Novel Antiarthritic Agents with γ-Sultam Skeleton
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 10 2045
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1222, 1146 cm-1; H NMR (CDCl3) δ 2.34-2.46 (m, 2H), 2.92
(200 mL), and the organic phase was washed with saturated
NaHCO3 (200 mL) and brine (200 mL), dried, and evaporated.
The residue was purified by chromatography on silica gel
eluting with hexane-AcOEt (1:1) to give 3.35 g (41%) of 13
and 0.12 g (1.5%) of 14. 13: mp 233-235 °C; IR (Nujol) 3556,
(s, 3H), 3.24-3.30 (m, 2H), 4.11-4.16 (m, 2H), 3.79 (s, 3H).
Anal. (C4H9NO3S) C, H, N, S.
N-(4-Ch lor oph en yl)-1,2-isoth iazolidin e-1,1-dioxide (5g).
To a stirred solution of 4-chloroaniline (5.24 g, 41.1 mmol) and
pyridine (25 mL) was added 3-chloropropanesulfonyl chloride
(7.28 g, 41.1 mmol) dropwise at -20 to -30 °C over a period
of 5 min. The reaction mixture was allowed to warm to room
temperature and stirred for additional 45 min. The mixture
was concentrated in vacuo, and the residue was purified by
chromatography on silica gel eluting with hexane-AcOEt (2:
1) to give 10.2 g (93%) of 3g. Compound 5g (68% yield) was
prepared in a similar manner described above as a colorless
crystal: mp 110.5-111.5 °C; IR (CHCl3) 3010, 2960, 1595,
3244, 2914, 1632, 1594, 1430, 1319, 1240 cm-1 1H NMR
;
(DMSO-d6) δ 1.40 (s, 18H), 3.02-3.13 (m, 2H), 3.22-3.34 (m,
2H), 6.92 (br t, J ) 7.2 Hz, 1H), 7.08 (t, J ) 2.4 Hz, 1H), 7.29
(s, 2H), 7.45 (s, 1H). Anal. (C18H27NO3S‚0.3H2O) C, H, N, S.
14; mp 161-164 °C; IR (CHCl3) 3620, 2954, 1432, 1371, 1312,
1241, 1157 cm-1; 1H NMR (CDCl3) δ 1.45 (s, 18H), 3.11 (dt, J
) 2.1, 6.7 Hz, 2H), 3.39-3.51 (m, 2H), 4.26-4.40 (br, 1H), 5.49
(s, 1H), 6.80 (t, J ) 2.1 Hz, 1H), 7.55 (s, 2H). Anal. (C18H27
NO3S) C, H, N, S.
-
1493, 1300, 1267, 1131 cm-1
(m, 2H), 3.35-3.43 (m, 2H), 3.76 (t, J ) 6.4 Hz, 2H), 7.16-
7.36 (m, 4H). Anal. (C9H10NO2SCl) C, H, N, S, Cl.
Compounds 5h -j were also prepared from 1 and the
corresponding arylamines using a procedure similar to that
described for the preparation of 5g.
