Brief Articles
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23 5851
mL of sulfuric acid 96% at 0 °C. Ethyl 4-chloroacetoacetate (10
mL, 74 mmol) was slowly added, and the mixture was stirred at
room temperature for 24 h. The reaction mixture was then poured
onto ice water (500 g), and the solid residue was filtered and washed
with water, yielding the desired coumarin as white solid (12.2 g,
78% yield). MS (EI) m/z 210 (M+); 1H NMR (acetone-d6, 300 MHz)
δ 9.50 (s, 1H, dis. with D2O), 7.73 (d, J ) 8.8 Hz, 1H), 6.91 (dd,
J1 ) 2.5 Hz, J2 ) 8.8 Hz, 1H), 6.80 (d, J ) 2.5 Hz, 1H), 6.40 (s,
1H), 4.92 (s, 2H).
7-[(3-Chlorobenzyl)oxy]-4-(chloromethyl)-2H-chromen-2-
one (5). 4-(Chloromethyl)-7-hydroxy-2H-chromen-2-one (4; 1.0 g,
4.8 mmol), anhydrous K2CO3 (0.66 g, 4.8 mmol), and 0.94 mL
(7.2 mmol) of 3-chlorobenzyl bromide were heated in refluxing
absolute ethanol (32 mL) for 2 h. The reaction mixture was cooled
to room temperature, and the inorganic precipitate was filtered off.
After solvent evaporation, the crude residue was treated with ethyl
ether and filtered giving a solid with a level of purity that allowed
its use as such in the next steps (1.3 g, 78% yield). 1H NMR (CDCl3,
300 MHz) δ 7.58 (d, J ) 8.8 Hz, 1H), 7.43 (br s, 1H), 7.37-7.27
(m, 3H), 6.96 (dd, J1 ) 2.5 Hz, J2 ) 8.8 Hz, 1H), 6.88 (d, J ) 2.5
Hz, 1H), 6.41 (s, 1H), 5.11 (s, 2H), 4.62 (s, 2H).
7-[(3-Chlorobenzyl)oxy]-4-[(methylamino)methyl]-2H-chromen-
2-one (2) Methanesulfonate. Compound 5 (0.80 g, 2.50 mmol)
and a 2.0 M solution of N-methylamine in THF (25.0 mL, 50 mmol)
were stirred at 55 °C under argon for 5 h. The mixture was cooled
to room temperature, and the inorganic precipitate was filtered off.
The solvent was evaporated and the resulting solid was purified
by column chromatography using AcOEt as eluent affording the
title compound as a free base (0.25 g, 28% yield). To a solution of
this free base (0.18 g, 0.55 mmol, in 3 mL of dry THF) was added
methanesulphonic acid (0.040 mL, 0.6 mmol). The resulting white
solid was filtered, washed with dry THF, and crystallized from
absolute ethanol (0.22 g, 95% yield). MS (ESI) m/z 330 (M + H)+;
1
mp 213-215 °C; H NMR (DMSO-d6, 300 MHz) δ 9.01 (s, 2H,
dis. with D2O), 7.77 (d, J ) 8.8 Hz, 1H), 7.54 (s, 1H), 7.44-7.37
(m, 3H), 7.14 (d, J ) 2.5 Hz, 1H), 7.10 (dd, J1 ) 2.5 Hz, J2 ) 8.8
Hz, 1H), 6.41 (s, 1H), 5.27 (s, 2H), 4.44 (s, 2H), 2.71 (s, 3H), 2.31
(s, 3H); Anal. (C19H20ClNO6S) C, H, N.
7-Hydroxy-4-(hydroxymethyl)-2H-chromen-2-one (6). A Pyr-
ex vessel was charged with a magnetic stirring bar, 1.0 g (4.8 mmol)
of 4, and 50 mL of water. Then it was introduced in the microwave
reactor and irradiated for 15 min at 150 °C, with a heating ramp of
5 min. Then the mixture was cooled to room temperature and the
product was crystallized from absolute water (0.77 g, 84% yield).
