Journal of Medicinal Chemistry
Article
The purity of synthesized compounds was checked by LC/MS. All
compounds have shown purity >95% (area percent, ESI+, TIC mode).
Content of halide counterions in synthesized salts 24−26, 53, 54, 65, 74,
82, 96, 97, and 104 was determined by argentometric titration with
0.1 N silver nitrate. Titrant was standardized with sodium chloride
solution before use.
All reagents and solvents were purchased from Sigma−Aldrich, Acros
Organic, Alfa Aesar, TCI Europe, and Apollo Scientific. Silica (0.035−
0.070 mm, Acros) was used for column chromatography. Reaction
conditions and yields were not optimized. All solvents were purified
before use by routine techniques.
(30b) and ethyl 4-bromobutanoate (1) by a similar protocol as 5a; yield
24%. 1H NMR (CDCl3, HMDSO) δ 1.25 (t, J = 7.1 Hz, 3H), 1.53−1.70
(m, 2H), 1.75 (quintet, J = 7.4 Hz, 2H), 1.80 (m, 2H), 1.99 (m, 2H),
2.06 (s, 3H), 2.21 (t, J = 7.4 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 2.73
(quintet, J = 7.9 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H). 13C NMR (CDCl3) δ
13.9, 14.2, 22.5, 27.9, 32.4, 37.7, 53.1, 60.2, 60.5, 173.6. HRMS m/z calcd
for C10H22NO2 [M + H]+, 200.1665; found, 200.1651.
Ethyl 4-[Cyclopentyl(methyl)amino]butanoate (5c). Com-
pound 5c was obtained from N-methylcyclopentanamine hydrochloride
(30c) and ethyl 4-bromobutanoate (1) by a similar protocol as 5a; oil,
yield 20%. 1H NMR (CDCl3, HMDSO) δ 1.24 (t, J = 7.2 Hz, 3H), 1.40−
1.58 (m, 4H), 1.62−1.74 (m, 2H), 1.78−1.89 (m, 4H), 2.29 (s, 3H),
2.32 (t, J = 7.3 Hz, 2H), 2.51 (t, J = 7.5 Hz, 2H), 2.76 (m, 1H), 4.12 (q,
J = 7.2 Hz, 2H). 13C NMR (CDCl3) δ 14.2, 21.8, 24.1, 30.1, 32.1, 39.8,
55.0, 60.3, 66.7, 173.4. HRMS m/z calcd for C12H24NO2 [M + H]+,
214.1807; found, 214.1797. Anal. Calcd for C12H23NO2: C 67.57,
H 10.87, N 6.57. Found: C 67.63, H 10.91, N 6.46.
4-Ethoxy-N-ethyl-N,N-dimethyl-4-oxobutan-1-aminium Bro-
mide (2). To a solution of ethyl 4-bromobutanoate (1) (19.5 g, 0.1 mol)
in dichloromethane at ice-bath temperature was added N,N-
dimethylethylamine (10.8 mL, 0.1 mol), and the mixture was stirred
at room temperature overnight. The reaction mixture was evaporated,
and the residue was triturated with acetone (50 mL) and kept at 0 °C for
0.5 h. The precipitate was filtered and dried in vacuo over P2O5 to afford
2 (22.274 g, 94%) as white hygroscopic crystals, mp 80.8−99.0 °C. 1H
NMR (CDCl3, hexamethyldisiloxane (HMDSO)) δ 1.26 (t, J = 7.2 Hz,
3H), 1.44 (t, J = 7.4 Hz, 3H), 2.00−2.11 (m, 2H), 2.52 (t, J = 6.6 Hz,
2H), 3.40 (s, 6H), 3.64−3.73 (m, 2H), 3.69 (q, J = 7.4 Hz, 2H), 4.14 (q,
Ethyl 4-(Dimethylamino)butanoate (5d). To a solution of ethyl
4-bromobutanoate (1) (20.0 g, 102.5 mmol) in anhydrous ethanol
(200 mL) was added a 33% (∼5.6 M) solution of dimethylamine in
ethanol (100 mL, 560 mmol), and the resulting mixture was stirred at
ambient temperature for 24 h. The reaction mixture was evaporated, and
the residue was dissolved in chloroform (200 mL), washed successively
with saturated solutions of NaHCO3 (4 × 50 mL) and NaCl (50 mL),
and dried (Na2SO4). The solution was evaporated and the residue
(12.15 g) was distilled in vacuo at 69−72 °C/13 mmHg to give 10.66 g
J = 7.2 Hz, 2H). 13C NMR (D2O) δ 7.4, 13.3, 17.4, 30.2, 50.0 [t, 1J(N,C)
=
4.0 Hz], 59.6 [t, 1J(N,C) = 2.6 Hz], 61.9, 62.1 [t, 1J(N,C) = 3.0 Hz], 174.6.
LC−MS (ESI) m/z 188 [M − Br−]+. Anal. Calcd for C10H22BrNO2·
0.67H2O: C 42.86, H 8.39, N 5.00. Found: C 42.86, H 8.54, N 4.97.
