Molecules 2003, 8
563
Recrystallization from ethyl acetate gave 2.13 g (77%) of 4-pyridin-4-yl-benzaldehyde (4) as yellow
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needles. LC: tr 2.41’; MS: 184 [M+H]+; H-NMR: 10.10 (s, 1H), 8.71 (d, 2H), 8.06 (s, 4H), 7.77 (d,
2H).
4-(4-Pyridin-4-yl-benzylamino)-piperidine-1-tert-butyl carbamate (5)
A solution of 4 (1.07 g, 5.33 mmol, 1 eq) and 1 (976 mg, 5.33 mmol, 1 eq) in methanol (30 mL)
was refluxed for 4 h. After cooling to r.t., NaBH4 (222 mg, 5.87 mmol, 1.1 eq) was added carefully
over 30 minutes. After 2 h of additional refluxing, the solution was carefully diluted with water and
extracted three times with ethyl acetate. The combined organic layers were washed twice with brine,
dried over MgSO4 and the solvent was evaporated to give 1.90 g (96%) of compound 5 as a yellow
solid which could be used in further transformations without purification [7]. LC: tr 2.68’; MS: 368
[M+H]+; 1H-NMR: 8.63 (d, 2H), 7.82-7.41 (m, 6H), 3.89-3.74 (m, 3H), 3.79 (s, 1H), 3.08-1.73 (m, 5H)
1.40 (br s, 9H) 1.28-1.09 (m, 2H).
4-[(4-trans-Pentyl-cyclohexanecarbonyl)-(4-pyridin-4-yl-benzyl)-amino]-piperidine-1-tert-butyl
carbamate (7)
To a solution of trans-4-pentylcyclohexanecarboxylic acid (485 mg, 2.45 mmol, 1 eq) in CH2Cl2
(20 mL) at 0°C was added oxalic acid chloride (0.35 mL, 4.14 mmol, 1.7 eq) and 3 drops of DMF. The
mixture was stirred in an N2 atmosphere for 1 h and carefully evaporated (40°C, 200 mbar, argon at
inlet) [12]. The obtained yellowish viscous acid chloride 6 was dissolved in an Ar atmosphere in
CH2Cl2 (10 mL), followed by the addition of NEt3 (1.2 mL, 8.61 mmol, 3.5 eq) and 5 (900 mg, 2.45
mmol, 1 eq) dissolved in CH2Cl2 (10 mL). Stirring was continued at r.t. for 12 h. The mixture was
diluted with ethyl acetate, washed once with saturated Na2CO3 solution and with brine, dried over
MgSO4 and the solvent was evaporated. The crude material was purified by column chromatography
(silica gel 60, DCM/Hex/MeOH 10:4:1) to give 623 mg (46%) of the amide 7 as white filaments [7].
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LC: tr 5.85’; MS: 548 [M+H]+; H-NMR in CDCl3 (shows both amide rotamers with a ratio of ~1:1):
8.63-8.52 (m, 2H), 7.65-7.14 (m, 6H), 4.73-4.60 (m, 1H), 4.31, 4.24 (s, 2H, benzylic methylene of both
rotamers), 4.19-3.92 (m, 2H), 2.77-0.56 (m, 36H).
4-trans-Pentyl-cyclohexanecarboxylic acid piperidin-4-yl-(4-pyridin-4-yl-benzyl)-amide hydrochloride
(8)
A solution of compound 7 (617 mg, 1.13 mmol, 1 eq) in 4 M HCl / dioxane (10 mL, 40 mmol, 35.4
eq) was stirred for 4 h at r.t. under argon. The solvent was evaporated to give 8 as a white solid in
quantitative yield [7]. LC: tr 3.67’ (purity of >95%), MS: 448 [M+H]+.