Journal of Medicinal Chemistry
Article
2.98, 3.18−3.28 and 3.50−3.68 (3m, 2H, CH2 morph), 3.78−4.03 (m,
4H, OCH3 + CHO morph), 4.16−4.32 (m, 1H, CHO morph), 4.80−
4.95 (m, 1H, OCH cyclopent), 6.85 (d, J = 8.0 Hz, 1H, H-5 Ar), 7.10
(dd, J = 8.0, 1.6 Hz, 1H, H-6 Ar), 7.29 (d, J = 1.6 Hz, 1H, H-2 Ar),
7.58 (s, 1H, CHN). IR (film) cm−1: 1600 (CN). Anal.
(C19H28N2O3) calcd for C, H, N.
room temperature, diethyl ether (20 mL) was added and the organic
phase was washed with water (20 mL), dried (MgSO4), and
concentrated under reduced pressure, yielding a light-yellow oil
which was purified by silicagel (100−200 mesh) column chromatog-
raphy using a gradient elution (from diethyl ether to a mixture of
diethyl ether/methanol (8:2) to give a light-yellow oil. Yield: 70%. 1H
NMR (CDCl3): δ 1.49−2.08 (m, 12H, 4CH2 cyclopent + 2CH2 pip),
2.08−2.33 (m, 2H, CH2-N chain), 2.38−2.61 (m, 4H, CH2-N pip),
2.65−2.87 (m, 1H, OH disappears with D2O), 2.87−3.08 (m, 1H, OH
disappears with D2O), 3.61−3.82 (m, 1H, CH-OH pip), 3.87 (s, 3H,
OCH3), 4.00−4.27 (m, 3H, CH2-O + CH-OH chain), 4.74−4.92 (m,
1H, OCH cyclopent), 6.84 (d, J = 8.0 Hz, 1H, H-5 Ar), 6.99 (d, J = 8.0
Hz, 1H, H-6 Ar), 7.20 (d, J = 1.0 Hz, 1H, H-2 Ar), 8.05 (s, 1H, CH
N). IR (KBr): cm−1: 3435 (OH). Anal. (C21H32N2O5) calcd for C, H,
N.
3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-[2-(4-Hy-
droxypiperidin-1-yl)-2-oxoethyl]oxime (6). To a suspension of
3-(cyclopentyloxy)-4-methoxybenzaldehyde oxime 16 (0.63 g, 2.68
mmol) and anhydrous K2CO3 (0.69 g, 5 mmol) in anhydrous DMF (2
mL), 1-(chloroacetyl)piperidin-4-ol (21) (1.1 g, 6 mmol) was added.
The reaction mixture was stirred at 50−60 °C for 18 h. After cooling
to room temperature, the mixture was poured into water (20 mL), the
aqueous phase was extracted with diethyl ether (2 × 20 mL), the
organic phases were washed with water (2 × 10 mL) and brine (2 ×
10 mL), dried (Na2SO4), and evaporated under reduced pressure. The
crude product was purified by silica gel (100−200 mesh) column
chromatography using a gradient elution [(from diethyl ether alone to
a mixture of chloroform/methanol (9:1)] to give a yellow oil.
Yield: 48%. 1H NMR (CDCl3): δ 1.40−2.02 (m, 12H, 4CH2
cyclopent + 2 CH2 pip), 2.49 (br s, 1H, OH, disappears with D2O),
3.17−3.35 (m, 2H, CH2−N), 3.63−4.18 (m, 6H, OCH3 + CH−OH +
CH2N), 4.72−4.91 (m, 3H, CH2O + OCH cyclopent), 6.83 (d, J = 8.0
Hz, 1H, H-5 Ar), 7.03 (d, J = 8.0 Hz, 1H, H-6 Ar), 7.19 (d, J = 1.8 Hz,
1H, H-2 Ar), 8.11 (s, 1H, CHN). IR (KBr): cm−1: 3430 (OH),
1671 (CO). Anal. (C20H28N2O5) calcd for C, H, N. GC-MS m/z:
376 (M+).
General Procedure for 3-(Cyclopentyloxy)-4-methoxyben-
zaldehyde O-[3-(Cycloamin-4-yl)-3-oxopropyl]oximes (7a,b).
