1014
A. Montero et al. / Bioorg. Med. Chem. 10 (2002) 1009–1018
(CDCl3) d 156.6, 136.6, 128.5, 128.1, 66.6, 39.6, 39.1,
32.6; MS (ES+) m/z 209 ([MH]+, 100).
Hz, 1H), 3.50 (t, J=12.0 Hz, 1H), 3.26 (t, 2H, J=6.7
Hz), 3.18 (t, 2H, J=6.7 Hz), 3.0 (d, 4H, J=12.0 Hz),
2.72 (m, 4H), 2.66 (m, 4H), 2.52 (m, 4H), 2.36 (q, 2H,
J=7.4 Hz), 2.34 (q, 2H, J=7.3 Hz), 2.0 (t, 4H,
J=12.0 Hz), 1.82 (d, 4H, J=12.0 Hz), 1.67 (q, 4H,
J=12.0 Hz), 1.62 (m, 4H), 1.61 (t, 2H, J=7.3 Hz), 1.63
(t, 2H, J=7.3 Hz); 13C NMR (CDCl3) d 173.7, 173.5,
140.0, 128.5, 128.3, 126.0, 60.1, 55.4, 53.1, 39.6, 39.1,
33.6, 32.7, 30.7, 26.7, 9.5; MS (ES+) m/z 318 ([MH]+,
100); MS (ESꢁ) m/z 352 ([MCl]ꢁ, 100).
1-(2-Phenethyl)-4-(N-benzyloxycarbonyl-N0-diaminopro-
pyl)piperidine (6). To 4 (2.2 g, 10.5 mmol) in anhydrous
MeOH (25 mL) was added a solution of concd HClg in
anhydrous MeOH until pH 6. To this solution were
successively added 1-phenethyl-4-piperidone (1.8 g, 8.75
mmol), NaBH3CN (820 mg, 13.1 mmol) and 3 A molec-
ular sieves. The solution was then acidified to pH 6 with
a solution of concd HClg in MeOH and stirred for 24 h
at ambient temperature. The reaction mixture was fil-
tered over a Celite bed which was then washed with
MeOH. Concentration of the combined filtrates in
vacuo gave a brown precipitate which was purified by
medium pressure chromatography on silica gel
(CH2Cl2/NH3(g) in MeOH, 9:1) to provide 6 (1.2 g) as a
N-[(2,3-di-tert-Butoxycarbonyl)guanidinopropyl]-N-[1-(2-
phenethyl)-4-piperidyl]propanamide (9). To a solution of
8 (2.0 g, 6.3 mmol), thiourea (1.7 g, 6.3 mmol) and 2 mL
of TEA (18.9 mmol) in 20 mL of anhydrous CH2Cl2
under N2 and at 0 C was added 2.2 g (8.2 mmol) of
HgCl2. The reaction mixture was stirred at 0ꢀC for 1 h.
The temperature was allowed to warm to ambient tem-
perature and the mixture was stirred for additional 24 h.
The mixture was diluted with EtOAc, filtered over
Celite. The filtrate was washed with H2O, washed with
brine, and dried over MgSO4. The solvent was evapo-
rated in vacuo. The residue was purified by medium
pressure chromatography on silica gel (EtOAc) to pro-
vide 9 (1.9 g) as a yellowishoil. Yield 51%. 1NMR
(CDCl3) d 12.01 (s, 2H), 11.50 (s, 2H), 7.26–7.21 (m,
4H), 7.17–7.14 (m, 6H), 4.42 (t, 1H, J=12.0 Hz), 3.53
(t, 1H, J=12.0 Hz), 3.40 (t, 2H, J=7.0 Hz), 3.38 (t, 2H,
J=7.0 Hz), 3.24 (m, 4H), 3.08 (d, 4H, J=12.0 Hz), 2.73
(m, 4H), 2.56 (m, 2H), 2.34 (q, 1H, |J|=7.3 Hz), 2.31 (q,
1H, J=7.3 Hz), 2.05 (t, 4H, J=12.0 Hz), 1.73–1.84 (m,
8H), 1.67 (m, 4H), 1.46 (s, 36H), 1.13 (t, 6H, J=7.3 Hz);
13C NMR (CDCl3) d 173.7, 173.5, 163.3, 156.1, 155.9,
140.0, 128.5, 128.3, 126.0, 83.2, 82.7, 60.2, 55.3, 53.1,
39.2, 38.7, 33.7, 30.7, 29.6, 28.2, 27.9, 26.8, 9.5; MS
(ESꢁ) m/z 352 ([MCl]ꢁ, 100).
yellowishsolid. Yield 45%, mp 131–133 ꢀC. H NMR
1
(CDCl3) d 7.13–7.17 (m, 3H), 7.22–7.25 (m, 2H), 7.25–
7.29 (m, 5H), 5.87 (br, 1H), 5.04 (s, 2H), 4.17 (br, 1H),
3.27 (t, 2H, J=6.5 Hz), 3.0 (d, 2H, J=12.0 Hz), 2.83 (t,
2H, J=6.6 Hz), 2.75 (m, 3H), 2.56 (m, 2H), 2.06 (t, 2H,
J=12.0 Hz), 2.02 (d, 2H, J=12.0 Hz), 1.91 (tt, 2H,
J=6.7 and 6.7 Hz), 1.70 (q, 2H, J=12.0 Hz); 13C NMR
(CDCl3) d 158.1, 139.8, 136.6, 128.7, 128.5, 128.4, 128.1,
128.0, 126.2, 67.7, 60.9, 56.1, 52.7, 43.8, 39.5, 34.4, 30.5,
28.8; MS (ES+) m/z 396 ([MH]+, 100).
