12
M. K. Purohit et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
in 1 mL of anhydrous dimethylformamide and was added dropwise
to the above suspension. The reaction was continued for an addi-
tional 2 h at 45 °C. The solvent was evaporated under vacuum,
and the crude was purified by flash chromatography on silica gel
using gradient 0–40% ethylacetate in hexanes to obtain the product
41 as a pale yellow solid (42 mg, 34%); mp 56–58 °C; 1H NMR
(CDCl3) d 1.47–1.65 (m, 2H), 1.77–1.98 (m, 6H), 2.13–2.22 (m,
3H), 2.29–2.43 (m, 3H), 4.35–4.51 (m, 1H), 4.95 (s, 2H), 5.25–
5.36 (m, 1H), 6.35 (s, 1H), 7.34–7.56 (m, 5H); MS ESI (+ve) for
(2 mL). Compound 12 (53 mg, 0.21 mmol) was dissolved in 2 mL
of anhydrous acetonitrile, and added dropwise to the above sus-
pension. The reaction was then heated to 60 °C for 2 h. The reaction
solvent was evaporated under vacuum and the resulting crude was
purified by flash chromatography on silica gel using gradient 0–
50% ethyl acetate in hexanes to give product 46 (24 mg, 32%); 1H
NMR (CDCl3) d 1.21–1.25 (t, J = 7.12 Hz, 3H), 2.18 (s, 3H), 2.34(s,
3H), 4.15–4.20 (q, J = 7.12, 7.16 Hz, 2H), 4.58 (s, 2H), 4.96 (s, 2H),
5.35 (s, 1H), 6.33 (s, 1H), 7.34–7.38 (m, 1H), 7.42–7.48 (m, 4H).
C
20H24N4O: calcd 337.203, found: 337.343 for (M+H+).
4.1.38. 2-(3-Methyl-5-((3-methyl-1-phenyl-1H-pyrazol-5-
yl)methoxy)-1H-pyrazol-1-yl)ethanamine (47)
4.1.33. 3-Methyl-1H-pyrazol-5-ol (42)
To a suspension of hydrazine hydrate (2.6 g, 20 mmol) in meth-
anol (5 mL), 3-keto-ethyl butanoate (1.0 g, 20 mmol) was added.
The reaction mixture was then refluxed for 2 h. The reaction sol-
vent was evaporated under vacuum to afford white solid product
42 (1.92 g, 98%); 1H NMR (CDCl3) d 2.08 (s, 3H), 5.20 (s, 1H),
10.07 (br s, 1H).
To a cold solution of compound 45 (40 mg, 0.09 mmol) in meth-
anol (2 mL) hydrazine hydrate (102 mg, 3.18 mmol) was added.
The reaction was warmed to rt and stirred overnight. The reaction
solvent was evaporated to dryness and the resulting crude was
purified by flash chromatography on silica gel using gradient 0–
10% methanol in dichloromethane to give an oily product 47 as a
colorless oil (23 mg, 82%); 1H NMR (CDCl3) d 2.15 (s, 3H), 2.33 (s,
3H), 2.95 (br m, 2H), 3.81–3.84 (t, J = 5.88 Hz, 2H), 4.96 (s, 2H),
5.31 (s, 1H), 6.32 (s, 1H), 7.34–7.37 (m, 1H), 7.41–7.48 (m, 4H);
MS ESI (+ve) for C17H21N5O (M+H+): calcd 312.18, found 312.28.
4.1.34. 2-(2-(5-Hydroxy-3-methyl-1H-pyrazol-1-
yl)ethyl)isoindoline-1,3-dione (43)
Compound 42 (500 mg, 5.10 mmol) and N-(2-bromoethyl)-
phthalimide (1.29 g, 5.58 mmol) were suspended in 1,4-dioxane
(3 mL) in a microwave reaction vial containing a Teflon stir bar.
The vial was capped and the reaction mixture was irradiated with
microwaves at 180 °C for 1 h at normal absorption with cooling
activated. The reaction solvent was evaporated under vacuum,
and the crude was purified by flash chromatography on silica gel
using gradient 0–10% methanol in dichloromethane to afford prod-
uct 43 (335 mg, 24%); 1H NMR (CDCl3) d 1.98 (s, 3H), 3.10 (s, 2H),
3.94 (s, 4H), 7.68–7.70 (m, 2H), 7.80–7.82 (m, 2H).
4.1.39. 2-(3-Methyl-5-((3-methyl-1-phenyl-1H-pyrazol-5-
yl)methoxy)-1H-pyrazol-1-yl)acetic acid (48)
Compound 46 (24 mg, 0.07 mmol) was dissolved in a mixture of
methanol and tetrahydrofuran (1:1, 2 mL). Lithium hydroxide
(29 mg, 1.62 mmol) was added to the above reaction mixture at
0 °C. The reaction was then warmed up to rt and stirred overnight.
