40 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1
Dutta et al.
EtOAc/hexane (1:4) mixture, 0.2 g (60%, yield); 1H NMR
(CDCl3) 1.19-2.01 (9H, m), 2.75-2.86 (2H, bd), 3.41-3.51 (4H,
m, NCH2 and OCH2CH2), 5.30 (1H, s, Ph2CHO), 6.88-7.60
(14H, m, 2Ph + PhF). Free base was converted into its oxa-
late salt, mp 168.8-169.9 °C. Anal. [C27H30FNO‚(COOH)2]
C, H, N.
P r oced u r e D: Syn th esis of 1-Nicotin oyl-4-[(eth oxy-
ca r bon yl)m eth yl]p ip er id in e (6a ). Hydrochloride salt of
amine ester 2 (0.47 g, 2.3 mmol) was added into 15 mL of
dry methylene chloride solution with triethylamine (1.3 g).
Nicotinoyl chloride (0.83 g, 4.6 mmol) was then added into
the solution in a portionwise manner. The solution was
stirred under nitrogen overnight. The crude product was col-
lected by removing methylene chloride and was chromato-
graphed over a silica gel column. Pure product was eluted
with EtOAc/MeOH (1%) solvent mixture, 0.55 g (87% yield),
as a colorless viscous liquid: 1H NMR (CDCl3) 1.18-1.32 (3H,
t, J ) 7.1 Hz, CH3CH2), 1.43-2.31 (7H, m), 2.74-3.18 (2H,
m), 4.03-4.24 (2H, q, J ) 7.0 Hz, CH2CH3), 4.59-4.76 (2H,
m), 7.28-8.66 (4H, m, aromatic-CH). Anal. (C15H20N2O3‚
0.2H2O) C, H, N.
3.41 (2H, s, NCH2), 4.01-4.22 (2H, q, J ) 7.0 Hz, CH2CH3),
7.13-7.46 (4H, m, PhBr). Anal. (C16H22NO2Br) C, H, N.
Syn t h esis of 1-[(3,4-Dich lor op h en yl)m et h yl]-4-[(et h -
oxyca r bon yl)m eth yl]p ip er id in e (3d ). R,3,4-Trichlorotolu-
ene (0.96 g, 4.9 mmol) was reacted with amine hydrochloride
2 (0.6 g, 2.8 mmol) in the presence of K2CO3 to furnish 3d ,
0.72 g (78% yield), as a colorless oil (procedure A): 1H NMR
(CDCl3) 1.17-1.31 (3H, t, J ) 7.1 Hz, CH3CH2), 1.45-2.11
(5H, m), 2.19-2.26 (2H, d, J ) 6.6 Hz, CH2CH), 2.75-2.86
(2H, m), 3.41 (2H, s, NCH2), 4.01-4.23 (2H, q, J ) 7.0
Hz, CH2CH3), 7.17-7.42 (3H, m, PhCl2). Anal. (C16H21NO2-
Cl2) C, H, N.
Syn th esis of 1-[(4-Meth oxyp h en yl)m eth yl]-4-[(eth oxy-
ca r bon yl)m eth yl]p ip er id in e (3e). Amine hydrochloride 2
(0.15 g, 0.72 mmol) was reacted with p-methoxy-R-chlorotolu-
ene (0.15 g, 0.95 mmol) to give 3e, 0.09 g (45% yield), as a
colorless oil (procedure A): 1H NMR (CDCl3) 1.17-1.31 (3H,
t, J ) 7.1 Hz, CH3CH2), 1.63-2.07 (5H, m), 2.18-2.25 (2H, d,
J ) 6.6 Hz, CH2CH), 2.78-2.90 (2H, m), 3.42 (2H, s, NCH2),
3.79 (3H, s, CH3O), 4.00-4.22 (2H, q, J ) 7.0 Hz, CH2CH3),
6.79-7.26 (4H, m, PhOCH3). Anal. (C17H25NO3) C, H, N.
Syn th esis of 1-[(4-Meth ylp h en yl)m eth yl]-4-[(eth oxy-
ca r bon yl)m eth yl]p ip er id in e (3f). Amine hydrochloride 2
(0.3 g, 1.44 mmol) was reacted with 4-methylbenzyl chloride
(0.32 g, 2.3 mmol) to give 3f, 0.28 g (72% yield), as a colorless
oil (procedure A): 1H NMR (CDCl3) 1.16-1.34 (3H, t, J ) 7.1
Hz, CH3CH2), 1.61-2.06 (5H, m), 2.18-2.24 (2H, d, J ) 6.6
Hz, CH2CH), 2.32 (3H, s, CH3Ph), 2.79-2.90 (2H, m), 3.44 (2H,
s, NCH2), 4.00-4.22 (2H, q, J ) 7.0 Hz, CH2CH3), 7.13-7.25
(4H, m, PhCH3). Anal. (C17H25NO2) C, H, N.