4-Ethoxy-N,N-diethyl-N-methyl-4-oxobutan-1-aminium Bro-
mide (3). A mixture of ethyl 4-bromobutanoate (1) (9.670, 49.57 mmol)
and diethylmethylamine (10.8 g, 123.9 mmol) in acetone (15 mL) was
stirred at room temperature for 8 days. The reaction mixture was
supplemented with diethyl ether (70 mL), and the precipitate was
filtered, washed with diethyl ether, and dried in vacuo over P2O5 to give 3
1
(65%) of 5d. H NMR [deuterated dimethyl sulfoxide (DMSO-d6),
HMDSO] δ 1.25 (t, J = 7.2 Hz, 3H). 1.78 (quintet, J = 7.4 Hz, 2H), 2.21
(s, 6H), 2.27 (t, J = 7.3 Hz, 2H), 2.32 (t, J = 7.5 Hz, 2H), 4.12 (q, J = 7.2
Hz, 2H). 13C NMR (CDCl3) δ 14.2, 23.0, 32.1, 45.4, 58.9, 60.2, 173.6.
LC-MS (ESI) m/z 160 [M + H]+.
1
N-Butyl-4-ethoxy-N,N-dimethyl-4-oxobutan-1-aminium Io-
dide (6). A mixture of ethyl 4-(dimethylamino)butanoate (5d) (1.26 g,
8.7 mmol) and 1-iodobutane (0.30 mL, 2.63 mmol) in acetonitrile
(10 mL) was stirred under argon at room temperature for 24 h and under
reflux for 1 h. The solvent was evaporated and the residue was triturated in
the ultrasound bath with ether (10 mL). The solid material was filtered
and dried in vacuo over P2O5 to give 6 (0.597 g, 87%), mp 98−100 °C.
1H NMR (D2O) δ 0.98 (t, J = 7.4 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.42
(sextet, J = 7.4 Hz, 2H), 1.77 (m, 2H), 2.10 (m, 2H), 2.54 (t, J = 7.0 Hz,
2H), 3.11 (s, 6H), 3.31−3.38 (m, 4H), 4.21(q, J = 7.2 Hz, 2H). 13C NMR
(D2O) δ 12.8, 13.3, 17.4, 19.0, 23.8, 30.2, 50.6 [t, 1J(N,C) = 3.8 Hz], 61.9,
(12.16 g, 87%) as white crystals, mp 126−129 °C. H NMR (D2O,
4,4-dimethyl-4-silapentane-1-sulfonic acid (DSS)) δ 1.27 (t, J = 7.2 Hz,
3H), 1.33 (t, J = 7.1 Hz, 6H), 2.04 (m, 2H), 2.52 (t, J = 6.9 Hz, 2H), 2.99
(s, 3H), 3.27 (m, 2H), 3.37 (q, J = 7.1 Hz, 4H), 4.19 (q, J = 7.2 Hz, 2H).
13C NMR (D2O) δ 7.0, 13.2, 16.9, 30.2, 46.8 [t, 1J(N,C) = 3.9 Hz], 56.5
[t, 1J(N,C) = 2.6 Hz], 58.9 [t, 1J(N,C) = 3.0 Hz], 61.9, 174.6. LC−MS (ESI)
m/z 202 [M − Br−]+. Anal. Calcd for C11H24BrNO2: C 46.81, H 8.57,
N 4.96. Found: C 46.70, H 8.72, N 4.97.
4-Ethoxy-N-(2-hydroxyethyl)-N,N-dimethyl-4-oxobutan-1-
aminium Bromide (4). Compound 4 was obtained from ethyl
4-bromobutanoate (1) and 2-(dimethylamino)ethanol by a similar
protocol as 2; yield 52%, mp 100−102 °C. 1H NMR (CDCl3, HMDSO)
δ 1.26 (t, J = 7.1 Hz, 3H), 2.10 (m, 2H), 2.49 (t, J = 6.8 Hz, 2H), 3.39 (s,
6H), 3.69 (m, 2H), 3.77 (m, 2H), 4.14 (q, J = 7.1 Hz, 2H), 4.15 (m, 2H),
5.04 (br s, 1H). 13C NMR (D2O) δ 13.2, 17.6, 30.2, 51.4 [t, 1J(N,C) = 3.8
Hz], 55.3, 61.9, 64.0 [t, 1J(N,C) = 2.8 Hz], 64.9 [t, 1J(N,C) = 2.8 Hz], 174.5.
LC−MS (ESI) m/z 204 [M − Br−]+. Anal. Calcd for C10H22BrNO3: C
42.26, H 7.80, N 4.93. Found: C 42.07, H 7.82, N 4.84.
