SSAO Inhibitors with Anti-inflammatory ActiVity
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7 2171
(c) N-tert-Butoxycarbonyl-N′-[2-(4-fluorophenyl)allyl]-N′-iso-
propylhydrazine (8c). The title compound was obtained as a white
semisolid (0.38 g, 66%). 1H NMR (CDCl3, 300 MHz): δ 1.05 (d,
J ) 3.3 Hz, 6H), 1.40 (s, 9H), 3.21 (br s, 1H), 3.73 (br s, 2H),
5.28 (br s, 1H), 5.42 (br s, 1H), 7.01 (t, J ) 5.2 Hz, 2H), 7.58 (br
s, 2H). ESMS: m/z 331.1 (M + Na)+.
J ) 7.2 Hz, 3H), 3.04 (q, J ) 6.9 Hz, 2H), 3.93 (s, 2H), 5.30 (s,
1H), 5.50 (s, 1H), 7.04 (t, J ) 9.0 Hz, 2H), 7.42 (t, J ) 9.0 Hz,
2H). ESMS: m/z 195 (M + H)+. Anal. (C11H16ClFN2) C, H, N.
(g) N′-[2-(4-Fluorophenyl)allyl]-N-isopropylhydrazine Hy-
drochloride (7c). The title compound was obtained as a white solid
1
(0.42 g, 82%). mp: 140-141 °C. H NMR (D2O, 300 MHz): δ
(d) N-tert-Butoxycarbonyl-N′-[2-(4-fluorophenyl)allyl]-N′-
benzylhydrazine (8d). The title compound was obtained as a white
1.12 (d, J ) 6.6 Hz, 6H), 3.25-3.44 (m, 1H), 3.92 (s, 2H), 5.29
(s, 1H), 5.50 (s, 1H), 7.04 (t, J ) 8.7 Hz, 2H), 7.40-7.47 (m, 2H).
ESMS: m/z 209 (M + H)+. Anal. (C12H18ClFN2) C, H, N.
(h) N′-[2-(4-Fluorophenyl)allyl]-N-benzylhydrazine Hydro-
chloride (7d). The title compound was obtained as a light yellow
solid (0.44 g, 90%). mp: 149-150 °C. 1H NMR (D2O, 300
MHz): δ 4.01 (s, 2H), 4.16 (s, 2H), 5.32 (s, 1H), 5.53 (s, 1H),
7.03 (t, J ) 8.7 Hz, 2H), 7.28-7.60 (m, 2H). ESMS: m/z 257 (M
+ H)+. Anal. (C16H18ClFN2) C, H, N.
1
semisolid (0.40 g, 60%). H NMR (CDCl3, 300 MHz): δ 1.38 (s,
9H), 3.96 (br s, 2H), 4.10 (br s, 2H), 5.28 (br s, 1H), 5.45 (br s,
2H), 7.00 (t, J ) 5.2 Hz, 2H), 7.19-7.22 (m, 5H), 7.48 (br s, 2H).
ESMS: m/z 379.1 (M + Na)+.
N,N′-Di(tert-butoxycarbonyl)-N′-[2-(4-chlorophenyl)allyl]-
N,N′-dimethylhydrazine (10). A mixture of 3b (0.42 g, 1.49 mmol)
and NaH (0.11 g, 4.58 mmol) in DMF (10 mL) was stirred at room
temperature for 20 min. To this stirred solution was added MeI
(0.64 g, 4.51 mmol). The resulting reaction mixture was stirring
under N2 at room temperature overnight. The TLC showed the
reaction was completed. The solvent was removed in vacuo. The
residue was purified by flash column chromatography (silica gel,
5% EtOAc/Hexane) to give a colorless oil (0.29 g, 63%). 1H NMR
(CDCl3, 300 MHz): δ 1.43 (s, 9H), 2.59 (s, 3H), 2.73 (s, 3H),
3.73 (br s, 2H), 5.22 (s, 1H), 5.43 (s, 1H), 7.33 (d, J ) 8.7 Hz,
2H), 7.41 (d, J ) 8.7 Hz, 2H). ESMS: m/z 333.1 (M + Na)+.
