598 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 4
Sasse et al.
CH-CH3), 0.80 (t, J ) 7.4 Hz, 3H, CH2-CH3); MS m/z 225 (M•+
,
Exp er im en ta l Section
12), 108 (100), 98 (17), 95 (43), 81 (44), 54 (16). Anal.
Ch em istr y. Gen er a l P r oced u r es. Melting points were
determined on an Electrothermal IA 9000 digital or a Bu¨chi
512 apparatus and are uncorrected. For all compounds 1H
NMR spectra were recorded on a Bruker AC 300 (300 MHz)
spectrometer. Chemical shifts are expressed in ppm downfield
from internal TMS as reference. 1H NMR data are reported
in the following order: multiplicity (br, broad; s, singlet; d,
doublet; t, triplet; m, multiplet; asterisk, exchangeable by D2O;
Im, imidazole; Mal, maleic acid), number of protons, and
approximate coupling constants in hertz (Hz). Mass spectra
were obtained on EI-MS Finnigan MAT CH7A and Finnigan
MAT 711 (high-resolution mass spectra), spectrometers resolv-
ing power 12 500. Only spectral data of parent compounds,
obtained by different synthesis, and of selected optically active
compounds are shown (1, 3, 5, 8, 10, 12, 16-20, 24). Optical
rotation was determined on a Perkin-Elmer 241 MC polarim-
eter. Elemental analyses (C, H, N) for all compounds were
measured on Perkin-Elmer 240 B or Perkin-Elmer 240 C
instruments and are within ( 0.4% of the theoretical values,
unless otherwise stated. Preparative, centrifugally accelerated,
rotatory chromatography was performed using a Chromatotron
7924T (Harrison Research) and glass rotors with 4 mm layers
of silica gel 60 PF254 containing gypsum (Merck). Column
chromatography was carried out using silica gel 63-200 µm
(Macherey, Nagel & Co.). TLC was performed on silica gel
PF254 plates (Merck), and the spots were visualized with iodine
vapor or fast blue salt BB.
Gen er a l Syn th etic P r oced u r e for Ca r ba m a tes 1-28
(u n less oth er w ise sta ted ). To a solution of trichloromethyl
chloroformate (0.6 g, 3 mmol) and a catalytic amount of
activated charcoal in 20 mL of dry ethyl acetate was added
rapidly the corresponding amine hydrochloride (2.5 mmol) as
a solid or a solution of the corresponding amine (2.5 mmol) in
10 mL of dry ethyl acetate. The reaction mixture was heated
to reflux for 4-5 h, the black solution was cooled and filtered,
and the solvent was evaporated carefully under reduced
pressure. The freshly prepared isocyanate was dissolved in 20
mL of dry acetonitrile and added to 3-(1H-imidazol-4-yl)-
propanol hydrochloride32 (0.4 g, 2.5 mmol) in 10 mL of dry
acetonitrile. The solution was refluxed for 4-5 h and concen-
trated in vacuo. The residue was purified by rotatory chro-
matography [eluent: CH2Cl2/MeOH (gradient from 99:1 to 90:
10), ammonia atmosphere]. Separation was controlled by thin-
layer chromatography [solvent: CHCl3/MeOH (9:1), ammonia
atmosphere]. The products were obtained as colorless oils and
crystallized as hydrogen maleates in Et2O/EtOH. Yields: 17-
85%.
3-(1H-Im id a zol-4-yl)p r op yl N-Eth ylca r ba m a te (1). The
carbamate was synthesized directly from ethyl isocyanate and
crystallized as free base: 1H NMR (Me2SO-d6) δ 7.36 (s, 1H,
Im-2-H), 6.97 (t, 1H, CONH*), 6.51 (s, 1H, Im-5-H), 3.82 (t, J
) 6.5 Hz, 2H, CH2-O), 3.17 (m, 2H, NH-CH2), 2.85 (m, 2H,
Im-CH2), 2.19 (m, 2H, Im-CH2-CH2), 0.64 (t, J ) 7.2 Hz, 3H,
CH3); MS m/z 197 (M•+, 29), 108 (44), 95 (47), 81 (35); HRMS;
calcd 197.11643, found 197.11648. Anal. (C9H15N3O2‚0.5H2O)
C, H; N: calcd, 20.83; found, 19.86.