Ethyl 4-[Cyclopropyl(methyl)amino]butanoate (5a). To a
solution of N-methylcyclopropanamine hydrochloride (30a) (2.299 g,
21.37 mmol) in acetonitrile (50 mL) were added successively triethyl-
amine (4.0 mL, 28.72 mmol) and a solution of ethyl 4-bromobutanoate
(1) (6.46 g, 33.81 mmol) in acetonitrile (50 mL). The reaction mixture
was stirred at room temperature under argon for 48 h, and then the
precipitate was filtered and washed with acetonitrile (10 mL). The filtrate
was evaporated; the residue was dissolved in water (70 mL) and a 5%
NaOH solution was added until the pH of the medium was 11. The
mixture was extracted with ethyl acetate (3 × 50 mL), washed with
saturated NaCl (20 mL), dried (Na2SO4), and evaporated. The residue
(1.7 g) was purified by column chromatography on silica gel with
chloroform/methanol (100:2) as eluent to afford 5a (1.379 g, 34%), oil.
1H NMR (CDCl3, HMDSO) δ 0.30−0.49 (m, 4H), 1.24 (t, J = 7.1 Hz,
1
1
62.6 [unresolved t, J(N,C) = 2.8 Hz], 63.9 [t, J(N,C) = 2.4 Hz], 174.5.
HRMS m/z calcd for C12H26NO2 [M − I−]+, 216.1964; found, 216.1978.
Anal. Calcd for C12H26INO2: C 41.99, H 7.63, N 4.08. Found: C 42.11,
H 7.66, N 3.91.
N-Benzyl-4-ethoxy-N,N-dimethyl-4-oxobutan-1-aminium
Bromide (7). Compound 7 was obtained from ethyl 4-(dimethylamino)
butanoate (5d) and benzylbromide by a similar protocol as 6; yield 96%,
mp 88−92 °C. 1H NMR (D2O) δ 1.27 (t, J = 7.2 Hz, 3H), 2.21 (m, 2H),
2.53 (t, J = 7.1 Hz, 2H), 3.07 (s, 6H), 3.35 (m, 2H), 4.19 (q, J = 7.2 Hz,
2H), 4.54 (s, 2H), 7.54−7.65 (m, 5H). 13C NMR (D2O) δ 13.2, 17.6,
30.3, 49.5 [t, 1J(N,C) = 3.8 Hz], 61.9, 62.8 [unresolved t, 1J(N,C) = 3.0 Hz],
68.0 [t, 1J(N,C) = 2.4 Hz], 126.9, 129.1, 130.7, 132.8, 174.5. HRMS m/z
calcd for C15H24NO2 [M − Br−]+, 250.1807; found, 250.1776. Anal.
Calcd for C15H24BrNO2·0.08H2O: C 54.31, H 7.34, N 4.22. Found: C
54.31, H 7.37, N 4.22.
N-(4-Ethoxy-4-oxobutyl)-N,N-dimethylcyclopropanaminium
Iodide (8). To a solution of ethyl 4-(cyclopropyl(methyl)amino)-
butanoate (5a) (1.379 g, 7.44 mmol) in acetonitrile (15 mL) was added
iodomethane (2.3 mL, 37.22 mmol). The reaction mixture was stirred at
room temperature for 24 h, the solvent was evaporated, and the residue
was triturated in an ultrasound bath with ether. The solid material was
filtered and dried in vacuo to afford 8 (2.164 g, 84%), mp 87−90 °C 1H
NMR (D2O, DSS) δ 0.96 (m, 2H), 1.22 (m, 2H), 1.27 (t, J = 7.2 Hz,
3H), 2.19 (m, 2H), 2.52 (t, J = 7.1 Hz, 2H), 2.98 (s, 6H), 3.16 (m, 1H),
3.46 (m, 2H), 4.19 (q, J = 7.2 Hz, 2H). 13C NMR (D2O) δ 1.6, 13.3, 17.7,
3H), 1.59 (tt, J = 3.7, 6.5 Hz, 1H), 1.80 (quintet, J = 7.4 Hz, 2H), 2.28 (t,
J = 7.4 Hz, 2H), 2.29 (s, 3H), 2.52 (t, J = 7.4 Hz, 2H), 4.11 (q, J = 7.1 Hz,
2H). 13C NMR(CDCl3) δ 6.7, 14.2, 22.6, 32.3, 38.7, 42.4, 57.3, 66.2, 173.7.
HRMS m/z calcd for C10H20NO2 [M + H]+, 186.1494; found, 186.1489.
Ethyl 4-[Cyclobutyl(methyl)amino]butanoate (5b). Com-
pound 5b was obtained from N-methylcyclobutanamine hydrochloride
1
1
30.3, 47.3 [t, J(N,C) = 4.2 Hz], 48.8 [t, J(N,C) = 3.8 Hz], 61.9, 66.2
[t, 1J(N,C) = 2.9 Hz], 174.6. HRMS m/z calcd for C10H22NO2 [M − I−]+,
2224
dx.doi.org/10.1021/jm401603e | J. Med. Chem. 2014, 57, 2213−2236