Vol. 65, No. 11 (2017)
Chem. Pharm. Bull.
1069
and saturated aqueous NaCl, dried over anhydrous Na SO4 8.55 (1H, s), 8.88 (1H, d, J=0.8Hz), 9.07 (1H, d, J=8.3Hz),
2
+
and concentrated in vacuo. The residue was purified by 9.50 (1H, d, J=7.5Hz). MS (ESI/APCI) m/z 476.2 [M+H] .
column chromatography (silica gel, hexane–ethyl acetate, HPLC purity: 99.4%. mp 260°C.
19:1 to 0:100) to afford 14 (102mg, 0.222mmol, 75%) as a
N-((1S)-2-Hydroxy-2-methyl-1-(4-(trifluoromethoxy)-
white solid after trituration with hexane–ethyl acetate (5:1). phenyl)propyl)-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo-
1
H-NMR (300MHz, DMSO-d ) δ: 1.02 (3H, s), 1.36 (3H, [1,5-a]pyrimidine-3-carboxamide (18) The title compound
6
s), 4.86 (1H, d, J=8.3Hz), 5.34 (1H, s), 6.75–6.81 (1H, m), was prepared as a white solid after trituration with diisopropyl
7
.23–7.33 (2H, m), 7.48–7.58 (2H, m), 7.76 (1H, d, J=7.5Hz), ether in 35% yield from 33 and 3-methyl-1H-1,2,4-triazole
8
.05 (1H, d, J=1.5Hz), 8.46 (1H, s), 9.02–9.14 (2H, m), 9.37 using the procedure analogous to that described for the syn-
+
(1H, d, J=7.5Hz). MS (ESI/APCI) m/z 461.1 [M+H] . HPLC thesis of 14, except that basic silica gel was employed in a
purity: 100%. mp 241°C.
column chromatography purification in place of silica gel.
1
N-((1S)-2-Hydroxy-2-methyl-1-(4-(trifluoromethoxy)-
H-NMR (300MHz, DMSO-d ) δ: 1.02 (3H, brs), 1.36 (3H, s),
6
phenyl)propyl)-5-(4-methyl-1H-imidazol-1-yl)pyrazolo[1,5- 2.47 (3H, brs), 4.86 (1H, d, J=8.1Hz), 5.43 (1H, s), 7.21–7.35
a]pyrimidine-3-carboxamide (15) The title compound was (2H, m), 7.47–7.59 (2H, m), 7.63 (1H, d, J=7.5Hz), 8.52 (1H,
prepared as a pale yellow solid after trituration with hexane– s), 9.06 (1H, d, J=8.1Hz), 9.46 (1H, d, J=7.5Hz), 9.55 (1H, s).
+
ethyl acetate (5:1) in 70% yield from 33 and 4-methyl-1H- MS (ESI/APCI) m/z 476.1 [M+H] . HPLC purity: 100%.
imidazole using the procedure analogous to that described for
(S)-N-(2-Hydroxy-2-methyl-1-(4-(trifluoromethoxy)-
the synthesis of 14, except that a preparative HPLC (column: phenyl)propyl)-6-methyl-5-(4-methyl-1H-1,2,3-triazol-1-yl)-
L-Column2 ODS 20mm ID×150mm L; mobile phase A: pyrazolo[1,5-a]pyrimidine-3-carboxamide (19) To a mix-
0
.1% TFA in water; mobile phase B: 0.1% TFA in acetonitrile; ture of 52a (2.81g, 10.9mmol) and 28 (3.26g, 11.4mmol) in
flow rate: 20mL/min) was employed in place of silica gel DMF (250mL) were added HOBt·H O (2.06g, 13.1mmol),
2
1
column chromatography. H-NMR (300MHz, DMSO-d ) δ: EDCI·HCl (2.55g, 13.1mmol) and triethylammonium acetate
6
1
.02 (3H, s), 1.35 (3H, s), 2.24 (3H, s), 4.87 (1H, d, J=8.3Hz), (TEA) (7.65mL, 54.4mmol). The mixture was stirred at r.t.
.31 (1H, s), 7.24–7.33 (2H, m), 7.47–7.57 (2H, m), 7.73 (1H, d, overnight and then quenched with water at r.t. The mixture
J=7.9Hz), 8.07 (1H, s), 8.45 (1H, s), 8.85 (1H, d, J=0.8Hz), was extracted with EtOAc, washed with saturated aqueous
5
9
.00 (1H, d, J=8.3Hz), 9.46 (1H, d, J=7.5Hz). MS (ESI/APCI) NaHCO , water, and then saturated aqueous NaCl, dried over
3
+
m/z 475.1 [M+H] . HPLC purity: 99.2%. mp 130°C.
