07
(br s, 1H), 7.33–7.26 (m, 4H), 5.34 (s, 1H), 4.04 (s, 2H), 1.25 (s,
9H); 13C NMR (125 MHz, DMSO-d6, d): 160.1, 148.6, 140.6, 132.4,
128.0, 126.0, 88.9, 34.1, 31.0, 28.2; HPLC method A (gradient;
ACN/H2O 0:100–80:20, 0–30 min, ACN/H2O 80:20–0:100, 30–
60 min; 0.1% TFA): rt = 22.88 min, purity = 96.9%; HPLC method B
(isocratic; MeOH/H2O 60:40, 60 min; 0.1% TFA): rt = 15.88 min,
purity = 98.8%.
4.1.16. 5-((4-Fluorophenylthio)methyl)-1H-pyrazol-3(2H)-one
(12)
In analogy to 5, compound 12 was prepared following the gen-
eral procedure of ASPII products. 4-Fluorobenzenethiol (0.84 mL,
7.80 mmol) was treated with ethyl 4-chloroacetoacetate
(1.06 mL, 7.80 mmol) and triethylamine (1.63 mL, 11.7 mmol) to
afford ethyl 4-(4-fluorophenylthio)-3-oxobutanoate (1.72 g,
7.67 mmol). Immediately after flash column ethyl 4-(4-fluorophe-
nylthio)-3-oxobutanoate (1.72 g, 7.67 mmol) was allowed to react
with hydrazine (2 N in EtOH, 4.00 mL, 8.00 mmol) to give 12 as a
white solid (0.71 g, 40%, two steps). 1H NMR (500 MHz, DMSO-d6,
d): 11.52 (br s, 1H), 9.40 (br s, 1H), 7.40–7.37 (m, 2H), 7.17 (t,
J = 8.8 Hz, 2H), 5.27 (s, 1H), 4.03 (s, 1H); 13C NMR (125 MHz,
DMSO-d6, d): 161.9, 160.0, 131.3, 116.1, 115.9, 89.4, 28.7; HPLC
method A (gradient; ACN/H2O 30:70–80:20, 0–20 min, ACN/H2O
80:20–30:70, 20–40 min; 0.1% TFA): rt = 6.58 min, purity = 98.8%;
HPLC method B (isocratic; MeOH/H2O 50:50, 60 min; 0.1% TFA):
rt = 7.48 min, purity = 99.5%.
4.1.13. 5-((4-Nitrophenylthio)methyl)-1H-pyrazol-3(2H)-one (9)
In analogy to 5, compound 9 was prepared following the
general procedure of ASPII products. 4-Nitrobenzenethiol
(1.00 g, 6.44 mmol) was treated with ethyl 4-chloroacetoacetate
(0.88 mL, 6.44 mmol) and triethylamine (1.35 mL, 9.67 mmol)
to afford ethyl 4-(4-nitrophenylthio)-3-oxobutanoate (1.56 g,
5.52 mmol). Immediately after flash column chromatography ethyl
4-(4-nitrophenylthio)-3-oxobutanoate (1.04 g, 3.67 mmol) was
allowed to react with hydrazine (2 N in EtOH, 2.07 mL, 4.14 mmol)
to give 9 as a white solid (0.40 g, 33%, two steps). 1H NMR
(500 MHz, DMSO-d6, d): 11. 64 (br s, 1H), 9.52 (br s, 1H), 8.13 (d,
J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 5.41 (s, 1H), 4.26 (s, 2H);
13C NMR (125 MHz, DMSO-d6, d): 161.0, 146.8, 144.6, 138.4,
126.4, 123.9, 90.2, 25.9; HPLC method A (isocratic; ACN/H2O
25:75, 60 min; 0.1% TFA): rt = 14.85 min, purity = 97.1%; HPLC
4.1.17. 5-((4-Bromophenylthio)methyl)-1H-pyrazol-3(2H)-one
(13)
In analogy to 5, compound 13 was prepared following the general
procedure of ASPII products. 4-Bromobenzenethiol (1.00 g,