1H NMR (DMSO-d6, 300 MHz) δ 10.49 (s, 1H, dis. with D2O),
7.49 (d, J ) 8.5 Hz, 1H), 6.74 (dd, J1 ) 2.4 Hz, J2 ) 8.5 Hz, 1H),
6.69 (d, J ) 2.4 Hz, 1H), 6.20 (s, 1H), 5.56 (t, J ) 4.9 Hz, 1H,
dis. with D2O), 4.67 (d, J ) 4.9 Hz, 2H).
Figure 3. Stereoplots of the analyzed inhibitors bound to MAO B
active site. (a) Safinamide (1) complex. (b) 7-(3-Chlorobenzyloxy)-4-
(methylamino)methyl-coumarin (2) complex. (c) 7-(3-Chlorobenzy-
loxy)-4-carboxaldehyde-coumarin (3) complex. Color code and orien-
tation are as in Figure 2b. Active site residues and the inhibitor are
drawn in gray and black, respectively. Water molecules are shown as
cyan spheres. Dashed lines show hydrogen bonds between the inhibitor
and protein residues. The terminal methyl group of the 4-(methylamino)-
methyl substituent of compound 2 is not visible in the electron density,
most likely reflecting a disordered conformation. The position of the
terminal methyl group displayed in Figure 3b is purely indicative and
shown to facilitate the correlation of the three-dimensional structure
with the chemical formula depicted in Figure 1.
7-Hydroxy-2-oxo-2H-chromene-4-carboxaldehyde (7). MnO2
(1.7 g, 20 mmol) was added to a solution of 0.77 g (4.0 mmol) of
6 in 30 mL of dry THF. The mixture was stirred at rt for 24 h and
then filtered over celite flowed by a washing with hot ethanol. The
combined solvents were concentrated to dryness and the resulting
crude solid was purified by column chromatography using as a
mixture of chloroform/methanol 9.5/0.5 (v/v) as eluent (0.52 g, 68%
Merck) by flash methodologies. Microwave reactions were per-
formed in a Milestone MicroSynth apparatus. Melting points (mp)
were determined only for the final products by the capillary method
on a Stuart Scientific SMP3 electrothermal apparatus and are
uncorrected. Elemental analysis (C, H, N) were determined only
on the target final products on an Europea 3000 analyzer and were
within (0.4% of the calculated values. 1H NMR spectra were
recorded at 300 MHz on a Varian Mercury 300 instrument.
Chemical shifts are expressed in δ (ppm) and coupling constants J
in hertz (Hz). The following abbreviations were used: br (broad
signal), s (singlet), d (doublet), t (triplet), dd (double doublet), m
(multiplet). Signals due to OH and NH protons were detected by
deuterium exchange with D2O. Synthesis of compounds 2 and 3
described below refers to Scheme 1.
1
yield). H NMR (DMSO-d6, 300 MHz) δ 10.67 (br s, dis. with
D2O, 1H), 10.05 (s, 1H), 8.29-8.26 (m, 1H), 6.87-6.80 (m, 2H),
6.68 (s, 1H).
7-[(3-Chlorobenzyl)oxy]-2-oxo-2H-chromene-4-carboxalde-
hyde (3). Intermediate 7 (0.19 g, 1.0 mmol) was dissolved in 10
mL of absolute ethanol and anhydrous K2CO3 (0.14 g, 1.0 mmol)
and 3-chlorobenzyl bromide (0.26 mL, 2.0 mmol) were added. The
mixture was refluxed for 2 h. The inorganic precipitate was filtered
off, and the solution was evaporated under vacuum affording an
oily residue that was purified by flash chromatography (CHCl3/
petroleum ether 7/3 v/v as the eluent) to give a pure yellow solid
that was crystallized from CHCl3/hexane (0.18 g, 56% yield). Mp
1
145-147 °C. H NMR (DMSO-d6, 300 MHz) δ 10.09 (s, 1H),
4-(Chloromethyl)-7-hydroxy-2H-chromen-2-one (4). The title
compound was prepared according to literature20 with slight
modifications. Resorcinol (10 g, 91 mmol) was dissolved in 100
8.38 (d, J ) 8.8 Hz, 1H), 7.54 (s, 1H), 7.44-7.39 (m, 3H), 7.16-
7.15 (m, 1H), 7.12-7.07 (m, 1H), 6.99-6.98 (m, 1H), 5.24 (s,
2H); Anal. (C17H11ClO4) C, H.