General Procedure for the Preparation of Compounds 4, 7,
9, and 11. To a solution of Boc protected hydrazine compounds
(1.0 equiv.) in anhydrous MeOH (3.0 mL) was added a solution of
HCl in ether (5.0 equiv.). The resulting mixture was stirred under
N2 at room temperature and monitored by TLC. When TLC showed
that the reaction was completed, it was concentrated in vacuo. The
residue was dissolved in H2O (20 mL). The resulting aqueous
solution was washed with ether (2 × 10 mL) and then was basified
to pH 10 by adding 1.0 N NaOH solution. The resulting basic
solution was saturated with solid NaCl and extracted with ether (3
× 30 mL). The combined organic layers were dried (MgSO4),
filtered and concentrated in vacuo. The residue was dissolved in
ether (5.0 mL). To this solution was added a solution of HCl in
ether (5 equiv.). The solid formed was collected by filtration,
washed with ether, and then dried in vacuo to give the final
compounds as hydrochloride salts.
(i) N′-[2-(4-Fluorophenyl)allyl]-N′-methylhydrazine Hydro-
chloride (9a). The title compound was obtained as a white solid
1
(0.40 g, 95%). mp: 138-140 °C. H NMR (D2O, 500 MHz): δ
2.72 (s, 3H), 4.05 (s, 2H), 5.43 (s, 1H), 5.62 (s, 1H), 7.06 (t, J )
8.7 Hz, 2H), 7.39-7.48 (m, 2H). ESMS: m/z 181 (M + H)+. Anal.
(C10H14ClFN2) C, H, N.
(j) N′-[2-(4-Fluorophenyl)allyl]-N′-ethylhydrazine Hydrochlo-
ride (9b). The title compound was obtained as a white solid (0.14
g, 90%). mp: 118-119 °C. 1H NMR (D2O, 500 MHz): δ 1.27 (t,
J ) 7.3 Hz, 3H), 3.24 (br s, 2H), 4.28 (br s, 2H), 5.61 (s, 1H),
5.78 (s, 1H), 7.18 (t, J ) 8.7 Hz, 2H), 7.54 (dd, J ) 5.3, 8.7 Hz,
2H). ESMS: m/ z 195 (M + H)+. Anal. (C11H16ClFN2) C, H, N.
(k) N′-[2-(4-Fluorophenyl)allyl]-N′-isopropylhydrazine Hy-
drochloride (9c). The title compound was obtained as a white solid
1
(0.22 g, 85%). mp: 146-147 °C. H NMR (D2O, 500 MHz): δ
1.31 (d, J ) 6.7 Hz, 3H), 3.56-3.71 (m, 1H), 4.10-4.30 (m, 2H),
5.63 (s, 1H), 5.78 (s, 1H), 7.19 (t, J ) 8.7 Hz, 2H), 7.54 (d, J )
5.3, 8.7 Hz, 2H). ESMS: m/z 209 (M + H)+. Anal. (C12H18ClFN2)
C, H, N.
(l) N′-[2-(4-Fluorophenyl)allyl]-N′-benzylhydrazine Hydro-
chloride (9d). The title compound was obtained as a white solid
1
(0.25 g, 90%). mp: 170-171 °C. H NMR (D2O, 500 MHz): δ
4.06 (s, 2H), 4.17 (s, 2H), 5.51 (s, 1H), 5.70 (s, 1H), 7.12 (t, J )
8.7 Hz, 2H), 7.28-7.37 (m, 2H), 7.38-7.50 (m, 5H). ESMS: m/z
257 (M + H)+. Anal. (C16H18ClFN2) C, H, N.
(a) N′-(2-Phenylallyl)hydrazine Hydrochloride (4a). The title
compound was obtained as a white solid (0.66 g, 90%). mp: 153-
154.5 °C. 1H NMR (D2O, 300 MHz): δ 4.05 (s, 2H), 5.40 (s, 1H),
5.60 (s, 1H), 7.25-7.42 (m, 5H). ESMS: m/z 149 (M + H)+. Anal.
(C9H13ClN2) C, H, N.
(b) N′-[2-(4-Chlorophenyl)allyl]hydrazine Hydrochloride (4b).
The title compound was obtained as a white solid (0.60 g, 100%).
mp: 124-126 °C. 1H NMR (D2O, 300 MHz): δ 4.06 (s, 2H), 5.43
(s, 1H), 5.65 (s, 1H), 7.35 (d, J ) 9.0 Hz, 2H), 7.40 (d, J ) 9.0
Hz, 2H). ESMS: m/z 183 (M + H)+. Anal. (C9H12Cl2N2) C, H, N.
(c) N′-[2-(4-Fluorophenyl)allyl]hydrazine Hydrochloride (4c).