5.29 mmol) was treated with ethyl 4-chloroacetoacetate (0.72 mL,
5.29 mmol) and triethylamine (1.11 mL, 7.93 mmol) to afford ethyl
4-(4-bromophenylthio)-3-oxobutanoate (1.56 g, 4.94 mmol). Imme-
diately after flash column ethyl 4-(4-fluorophenylthio)-3-oxobut-
anoate (1.72 g, 7.67 mmol) was allowed to react with hydrazine
(2 N in EtOH, 1.67 mL, 3.34 mmol) to give 13 as a white solid
(0.69 g, 67%, two steps). 1H NMR (500 MHz, DMSO-d6, d): 11.45 (br
s, 1H), 9.79 (br s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz,
2H), 5.32 (s, 1H), 4.08 (s, 2H); 13C NMR (125 MHz, DMSO-d6, d):
160.0, 140.6, 135.5, 131.7, 130.0, 118.8, 88.8, 27.9; HPLC method A
(gradient; ACN/H2O 30:70–80:20, 0–20 min, ACN/H2O 80:20–
30:70, 20–40 min; 0.1% TFA): rt = 8.88 min, purity = 99.0%; HPLC
method
B (isocratic; MeOH/H2O 50:50, 60 min; 0.1% TFA):
rt = 9.98 min, purity = 99.9%.
4.1.14. 5-((4-Methoxyphenylthio)methyl)-1H-pyrazol-3(2H)-
one (10)
In analogy to 5, compound 10 was prepared following the gen-
eral procedure of ASPII products. 4-Methoxybenzenethiol (0.87 mL,
7.07 mmol) was treated with ethyl 4-chloroacetoacetate (0.97 mL,
7.12 mmol) and triethylamine (1.50 mL, 10.8 mmol) to afford ethyl
4-(4-methoxyphenylthio)-3-oxobutanoate (1.85 g, 6.89 mmol).
Immediately after flash column chromatography ethyl 4-(4-meth-
oxyphenylthio)-3-oxobutanoate (1.78 g, 6.63 mmol) was allowed
to react with hydrazine (2 N in EtOH, 3.32 mL, 6.63 mmol) to give
10 as a white solid (0.34 g, 21%, two steps). 1H NMR (500 MHz,
DMSO-d6, d): 11.45 (br s, 1H), 9.36 (br s, 1H), 7.29 (d, J = 8.5 Hz,
2H), 6.89 (d, J = 9.0 Hz, 2H), 5.22 (s, 1H), 3.93 (s, 2H), 3.73 (s,
3H); 13C NMR (125 MHz, DMSO-d6, d): 161.5, 158.5, 140.2, 132.3,
125.6, 114.7, 89.7, 55.2, 29.8; HPLC method A (isocratic; ACN/
H2O 40:60, 60 min; 0.1% TFA): rt = 5.55 min, purity = 95.4%; HPLC
method
B (isocratic; MeOH/H2O 50:50, 60 min; 0.1% TFA):
rt = 15.72 min, purity = 99.8%.
4.1.18. 5-((2-Chlorophenylthio)methyl)-1H-pyrazol-3(2H)-one
(14)
In analogy to 5, compound 14 was prepared following the general
procedure of ASPII products. 2-Chlorobenzenethiol (0.50 g,
3.46 mmol) was treated with ethyl 4-chloroacetoacetate (0.47 mL,
3.46 mmol) and triethylamine (0.72 mL, 5.19 mmol) to afford ethyl
4-(2-chlorophenylthio)-3-oxobutanoate (0.96 g, 3.46 mmol). Imme-
diately after flash column ethyl 4-(2-chlorophenylthio)-3-oxobut-
anoate (0.96 g, 3.46 mmol) was allowed to react with hydrazine
method
B (isocratic; MeOH/H2O 50:50, 60 min; 0.1% TFA):
rt = 7.65 min, purity = 99.6%.