4076 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Abe et al.
(1H, dd, J ) 17, 4 Hz), 3.92 (1H, dd, J ) 17, 5 Hz), 4.78 (1.2H,
s), 4.90 (0.8H, s), 6.15 (1H, br d, J ) 5 Hz), 6.51 (1H, d, J ) 15
Hz), 6.67 (1H, br t, J ) 5 Hz), 7.29 (1H, overlapped with H2O),
56, 58-63a ,b, and 69a ,b-71a ,b were prepared following a
procedure similar to method A.
Met h od B. 8-[[2,6-Dich lor o-3-[N-m et h yl-N-[(E)-4-(N-
m et h ylca r b a m oyl)cin n a m a m id oa cet yl]a m in o]b en zyl]-
oxy]-2-m eth ylqu in olin e Hyd r och lor id e (54a ). To a sus-
pension of 62a (500 mg, 0.845 mmol) in MeOH (5 mL) was
added 10% hydrogen chloride in MeOH (2 mL) at ambient
temperature. After 10 min, the solution was evaporated in
vacuo. The residue was crystallized from MeCN to give 54a
(498 mg, 93.8%) as colorless crystals: mp 160-165 °C; 1H
NMR (CDCl3-CD3OD) δ 2.98 (3H, s), 3.10 (3H, s), 3.31 (3H,
s), 3.89 (1H, d, J ) 17 Hz), 4.05 (1H, d, J ) 17 Hz), 5.59 (1H,
d, J ) 10 Hz), 5.75 (1H, d, J ) 10 Hz), 6.65 (1H, d, J ) 16 Hz),
7.37-7.73 (6H, m), 7.73-8.00 (5H, m), 8.92 (1H, d, J ) 8 Hz);
MS (FAB) m/z 591; IR (KBr) 3491, 3418, 3238, 3038, 1673,
1660, 1635, 1612, 1596, 1541. Anal. (C31H28Cl2N4O4‚HCl‚H2O)
C, H, N.
7.45-7.62 (4H, m), 7.76 (2H, d, J ) 8 Hz). Anal. (C21H20
-
BrCl2N3O3) C, H, N.
1-Acetoxym eth yl-2,6-d im eth ylben zen e (40). A mixture
of 39 (13.6 g, 100 mmol) and acetic anhydride (11.3 mL, 120
mmol) was stirred at 70 °C for 5 h during which time to the
mixture was added 4-(dimethylamino)pyridine (10 mg). After
cooling, the reaction mixture was evaporated in vacuo. The
residue was dissolved in AcOEt and washed with water twice.
The organic layer was dried and evaporated in vacuo. The
residue was purified by flash silica gel chromatography
(hexane-AcOEt, 10:1) to give 40 (17.5 g, 98.2%) as a colorless
oil: 1H NMR (CDCl3) δ 2.07 (3H, s), 2.38 (6H, s), 5.19 (2H, s),
7.05 (2H, d, J ) 8 Hz), 7.15 (1H, t, J ) 8 Hz). Anal. (C11H14O2)
C, H, N.
Compounds 54b-d , 57a , 64c, 76a , 81a ,b, 86, 88a ,c, 90a -
d , 93b,c, 95, and 98 were prepared following a procedure
similar to method B.
1-Acetoxym eth yl-2,6-d im eth yl-3-n itr oben zen e (41). To
a solution of acetic anhydride (34 mL) and AcOH (17 mL) was
added copper(II) nitrate trihydrate (16.3 g, 67.3 mmol) in an
ice-water bath. To this stirred mixture was added dropwise
a solution of 40 (10.0 g, 56.1 mmol) in acetic anhydride (10
mL) and AcOH (5 mL) over 30 min. The reaction mixture was
stirred for 30 min in an ice-water bath and 30 min at ambient
temperature. This mixture was poured onto ice (250 g) and
extracted with AcOEt twice. The organic layer was washed
with water (3×) and brine, dried, and evaporated in vacuo.
The residue was purified by flash silica gel chromatography
(hexane-AcOEt, 5:1) to give 41 (9.59 g, 94.3%) as a pale-yellow
oil: 1H NMR (CDCl3) δ 2.08 (3H, s), 2.47 (3H, s), 2.50 (3H, s),
5.22 (2H, s), 7.18 (1H, d, J ) 8 Hz), 7.69 (1H, d, J ) 8 Hz).