The title compound was obtained as a off-white solid (0.55 g, 90%).
mp: 149-150 °C. 1H NMR (D2O, 300 MHz): δ 4.16 (s, 2H), 5.49
(s, 1H), 5.70 (s, 1H), 7.07 (t, J ) 8.7 Hz, 2H), 7.42 (dd, J ) 5.4,
8.7 Hz, 2H). ESMS: m/z 167 (M + H)+. Anal. (C9H12ClFN2) C,
H, N.
(m) N′-[2-(4-Chlorophenyl)allyl]-N,N′-dimethylhydrazine Hy-
drochloride (11). The title compound was obtained as a white solid
(0.17 g, 74%). mp: 108-110 °C. H NMR (D2O, 300 MHz): δ
2.58 (s, 3H), 2.69 (s, 3H), 3.93 (s, 2H), 5.42 (s, 1H), 5.60 (s, 1H).
HRMS (MALDI-FTMS). Calcd for C11H15ClN2H: 211.0995.
Found: 211.0995.
1
N′-[(E)-(2-Phenyl-3-fluoroallyl)]-N′-tert-butoxycarbonylami-
nophthalimide (14). To a cooled solution of (E)-2-phenyl-3-
fluoroallyl alcohol 12 17a (1.1 g, 7.47 mmol), PPh3 (2.94 g, 11.22
mmol), and N-tert-butoxycarbonylaminophthalimide 13 17b (1.95 g,
7.47 mmol) in tetrahydrofuran (THF; 120 mL) was added dropwise
a solution of diethyl azodicarboxylate (DEAD) (1.8 mL, 11.09
mmol) in THF (5.0 mL). The resulting mixture was stirred under
N2 at room temperature overnight and then concentrated in vacuo.
The residue was purified by flash column chromatography (silica
1
gel, 10% EtOAc/haxane) to give a colorless oil (1.3 g, 44%). H
(d) N′-[2-(2-Methylphenyl)allyl]hydrazine Hydrochloride (4d).
The title compound was obtained as a white powder (0.56 g, 95%).
mp: 107-108.5 °C. H NMR (D2O, 300 MHz): δ 2.30 (s, 3H),
NMR (CDCl3, 300 MHz): δ 1.30, 1.44 (two s, total 9H), 4.55,
4.63 (two s, 2H), 6.81 (two d, J ) 81.0 Hz, 1H), 7.23-7.45 (m,
5H), 7.71-7.95 (m, 4H). ESMS: m/z 419.1 (M + Na)+.
1
4.02 (s, 2H), 5.35 (s, 1H), 5.65 (s, 1H), 7.16-7.28 (m, 2H), 7.28-
7.34 (m, 2H). ESMS: m/z 163 (M + H)+. Anal. (C10H15ClN2) C,
H, N.
N′-[(E)-(2-Phenyl-3-fluoroallyl)]hydrazine Hydrochloride (15).
A mixture of 14 (1.3 g, 3.28 mmol), NH2NHMe (0.26 mL, 4.72
mmol) in THF (50 mL) was stirred under N2 at room temperature
for 24 h and then concentrated in vacuo. The residue was diluted
with EtOAc. The solid formed was filtered and washed with EtOAc.
The combined filtrate was concentrated in vacuo to give a semisolid
(0.98 g). It was used directly in the next step without any further
purification. It was dissolved in MeOH (5.0 mL). To this solution
was added HCl solution in 1,4-dioxane (4.0 M, 4.0 mL, 16 mmol).
The resulting mixture was stirred under N2 at room temperature
overnight and then concentrated in vacuo. The residue was diluted
with ether (30 mL) and filtered. The solid was washed with ether
(e) N′-[2-(4-Fluorophenyl)allyl]-N-methylhydrazine Hydro-
chloride (7a). The title compound was obtained as a white solid
1
(0.52 g, 90%). mp: 128-129 °C. H NMR (D2O, 300 MHz): δ
2.66 (s, 3H), 3.95 (s, 2H), 5.29 (s, 1H), 5.50 (s, 1H), 7.03 (t, J )
9.0 Hz, 2H), 7.42 (t, J ) 9.0 Hz, 2H). ESMS: m/z 181 (M + H)+.
Anal. (C10H14ClFN2) C, H, N.
(f) N′-[2-(4-Fluorophenyl)allyl]-N-ethylhydrazine Hydrochlo-
ride (7b). The title compound was obtained as a white solid (0.44
g, 90%). mp: 117-118 °C. 1H NMR (D2O, 300 MHz): δ 1.10 (t,