;
1H NMR (CDCl3) δ 2.47-2.61
(E)-2-(2-Hyd r oxyeth yl)-5-(3,5-d i-ter t-bu tyl-4-h yd r oxy-
ben zylid en e)-1,2-isoth ia zolid in e-1,1-d ioxid e (15a ). To a
stirred suspension of 13 (675 mg, 2.0 mmol), a catalytic amount
of N-benzyltrimethylammonium chloride, 2-iodoethanol (0.624
mL, 8.0 mmol) in CH2Cl2 (20 mL), and water (10 mL) was
added 2 N NaOH (1.5 mL) at room temperature. The reaction
mixture was refluxed for 3 days and diluted with water. The
organic layer was separated and washed with brine, dried, and
evaporated. The crude residue was purified by chromatography
on silica gel eluting with hexane-AcOEt (7:3) to give 15a (190
mg, 25%) as a colorless crystal: mp 156-157 °C; IR (CHCl3)
(E)-2-Eth yl-5-(3,5-d i-ter t-bu tyl-4-h yd r oxyben zylid en e)-
1,2-isoth ia zolid in e-1,1-d ioxid e (10b) a n d Its (Z)-Isom er
(12b). To a stirred solution of diisopropylamine (15.5 mL, 111
mmol), BuLi in hexane (1.60 M, 69.5 mL, 111 mmol) was added
dropwise under ice-cooling over a period of 20 min. After
completion of the addition, stirring was continued for another
15 min and the reaction mixture was cooled to -78 °C, followed
by the addition of THF (100 mL). To this mixture were added
5b (15 g, 101 mmol), 3,5-di-tert-butyl-4-methoxymethyloxy-
benzaldehyde (7) (25 g, 90.5 mmol), and hexamethylphospha-
mide (HMPA) (Caution! Cancer suspect agent.) (30 mL) in THF
(70 mL) dropwise over a period of 20 min. The reaction mixture
was stirred for 30 min at the same temperature and then
warmed to room temperature. The mixture was poured into 2
N HCl (100 mL) under ice-cooling and extracted with AcOEt
(250 mL). The organic layer was washed with saturated
NaHCO3 (300 mL) and brine (300 mL), then dried, and
evaporated. The residue was purified by chromatography on
silica gel eluting with hexane-AcOEt (4:1 to 1:1) to give 21.3
g (55%) of 8b as a colorless solid. To a solution of 8b (8.5 g,
19.9 mmol) in toluene (150 mL) was added p-TsOH (2.49 g,
13 mmol), and the mixture was refluxed for 30 min. After
cooling to room temperature, the mixture was poured into
saturated NaHCO3 (150 mL) and extracted with AcOEt (150
mL). The organic layer was washed with water (150 mL) and
brine (150 mL) and then dried and evaporated. The residue
was subjected to column chromatography on silica gel, eluting
with hexane-AcOEt (3:1); E-isomer 10b (2.59 g, 36%) and
Z-isomer 12b (376 mg, 7%) were obtained as crystals from the
less polar and polar fractions, respectively. 10b: mp 135-137
°C; IR (KBr) 3610, 3440, 2970, 2880, 1645, 1597, 1430, 1290,
1173, 1151, 1139 cm-1; 1H NMR (CDCl3) δ 1.29 (t, J ) 7.2 Hz,
3H), 1.45 (s, 18H), 3.07-3.19 (m, 4H), 3.28 (q, J ) 7.2 Hz, 2H),
5.50 (s, 1H), 7.24-7.26 (m, 3H). Anal. (C20H31NO3S) C, H, N,
S. 12b: mp 160.5 °C; IR (KBr) 3560, 2975, 1637, 1600, 1431,
1289, 1275, 1168, 1150, 1111 cm-1; 1H NMR (CDCl3) δ 1.26 (t,
J ) 7.2 Hz, 3H), 1.45 (s, 18H), 3.00 (dt, J ) 2.0, 6.0 Hz, 2H),
3.15 (q, J ) 7.2 Hz, 2H), 3.25 (t, J ) 6.0 Hz, 2H), 5.47 (s, 1H),
6.73 (t, J ) 2.0 Hz, 1H), 7.52 (s, 2H). Anal. (C20H31NO3S) C,
H, N, S.
3620, 2956, 1434, 1290, 1240, 1151, 1066 cm-1 1H NMR
;
(CDCl3) δ 1.45 (s, 18H), 3.16 (dt, J ) 2.4, 6.5 Hz, 2H), 3.30 (m,
2H), 3.41 (t, J ) 6.5 Hz, 2H), 3.87 (t, J ) 5.2 Hz, 2H), 5.53 (s,
1H), 7.23-7.29 (m, 3H). Anal. (C20H31NO4S) C, H, N, S.
Compound 15b was prepared using a procedure similar to
that described for the preparation of 15a .
