Journal of Medicinal Chemistry
ARTICLE
2.37ꢀ2.20 (m, 2H), 1.65ꢀ1.52 (m, 3H), 1.47 (s, 9H), 1.31 (d, J = 7 Hz,
6H); 13C NMR (125 MHz, CDCl3) δ 168.2, 154.8, 150.6, 150.4, 143.5,
136.8, 127.3, 126.3, 111.1, 79.5, 35.1, 33.8, 28.5, 28.4, 27.3, 23.8; HRMS
calcd for C23H32N3O4 (M + H)+ 414.2387, found 414.2385.
was added a 10% KOH solution (40 mL) in one portion. The reaction
mixture was stirred at rt for 24 h. MeOH was removed in vacuo, and the
water layer was acidified to pH 2 with 6 N HCl at 0 ꢀC. The precipitate
was collected by vacuum filtration. The crude solid was dissolved in
p-xylene (30 mL) and refluxed overnight at 170 ꢀC. The crude mixture
was purified by flash chromatography (10% EA/Hex) to yield 13 (1.42 g,
93%) as a white solid: TLC Rf = 0.17 (10% EA/Hex); 1H NMR (500
MHz, CDCl3) δ 7.28ꢀ7.14 (m, 3H), 7.09ꢀ7.03 (m, 2H), 6.73ꢀ6.65
(m, 2H), 6.61ꢀ6.55 (m, 1H), 5.92 (s, 2H), 3.38ꢀ3.28 (m, 1H),
2.91ꢀ2.82 (m, 2H), 2.70ꢀ2.54 (m, 2H); 13C NMR (125 MHz, CDCl3)
δ 177.1, 147.6, 146.2, 139.3, 137.0, 129.2, 128.3, 126.3, 120.6, 108.2,
107.7, 100.9, 43.4, 43.1, 39.9; MS calcd for C17H17O4 (M + H)+
285.1121, found 285.1116.
(()-3-(Benzo[d][1,3]dioxol-5-yl)-4-phenylbutan-1-ol (14). 13 (4.9
mmol, 1.39 g) in dry THF (50 mL) was added dropwise to a slurry of
lithium aluminum hydride (9.8 mmol, 372 mg) in dry THF (30 mL) at
0 ꢀC over 30 min. The reaction mixture was stirred and gradually
warmed to rt over 4 h. The reaction mixture was cooled again to 0 ꢀC,
and water was added until evolution of gas ceased. The resultant slurry
was filtered over Celite with washing with Et2O. THF was removed in
vacuo. The crude residue was purified by flash chromatography (30%
EA/Hex) to yield 14 (1.14 g, 86%) as a clear oil: TLC Rf = 0.27 (30%
EA/Hex); 1H NMR (500 MHz, CDCl3) δ 7.25ꢀ7.10 (m, 3H),
7.08ꢀ7.03 (m, 2H), 6.74ꢀ6.66 (m, 2H), 6.59ꢀ6.54 (m, 1H), 5.92 (s,
2H), 3.55ꢀ3.47 (m, 1H), 3.46ꢀ3.38 (m, 1H), 2.99ꢀ2.90 (m, 1H),
2.89ꢀ2.82 (m, 2H), 1.98ꢀ1.88 (m, 1H), 1.85ꢀ1.73 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 147.6, 145.8, 140.2, 138.1, 129.1, 128.1, 125.9,
120.8, 108.0, 107.6, 100.7, 60.9, 44.1, 43.9, 38.3; MS calcd for C17H19O3
(M + H)+ 271.1329, found 271.1326.