3-(1H-Im idazol-4-yl)pr opyl N-P r opylcar bam ate (3). The
isocyanate was not separated by distillation from excess
diphosgene, but the crude reaction product was directly added
to 3-(1H-imidazol-4-yl)propanol hydrochloride32 in dry aceto-
nitrile: 1H NMR (Me2SO-d6) δ 8.87 (s, 1H, Im-2-H), 7.40 (s,
1H, Im-5-H), 7.10 (m, CONH*), 6.05 (s, 2H, Mal), 3.96 (t, J )
6.5 Hz, 2H, CH2-O), 2.92 (m, 2H, NH-CH2), 2.67 (t, J ) 7.5
Hz, 2H, Im-CH2), 1.89 (m, 2H, Im-CH2-CH2), 1.39 (m, 2H, CH2-
CH3), 0.83 (t, J ) 7.4 Hz, 3H, CH3); MS m/z 211 (M•+, 13), 108
(100), 95 (89), 81 (92), 54 (29), 41 (29), 28 (35). Anal.
(C10H17N3O2‚C4H4O4) C, H, N.
(C11H19N3O2‚C4H4O4‚0.5 H2O) C, H, N.
3-(1H-Im id a zol-4-yl)p r op yl N-Bu tylca r ba m a te (8). The
isocyanate was not separated by distillation from excess
diphosgene, but the crude reaction product was directly added
to 3-(1H-imidazol-4-yl)propanol hydrochloride32 in dry aceto-
nitrile: 1H NMR (Me2SO-d6) δ 8.89 (s, 1H, Im-2-H), 7.40 (s,
1H, Im-5-H), 7.08 (m, 1H, CONH*), 6.06 (s, 2H, Mal), 3.96 (t,
J ) 6.4 Hz, 2H, CH2-O), 2.96 (m, 2H, NH-CH2), 2.67 (t, J )
7.5 Hz, 2H, Im-CH2), 1.89 (m, 2H, Im-CH2-CH2), 1.41-1.21
(m, 4H, CH2-CH2-CH3), 0.86 (t, J ) 7.2 Hz, 3H, CH3); MS m/z
225 (M•+, 12), 108 (100), 95 (99), 81 (85), 72 (59), 54 (57), 45
(51), 26 (86). Anal. (C11H19N3O2‚C4H4O4) C, H, N.
(R)-(-)-3-(1H-Im id a zol-4-yl)p r op yl N-(1-Meth ylbu tyl)-
ca r ba m a te (10). A mixture of phthalimide (1.47 g, 10 mmol),
triphenylphosphine (2.62 g, 10 mmol), and (S)-(+)-2-pentanol
(0.88 g, 10 mmol) in 10 mL of dry THF was cooled to 0 °C.
Diethyl azodicarboxylate (DEAD) (1.74 g, 10 mmol) in 10 mL
of dry THF was slowly added dropwise (30 min); the reaction
mixture was then allowed to warm to room temperature and
stirred overnight. Solvent was evaporated under reduced
pressure and the residue suspended in Et2O. After the
precipitate was filtered, the solvent was evaporated and the
residue purified by column chromatography (eluent: CH2Cl2)
to afford (R)-(-)-N-(1-methylbutyl)phthalimide (yield 75%):
[R]20 -11.93° (c 3.00, EtOH).
546
(R)-(-)-N-(1-Methylbutyl)phthalimide (2.3 g, 10 mmol) and
hydrazine hydrate (0.62 g, 10 mmol) in 40 mL of EtOH were
refluxed for 15 min. The suspension was cooled, filtered,
acidified with hydrochloric acid, and once more filtered. The
filtrate was concentrated under reduced pressure; the crystal-
line (R)-(+)-(1-methylbutyl)amine hydrochloride ([R]20546 +3.00°
(c 1.50, MeOH)) was washed with diethyl ether and used for
further synthesis.
