DOI: 10.1080/14756366.2016.1220377
New inhibitors of acetylcholinesterase
3
residue was extracted using ethyl acetate. After evaporation of the CDCl3) ꢁ 21.5, 25.6, 26.5, 27.0, 32.7, 53.1, 58.1, 62.5, 126.2,
solvent under reduced pressure, usually pure dibenzylamino 127.8, 128.1, 129.9, 137.7, 138.6; EIMS, m/z: M.+ absent, 238
alcohol was obtained (48–79% yields). Dibenzylamino alcohol (1%), 105 (100%), 79 (21%).
thus obtained (0.7 mmol), N,N-dimethylaminocarbamoyl chloride
3-(Bis(4-fluorobenzyl)amino)propan-1-ol (15i): 1H NMR
(1.0 mmol) and freshly distilled pyridine (1.0 mmol) in CH2Cl2 (200 MHz, CDCl3) ꢁ 1.77–1.89 (m, 2H), 2.73 (t, J ¼ 6.0 Hz,
(2.0 mL) were kept under stirring at room temperature for three 2H), 3.65 (m, 6H), 7.09–7.00 (m, 4H), 7.38–7.31 (m, 4H); 13C
days; then the solvent was evaporated under reduced pressure and NMR (50 MHz, CDCl3)
d 28.1, 52.5, 57.5, 63.1, 115.2
the product was purified by flash column chromatography (n- (d, J ¼ 21.3 Hz), 130.7 (d, J ¼ 8.0 Hz), 133.6 (d, J ¼ 3.2 Hz),
hexane: ethyl acetate from 9:3 to 7:3 as eluent). Yields: 5–15%.
Route B. To a solution of amino alcohol (1.0 mmol) in 5.0 mL (25%), 123 (34%), 109 (100%), 95 (30%).
162.0 (d, J ¼ 245.3 Hz); EIMS, m/z: M.+ absent, 231 (7%), 136
MeCN, HCl gas was bubbled for 3–4 min; then N2 gas was
4-(Bis(4-fluorobenzyl)amino)butan-1-ol (15 l): 1H NMR
bubbled into the mixture to eliminate HCl excess. N,N- (200 MHz, CDCl3) ꢁ 1.60–1.63 (m, 2H), 2.64 (t, J ¼ 5.4 Hz,
dimethylaminocarbamoyl chloride (1.0 mmol) was added to the 2H), 3.55 (t, J ¼ 5.0 Hz, 2H), 3.71 (s, 4H), 6.93–7.01 (m, 4H),
mixture and the solution was refluxed for 12 h. The product was 7.21–7.28 (m, 4H); 13C NMR (50 MHz, CDCl3) ꢁ 28.3, 32.2, 49.2,
used in the following reaction without further purification. Benzyl 53.1, 62.4, 115.2 (d, J ¼ 21.2 Hz), 129.8 (d, J ¼ 8.0 Hz), 134.9 (d,
bromide (3.0 mmol) was added to the solution and the mixture J ¼ 3.2 Hz), 162.0 (d, J ¼ 245.0 Hz); EIMS, m/z: M.+ absent, 246
was kept at room temperature under stirring for 3 h; the mixture (11%), 109 (100%), 83 (18%).
refluxed for 12 h, then triethylamine (3.0 mmol) was added and
6-(Bis(4-fluorobenzyl)amino)hexan-1-ol (15m):1H NMR
the mixture refluxed for 2 days. The solvent was evaporated under (200 MHz, CDCl3) ꢁ 1.25–1.32 (m, 2H), 1.40–1.58 (m, 2H),
reduced pressure and the product was purified by flash column 2.37–2.49 (m, 2H), 3.57–3.64 (m, 6H), 6.99–7.07 (m, 4H), 7.30–
chromatography (n-hexane: ethyl acetate from 9:3 to 7:3 as 7.37 (m, 4H); 13C NMR (50 MHz, CDCl3) ꢁ 25.5, 26.7, 27.0, 32.6,
eluent). Yields: 15–40%.
53.0, 57.3, 62.6, 114.9 (d, J ¼ 21.2 Hz), 130.3 (d, J ¼ 7.8 Hz),
134.9 (d, J ¼ 2.9 Hz), 161.9 (d, J ¼ 244.4 Hz); EIMS, m/z:
M.+ absent, 246 (1%), 109 (100%), 83 (21%).
Characterization data
1
3-(Bis(4-(trifluoromethyl)benzyl)amino)propan-1-ol (15n): H
The characterization data for the synthesized compounds are
given below.
