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Z. Guo et al. / Bioorg. Med. Chem. 8 (2000) 1041±1058
ꢀ,ꢀ0-Bis(3-acetylcarboxylpyridiniumyl)-p-xylene dibro-
mide (3). 3-Acetylpyridine (1) (51.0 g, 421 mmol)
was reacted with a,a0-dibromo-p-xylene (2) (52.7 g,
200 mmol). The precipitate was collected and recrys-
tallized from methanol:water (5:1 v/v) to obtain 85.5 g
(84.7%) of 3, mp 272.5±273.6 ꢀC; IR (KBr) 1630
(d ppm) 7.29 (d, J=4.9 Hz, 1H, Ar-CH:COCH2CH3),
6.90±6.96 (m, 2H, Ar-CH:CH), 4.57 (s, 2H, CH2
C:COCH2CH3), 4.52 (s, 2H, CH2C:CH:COCH2CH3),
4.14 (q, J=7.0 Hz, 2H, OCH2CH3), 1.49 (t, J=7.0 Hz,
OCH2CH3).
Step 3. 2-Ethoxy-ꢀ,ꢀ0 -bis[3-(N,N-diethylcarbamoyl)-
piperidino]-p-xylene dihydrochloride (8a). To a solution
of N,N-diethylnipecotamide (3.50 g, 20 mmol) in 100 mL
of THF, K2CO3 (4.5 g, 32.0 mmol) was added, followed
by the slow addition of a solution of 2-ethoxy-a,a0-
dibromo-p-xylene (7a) (2.0 g, 6.5 mmol) in 40 mL of
THF. Stirring was continued for a total of 72 h at room
temperature. After ®ltration and removal of the solvent,
the residue was puri®ed by column chromatography on
silica gel, using CHCl3:MeOH (24:1, v/v) as the solvent.
The free base was dissolved in 200 mL anhydrous ether
and dry HCl gas was passed through the solution to
aord a solid which was recrystallized from acetonitrile:
ether ꢀ(1:4 v/v) to obtain 2.8 g (74.5%) of 8a, mp 202.2±
1
(CO); H NMR (D2O) (d ppm) 9.44 (s, 2H, CH:N:
CH:CCO), 9.01±9.08 (m, 4H, CH:CHCH:N:CH:CCO),
8.21 (q, 2H, J=6.5 Hz, CH:CHCO), 7.56 (s, 4H,
phenyl), 5.95 (s, 4H, phCH2), 2.73 (s, 6H, COCH3).
ꢀ,ꢀ0-Bis(3-acetylpiperidino)-p-xylene dihydrochloride (4a).
Catalytic reduction (0.5 g PtO2, 60±65 psi, 25 ꢀC) of
a,a0-bis(3-acetylcarboxyl pyridiniumyl)-p-xylene dibro-
mide (3) (7.5 g, 37.0 mmol) in ethanol (250mL), followed
by recrystallization of the product from methanol:
ethanol (1:2 v/v) gave 3.5 g of the dihydrobromide salt.
The latter was dissolved in 10 mL of water and neu-
tralized with 30% NaCO3. The free base (2.0 g) was
extracted with 4Â50 mL of ether. The residue was puri-
®ed by column chromatography on silica gel, using
CHCl3:MeOH (99:1, v/v) as the eluent. The solvent was
evaporated, the residue dissolved in 100 mL anhyd
ether, and dry HCl gas was passed through the solution
to aord a solid which was recrystallized from methanol:
ether ꢀmixture to obtain 4a (0.45 g, 7.1%), mp 258.2±
.
204.3 C (dec.); anal. (C30H50N4O3 2HCl) C, H, N, Cl;
1H NMR (CDCl3) (d ppm) 7.25 (d, 1H, J=5.5 Hz, Ar-
CH:COCH2CH3), 6.81±6.87 (m, 2H, Ar-CH:CH), 4.01
(q, J=7.0 Hz, 2H, OCH2CH3), 3.61 (s, 2H, CH2 C:
COCH2CH3), 3.48 (s, 2H, CH2C:CH:COCH2CH3),
3.30±3.38 (m, 8H, N[CH2CH3]2), 1.40 (t, 3H, J=7.0 Hz,
OCH2CH3), 1.06±1.19 (m, 12H,[CH2CH3]2).
.
259.4 C. Anal. (C22H32N2O2 2HCl) C, H, N, Cl; IR
1
(KBr) 1708 (CO); H NMR (CDCl3) (d ppm) 7.25 (s,
4H, ArH), 2.11 (s, 6H, COCH3), 3.50 (s, 4H, ArCH2),
2.71±2.95 (m, 4H, NCH2CHCO), 2.57±2.66 (m, 2H,
NCH2CHCO) 1.98±2.22 (m, 4H, CH2NCH2CHCO),
1.36±1.91 (m, 8H, CHCH2CH2CH2N).
2-Methoxy-ꢀ,ꢀ0-bis[3-(N,N-diethylcarbamoyl)piperidino]-
p-xylene dihydrochloride (8b). Yield: 43.0%. Mp 211.2±
ꢀ
.