To a suspension of 3-(cyclopentyloxy)-4-methoxybenzaldehyde
oxime 16 (0.9 g, 3.8 mmol) and anhyd K2CO3 (1,1 g, 8 mmol) in
anhyd DMF (4 mL), the suitable 3-chloropropanoyl-4-cycloamine
20c,d (9.6 mmol) dissolved in anhyd DMF (1 mL) was added. The
mixture was heated at 100 °C for 24 h. After cooling to room
temperature, the mixture was poured into water (50 mL) and extracted
with diethyl ether (3 × 20 mL). The organic phases were washed with
water (2 × 10 mL) and brine (2 × 10 mL), dried (Na2SO4), and
concentrated under reduced pressure.
1-{2-(Acetyloxy)-3-[({[3-(cyclopentyloxy)-4-methoxyphenyl]-
methylene}amino)oxy]propyl}piperidin-4-yl Acetate (9). A
suspension of 3-(cyclopentyloxy)-4-methoxybenzaldehyde O-[2-hy-
droxy-3-(4-hydroxypiperidin-1-yl)propyl]oxime 8 (0.64 g, 1.63 mmol)
and sodium acetate (0.2 g, 2.4 mmol) in acetic anhydride (5 mL) was
heated at 40−50 °C for 5 h. After cooling to room temperature, the
mixture was poured into water (100 mL) and extracted with diethyl
ether (3 × 10 mL); the organic phases were washed with water (3 ×
20 mL) and brine (3 × 20 mL), dried (MgSO4), and concentrated
under reduced pressure, yielding an oil which was purified by silicagel
(100−200 mesh) column chromatography using as eluent first
dichloromethane, then diethyl ether. The pure product was obtained
1
as yellow oil. Yield: 64%. H NMR (CDCl3): δ 1.52−2.02 (m, 12H,
4CH2 cyclopent + 2CH2 pip), 2.08 (s, 3H, CH3), 2.18 (s, 3H, CH3),
2.77−3.20 (m, 5H, 2CH2N pip + CHO pip), 3.89 (s, 3H, OCH3), 4.32
(d, J = 4.0 Hz, 2H, CH2N chain), 4.77−5.03 (m, 3H, CH2-O + CH-
OH chain), 5.41−5.60 (m, 1H, OCH cyclopent), 6.86 (d, J = 8.0 Hz,
1H, H-5 Ar), 7.03 (dd, J = 8.0, 1.0 Hz, 1H, H-6 Ar), 7.20 (d, J = 1.0
Hz, 1H, H-2 Ar), 8.02 (s, 1H, CHN). IR (CHCl3): cm−1: 1740−
170 (CO). Anal. (C25H36N2O7) calcd for C, H, N.
3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-[2-Hydroxy-
3-(morpholin-4-ylamino)propyl]oxime (10a). To a solution of 3-
(cyclopentyloxy)-4-methoxybenzaldehyde O-(oxiran-2-ylmethyl)-
oxime 17 (0.73 g, 2.5 mmol)15 in absolute ethanol (5 mL),
morpholin-4-amine hydrochloride (0.53 g, 3.85 mmol) was added
and the mixture was heated at 40−50 °C, then triethylamine (0.73 g,
7.23 mmol) was slowly added and the mixture was heated at 50 °C for
further 18 h. After cooling to room temperature, the solvent was
removed under reduced pressure and the crude was solved in CH2Cl2
(15 mL) and washed with water (3 × 5 mL). The organic phase was
dried (Na2SO4) and concentrated under reduced pressure, yielding a
crude light-yellow oil which was purified by silicagel (100−200 mesh)
column chromatography using a gradient elution [(from diethyl ether
alone to diethyl ether/methanol (9:1)]. The pure oil obtained (0.28 g,
0.71 mmol) was crystallized by addition of a mixture of diethyl ether/
petroleum ether (boiling point 40−60 °C) (1:1), yielding a white
solid. Yield 28%; mp 78−79 °C. 1H NMR (CDCl3): δ 1.55−2.15 (m,
8H, 4CH2 cyclopent), 2.65−3.22 (m, 6H, 3CH2N), 3.68−3.80 and
3.82−4.02 (2m, 7H, OCH3 + 2CH2O morph), 4.18−4.39 (m, 3H,
OCH2 + CH-OH), 4.78−4.94 (m, 1H, OCH cyclopent), 6.85 (d, J =
8.4 Hz, 1H, H-5 Ar), 7.00 (dd, J = 8.4, 1.8 Hz, 1H, H-6 Ar), 7.19 (d, J
= 1.8 Hz, 1H, H-2 Ar), 8.51 (s, 1H, CH=N). IR (KBr) cm−1: 3690
(OH + NH). Anal. (C20H31N3O5) calcd for C, H, N.
