PAPER
Synthesis of N-Aryl- and N-Aryl-N¢-methylpiperazines on a Novel Poly(ethylene glycol) Resin
3461
1-(4-Fluorophenyl)piperazine Oxalate (3g)
Light-brown crystals; yield: 0.93 g (23%); mp 172–173 °C.
1H NMR (500 MHz, D2O): d = 3.32–3.40 (m, 8 H), 7.07–7.12 (m, 4
H).
13C NMR (62.5 MHz, D2O): d = 166.3, 157.8, 146.3, 120.2, 120.2,
116.4, 116.2, 48.1, 43.5.
was filtered and the resin washed successively with THF (3 × 50
mL), 1 M aq HCl (3 × 50 mL), THF (1 × 50 mL), 1 M aq HCl (3 ×
50 mL), and THF (3 × 50 mL). The filtrate was filtered through
Celite and the THF was removed under reduced pressure. The aque-
ous phase was made strongly acidic with concd aq HCl and was
washed with EtOAc (2 × 25 mL). The aqueous phase was then made
basic with aq NH3 (25% w/v, 50 mL). The resulting suspension of
salts was shaken with toluene (50 mL) and filtered. The solid was
washed with toluene (2 × 50 mL). The filtrate was separated and the
aqueous phase was washed with toluene (3 × 50 mL). The combined
organic phases were washed with sat. aq NaHCO3 (25 mL), sat. aq
NaCl (25 mL), and H2O (2 × 40 mL), dried (Na2SO4), and evaporat-
ed to give a brown oil (134 mg). Purification through automated
flash chromatography yielded 5 as a slightly yellow oil that solidi-
fied upon standing.
Anal. Calcd for C12H15N2O4F: C, 53.33; H, 5.59; N, 10.37. Found:
C, 53.35; H, 5.68; N, 10.37.
1-(3,4-Dichlorophenyl)piperazine Oxalate (3h)
Recrystallized (i-PrOH). Light-brown crystals; yield: 0.27 g (6%);
mp 230–232 °C.
1H NMR (500 MHz, D2O): d = 3.22–3.32 (m, 8 H), 6.86 (dd, J1 =
8.9 Hz, J2 = 2.8 Hz, 1 H), 7.11 (d, J = 2.8 Hz, 1 H), 7.32 (d, J = 9.0
Hz, 1 H).
Yield: 53 mg (2.7%); mp 77–79 °C.
1H NMR (500 MHz, CDCl3): d = 2.34 (s, 3 H), 2.39–2.74 (m, 4 H),
2.89 (t, J = 4.8 Hz, 4 H), 4.07 (s, 2 H), 7.08–7.28 (m, 9 H).
13C NMR (62.5 MHz, D2O): d = 149.7, 131.2, 119.1, 117.6, 46.7,
43.3.16
13C NMR (62.5 MHz, CDCl3): d = 152.0, 142.2, 137.0, 131.3,
129.4, 128.7, 127.5, 126.1, 124.4, 121.0, 56.1, 53.0, 46.6, 37.0.
Anal. Calcd for C12H14N2O4Cl2: C, 44.81; H, 4.39; N, 8.71. Found:
C, 45.21; H, 4.61; N, 8.58.
Anal Calcd for C18H22N2: C, 81.16; H, 8.33; N, 10.20. Found: C,
80.72; H, 8.37; N, 10.46.
Methyl 4-(4-methoxyphenyl)piperazine-1-carboxylate (4)
Resin 1 (10.0 g, 14.8 mmol) was suspended in MIBK (100 mL). 4-
Methoxyaniline (8.9 g, 75 mmol, 5 equiv) and KI (0.48 g, 3 mmol,
0.2 equiv) were added, followed by py (6 mL, 75 mmol, 5 equiv).
The mixture was heated to 100 °C for 15 h. The resin was washed
successively with THF (2 × 100 mL), MeOH (2 × 100 mL), H2O
(2 × 100 mL), THF (2 × 100 mL), and MeOH (2 × 100 mL), and
then was suspended in MeOH (100 mL). Then, KOH (8.2 g, 140
mmol, 10 equiv) was added and the suspension was refluxed for 3.5
h. The suspension was filtered and the resin was washed successive-
ly with THF (2 × 100 mL), 1 M HCl (2 × 100 mL), THF (1 × 100
mL), 1 M HCl (2 × 100 mL), and THF (1 × 100 mL). The THF was
removed by evaporation in vacuo and the remaining solution was
washed with EtOAc (2 × 50 mL). The aqueous phase was made ba-
sic with aq NH3 (25 w/v, 25 mL) and extracted with Et2O (5 × 100
mL). The combined organic phases were washed with sat. aq
NaHCO3 (50 mL), sat. aq NaCl (50 mL), and H2O (2 × 50 mL),
dried (anhyd Na2SO4), and evaporated to give compound 4 as an oil
that solidified upon standing.
