Novel Lipophilic Acetylcholine Analogue
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7 2581
g, 5.0 mmol) was dissolved in 10 mL methylene chloride, and
pyridine (790 mg, 10 mmol) was added. To this solution, acetyl
chloride (630 mg, 8.0 mmol) was added and the reaction
mixture was kept at room temperature for 3 h. After adding
100 mL ethyl acetate, the organic layer of the mixture was
washed with water, 5% HCl, water, saturated NaHCO3, and
finally water. The organic solution was then dried over
anhydrous MgSO4. The residue that was obtained by evapo-
rating the solvent was purified by column chromatography
(silica gel C-200, hexane/ethyl acetate ) 4/1), yielding N-tert-
butoxycarbonylpiperidin-4-yl acetate (1.01 g, 83%). The com-
pounds were assigned according to the previously reported
NMR spectra.1
N-tert-Butoxycarbonylpiperidin-4-yl acetate (500 mg, 2.06
mmol) was dissolved in 5 mL ethyl acetate, and 5 mL 4 M
HCl/ethyl acetate was added under ice-cold condition. After
the solution was allowed to stand for 1 h at room temperature,
ethyl acetate was evaporated under vacuum at less than room
temperature, yielding piperidin-4-yl acetate hydrochloride (380
mg). This compound was dissolved in 5 mL chloroform, and 5
mL saturated NH3-chloroform solution was added under ice-
cold conditions. After the mixture was reacted for 5 min at
room temperature, the solution was filtered to remove the
insoluble solid and the solvent was then evaporated under
diminished pressure, yielding piperidin-4-yl acetate. The
compounds were assigned according to the reported NMR
spectra.1
Piperidin-4-yl acetate (200 mg, 1.4 mmol) was dissolved in
40 mL methylene chloride and 10 mL 30% acetaldehyde and
triacetoxy borohydride (850 mg, 4.0 mmol) were added. The
solution was allowed to stand for 2 h at room temperature.
After adding 100 mL ethyl acetate, the organic layer of the
mixture was washed with water. The organic solution was then
dried over anhydrous MgSO4. The residue that was obtained
by evaporating the solvent was purified by column chroma-
tography (Chromatorex NH silica gel, hexane/ethyl acetate )
4/1) to yield N-ethylpiperidin-4-yl acetate (1) (165 mg, 69%).
N-Ethylpiperidin-4-yl acetate (1): 1H NMR (δ, CDCl3): 1.03
(3H, t, CH3), 1.59-1.70 (2H, m, 2×CH), 1.82-1.89 (2H, m,
2×CH,), 1.99 (3H, s, CH3), 2.11-2.19 (2H, m, 2×CH), 2.35 (2H,
q, CH2), 2.63-2.69 (2H, m, 2×CH), 4.68-4.74 (1H, m, CH).
13C NMR (CDCl3): 12.19, 21.29, 30.81, 50.47, 52.15, 70.43,
170.52. Anal. (C9H17NO2): C, H, N. IR (neat) cm-1 1705.
Other N-ethyl compounds (2-5S) were synthesized by the
same manner as described above from the corresponding
N-tert-butoxycarbonylpiperidinemethanols as a starting mate-
rial. The reference compounds (MP4A, MP4P, and FEtP4MA)
were prepared using the method in the literature including
radiolabeling.2,3
28.40, 35.34, 44.05, 46.93, 66.15, 79.42, 154.79, 174.38. Anal.
(C14H25NO4): C, H, N. IR (neat) cm-1 1692, 1742.
Piperidin-4-ylmethyl acetate: 1H NMR (δ, CDCl3): 1.13-
1.22 (2H, m, 2×CH), 1.63-1.74 (3H, m, 2×CH, CH), 2.00 (3H,
s, CH3), 2.05 (1H, s, NH), 2.51-2.61 (2H, m, 2×CH), 3.03-
3.09 (2H, m, 2×CH), 3.85-3.88 (2H, m, CH2). 13C NMR
(CDCl3): 20.83, 29.83, 46.03, 53.64, 69.02, 171.1. Anal. (C8H15-
NO2): C, H, N. IR (neat) cm-1 3374, 1736.