Compound 3-(cyclopentyloxy)-4-methoxybenzaldehyde O-(3-mor-
pholin-4-yl-3-oxopropyl)oxime 7a crystallized as a white solid by
addition of a mixture of diethyl ether/petroleum ether (boiling point
40−60 °C) (1:1).
Compound 3-(cyclopentyloxy)-4-methoxybenzaldehyde O-[3-(2,6-
dimethylmorpholin-4-yl)-3-oxopropyl]oxime 7b was purified by
silicagel (100−200 mesh) column chromatography using a gradient
elution [(from diethyl ether alone to a mixture of chloroform/
methanol (9:1)], yielding a pure yellow oil.
3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(3-morpholin-4-
yl-3-oxopropyl)oxime (7a). Yield 44%; mp 76−77 °C. 1H NMR
(CDCl3): δ 1.60−2.09 (m, 8H, 4CH2 cyclopent), 2.82 (t, J = 3.2 Hz,
2H, CH2CO), 3.48−3.69 (m, 8H, 4CH2 morph), 3.89 (s, 3H, OCH3),
4.51 (t, J = 3.2 Hz, 2H, CH2O), 4.81−4.96 (m, 1H, OCH cyclopent),
6.87 (d, J = 8.3 Hz, 1H, H-5 Ar), 7.05 (dd, J = 8.3, 1.6 Hz, 1H, H-6
Ar), 7.22 (d, J = 1.6 Hz, 1H, H-2 Ar), 8.01 (s, 1H, CHN). IR (KBr)
cm−1: 1627 (CO). Anal. (C20H28N2O5) calcd for C, H, N.
3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-[3-(2,6-dimethyl-
1
morpholin-4-yl)-3-oxopropyl]oxime (7b). Yellow oil. Yield: 52%. H
NMR (CDCl3): δ 1.22 (d, J = 6.3 Hz, 6H, 2CH3 morph), 1.59−2.07
(m, 8H, 4CH2 cyclopent), 2.28−2.47 (m, 1H, HA CH2 morph), 2.64−
3.02 (m, 3H, HB CH2 morph + CH2CO), 3.44−3.63 (m, 4H, morph),
3.89 (s, 3H, OCH3), 4.49 (t, J = 6.8 Hz, 2H, CH2O), 4.81−4.92 (m,
1H, OCH cyclopent), 6.85 (d, J = 8.3 Hz, 1H, H-5 Ar), 7.06 (dd, J =
8.3, 1.8 Hz, 1H, H-6 Ar), 7.22 (d, J = 1.8 Hz, 1H, H-2 Ar), 8.00 (s, 1H,
CHN). IR (CHCl3) cm−1: 1639 (CO). Anal. (C22H32N2O5)
calcd for C, H, N.
3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-[2-hydroxy-
3-(4-hydroxypiperidin-1-yl)propyl]oxime (8). A solution of 3-
(cyclopentyloxy)-4-methoxybenzaldehyde O-(oxiran-2-ylmethyl)-
oxime 17 (1 g, 3.43 mmol) and piperidin-4-ol (0.7 g, 6.92 mmol) in
anhydrous THF (4 mL) was heated at 50 °C for 18 h. After cooling to
3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-{3-[(2,6-Di-
methylmorpholin-4-yl)amino]-2-hydroxypropyl}oxime (10b).
A mixture of 3-(cyclopentyloxy)-4-methoxybenzaldehyde O-(oxiran-
2-ylmethyl)oxime 17 (1.5 g, 5.15 mmol) and 2.6-dimethylmorpholin-
4-amine (3.9 g, 30 mmol) was heated at 50 °C overnight. After cooling
to room temperature, the crude was solved in diethyl ether (20 mL)
and the organic phase was washed with water (3 × 20 mL), then
extracted with 1 N HCl solution (3 × 20 mL). Subsequently, the acid
solution was made alkaline with NaOH and extracted with CH2Cl2 (3
× 20 mL). The organic phases were washed with water (20 mL), dried
(MgSO4), and concentrated under reduced pressure, yielding brown
oil that was purified by distillation in high vacuum. Yield 33%; bp 150
I
dx.doi.org/10.1021/jm500855w | J. Med. Chem. XXXX, XXX, XXX−XXX