Anal. (C11H13NO4) C, H, N.
Meth od C. 8-[[2,6-Dich lor o-3-[N-m eth yl-N-[(E)-3-[6-(N-
m et h ylca r b a m oyl)p yr id in -3-yl]a cr yloylglycyl]a m in o]-
ben zyl]oxy]-2-m eth ylqu in olin e (62c). To a solution of 83a
(100 mg, 0.173 mmol) in dry DMF (1 mL) were added
methylamine hydrochloride (14 mg, 0.207 mmol), WSCD (38
mg, 0.242 mmol), and HOBt (37 mg, 0.277 mmol) at ambient
temperature. After 3 h, this mixture was partitioned between
AcOEt and saturated aqueous sodium bicarbonate solution.
The organic layer was washed with water (3×) and brine,
dried, and evaporated in vacuo. The residue was purified by
flash silica gel column chromatography (CH2Cl2-MeOH, 20:
1) to give 62c (65 mg, 63.8%) as a colorless amorphous solid:
1H NMR (CDCl3) δ 2.73 (3H, s), 3.04 (3H, d, J ) 5 Hz), 3.28
(3H, s), 3.70 (1H, dd, J ) 18, 4 Hz), 3.95 (1H, dd, J ) 18, 5
Hz), 5.64 (2H, s), 6.64 (1H, d, J ) 16 Hz), 6.76 (1H, br s), 7.21-
7.37 (3H, m), 7.37-7.54 (3H, m), 7.60 (1H, d, J ) 16 Hz), 7.88-
8.09 (3H, m), 8.19 (1H, d, J ) 8 Hz), 8.62 (1H, br d, J ) 5 Hz);
MS (FAB) m/z 592 (M + 1). Anal. (C30H27Cl2N5O4) C, H, N.
Compounds 62d , 63c, and 84 were prepared following a
procedure similar to method C.
8-[[2,6-Dich lor o-3-[N-m eth yl-N-(N-p h th a lim id oa cetyl)-
a m in o]ben zyl]oxy]-2-m eth ylqu in olin e (68a ). To a solution
of 65a (4.33 g, 11.0 mmol) and triethylamine (1.67 g, 16.5
mmol) in dry CH2Cl2 (43 mL) was added dropwise methane-
sulfonyl chloride (1.39 g, 12.1 mmol) in an ice-water bath
under nitrogen. After 30 min, the reaction mixture was
washed with water, saturated aqueous sodium bicarbonate,
and brine. The organic layer was dried and evaporated in
vacuo to give 5.18 g of a pale-yellow oil. Following a procedure
similar to method A, the title compound was obtained in 91.6%
yield from 8-hydroxy-2-methylquinoline and the preceding oil
as colorless crystals after crystallization from MeOH: mp 211-
213 °C; 1H NMR (CDCl3) δ 2.72 (3H, s), 3.23 (3H, s), 4.08 (2H,
s), 5.66 (1H, d, J ) 10 Hz), 5.72 (1H, d, J ) 10 Hz), 7.20-7.49
(4H, m), 7.48 (1H, d, J ) 8 Hz), 7.55 (1H, d, J ) 8 Hz), 7.65-
7.77 (2H, m), 7.80-7.93 (2H, m), 8.00 (1H, d, J ) 8 Hz). Anal.
(C28H21Cl2N3O4) C, H, N.