22.7 C (dec.); anal. (C29H48N4O3 2HCl) C, H, N, Cl;
1H NMR (CDCl3) (d ppm) 7.25 (s, 1H, Ar-CH:
COCH3), 6.84±6.88 (m, 2H, Ar-CH:CH), 3.82 (s, 3H,
OCH3), 3.58 (s, 2H, CH2C:COCH3), 3.50 (s, 2H,
CH2C:CH:COCH3).
General procedure for the synthesis of bisnipecotamides
with dierent connecting bridges (8a, b, c, d, g, h, i, j, k,
l, m, n, o). The synthesis of 2-ethoxy-a,a0-bis[3-(N,N-
diethylcarbamoyl)piperidino]-p-xylene dihydrochloride
(8a) is described in detail, as an example.
2-Hexyloxy-ꢀ,ꢀ0-bis[3-(N,N-diethylcarbamoyl)piperidino]-
p-xylene dioxalate (8c). Yield: 44.4%. Mp 186.1±
ꢀ
.
188.3 C (dec.); anal. [C34H58N4O3 2(COOH)2] C, H,
1
1
Step 1. 2-Ethoxy-p-xylene (5a). A mixture of 2,5-di-
methylphenol (18.3 g, 150 mmol), iodoethane (31.2 g,
200 mmol), K2CO3 (27.6 g, 200 mmol), and 150 mL of
acetone was re¯uxed for 48 h, then cooled to room
temperature and ®ltered. After removal of the solvent,
the residue was dissolved in 200 mL of ether and washed
with 10 N NaOH (2Â20mL). After drying and removing
of the solvent, the residue was puri®ed by vacuum dis-
tillation to obtain 18.6g (82.7%) of 6a, bp2mmHg 86±88 ꢀC;
MS (EI) m/z 150 (M+); 1H NMR (CDCl3) (d ppm) 7.04
(d, J=7.3 Hz, 1H, Ar-CH:COCH2CH3), 6.69 (d, J=
10.3 Hz, 2H, Ar-CH:CH), 4.05 (q, J=6.4 Hz, 2H, OCH2
CH3), 2.35 (s, 3H, CH3 C:COCH2CH3), 2.22 (s, 3H,
CH3C:CH:COCH2CH3), 1.46 (t, J=5.9 Hz, OCH2CH3).
N; H NMR (CDCl3) (d ppm) 7.23 (d, J=5.6 Hz, H,
Ar-CH:COC6H13), 6.82±6.87 (m, 2H, Ar-CH:CH), 3.95
(t, J=6.5 Hz, 2H, OCH2C5H11), 3.60 (s, 2H, CH2
C:COC6H13), 3.48 (s, 2H, CH2C:CH:COC6H13), 157±
1.66 (m, 2H, OCH2CH2C4H9), 1.43±1.54 (m, 2H, OCH2
CH2CH2CH2CH2CH3), 1.30±1.37 (m, 4H, OCH2CH2
CH2CH2CH2CH3), 0.90±0.98 (m, 3H, OCH2CH2CH2
CH2CH2CH3).
2-Nitro-ꢀ,ꢀ0-bis[3-(N,N-diethylcarbamoyl)piperidino]-p-
xylene dihydrochloride (8d). Yield: 83.2%. Mp 219.5±
ꢀ
.
220.9 C (dec.); anal. (C28H45N5O4 2HCl) C, H, N, Cl;
IR (KBr) 1633 (s); 1H NMR (CDCl3) (d ppm) 7.78
(d, J=2.4 Hz, 1H, Ar-CH:CNO2), 7.42 (s, 2H, Ar-CH:
CH), 3.75 (s, 2H, NCH2C6H4CH2), 3.54 (s, 2H, NCH2
C6H4CH2).
Step 2. 2-Ethoxy-ꢀ,ꢀ0-dibromo-p-xylene (6a). To a stir-
red solution of 2-ethoxy-p-xylene (6a) (7.5 g, 50 mmol)
in 200 mL of anhydrous carbon tetrachloride (CCl4),
N-bromosuccinimide (21.4 g, 120 mmol) and benzoyl
peroxide (0.25 g) were slowly added. The reaction mix-
ture was re¯uxed for 5 h. After ®ltration and removal of
the solvent, the residue was recrystallized from ether:
hexanes (2:1 v/v) to obtain 5.6 g (36.4%) of 7a mp 97.5±
98.9 ꢀC; MS (EI) m/z 308 (M+); 1H NMR (CDCl3)
2-Amino-ꢀ,ꢀ0 -bis[3-(N,N-diethylcarbamoyl)piperidino]-
p-xylene dihydrochloride (8e). 2-Nitro-a,a0-bis[3-(N,N-
diethylcarbamoyl)piperidino]-p-xylene (8d) (7.2 g,
14.0 mmol), in 150 mL ethanol was catalytically reduced
over PtO2. After removal of the solvent, the residue was
dissolved in 200 mL of ether. Dry HCl gas was passed
through the solution and the precipitate was collected