N-[(N0-Benzyloxycarbonyl)aminopropyl]-N-[1-(2-phenethyl)-
4-piperidyl]propanamide (7). A solution of 6 (6.1 g, 15.4
mmol) in propionic anhydride (50 mL) was stirred and
heated to reflux for 3 h. After cooling, the solution was
poured on ice, basified withNH OH (30%) and extrac-
4
ted withEtOAc. Teh combined organic layers were
dried over MgSO4 and concentrated in vacuo. To the
residue dissolved in EtOAc was added Et2O, the pre-
cipitate was filtered. The filtrate was concentrated to
give the crude product which was purified by flash
chromatography on silica gel (EtOAc/MeOH, 9:1) to
N-[1-(2-Phenethyl)-4-piperidyl]-N-(guanidinopropyl)pro-
panamide (10). A solution of 9 (1.6 g, 2.89 mmol) in a
mixture 1:1 of CH2Cl2/TFA was stirred at room tem-
perature for 4 h. After evaporation of the solvents in
vacuo, the residue was dried in vacuo to give 10 (1.6 g)
1
provide 7 (5.0 g) as an orange oil. Yield 72%. H NMR
(CDCl3) d 7.32–7.25 (m, 10H), 7.23–7.17 (m, 4H), 7.12–
7.10 (m, 6H), 5.0 (s, 4H), 4.32 (t, 1H, J=12.0 Hz), 3.47
(t, 1H, J=12.0 Hz), 3.25 (m, 4H), 3.06 (m, 4H), 2.97 (d,
4H, J=12.0 Hz), 2.69 (m, 4H), 2.51 (m, 4H), 2.27 (q,
2H, J=7.4 Hz), 2.20 (q, 2H, J=7.4 Hz), 1.98 (t, 4H,
J=12.0 Hz), 1.77 (d, 4H, J=12.0 Hz), 1.72–1.60 (m,
8H), 1.06 (t, 3H, J=7.3 Hz), 1.03 (t, 3H, J=7.3 Hz);
13C NMR (CDCl3) d 173.8, 156.4, 139.8, 136.6, 128.4,
128.2, 127.8, 127.7, 127.6, 125.8, 66.1, 60.0, 55.4, 53.0,
38.5, 38.2, 33.5, 30.6, 29.5, 26.6, 9.5; MS (ES+) m/z 452
([MH]+, 100), 474 ([MNa]+); MS (ESꢁ) m/z 486
([MCl]ꢁ).
as a trifluoroacetic salt. Yield 98%, mp 158–160 ꢀC. H
1
NMR (D2O) d 7.31–7.26 (m, 4H), 7.23–7.19 (m, 6H),
4.12 (t, 1H, J=12.0 Hz), 4.0 (t, 1H, J=12.0 Hz), 3.59
(m, 4H), 3.25 (m, 4H), 3.23 (m, 4H), 3.08 (m, 4H), 3.06
(m, 2H), 2.98 (m, 4H), 2.36 (q, 2H, |J|=7.4 Hz), 2.27 (q,
2H, J=7.4 Hz), 2.06 (q, 2H, J=12.0 Hz), 1.96 (d, 4H,
J=1.02 Hz), 1.67 (tt, 2H, J=7.4 and 7.4 Hz), 1.64 (tt,
2H, J=7.4 and 7.4 Hz), 0.95 (t, 3H, J=7.4 Hz), 0.94 (t,
3H, J=7.4 Hz); 13C NMR (D2O) d 177.8, 177.5, 163.0
(d, JCCF=35.2 Hz), 156.9, 136.3, 129.2, 128.9, 127.5,
116.4 (d, JCF=291.6 Hz), 58.0, 52.5, 52.1, 51.3, 43.0,
39.0, 30.0, 28.1, 27.4, 26.5, 9.1. The chloride salt of 10
was formed by treating an aqueous solution of the tri-
fluoroacetic salt withAmberlite IRA 400 resine: MS
(ES+) m/z 180 [(M+2H)/2]2+, 360 ([MH]+, 100%).
N-(Aminopropyl)-N-[1-(2-phenethyl)-4-piperidyl]propana-
mide (8). A mixture of 7 (340 mg, 0.76 mmol), 10% Pd/C
(15 mg) and glacial AcOH (1 mL) in MeOH (30 mL)
was shaken under H2 (35–40 psi) for 6 h. After filtration
and evaporation of the solvent, the residue was dis-
solved in NaOH (2.5 N) and extracted withEtOAc. The
organic layer was dried over MgSO4 and concentrated
in vacuo to give 8 (235 mg) as a lighly yellowish oil.
Yield 98%. 1H NMR (CDCl3) d 7.23–7.18 (m, 4H),
7.12–7.10 (m, 6H), 5.78 (s, 4H, 2H), 4.45 (t, J=12.0
.
Anal.
52.26(52.10); H: 8.35(8.15); N: 15.24(14.96).
(C20H33N5O.2HCl 1.5H2O)
(found)
C:
N-[1-(2-Phenethyl)-4-piperidyl]-N-[N0-(4,5-dihydro-1H-
imidazol-2-yl)aminopropyl]propanamide (11). A solution
of 8 (248 mg, 0.78 mmol) and 2-(methylthio)imidazoli-