anhydrous Na SO , and concentrated in vacuo. The residue
2
4
(
S)-N-(2-Hydroxy-2-methyl-1-(4-(trifluoromethoxy)- was purified by column chromatography (silica gel, hexane–
phenyl)propyl)-5-(4-(trifluoromethyl)-1H-imidazol-1-yl)- ethyl acetate, 100:0 to 3:17) to give 19 (3.86g, 7.89mmol,
1
pyrazolo[1,5-a]pyrimidine-3-carboxamide (16) The title 73%) as a white solid. H-NMR (300MHz, CDCl ) δ: 1.17
3
compound was prepared as a pale yellow solid after tritura- (3H, s), 1.48 (3H, s), 1.74 (1H, s), 2.50 (3H, d, J=0.8Hz),
tion with hexane–ethyl acetate (5:1) in 70% yield from 33 2.84 (3H, d, J=0.8Hz), 5.05(1H, d, J=8.3Hz), 7.17 (2H, d,
and 4-(trifluoromethyl)-1H-imidazole using the procedure J=7.9Hz), 7.38–7.48 (2H, m), 8.60 (1H, s), 8.69–8.82 (3H,
1
analogous to that described for the synthesis of 14. H-NMR m). The obtained product (3.86g, 7.89mmol) was dissolved
(
300MHz, DMSO-d ) δ: 1.02 (3H, s), 1.34 (3H, s), 4.86 (1H, in EtOAc (277mL) at 50–60°C. To this solution was added
6
d, J=8.3Hz), 5.36 (1H, s), 7.23–7.33 (2H, m), 7.47–7.58 (2H, hexane (150mL) at the same temperature and a white solid
m), 7.89 (1H, d, J=7.5Hz), 8.53 (1H, s), 8.92–9.02 (2H, m), precipitated. After 2h of stirring at r.t., further hexane (88mL)
9
.15 (1H, s), 9.62 (1H, d, J=7.5Hz). MS (ESI/APCI) m/z 529.1 was added to the mixture, which was stirred at r.t. for 10min.
+
[
M+H] . HPLC purity: 100%. mp 220°C.
The white precipitate was collected by filtration, washed with
N-((1S)-2-Hydroxy-2-methyl-1-(4-(trifluoromethoxy)- hexane–ethyl acetate, and dried to give 19 (3.17g, 6.48mmol,
1
phenyl)propyl)-5-(4-methyl-1H-1,2,3-triazol-1-yl)pyrazolo- 82%) as a white solid. H-NMR (300MHz, CDCl ) δ: 1.17
3
[
(
1
1,5-a]pyrimidine-3-carboxamide (17) A mixture of 33 (3H, s), 1.48 (3H, s), 1.74 (1H, s), 2.50 (3H, d, J=0.8Hz),
430mg, 1.00mmol), 4-methyl-1H-1,2,3-triazole (100mg, 2.84 (3H, d, J=0.8Hz), 5.05 (1H, d, J=8.3Hz), 7.17 (2H, d,
.20mmol) and K CO (208mg, 1.50mmol) in DMF (4mL) J=8.3Hz), 7.39–7.48 (2H, m), 8.60 (1H, s), 8.69–8.83 (3H, m).
2
3
+
was stirred at 80°C for 2h. The mixture was quenched with MS (ESI/APCI) m/z 490.2 [M+H] . HPLC purity: 100%. mp
water at r.t. and extracted with EtOAc. The organic layer was 238–239°C. Anal. Calcd for C H F N O : C, 53.99; H, 4.53;
2
2
22
3
7
3
separated, washed with water and saturated aqueous NaCl, F, 11.64; N, 20.03. Found: C, 53.82; H, 4.42; F, 11.64; N, 19.81.
dried over anhydrous MgSO4 and concentrated in vacuo (S)-N-(2-Hydroxy-2-methyl-1-(4-(trifluoromethoxy)-
508.7mg). The residue was purified by using preparative phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)-
(
HPLC (column: L-Column2 ODS 20mm ID×150mm L; pyrazolo[1,5-a]pyrimidine-3-carboxamide (20) To a sus-
mobile phase A: 0.1% TFA in water; mobile phase B: 0.1% pension of 52b (606mg, 2.35mmol) in DMF (12mL)
TFA in acetonitrile; flow rate: 20mL/min). The first eluting were added 28 (805mg, 2.82mmol), EDCI·HCl (540mg,
factions (tR1) were concentrated to dryness, and washed with 2.82mmol), HOBt·H O (431mg, 2.82mmol), and TEA
2
saturated aqueous NaHCO , extracted with EtOAc. The or- (0.392mL, 2.82mmol) at r.t. The mixture was stirred at r.t.
3
ganic layer was separated, washed with water and saturated for 2h. The mixture was poured into water and extracted
aqueous NaCl, dried over anhydrous MgSO and concentrated with EtOAc. The organic layer was separated, washed with
4
in vacuo. The residue (42.7mg) was crystallized from hex- saturated aqueous NaCl, dried over anhydrous MgSO4 and
ane–ethyl acetate to give 17 (34.4mg, 0.072mmol, 7.2%) as concentrated in vacuo. The residue was purified by column
1
a white solid. H-NMR (300MHz, DMSO-d ) δ: 1.04 (3H, s), chromatography (basic silica gel, hexane–ethyl acetate, 4:1 to
6
1
.37 (3H, s), 2.44 (3H, s), 4.87 (1H, d, J=8.3Hz), 5.39 (1H, s), 1:9) to give 20 (858mg, 1.75mmol, 75%) as a white solid after
1
7.23–7.34 (2H, m), 7.48–7.58 (2H, m), 7.93 (1H, d, J=7.5Hz), recrystallization from diisopropyl ether/ethyl acetate. H-NMR