Piperidin-4-ylmethyl propionate: 1H NMR (δ, CDCl3): 1.09
(3H, t, CH3), 1.07-1.12 (1H, m, CH), 1.39-1.48 (1H, m, CH),
1.59-1.65 (1H, m, CH), 1.66 (1H, s, NH), 1.71-1.79 (2H, m,
2×CH), 2.24-2.35 (3H, m, CH, CH2), 2.46-2.55 (1H, m, CH),
2.92-2.97 (1H, m, CH), 3.02-3.06 (1H, m, CH), 3.80-3.93 (2H,
m, CH2). 13C NMR (CDCl3): 9.10, 25.90, 27.49, 27.76, 36.63,
46.84, 49.89, 67.05, 174.42. Anal. (C9H17NO2): C, H, N. IR
(neat) cm-1 1734, 3372.
(R)- and (S)-Piperidin-3-ylmethyl acetate; R isomer: [R]D20
+13.9° (c ) 1, CHCl3), S isomer: [R]20 -15.4° (c ) 1, CHCl3).
1H NMR (δ, CDCl3): 1.06-1.11 (1H,Dm, CH), 1.30-1.48 (1H,
m, CH), 1.59-1.65 (1H, m, CH), 1.72-1.76 (2H, m, 2×CH),
1.99 (3H, s, CH3), 2.00 (1H, s, NH), 2.27-2.34 (1H, m, CH),
2.46-2.54 (1H, m, CH), 2.93-3.06 (2H, m, 2×CH), 3.78-3.91
(2H, m, 2×CH). 13C NMR (CDCl3): 20.78, 25.74, 27.67, 36.44,
46.72, 49.73, 67.16, 171.01. Anal. (C8H15NO2): C, H, N. IR
(neat) cm-1 1735.
(R)- and (S)-Piperidin-3-ylmethyl propionate; R isomer:
[R]2D0 +10.5° (c ) 1, CHCl3), S isomer: [R]20 -11.9° (c ) 1,
CHCl3). 1H NMR (δ, CDCl3): 0.86 (3H, t, CH3D), 1.06-1.12 (1H,
m, CH), 1.36-1.49 (1H, m, CH), 1.61-1.71 (1H, m, CH), 1.76-
1.80 (2H, m, 2×CH), 1.86 (3H, s, CH3), 2.05 (1H, s, NH), 2.31-
2.36 (1H, m, CH), 2.41-2.53 (1H, m, CH), 2.99-3.12 (2H, m,
2×CH), 3.81-3.96 (2H, m, 2×CH). 13C NMR (CDCl3): 16.52,
21.28, 24.90, 28.10, 37.22, 48.23, 49.30, 66.79, 172.25. Anal.
(C9H17NO2): C, H, N. IR (neat) cm-1 1735.
N-Ethylpiperidin-4-ylmethyl acetate (2): 1H NMR (δ,
CDCl3): 1.02 (3H, t, CH3), 1.20-1.34 (2H, m, CH2), 1.59-1.68
(3H, m, 2×CH, CH), 1.79-1.87 (2H, m, 2×CH), 1.99 (3H, s,
CH3), 2.33 (2H, q, CH2), 2.88-2.92 (2H, m, 2×CH), 3.87 (2H,
d, CH2). 13C NMR (CDCl3): 12.06, 20.82, 28.83, 35.28, 52.51,
52.84, 68.78, 171.06. Anal. (C10H19NO2): C, H, N. IR (neat)
cm-1 1736.
N-Ethylpiperidin-4-ylmethyl propionate (4): 1H NMR (δ,
CDCl3): 1.04 (3H, t, CH3), 1.10 (3H, t, CH3),1.28-1.32 (2H,
m, CH2), 1.59-1.67 (3H, m, 2×CH, CH), 1.80-1.88 (2H, m,
2×CH), 2.28 (2H, q, CH2), 2.35 (2H, q, CH2), 2.89-2.93 (2H,
m, 2×CH), 3.89 (2H, d, CH2). 13C NMR (CDCl3): 9.11, 12.10,
27.50, 28.88, 35.38, 52.55, 52.89, 68.66, 174.49. Anal. (C11H21-
NO2): C, H, N. IR (neat) cm-1 1723.
(R)- and (S)-N-Ethylpiperidin-4-ylmethyl acetate (3R, 3S);
N-tert-Butoxycarbonylpiperidin-4-ylmethyl acetate: 1H NMR
(δ, CDCl3): 1.08-1.22 (2H, m, 2×CH), 1.43 (9H, s, t-Bu), 1.64-
1.68 (2H, m, 2×CH), 1.72-1.81 (1H, m, CH), 2.03 (3H, s, CH3),
2.63-2.71 (2H, m, 2×CH), 3.90 (2H, d, CH2), 4.07-4.11 (2H,
m, 2×CH). 13C NMR (CDCl3): 20.82, 28.37, 28.61, 35.47, 43.28,
68.40, 79.35, 154.72, 171.02. Anal. (C13H23NO4): C, H, N. IR
(neat) cm-1 1689, 1738.