Acknowledgement
We gratefully acknowledge the assistance of the Analytical Depart-
ment at H. Lundbeck A/S for invaluable help with setting up the
analysis, Mrs. Anne Marie Munk Jørgensen of the H. Lundbeck
A/S Department of Computational Chemistry for providing valua-
ble information on Sifaprazine and The Danish Ministry of Science,
Technology and Development for funding.
References
(1) (a) Raillard, S. P.; Ji, G.; Mann, A. D.; Baer, T. A. Org.
Process Res. Dev. 1999, 3, 177. (b) Meisenbach, M.;
Allmendinger, T.; Mak, C.-P. Org. Process Res. Dev. 2003,
7, 553.
(2) Price for 100 g of Versabeads™ VO400 loading 2 mol·kg–1
(as used in this article): € 739 equal to € 370 per mol. Price
for 100 g of Rapp Polymere hydroxymethyl polystyrene
loading 1.5 mol·kg–1: € 360 equal to € 240 per mol (price
for 100 g of Rapp Polymere TentaGel Standard (water
compatible), loading 0.3 mol·kg–1: € 1010 equal to € 33667
per mol)
Yield: 1.15 g (32%); mp 94–97 °C.
1H NMR (500 MHz, CDCl3): d = 3.00–3.04 (m, 4 H), 3.59–3.65 (m,
4 H), 3.73 (s, 3 H), 3.77 (s, 3 H), 6.84 (ddd, J1 = 9.4 Hz, J2 = 3.3 Hz,
J3 = 2.8 Hz, 2 H), 6.90 (ddd, J1 = 9.4 Hz, J2 = 3.3 Hz, J3 = 2.8 Hz, 2
H).
13C NMR (62.5 MHz, CDCl3): d = 156.3, 154.7, 146.0, 119.3,
114.9, 55.9, 53.0, 51.3, 44.3.
(3) (a) Rademann, J.; Grøtli, M.; Meldal, M.; Bock, K. J. Am.
Chem. Soc. 1999, 121, 5459. (b) Christensen, S. F.;
Michael, R. Chimica Oggi/Chemistry Today (Focus on
Peptides & Amino Acids) 2004, 48. (c) Christensen, S. F.;
Ramos, M.; Michael, R. PharmaChem 2004, 9, 59.
(4) (a) López-Rodriguez, M. L.; Ayala, D.; Benhamú, B.;
Morcillo, M. J.; Viso, A. Curr. Med. Chem. 2002, 9, 443.
(b) Bettinetti, L.; Schlotter, K.; Hübner, H.; Gmeiner, P. J.
Med. Chem. 2002, 45, 4594. (c) Grundt, P.; Carlson, E. E.;
Cao, J.; Bennett, C. J.; McElveen, E.; Taylor, M.; Luedke, R.
R.; Newman, A. H. J. Med. Chem. 2005, 48, 839.
(d) Toogood, P. L.; Harvey, P. J.; Repine, J. T.; Sheehan, D.
J.; VanderWel, S. N.; Zhou, H.; Keller, P. R.; McNamara, D.
J.; Sherry, D.; Zhu, T.; Brodfuehrer, J.; Choi, C.; Barvian, M.
R.; Fry, D. W. J. Med. Chem. 2005, 48, 2388. (e) López-
Rodríguez, M. L.; Morcillo, M. J.; Fernández, E.; Benhamú,
B.; Tejada, I.; Ayala, D.; Viso, A.; Campillo, M.; Pardo, L.;
Anal Calcd for C13H18N2O3: C, 62.38; H, 7.25; N, 11.19. Found: C,
62.06; H, 7.30; N, 11.06.
Sifaprazine (5)
Resin 1 (5.1 g, 7.5 mmol) was suspended in MIBK (40 mL) with 2-
benzylaniline (6.87 g, 37 mmol, 5 equiv) and KI (3.74 g, 22.5 mmol,
3 equiv). Then, py (6 mL, 5.6 g, 71 mmol, 9.5 equiv) was added and
the suspension was heated to 100 °C for 67 h with magnetic stirring.
The resin was washed successively with NMP (3 × 50 mL), THF
(3 × 50 mL), MeOH (3 × 50 mL), H2O (3 × 50 mL), NMP (3 × 50
mL), THF (3 × 50 mL), MeOH (3 × 50 mL), and THF (3 × 50 mL),
and then dried. The resin was suspended in THF (50 mL). Pellets of
LiAlH4 (2.8 g, 75 mmol, 10 equiv) were added and the suspension
was refluxed for 19 h with magnetic stirring.17 The suspension was
cooled on ice and quenched by the sequential addition of H2O (3
mL), aq NaOH (13% w/v, 3 mL), and H2O (10 mL). The suspension
Synthesis 2005, No. 19, 3456–3462 © Thieme Stuttgart · New York