R-Amino Acid Phenolic Ester Derivatives
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 22 3589
bromide (200 mg, 2.30 mmol) in toluene (50 mL). The mixture
was heated to 100 °C for 72 h and then, after cooling, was
washed with water (2 × 50 mL), dried (Na2SO4), and filtered,
and the solvent was removed in vacuo to leave a residue which
was purified by chromatography on basic alumina using
toluene:ethyl actetate (9:1) as eluant. The free base was
dissolved in dichloromethane and excess dry hydrogen chloride
gas added. The salt was precipitated with diethyl ether,
filtered, and recrystallized from dichloromethane/diethyl ether.
This gave the title compound as a white crystalline solid (2.43
g, 31%): 1H NMR (CDCl3 + C5D5N) δ 2.59-2.69 (m, 2H), 2.69-
2.80 (m, 2H), 3.66 (s, 6H), 3.75-3.87 (m, 4H), 4.41 (s, 1H), 6.55
(d, 2H, J ∼ 8.5), 6.78 (br s, 1H), 7.10 (t, 1H, J ∼ 8.5), 7.33-
7.44 (m, 3H), 7.60-7.68 (m, 2H); IR (KBr) 3421, 2954, 2378,
1771, 1608, 1483, 1260, 1169, 1112 cm-1; m/z (ES) [M+H]+
358; Found: 358.1655, C20H24NO5 requires 358.1648. Anal.
(C20H24ClNO5) C, H, N.
N-(2-Am in oeth yl)tetr a h yd r oisoqu in olin e: 2-Bromoeth-
ylamine hydrobromide (10.0 g, 48.8 mmol) and 1,2,3,4-tet-
rahydroisoquinoline (21.4 mL, 168 mmol) in toluene (100 mL)
were heated at reflux for 9 h and then left to cool overnight.
The reaction mixture was filtered and the filtrate washed with
water (100 mL). The aqueous layer was then saturated with
sodium chloride and washed with more toluene (3 × 100
mL). The combined organic layers were dried (Na2SO4) and
filtered, and the solvent was removed in vacuo to give a resi-
due which was purified by chromatography on alumina
using dichloromethane:methanol:ammonia (9:1:0.2) as eluant.
The title compound was isolated as an oil (1.54 g, 18%): 1H
NMR (CDCl3) δ 1.52 (br s, 2H), 2.61 (t, 2H, J ∼ 5.5), 2.77
(t, 2H, J ∼ 5.5), 2.82-2.99 (m, 4H), 3.64 (s, 2H), 6.95-7.31
(m, 4H).
The following compound was similarly prepared except that
2-bromoethanol was used instead of 2-bromoethylamine hy-
drobromide:
N-(2-Hyd r oxyeth yl)tetr a h yd r oisoqu in olin e: 20%; 1H
NMR (CDCl3) δ 2.56 (br s, 1H), 2.66-2.76 (m, 2H), 2.77-2.87
(m, 2H), 2.88-2.98 (m, 2H), 3.63-3.77 (m, 4H), 6.94-7.20 (m,
4H).
The following compounds were similarly prepared in the
absence of lithium bromide and, where stated, without tri-
ethylamine:
(()-2-Mor p h olin obu tyr ic a cid , 2′,6′-d im eth oxyp h en yl
1
ester h yd r och lor id e (10): No triethylamine used, 45%; H
NMR (CDCl3 + C5D5N) δ 1.11 (t, 3H, J ∼ 7), 1.93-2.11 (m,
2H), 2.92-3.10 (m, 4H), 3.58 (dd, 1H, J ∼ 9, 7.5), 3.82 (s, 6H),
3.83-3.97 (m, 4H), 6.62 (d, 2H, J ∼ 8.5), 6.64 (br s, 1H), 7.16
(t, 1H, J ∼ 8.5); IR (KBr) 3454, 2935, 2224, 1759, 1611, 1482,
1305, 1176, 1114 cm-1; m/z (ES) [M+H]+ 310; Found: 310.1663,
N -2-[2-(1,2,3,4-Te t r a h yd r oisoq u in olin yl)]e t h yl-2′,6′-
d im eth oxyben za m id e h yd r och lor id e (6): A solution of
N-(2-aminoethyl)tetrahydroisoquinoline (1.50 g, 8.50 mmol) in
toluene (15 mL) was added to a stirred mixture of 2,6-
dimethoxybenzoyl chloride (1.88 g, 90%, 8.43 mmol) and
triethylamine (1.20 mL, 8.60 mmol) in toluene (15 mL). The
reaction mixture was stirred at room temperature for 2.5 h
and was then washed with water (2 × 25 mL), dried (Na2SO4),
and filtered, and the solvent was removed in vacuo. The
residue was dissolved in dichloromethane, and excess dry
hydrogen chloride gas was added. Diethyl ether was added,
and the precipitate was isolated by filtration and dried in
vacuo. The title compound was isolated as a white solid (1.28
g, 40%): 1H NMR (CDCl3 + C5D5N) δ 3.21-3.33 (m, 2H), 3.38-
3.58 (m, 4H), 3.76 (s, 6H), 3.96-4.06 (br s, 2H), 6.54 (d, 2H, J
∼ 8.5), 7.11 (d, 1H, J ∼ 7), 7.18-7.34 (m, 4H), 7.55 (br s, 1H);
m/z (ES) [M+H]+ 341; Found: 341.1864, C20H25N2O3 requires
341.1857. Anal. (C20H25ClN2O3‚0.2H2O) C, H; N: calcd, 7.32;
found, 6.86; Cl: calcd, 9.26; found, 8.27.