The solvent was removed under vacuum, water (1 mL) was added
and the crude mixture was neutralized with 10% HCl at 0 °C. The
aqueous layer was extracted with ethyl acetate, and the organic
layer was died with anhydrous Na2SO4. The solvent was removed
under vacuum and the resultant crude was purified by short col-
umn chromatography on silica gel using gradient 1–10% methanol
in dichloromethane to obtain compound 48 as a yellow solid
(21 mg, 91%); mp 148–150 °C; 1H NMR (CDCl3) d 2.16 (s, 3H),
2.34 (s, 3H), 4.63 (s, 2H), 4.96 (s, 2H), 5.34 (s, 1H), 6.33 (s, 1H),
7.34–7.35 (m, 1H), 7.40–7.44 (m, 4H). MS ESI (+ve) C17H18N4O3
(M+H+): calcd 327.14, found 327.20.
4.1.35. Ethyl-2-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-
yl)acetate (44)
To a flask containing compound 42 (547 mg, 5.58 mmol) was
added ethyl bromoacetate (932 mg, 5.58 mmol) and refluxed for
4 h. Then, the reaction was cooled, diluted with ice-cooled water
(2 mL), neutralized with cold saturated solution of NaHCO3 and
stirred for 15 min at rt. The aqueous reaction mixture was ex-
tracted with ethyl acetate and the organic layer was washed with
brine, dried over Na2SO4 and concentrated. The crude was then
purified by silica gel flash chromatography using gradient 0–10%
methanol in dichloromethane to yield compound 44 as a white so-
lid (138 mg, 13%); 1H NMR (CDCl3) d 1.28 (t, J = 1.00 Hz, 8H), 2.15
(s, 3H), 3.26 (br s, 1H), 3.73 (br s, 1H), 4.22 (q, J = 8.00 Hz, 2H),
4.45 (s, 2H).
4.1.40. 3-Methyl-5-((3-methyl-1H-pyrazol-5-yloxy)methyl)-1-
phenyl-1H-pyrazole (49) and 3-methyl-1-((3-methyl-1-phenyl-
1H-pyrazol-5-yl)methyl)-1H-pyrazol-5-ol (50)
Compound 42 (104 mg, 1.06 mmol) and cesium carbonate
(346 mg, 1.06 mmol) were suspended in anhydrous acetonitrile
(2 mL). Compound 12 (266 mg, 1.06 mmol) was dissolved in 2 mL
of anhydrous acetonitrile and added dropwise to above suspen-
sion. The reaction was then continued 80 °C for 2 h. The solvent
was removed evaporated and the resulting crude was purified by
column chromatography on silica gel using gradient 0–3% metha-
nol in dichloromethane to give products 49 (19 mg, 7%) and 50
(8 mg, 3%) as white solids. Compound 49: mp 186–188 °C, 1H
NMR (CDCl3) d 2.23 (s, 3H), 2.34 (s, 3H), 5.11 (s, 2H), 5.52 (s, 1H),
6.37 (s, 1H), 7.30–7.36 (m, 1H), 7.42 (t, J = 7.91 Hz, 2H), 7.55 (d,
4.1.36. 2-(2-(3-Methyl-5-((3-methyl-1-phenyl-1H-pyrazol-5-
yl)methoxy)-1H-pyrazol-1-yl)ethyl) isoindoline- 1,3-dione (45)
Compound 43 (144 mg, 0.53 mmol) and cesium carbonate
(519.03 mg, 1.59 mmol) were suspended in anhydrous acetonitrile
(2 mL). Compound 12 (128 mg, 0.51 mmol) was dissolved in 2 mL
of anhydrous acetonitrile and added dropwise to above reaction
suspension. The reaction was then heated to 60 °C overnight. The
reaction solvent was removed under vacuum and the resulting
crude was purified by flash chromatography on silica gel using gra-
dient 0–50% ethyl acetate in hexanes to afford product 45 (40 mg,
18%); 1H NMR (CDCl3) d 1.99 (s, 3H), 2.28 (s, 3H), 3.88–3.91 (t,
J = 5.7 Hz, 2H), 4.09–4.12 (t, J = 5.2 Hz, 2H), 4.79 (s, 2H), 5.24 (s,
1H), 6.12 (s, 1H), 7.31–7.35 (m, 1H), 7.38–7.45 (m, 4H), 7.61–
7.63 (m, 2H), 7.70–7.72 (m, 2H).
J = 7.53 Hz, 2H); MS ESI (+ve) for
C
15H16N4O (M+H+): calcd
269.14; found: 263.23. Compound 50: 1H NMR (CDCl3) d 1.92 (s,
3H), 2.28 (s, 3H), 5.00 (s, 2H), 5.40 (s, 1H), 5.97 (s, 1H), 7.32–7.58
(m, 5H); MS ESI (+ve) for C15H16N4O (M+H+): calcd 269.14, found:
269.23.
4.1.41. 1-Benzyl-2-(bromomethyl)pyrrolidine (52)
4.1.37. Ethyl-2-(3-methyl-5-((3-methyl-1-phenyl-1H-pyrazol-5-
yl)methoxy)-1H-pyrazol-1-yl)acetate (46)
Compound 44 (40 mg, 0.21 mmol) and cesium carbonate
(212 mg, 0.65 mmol) were suspended in anhydrous acetonitrile
In a flask containing carbon tetrabromide (1.7 g, 5.12 mmol)
and triphenylphosphine (1.44 g, 5.49 mmol) in anhydrous tetrahy-
drofuran (5 mL), 1-benzylpyrrolidin-2-yl-methanol (700 mg,
3.66 mmol) was added at 0 °C. The reaction was allowed to stir