NMR (200 MHz, CDCl3) ꢁ 1.75–1.87 (m, 2H), 2.65 (t, J ¼ 6.1 Hz,
2H), 3.64 (s, 4H), 3.68 (t, J ¼ 5.6 Hz, 2H), 7.45 (d, J ¼ 8.2 Hz,
4H), 7.60 (d, J ¼ 8.2 Hz, 4H); 13C NMR (50 MHz, CDCl3) ꢁ 28.4,
52.9, 58.2, 63.1, 124.1 (q, J ¼ 271.9 Hz), 125.5 (q, J ¼ 3.8 Hz),
129.2, 129.7 (q, J ¼ 32.4 Hz), 142.3; EIMS, m/z: M.+ absent, 159
(100%), 140 (8%), 109 (41%), 69 (5%).
3-(Dibenzylamino)propan-1-ol (15a): 1H NMR (200 MHz,
CDCl3) ꢁ 1.73–1.83 (m, 2H), 2.67 (t, J ¼ 5.9 Hz, 2H), 3.61 (s,
4H), 3.64 (t, J ¼ 5.4 Hz, 2H), 7.25–7.35 (m, 10H); 13C NMR
(50 MHz, CDCl3) ꢁ 27.9, 52.9, 58.4, 63.5, 126.8, 128.4, 129.0,
137.8; EIMS, m/z: M.+ absent, 210 (17%), 91 (100%), 65 (24%),
44 (36%).
4-(Bis(4-(trifluoromethyl)benzyl)amino)butan-1-ol (15o): 1H
NMR (200 MHz, CDCl3) ꢁ 1.55–1.71 (m, 4H), 2.50 (t, J ¼ 6.2 Hz,
2H), 3.61 (t, J ¼ 5.7 Hz, 2H), 3.65 (s, 4H), 7.48 (d, J ¼ 8.2 Hz,
4H), 7.60 (d, J ¼ 8.2 Hz, 4H); 13C NMR (50 MHz, CDCl3) d 23.9,
30.7, 53.8, 58.0, 62.4, 124.2 (q, J ¼ 271.8 Hz), 125.2 (q,
J ¼ 3.8 Hz), 129.1, 129.3 (q, J ¼ 32.2 Hz), 143.1; EIMS, m/z:
M.+ absent, 346 (21%), 159 (100%), 140 (9%), 109 (31%).
6-(Bis(4-(trifluoromethyl)benzyl)amino)hexan-1-ol (15p): 1H
NMR (200 MHz, CDCl3) ꢁ 1.27–1.33 (m, 4H), 1.50–1.57 (m,
4H), 2.43 (t, J ¼ 6.9 Hz, 2H), 3.64–3.58 (m, 6H), 7.47 (d,
J ¼ 8.0 Hz, 4H), 7.58 (d, J ¼ 8.0 Hz, 4H); 13C NMR (50 MHz,
4-(Dibenzylamino)butan-1-ol (15b) 1H NMR (200 MHz,
CDCl3) ꢁ 1.55–1.64 (m, 2H), 1.71–1.77 (m, 2H), 2.57 (t,
J ¼ 6.3 Hz, 2H), 3.58 (t, J ¼ 5.7 Hz, 2H), 3.70 (s, 4H), 7.27–7.42
(m, 10H); 13C NMR (50 MHz, CDCl3) ꢁ 23.9, 30.9, 53.4, 58.1,
62.1, 127.5, 128.4, 129.5, 137.5; EIMS, m/z: M.+ absent, 210
(13%), 148 (18%), 91 (100%), 65 (20%).
5-(Dibenzylamino)pentan-1-ol (15c): 1H NMR (200 MHz,
CDCl3) ꢁ 1.25–1.61 (m, 6H), 2.47 (t, J ¼ 7.0 Hz, 2H), 3.56–7.62
(m, 6H), 7.25–7.41 (m, 10H); 13C NMR (50 MHz, CDCl3) ꢁ 23.3,
26.5, 32.4, 53.0, 58.2, 62.8, 127.0, 128.2, 129.0, 139.0; EIMS,
m/z: 283 (M.+, 1%), 210 (32%), 91 (100%), 65 (11%).
6-(Dibenzylamino)hexan-1-ol (15d): 1H NMR (200 MHz,
CDCl3) ꢁ 1.25–1.30 (m, 2H), 1.44–1.56 (m, 2H), 2.45 (t,
J ¼ 7.2 Hz, 2H), 3.56–7.63 (m, 6H), 7.25–7.42 (m, 10H); 13C
NMR (50 MHz, CDCl3) ꢁ 25.4, 26.8, 32.7, 52.9, 58.1, 62.9, 127.0,
128.2, 129.0, 139.0; EIMS, m/z: M.+ absent, 210 (30%), 91
(100%), 73 (25%).