The following compound was similarly prepared except that
the reaction mixture was heated at reflux for 4 h prior to
workup:
N-2-[2(1,2,3,4-Tetr a h yd r oisoqu in olin yl)]eth yl 2′,6′-d i-
m eth oxyben zoa te h yd r och lor id e (7): 20%; mp 172-177 °C;
1H NMR (CDCl3 + C5D5N) δ 3.19-3.28 (m, 2H), 3.40-3.51 (m,
4H), 3.77 (s, 6H), 4.32 (s, 2H), 4.85-4.93 (m, 2H), 6.57 (d, 2H,
J ∼ 8.5), 7.05 (d, 1H, J ∼ 7), 7.14-7.28 (m, 3H), 7.28-7.37
(m, 1H); IR (KBr) 3440, 2951, 2490, 1731, 1597, 1476, 1432,
1298, 1257, 1109 cm-1; m/z (ES) [M+H]+ 342; Found: 342.1702,
C20H24NO4 requires 342.1697. Anal. (C20H24ClNO4) C; H: calcd,
6.40; found, 5.77; N: calcd, 3.71; found, 3.12.
C
16H24NO5 requires 310.1644. Anal. (C16H24ClNO5‚0.2 H2O) C,
H, N, Cl.
(()-2-Mor p h olin obu tyr ic a cid , 2′,6′-d im eth oxy-4′-m eth -
1
ylp h en yl ester h yd r och lor id e (11): 27%; H NMR (CDCl3
+ C5D5N) δ 1.12 (t, 3H, J ∼ 7), 1.92-2.17 (m, 2H), 2.35 (s,
3H), 2.99-3.14 (m, 4H), 3.60 (dd, 1H, J ∼ 9, 7.5), 3.79 (s, 6H),
3.84-4.00 (m, 4H), 6.43 (s, 2H); IR (KBr) 3499, 2970, 2386,
1760, 1610, 1509, 1473, 1247, 1172, 1139 cm-1; m/z (ES)
[M+H]+ 324; Found: 324.1809, C17H26NO5 requires 324.1803.
Anal. (C17H26ClNO5) C, H, N, Cl.
(()-2-(1,2,5,6-Tet r a h yd r op yr id yl)b u t yr ic a cid , 2′,6′-
d im eth oxy-4′-m eth ylp h en yl ester h yd r och lor id e (12): No
triethylamine used, 85%; 1H NMR (CDCl3 + C5D5N) δ 1.18 (t,
3H, J ∼ 7.5), 2.01-2.19 (m, 1H), 2.36 (s, 3H), 2.41-2.58 (m,
2H), 2.68-2.86 (m, 1H), 3.31-3.44 (m, 2H), 3.72-3.84 (m, 7H),
3.90-4.05 (m, 2H), 5.71 (br d, 1H, J ∼ 13), 5.97 (br d, 1H, J ∼
13), 6.43 (s, 2H); IR (KBr) 2946, 2106, 1763, 1605, 1471, 1247,
1158, 1134 cm-1; m/z (ES) [M+H]+ 320; Found: 320.1851,
IR (KBr) 3242, 2939, 2538, 1657, 1596, 1474, 1252, 1109 cm-1
;
C
18H26NO4 requires 320.1857. Anal. (C18H26ClNO4) C, H, N,
Cl.