tert-Butyl 4-(4-((3,5-Dimethylphenyl)carbamoyl)-1-(4-isopropyl-
phenyl)-1H-pyrazol-5-yl)piperidine-1-carboxylate (10). To a stirred
solution of 9 (3.05 mmol, 1.26 g) and DMAP (0.30 mmol, 37 mg) in
DCM (10 mL) at 0 ꢀC were added DCC (3.35 mmol, 691 mg) and 3,5-
dimethylaniline (3.35 mmol, 483 mg) sequentially. The reaction mixture
was gradually warmed to rt and ran for 48 h. DCM was removed in
vacuo, and the crude mixture was purified by flash chromatography
(30% EA/Hex) to give 10 (745 mg, 47%) as a brownish solid: 1H NMR
(500 MHz, CDCl3) δ 7.85 (s, 1H), 7.69 (s, 1H), 7.33 (d, J = 8.3 Hz, 2H),
7.24 (d, J = 8.3 Hz, 2H), 7.20 (s, 1H), 6.76 (s, 1H), 4.25ꢀ3.97 (m, 2H),
3.16 (app t, J = 12 Hz, 1H), 3.00 (app p, J = 7 Hz, 1H), 2.71ꢀ2.48 (m,
2H), 2.30 (s, 6H), 2.26ꢀ2.17 (m, 2H), 1.67ꢀ1.56 (m, 2H), 1.42 (s, 9H),
1.29 (d, J = 7 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 161.6, 154.8,
150.42, 148.9, 138.8, 138.5, 137.7, 137.2, 127.3, 126.5, 126.1, 117.9,
115.9, 79.3, 35.1, 33.9, 30.3, 29.4, 28.4, 23.9, 21.4; Rf = 0.33 (30%
EA/Hex); MS calcd for C31H39N4O3 (M ꢀ H)ꢀ 515.3028, found
515.3030.
N-(3,5-Dimethylphenyl)-1-(4-isopropylphenyl)-5-(piperidin-4-yl)-
1H-pyrazole-4-carboxamide (3). To a stirred solution of 10 (1.44
mmol, 745 mg) in DCM (5 mL) at 0 ꢀC was added TFA (5 mL).
The reaction mixture was warmed to rt and stirred for 1 h. The solvents
were removed in vacuo. The organic residue was redissolved in DCM.
The organic layer was washed with saturated sodium bicarbonate and
then brine and dried over MgSO4. The solvent was removed in vacuo to
yield 3 (590 mg, 98%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ
7.86 (s, 1H), 7.49 (s, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz,
2H), 6.79 (s, 1H), 3.34ꢀ3.27 (m, 2H), 3.26ꢀ3.19 (m, 1H), 3.09ꢀ2.95
(m, 1H), 2.72 (app t, J = 13.2 Hz, 2H), 2.46 (qd, J = 13, 9.7, 3.7 Hz, 2H),
2.32 (s, 6H), 1.74 (d, J = 15 Hz, 2H), 1.32 (d, J = 7 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ 161.8, 150.3, 149.1, 138.73, 138.69, 137.8, 137.0,
127.4, 126.2, 126.1, 118.0, 115.8, 46.2, 34.9, 33.9, 30.2, 23.8, 21.4; MS
calcd for C26H33N4O (M + H)+ 417.2649, found 417.2646.
(()-3-(Benzo[d][1,3]dioxol-5-yl)-4-phenylbutanal (15). To a stirred
solution of 14 (4.04 mmol, 1.09 g), triethylamine (20.2 mmol, 2.8 mL),
and DMSO (109 mmol, 7.7 mL) in DCM (20 mL) at 0 ꢀC was added
SO3 Py (20.2 mmol, 3.21 g) portionwise over 5 min. The reaction
3
mixture was stirred for 2 h and subsequently warmed to rt. Excess
sodium bicarbonate was then added and the mixture stirred until all
remaining SO3 Py was consumed. The organic solution was diluted
3
Diethyl 2-(Benzo[d][1,3]dioxol-5-ylmethylene)malonate (11). To a
solution of diethyl malonate (31.2 mmol, 5.0 g) and piperonal (37.4,
5.61 g) in toluene (80 mL) was added piperidine (3.12 mmol, 0.308 mL)
followed by acetic acid (3.12 mmol, 0.179 mL). The reaction was
refluxed at 150 ꢀC under DeanꢀStark conditions for 24 h. The reaction
mixture was purified by flash chromatography (20% EA/Hex) to give an
inseparable mixture of 8 and aldehyde (3.83 g, 42%) as a clear oil: TLC
Rf = 0.31 (20% EA/Hex). 1H NMR showed 11 constituted 86% of the
with DCM, washed with brine, and dried over MgSO4, and solvent was
removed in vacuo. The crude residue was purified by flash chromatog-
raphy (20% Et2O/Hex) to give 15 (871 mg, 80%) as a yellowish oil:
TLC Rf = 0.24 (20% Et2O/Hex); 1H NMR (500 MHz, CDCl3) δ 9.59
(s, 1H), 7.29ꢀ7.15 (m, 3H), 7.09ꢀ7.03 (2H), 6.73ꢀ6.65 (m, 2H),
6.63ꢀ6.56 (m, 1H), 5.92 (s, 2H), 3.47ꢀ3.37 (m, 1H), 2.95ꢀ2.80 (m,
2H), 2.70 (d, J = 8.1 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 201.5,
147.8, 146.2, 139.2, 137.0, 129.1, 128.3, 126.3, 120.6, 108.2, 107.6, 100.9,
49.1, 43.4, 41.8; MS calcd for C17H15O3 (M ꢀ H)ꢀ 267.1027, found
267.1030.