3-(Bis(4-methylbenzyl)amino)propan-1-ol (15e): 1H NMR
(200 MHz, CDCl3) ꢁ 1.86–1.91 (m, 2H), 2.37 (s, 6H), 2.77–2.80
(m, 2H), 3.69–3.74 (m, 6H), 7.12–7.29 (m, 8H); 13C NMR
(50 MHz, CDCl3) d 21.4, 27.9, 52.7, 58.3, 63.0, 126.4, 128.3,
128.4, 130.1, 137.1, 138.0; EIMS, m/z: M.+ absent, 238 (19%),
105 (100%), 77 (12%).
4-(Bis(4-methylbenzyl)amino)butan-1-ol (15f): 1H NMR
(200 MHz, CDCl3) ꢁ 1.58–1.74 (m, 4H), 2.34 (s, 6H), 2.52 (t,
J ¼ 6.1 Hz, 2H), 3.58 (t, J ¼ 5.4 Hz, 2H), 3.61 (s, 4H), 7.07–7.28
(m, 8H); 13C NMR (50 MHz, CDCl3) ꢁ 21.4, 24.2, 31.1, 53.4,
58.1, 62.5, 126.5, 128.1, 128.3, 130.3, 137.2, 137.9; EIMS, m/z:
297 (M.+, 1%), 238 (19%), 105 (100%), 84 (23%).
CDCl3)
ꢁ 25.5, 26.9, 32.6, 53.7, 58.0, 62.6, 124.3 (q,
J ¼ 273.3 Hz), 125.4 (q, J ¼ 3.8 Hz), 128.8, 129.2 (q,
J ¼ 32.2 Hz), 144.0; EIMS, m/z: M.+ absent, 346 (12%), 159
(100%), 140 (7%), 109 (19%).
3-(Dibenzylamino)propyl dimethylcarbamate1: 1H NMR
(200 MHz, CDCl3) ꢁ 1.81–1.88 (m, 2H), 2.50–2.62 (m, 2H),
2.62 (bs, 3H), 2.87 (bs, 3H), 3.58 (s, 4H), 4.11 (t, J ¼ 6.3 Hz, 2H),
7.26–7.40 (m, 10H); 13C NMR (50 MHz, CDCl3) ꢁ 26.6, 35.6,
36.3, 49.5, 58.3, 63.1, 126.7, 128.2, 128.7, 139.7, 156.5; EIMS,
m/z: M.+ absent, 145 (100%), 117 (35%), 102 (15%), 91 (62%),
72 (41%).
4-(Dibenzylamino)butyl dimethylcarbamate2: 1H NMR
(200 MHz, CDCl3) ꢁ 1.60–1.63 (m, 4H), 2.43–2.47 (m, 2H),
2.88 (s, 6H), 3.57 (bs, 4H), 4.01 (t, J ¼ 6.0 Hz, 2H), 7.23–7.40 (m,
10H); 13C NMR (50 MHz, CDCl3) ꢁ 23.5, 26.9, 35.9, 36.3, 53.0,
58.3, 65.2, 126.8, 128.2, 128.7, 139.8, 156.7; EIMS, m/z:
M.+ absent, 158 (68%), 118 (29%), 91 (100%), 72 (52%).
4-(Dibenzylamino)pentyl dimethylcarbamate3: 1H NMR
(200 MHz, CDCl3) ꢁ 1.34–1.43 (m, 2H), 1.49–1.59 (m, 4H),
2.45 (t, J ¼ 6.9 Hz, 2H), 2.90 (s, 6H), 3.57 (bs, 4H), 4.04 (t,
J ¼ 6.4 Hz, 2H), 7.24–7.41 (m, 10H); 13C NMR (50 MHz, CDCl3)
d 23.6, 26.6, 28.9, 35.9, 36.2, 53.1, 58.3, 65.3, 126.8, 128.1,
128.8, 139.8, 156.8; EIMS, m/z: M.+ absent, 263 (13%), 210
(51%), 91 (100%), 72 (17%).
6-(Bis(4-methylbenzyl)amino)hexan-1-ol (15 h): 1H NMR
(200 MHz, CDCl3) ꢁ 1.28–1.33 (m, 4H), 1.43–1.64 (m, 4H),
2.36 (s, 6H), 2.49–2.56 (m, 2H), 3.60 (t, J ¼ 6.4 Hz, 2H), 3.69 (s,
4H), 7.09–7.12 (m, 4H), 7.23–7.27 (m, 4H); 13C NMR (50 MHz,