R isomer: [R]2D0 +7.8° (c ) 0.4, CHCl3), S isomer: [R]20 -8.7°
D
1
(c ) 1, CHCl3). H NMR (δ, CDCl3): 1.01 (3H, t, CH3), 1.24-
1.32 (3H, m, CH, CH2), 1.50-1.69 (2H, m, 2×CH), 1.75-1.88
(2H, m, 2×CH) 1.98 (3H, s, CH3), 2.33 (2H, q, CH2), 2.78-
2.87 (2H, m, 2×CH), 3.78-3.84 (1H, m, CH), 3.89-3.94 (1H,
m, CH). 13C NMR (CDCl3): 11.97, 20.88, 24.81, 27.40, 38.83,
52.75, 53.62, 56.77, 67.37, 171.11. Anal. (C10H19NO2): C, H,
N. IR (neat) cm-1 1718.
N-tert-Butoxycarbonylpiperidin-4-ylmethyl propionate: 1H
NMR (δ, CDCl3): 1.09-1.23 (5H, m, CH3, 2×CH), 1.42 (9H, s,
t-Bu), 1.63-1.67 (2H, m, 2×CH), 1.72-1.81 (1H, m, CH), 2.30
(2H, q, CH2), 2.62-2.71 (2H, m, 2×CH), 3.90 (2H, d, CH2),
4.07-4.10 (2H, m, 2×CH). 13C NMR (CDCl3): 9.11, 27.49,
28.40, 28.65, 35.56, 43.34, 68.26, 79.37, 154.76, 174.42. Anal.
(C14H25NO4): C, H, N. IR (neat) cm-1 1697, 1722.
(R)- and (S)- N-tert-Butoxycarbonylpiperidin-3-ylmethyl
acetate; R isomer: [R]D20 -16.2° (c ) 1, CHCl3), S isomer
[R]2D0 +17.8° (c ) 1, CHCl3). The compounds were assigned
according to the reported NMR spectra1.
(R)- and (S)-N-Ethylpiperidin-4-ylmethyl propionate (5R,
5S); R isomer: [R]D20 +8.0° (c ) 1.1, CHCl3), S isomer: [R]20
D
-8.9° (c ) 1.1, CHCl3).1H NMR (δ, CDCl3): 0.98-1.10 (6H,
m, 2×CH3) 1.19-1.33 (3H, m, CH, CH2), 1.54-1.69 (3H, m,
3×CH), 1.74-1.97 (2H, m, 2×CH), 2.22-2.36 (3H, m, CH,
CH2), 2.77-2.87 (2H, m, 2×CH), 3.78-3.95 (2H, m, 2×CH).
13C NMR (CDCl3): 9.11, 11.95, 24.81, 27.40, 27.51, 35.87,
52.71, 53.60, 56.77, 67.14, 174.41. Anal. (C11H21NO2): C, H,
N. IR (neat) cm-1 1731.
Preparation of N-Fluoroethylpiperidin-4-ylmethyl
Acetate (6). Piperidin-4-ylmethyl acetate (500 mg, 3.2 mmol),
1-fluoro-2-tosylethane (1.38 g, 6.35 mmol), and 150 mg K2CO3
were dissolved in 4 mL dimethylformamide for 2.5 h at 80 °C.
After adding 100 mL ethyl acetate, the organic layer of the
mixture was washed with water, 27% NH3, and finally
saturated NaCl. The organic solution was then dried over
anhydrous MgSO4. The residue that was obtained by evapo-
(R)- and (S)- N-tert-Butoxycarbonylpiperidin-3-ylmethyl pro-
pionate; R isomer: [R]D20 -14.7° (c ) 1, CHCl3), S isomer:
[R]2D0 +16.3° (c ) 1, CHCl3). H NMR (δ, CDCl3): 1.12 (3H, t,
1
CH3), 1.19-1.25 (1H, m, CH), 1.43 (10H, s, t-Bu, CH), 1.60-
1.67 (1H, m, CH), 1.73-1.79 (2H, m, 2×CH), 2.29 (2H, q, CH2),
2.59 (1H, broad s, CH), 2.74-2.81 (1H, m, CH), 3.83-3.99 (4H,
m, CH2, 2×CH). 13C NMR (CDCl3): 9.13, 24.43, 27.23, 27.50,