Syn th esis of 1-[(4-Ch lor op h en yl)m eth yl]-4-(2-h yd r oxy-
eth yl)p ip er id in e (4b). Ester 3b (0.46 g, 1.5 mmol) was
converted into product 4b, 0.36 g (92% yield), as a colorless
oil (procedure B): 1H NMR (CDCl3) 1.25-2.03 (9H, m), 2.75-
2.86 (2H, m), 3.41 (2H, s, NCH2), 3.56-3.68 (2H, t, J ) 6.3
Hz, CHCH2O), 7.23-7.27 (4H, m, PhCl); MS (CI) m/e 253.59
(M + H)+.
Syn th esis of 1-[(4-Br om op h en yl)m eth yl]-4-(2-h yd r oxy-
eth yl)p ip er id in e (4c). Ester 3c (0.3 g, 0.92 mmol) was
converted into product 4c, 0.22 g (82% yield), as a colorless
viscous oil (procedure B): 1H NMR (CDCl3) 1.10-2.08 (9H, m),
2.75-2.95 (2H, m), 3.45 (2H, s, NCH2), 3.60-3.75 (2H, t, J )
6.3 Hz, CHCH2O), 7.15-7.52 (4H, m, PhBr); MS (CI) m/e
299.04 (M + H)+.
Syn th esis of 1-[(3,4-Dich lor op h en yl)m eth yl]-4-(2-h y-
d r oxyeth yl)p ip er id in e (4d ). Ester 3d (0.43 g, 1.3 mmol)
was converted into product 4d , 0.3 g (81% yield), as a colorless
oil (procedure B): 1H NMR (CDCl3) 1.10-2.05 (9H, m), 2.74-
2.86 (2H, m), 3.58-3.70 (2H, t, J ) 6.3 Hz, CHCH2O), 4.62-
(2H, s, NCH2), 7.19-7.44 (3H, m, PhCl2); MS (CI) m/e 289.03
(M + H)+.
Syn t h esis of 1-[(4-Met h oxyp h en yl)m et h yl]-4-(2-h y-
d r oxyeth yl)p ip er id in e (4e). Ester 3e (0.08 g, 0.27 mmol)
was converted into product 4e, 0.065 g (95% yield), as a viscous
liquid (procedure B): 1H NMR (CDCl3) 1.23-2.00 (9H, m),
2.80-2.91 (2H, m), 3.42 (2H, s, CH2N), 3.61-3.74 (2H, t, J )
6 Hz, CH2CH2O), 3.79 (3H, s, CH3O), 6.79-7.26 (4H, m,
PhOCH3); MS (CI) m/e 250.15 (M + H)+.
Syn th esis of 1-[(4-Meth ylp h en yl)m eth yl]-4-(2-h yd r oxy-
eth yl)p ip er id in e (4f). Ester 3f (0.2 g, 0.72 mmol) was
converted into product 4f, 0.13 g (81%, yield), as a colorless
oil (procedure B): 1H NMR (CDCl3) 1.10-2.08 (9H, m), 2.35
(3H, s, CH3Ph), 2.85-2.95 (2H, m), 3.45 (2H, s, NCH2), 3.60-
3.80 (2H, t, J ) 6.3 Hz, CHCH2O), 7.00-7.28 (4H, m, PhCH3);
MS (CI) m/e 234.16 (M + H)+.
Syn th esis of 4-[2-(Dip h en ylm eth oxy)eth yl]-1-[(4-ch lo-
r op h en yl)m eth yl]p ip er id in e (5b). Compound 4b (0.3 g,
1.18 mmol) was reacted with benzhydrol (0.71 g, 3.9 mmol) to
give 5b, 0.3 g (62% yield), as a viscous liquid (procedure C):
1H NMR (CDCl3) 1.12-2.01 (9H, m), 2.73-2.84 (2H, m), 3.39-
3.51 (4H, m, CH2CH2O + NCH2), 5.30 (1H, s, Ph2CH), 7.22-
7.59 (14H, m, 2Ph + PhCl). Free base was converted into its
oxalate salt, mp 179.6-181.6 °C. Anal. [C27H30NOCl‚
(COOH)2] C, H, N.