1
mixture (3.29 g, 36%): H NMR (500 MHz, CDCl3) δ 7.61 (s, 1H),
7.01ꢀ6.98 (m, 1H), 6.96ꢀ6.94 (m, 1H), 6.82ꢀ6.78 (m, 1H), 6.00 (s,
2H), 4.36 (q, J = 7.1 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.32 (2t, J = 7.2
Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 190.2, 166.9, 164.2, 149.8,
148.2, 141.6, 128.5, 126.9, 126.1, 124.0, 108.5, 108.3, 108.3, 106.8, 102.0,
101.6, 61.6, 61.4, 14.1, 13.8; HRMS calcd for C15H17O6 (M + H)+
293.1020, found 293.1025.
(()-Diethyl 2-(1-(Benzo[d][1,3]dioxol-5-yl)-2-phenylethyl)malonate
(12). Under argon, 11 (9.61 mmol, 2.81 g) in dry Et2O (30 mL) was
added slowly via cannula to a suspension of CuCl (0.481 mmol, 48 mg)
and benzyl magnesium chloride (11.5 mmol, 5.75 mL) at ꢀ78 ꢀC. The
mixture was stirred while the temperature was gradually raised to rt
overnight. Saturated NH4Cl was added. The aqueous layer was extracted
with Et2O (3ꢁ). The combined organic extracts were washed with brine
and dried over MgSO4. The crude residue was purified by flash chroma-
tography (10% EA/Hex) to give 12 (2.26 g, 98%) as a yellowish oil. The
product was directly used for the following step without further purifica-
tion. MS: calcd for C22H25O6 (M + H)+ 385.1646, found 385.1654
(()-3-(Benzo[d][1,3]dioxol-5-yl)-4-phenylbutanoic Acid (13). To a
stirred solution of 12 (5.37 mmol, 2.06 g) in MeOH/H2O (1:1, 40 mL)
4-(((3-(Benzo[d][1,3]dioxol-5-yl)-4-phenylbutyl)amino)-
methyl)-N,N-dimethylaniline (2). Under argon a flask was
charged with 15 (36 mg, 0.13 mmol), THF (2 mL), and 4-(dime-
thylamino)benzylamine dihydrochloride (58 mg, 0.26 mmol). Na-
(AcO)3BH (55 mg, 0.26 mmol) was added with stirring at rt. After 20
h, 1 M NaOH (2 mL) was added. The mixture was extracted with
Et2O (3 ꢁ 10 mL). The extract was dried over MgSO4 and solvent
removed in vacuo. The crude material was purified by column
chromatography (2%ꢀ5% (10% NH4OH/MeOH)/DCM) to give
2 (13 mg, 25%) as a colorless oil: TLC Rf = 0.18 (5% (10% NH4OH/
MeOH/DCM); 1H NMR (500 MHz, CDCl3) δ 7.24ꢀ7.10 (m, 5H),
7.05ꢀ6.98 (m, 2H), 6.70ꢀ6.62 (m, 4H), 6.55ꢀ6.48 (m, 1H), 5.90 (d,
J = 5 Hz, 2H), 3.69ꢀ3.52 (m, 2H), 2.91 (s, 6H), 2.82 (s, 3H),
2.53ꢀ2.45 (m, 2H), 2.00ꢀ1.77 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 150.0, 147.5, 145.7, 140.1, 138.0, 129.5, 129.1, 128.0,
125.8, 120.8, 112.5, 108.0, 107.6, 100.7, 52.5, 46.4, 45.6, 43.9, 40.6,
34.8; MS calcd for C26H31N2O2 (M + H)+ 403.2380, found 403.2385.
7203
dx.doi.org/10.1021/jm200782y |J. Med. Chem. 2011, 54, 7193–7205