(R)-(-)-3-(1H-Imidazol-4-yl)propyl N-(1-methylbutyl)car-
bamate (10) was prepared following the general procedure
described above: 1H NMR (Me2SO-d6) δ 8.80 (s, 1H, Im-2-H),
7.39 (s, 1H, Im-5-H), 6.90 (d, J ) 8.2 Hz, 1H, CONH*), 6.05
(s, 2H, Mal), 3.96 (t, J ) 6.4 Hz, 2H, CH2-O), 3.47 (m, 1H,
CH), 2.68 (t, J ) 7.5 Hz, 2H, Im-CH2), 1.90 (m, 2H, Im-CH2-
CH2), 1.30-1.20 (m, 4H, CH2-CH2-CH3), 1.00 (d, J ) 6.6 Hz,
3H, CH-CH3), 0.85 (t, J ) 7.0 Hz, 3H, CH2-CH3); MS m/z 239
(M•+, 21), 108 (100), 98 (17), 95 (63), 81 (38), 54 (14). Anal.
(C12H21N3O2‚C4H4O4) C, H, N.
(S)-(+)-3-(1H-Im id a zol-4-yl)p r op yl N-(1-m eth ylp r op yl)-
ca r ba m a te (12): 1H NMR (Me2SO-d6) δ 8.90 (s, 1H, Im-2-H),
7.40 (s, 1H, Im-5-H), 7.10 (m, 1H, CONH*), 6.00 (s, 2H, Mal),
4.00 (t, J ) 6.6 Hz, 2H, CH2-O), 2.90 (m, 2H, NH-CH2), 2.70
(t, J ) 7.6 Hz, Im-CH2), 1.90 (m, 2H, Im-CH2-CH2), 1.40-1.30
(m, 2H, CH2-CH3), 1.10-1.00 (m, 1H, CH), 0.90 (m, 6H, 2‚
CH3); MS m/z 239 (M•+, 18), 109 (28), 108 (100), 95 (58), 81
(37), 72 (17). Anal. (C12H21N3O2‚C4H4O4) C, H, N.
3-(1H-Im id a zol-4-yl)p r op yl N-(3-m eth ylsu lfa n yl-1-p r o-
1
p yl)ca r ba m a te (16): H NMR (Me2SO-d6) δ 8.84 (s, 1H, Im-
2-H), 7.38 (s, 1H, Im-5-H), 7.14 (s, 1H, CONH*), 6.04 (s, 2H,
Mal), 3.96 (t, J ) 6.5 Hz, 2H, CH2-O), 3.04 (m, 2H, NH-CH2),
2.66 (t, J ) 7.6 Hz, 2H, Im-CH2), 2.44 (t, J ) 7.3 Hz, 2H, CH2-
S), 2.02 (s, 3H, CH3), 1.88 (m, 2H, Im-CH2-CH2), 1.65 (m, 2H,
CH2-CH2-S); MS m/z 257 (M•+, 29), 242 (40), 211 (22), 183 (31),
109 (100), 98 (29), 81 (47), 72 (36), 54 (29). Anal. (C11H19N3O2S‚
C4H4O4) C, H, N.
(R/S)-(()- 3-(1H-Im id a zol-4-yl)p r op yl N-(1-Meth ylp en -
tyl)ca r ba m a te (17). A mixture of potassium phthalimide
(1.85 g, 10 mmol), K2CO3 (4.0 g, 30 mmol), and benzyltriethyl-
ammonium chloride (0.3 g, 1 mmol) in 50 mL of acetone was
refluxed for 40 min. (R/S)-(()-1-Methylpentyl bromide (1.65
g, 10 mmol) in 10 mL of acetone was added dropwise and
refluxed for additional 4 h. The precipitate was filtered and
the solvent evaporated under reduced pressure. The oily
residue was dissolved in 50 mL of CH2Cl2 and washed twice
with NaOH solution (2%) and water. The organic phase was
dried with anhydrous sodium sulfate and concentrated in
(R)-(-)-3-(1H-Im id a zol-4-yl)p r op yl N-(1-m eth ylp r op yl)-
1
ca r ba m a te (5): H NMR (Me2SO-d6) δ 8.80 (s, 1H, Im-2-H),
7.37 (s, 1H, Im-5-H), 6.95 (d, J ) 7.7 Hz, 1H, CONH*), 6.00
(s, 2H, Mal), 4.00 (t, J ) 6.50 Hz, 2H, CH2-O), 3.30 (m, 1H,
CH), 2.70 (t, J ) 7.7 Hz, 2H, Im-CH2), 1.90 (m, 2H, Im-CH2-
CH2), 1.40-1.30 (m, 2H, CH2-CH3), 1.05 (d, J ) 6.59 Hz, 3H,