P r oced u r e E: Syn th esis of 1-[(2-Th ien yl)m eth yl]-4-
[(eth oxyca r bon yl)m eth yl]p ip er id in e (9a ). Amine hydro-
chloride 2 (0.2 g, 0.96 mmol) and 1-thiophenecarbomethoxal-
dehyde (0.15 g, 1.3 mmol) were dissolved in 25 mL of dry
MeOH with 0.4 g of triethylamine. Into the solution was added
4A molecular sieves (4 g), and the reaction mixture was stirred
at room temperature for 1.5 h. Sodium cyanoborohydride (0.15
gm, 2.38 mmol) was added into the solution, and the reaction
was continued for an additional 12 h. The reaction mixture
was filtered through Celite, and the filtrate was collected.
Crude material was chromatographed over a silica gel column.
Pure compound was eluted with 30% EtOAc/hexane mixture,
0.17 g (68% yield), as a colorless liquid: 1H NMR (CDCl3) 1.16-
1.31 (3H, t, J ) 7.0 Hz, CH3CH2), 1.36-2.25 (7H, m), 2.84-
2.95 (2H, m), 3.70 (2H, s, NCH2), 4.00-4.22 (2H, q, J ) 7.1
Hz, CH3CH2), 6.89-7.25 (3H, m, aromatic-CH). Anal. (C14H21
NO2S) C, H, N.
-
P r oced u r e F : Syn th esis of 4-[2-[(2-Th ien yl)p h en yl-
m eth oxy]eth yl]-1-(p h en ylm eth yl)p ip er id in e (13a ). Phen-
yl(2-thienyl)methanol (0.39 g, 2 mmol) was dissolved in 25 mL
of dry benzene, and into it was added thionyl chloride (0.39 g,
2 mmol). The solution was refluxed for 1 h, and benzene along
with excess thionyl chloride was removed in vacuo. The
residue was dried in the pump. Crude chloride was dissolved
in toluene, and into it was added 1-benzyl-4-(2-hydroxyethyl)-
piperidine (12a ) (0.15 g, 0.68 mmol). The solution was refluxed
under nitrogen for 1.5 h, and thin layer chromatography
showed the formation of a new product. Solvent was removed
in vacuo, and the crude compound was taken in saturated
NaHCO3 solution. Crude product was extracted into ethyl
acetate layer and was dried over Na2SO4. Crude product was
chromatographed over a silica gel column, and the pure
product was eluted with (1:1) EtOAc/hexane mixture to give
13a , 0.2 g (77% yield), as a viscous liquid: 1H NMR (CDCl3)
1.10-1.75 (7H, m), 1.82-2.05 (2H, t, J ) 10.8 Hz, NCH2CH2),
2.75-2.95 (2H, m), 3.40-3.60 (4H, m), 5.52 (1H, s, Ph(2-
thiophene)CH), 6.75-7.50 (13H, m, aromatic-CH). Free base
was converted into its oxalate salt, mp 171.9-173 °C. Anal.
[C25H29NOS‚(COOH)2‚0.3H2O] C, H, N.
Syn th esis of 1-[(4-Ch lor op h en yl)m eth yl]-4-[(eth oxy-
ca r bon yl)m eth yl]p ip er id in e (3b). 4-Chlorobenzyl chloride
(0.27 g, 1.7 mmol) was reacted with amine hydrochloride 2
(0.3 g, 1.4 mmol) in the presence of K2CO3 to furnish 3b, 0.3
g (73%), as a colorless oil (procedure A): 1H NMR (CDCl3)
1.17-1.31 (3H, t, J ) 7.1 Hz, CH3CH2), 1.43-2.09 (5H, m),
2.18-2.25 (2H, d, J ) 6.7 Hz, CH2CH), 2.75-2.87 (2H, m),
3.42 (2H, s, NCH2), 4.01-4.22 (2H, q, J ) 7.0 Hz, CH2CH3),
7.24-7.31 (4H, m, PhCl). Anal. (C16H22NO2Cl) C, H, N.
Syn th esis of 1-[(4-Br om op h en yl)m eth yl]-4-[(eth oxy-
ca r bon yl)m eth yl]p ip er id in e (3c). 4-Bromobenzyl bromide
(0.9 g, 3.6 mmol) was reacted with amine hydrochloride 2 (0.3
g, 1.4 mmol) in the presence of K2CO3 to furnish 3c, 0.38 g
(88% yield), as a colorless oil (procedure A): 1H NMR (CDCl3)
1.17-1.31 (3H, t, J ) 7.1 Hz, CH3CH2), 1.61-2.09 (5H, m),
2.18-2.25 (2H, d, J ) 6.6 Hz, CH2CH), 2.75-2.87 (2H, m),
Syn th esis of 4-[2-(Dip h en ylm eth oxy)eth yl]-1-[(4-br o-
m op h en yl)m eth yl]p ip er id in e (5c). Compound 4c (0.2 g,