1-Ch lor om eth yl-2,6-d im eth yl-3-[N-m eth yl-N-[(E)-4-(N-
m et h ylca r b a m oyl)cin n a m a m id oa cet yl]a m in o]b en zen e
(50b). To a solution of 49b (2.00 g, 4.89 mmol) and triethyl-
amine (990 mg, 9.78 mmol) in dry DMF (100 mL) was added
methanesulfonyl chloride (784 mg, 6.85 mmol) in an ice-water
bath under nitrogen. After 30 min, the reaction mixture was
stirred at ambient temperature for 14 h. The mixture was
partitioned between CH2Cl2 and water. The organic layer was
washed with water (4×) and brine, dried, and evaporated in
vacuo. The residue was crystallized from AcOEt to give 50b
(1.89 g, 90.4%) as colorless crystals: mp 232-233 °C; 1H NMR
(CDCl3) δ 2.29 (3H, s), 2.46 (3H, s), 3.03 (3H, d, J ) 5 Hz),
3.24 (3H, s), 3.59 (1H, dd, J ) 17, 5 Hz), 3.82 (1H, dd, J ) 17,
4 Hz), 4.67 (2H, s), 6.20 (1H, m), 6.50 (1H, d, J ) 15 Hz), 6.70
(1H, d, J ) 5 Hz), 7.04 (1H, d, J ) 9 Hz), 7.14 (1H, d, J ) 9
Hz), 7.50-7.60 (3H, m), 7.75 (2H, d, J ) 9 Hz). Anal. (C23H26
ClN3O3) C, H, N.
-
Compound 50c was prepared using a similar procedure to
that used for 50b.
Meth od A. 8-[[2,6-Dich lor o-3-[N-m eth yl-N-[(E)-4-(N-
m et h ylca r b a m oyl)cin n a m a m id oa cet yl]a m in o]b en zyl]-
oxy]-2-m eth ylqu in olin e (62a ). To a solution of 8-hydroxy-
2-methylquinoline (100 mg, 0.628 mmol) in dry DMF (2 mL)
was added 60% sodium hydride in oil (27 mg, 0.659 mmol) in
an ice-water bath under nitrogen. After 30 min, 50a (256
mg, 0.598 mmol) was added therein, followed by stirring at
ambient temperature for 2 h. The mixture was poured into
water and extracted with CHCl3 twice. The extracts were
washed with water (3×) and brine, dried, and evaporated in
vacuo. The residue was purified by flash silica gel column
chromatography (CH2Cl2-MeOH, 30:1) followed by crystal-
lization from AcOEt to give a colorless solid (315 mg, 88.7%).
The solid was recrystallized from MeOH to afford 62a (280
mg, 78.9%) as colorless crystals: mp 232-234 °C; 1H NMR
(CDCl3) δ 2.71 (3H, s), 3.00 (3H, d, J ) 5 Hz), 3.26 (3H, s),
3.64 (1H, dd, J ) 17, 4 Hz), 3.94 (1H, dd, J ) 17, 5 Hz), 5.65
(2H, s), 6.41 (1H, br d, J ) 5 Hz), 6.53 (1H, d, J ) 15 Hz), 6.73
(1H, br s), 7.30 (2H, d, J ) 8 Hz), 7.37-7.61 (7H, m), 7.76
Compounds 66, 67a ,b, and 68b were prepared using a
similar procedure to that used for 68a .
Meth od D. 8-[[3-[N-(E)-Cin n a m a m id oa cetyl-N-m eth yl-
a m in o]-2,6-d ich lor oben zyl]oxy]-2-m eth ylqu in olin e (80a ).
To a solution of 71a (100 mg, 0.247 mmol) and triethylamine
(38 mg, 0.375 mmol) in dry CH2Cl2 (2 mL) was added
(E)-cinnamoyl chloride (45 mg, 0.270 mmol) in an ice-water
bath under nitrogen. The reaction mixture was stirred at the
same temperature for 30 min and then stirred at ambient
temperature for 1 h. The reaction mixture was washed with
water, saturated aqueous sodium bicarbonate, and brine,
dried, and evaporated in vacuo. The residue was then purified
by flash silica gel column chromatography (hexane-AcOEt,
1:4) to give 80a (118 mg, 89.4%) as a colorless amorphous
solid: 1H NMR (CDCl3) δ 2.73 (3H, s), 3.26 (3H, s), 3.65 (1H,
dd, J ) 17, 4 Hz), 3.85 (1H, dd, J ) 17, 5 Hz), 5.65 (2H, s),
6.48 (1H, d, J ) 16 Hz), 6.65 (1H, br t, J ) 5 Hz), 7.19-7.53
(2H, d, J ) 8 Hz), 8.03 (1H, d, J ) 8 Hz). Anal. (C31H28
Cl2N4O4) C, H, N.
-
Compounds 14a ,b, 20d , 23, 46a ,b, 51, 52a -j,l,m , 53, 55,