(()-2-[N-Bis(2-m eth oxyeth yl)a m in o]bu tyr ic a cid , 2′,6′-
d im eth oxyp h en yl ester h yd r och lor id e (13): 13%; 1H NMR
(CDCl3 + C5D5N) δ 1.13 (t, 3H, J ∼ 7.5), 1.96-2.09 (m, 2H),
3.08-3.17 (m, 2H), 3.20-3.30 (m, 2H), 3.38 (s, 6H), 3.56-3.65
(m, 2H), 3.66-3.75 (m, 2H), 3.76-3.89 (m, 7H), 6.60 (d, 2H, J
∼ 8.5), 7.14 (t, 1H, J ∼ 8.5); IR (KBr) 3507, 2946, 2531, 1762,
1606, 1483, 1264, 1174, 1112 cm-1; m/z (ES) [M+H]+ 356;
Found: 356.2062, C18H30NO6 requires 356.2068. Anal. (C18H30
-
Eth yl 2-m or p h olin op r op ion a te: Ethyl 2-bromopropionate
(32.6 mL, 0.25 mol) and morpholine (55.1 mL, 0.63 mol) in
toluene (150 mL) was stirred at room temperature for 2 h. The
precipitate was filtered off and the filtrate evaporated in vacuo
to give an oily residue that was purified by vacuum distillation.
The title compound was isolated as a colorless oil (28.4 g,
60%): bp 80-82 °C at 1.2 mmHg (lit. 69-70 °C at 1 mmHg);24
1H NMR (CDCl3) δ 1.29 (t, 6H, J ∼ 7), 2.62 (dd, 4H, J ∼ 5, 4),
3.24 (q, 1H, J ∼ 7), 3.73 (dd, 4H, J ∼ 5, 4), 4.20 (q, 2H, J ∼ 7).
Eth yl r-m eth yl-2-m or p h olin op r op ion a te: Ethyl 2-mor-
pholinopropionate (28.2 g, 0.15 mol) in dry THF (83 mL) was
added over 40 min, under nitrogen, to a 2 M solution of lithium
diisopropylamide in toluene (83.3 mL, 0.17 mol) at -65 °C.
Stirring was continued for 1 h whereupon methyl iodide (19.6
mL, 0.32mol) was added. The mixture was warmed to room
temperature and after a further 30 min was poured onto iced
water (1.20 L). The product was extracted with diethyl ether
(3 × 500 mL), and the combined organic phase was then
washed with brine, dried (Na2SO4), and filtered and the solvent
removed in vacuo to give the title compound as an oil (28.6 g,
ClNO6‚1.0H2O) C, H, N, Cl.
(()-2-[N-Bis(2-m eth oxyeth yl)a m in o]bu tyr ic a cid , 2′,6′-
d im eth oxy-4′-m eth ylp h en yl ester h yd r och lor id e (14):
29%; 1H NMR (CDCl3 + C5D5N) δ 1.13 (t, 3H, J ∼ 7.5), 1.92-
2.13 (m, 2H), 2.34 (s, 3H), 3.10-3.21 (m, 2H), 3.23-3.35 (m,
2H), 3.37 (s, 6H), 3.56-3.65 (m, 2H), 3.68-3.81 (m, 8H), 3.82-
3.91 (m, 1H), 6.42 (s, 2H); IR (KBr) 2944, 2278, 1768, 1607,
1470, 1248, 1196, 1119 cm-1; m/z (ES) [M+H]+ 370; Found:
370.2217, C19H32NO6 requires 370.2227. Anal. (C19H32ClNO6)
C, H, N, Cl.
(()-2-[N-Bis(2-m eth oxyeth yl)am in o]h exan oic acid, 2′,6′-
d im eth oxyp h en yl ester h yd r och lor id e (17): 61%; 1H NMR
(CDCl3 + C5D5N) δ 0.95 (t, 3H, J ∼ 7), 1.34-1.48 (m, 2H),
1.49-1.60 (m, 2H), 1.97 (q, 2H, J ∼ 9), 3.06-3.18 (m, 2H),
3.18-3.30 (m, 2H), 3.37 (s, 6H), 3.55-3.64 (m, 2H), 3.65-3.74
(m, 2H), 3.80 (s, 6H), 3.87-3.96 (m, 1H), 6.05 (br s, 1H), 6.60
(d, 2H, J ∼ 8.5), 7.12 (t, 1H, J ∼ 8.5); IR (KBr) 2839, 1760,
1262, 1114 cm-1; m/z (ES) [M+H]+ 384; Found: 384.2370,
C
20H34NO6 requires 384.2386. Anal. (C20H34ClNO6) C, H, N.