(E)-2-Ca r b oxym et h yl-5-(3,5-d i-ter t-b u t yl-4-h yd r oxy-
ben zylid en e)-1,2-isoth ia zolid in e-1,1-d ioxid e (15c). A mix-
ture of 13 (14.0 g, 41.6 mmol), ethyl iodoacetate (7.38 mL, 62.4
mmol), and K2CO3 (8.60 g, 62.2 mmol) in DMF (80 mL) was
stirred for 3 h at room temperature. The reaction mixture was
poured into AcOEt (500 mL) and water (400 mL), and the
organic phase was washed with water (400 mL) and brine (400
mL). The solvent was removed, and the residue was purified
by chromatography on silica gel eluting with hexane-AcOEt
to give an ethyl ester derivative as a pale red solid (7.43 g,
72%). To a stirred solution of this compound (15.9 g, 37.5
mmol) in THF (200 mL) and MeOH (50 mL) was added 2 N
NaOH (37.5 mL) with ice-cooling, and the mixture was stirred
for 30 min at the same temperature. To this mixture were
added 1 N HCl (250 mL) and AcOEt (450 mL), and the organic
phase was washed with water (300 mL) and brine (300 mL),
dried, and concentrated to give a colorless oil. Crystallization
from isopropyl ether gave pure 15c (9.6 g, 65%) as a colorless
crystal: mp 175-177 °C; IR (Nujol) 3596, 2914, 1733, 1645,
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1594, 1460, 1430, 1290, 1243, 1213 cm-1; H NMR (CDCl3) δ
1.45 (s, 18H), 3.21 (dt, J ) 2.4, 6.6 Hz, 2H), 3.51 (t, J ) 6.6
Hz, 2H), 3.95 (s, 2H), 5.54 (s, 1H), 7.25-7.30 (m, 3H). Anal.
(C20H29NO5S) C, H, N, S.
(E)-2-Acetyl-5-(3,5-di-ter t-bu tyl-4-h ydr oxyben zyliden e)-
1,2-isoth ia zolid in e-1,1-d ioxid e (15d ). To a stirred solution
of 13 (585 mg, 1.74 mmol) in pyridine (10 mL) were added a
catalytic amount of 4-N,N-(dimethylamino)pyridine (DMAP)
and acetic anhydride (6 mL) under ice-cooling. The reaction
mixture was stirred for 1 h at room temperature and then
concentrated in vacuo. The residue was purified by chroma-
tography on silica gel to afford 15d (360 mg, 55%) as a colorless
crystal: mp 177-179 °C; IR (CHCl3) 3618, 2958, 1695, 1435,
1379, 1297, 1153, 1117 cm-1; 1H NMR (CDCl3) δ 1.46 (s, 18H),
2.53 (s, 3H), 3.20 (dt, J ) 2.2, 7.0 Hz, 2H), 3.86 (t, J ) 7.0 Hz,
2H), 5.60 (s, 1H), 7.52 (s, 2H), 7.39 (t, J ) 2.2 Hz, 1H). Anal.
(C20H29NO5S) C, H, N, S.
(E)-5-(3,5-Di-ter t-b u t yl-4-h yd r oxyb en zylid en e)-2-(N-
m eth oxy-N-m eth ylca r ba m oyl)-1,2-isoth ia zolid in e-1,1-d i-
oxid e (15f). To a solution of 13 (450 mg, 1.33 mmol) and
N-methoxy-N-methyl phenyl carbamate (300 mg, 1.66 mmol)
in THF (10 mL) and HMPA (Caution! Cancer suspect agent.)
(10 mL) was slowly added LHMDS (1.0 M in THF) (3.2 mL,
3.2 mmol) at -40 °C. The reaction mixture was allowed to
Compounds 10a , 10c-m , 12a , 12c, 12g, 12h , 12k -m , 11,
and 19 were prepared from 7 and the corresponding γ-sultams,
6, or 18 using a procedure similar to that described for the
preparation of 10b and 12b. Compounds 20-24 were also
prepared from 5b and the corresponding protected aldehydes
using the procedure described above.
(E)-5-(3,5-Di-ter t-bu tyl-4-h ydr oxyben zyliden e)-1,2-isoth i-
a zolid in e-1,1-d ioxid e (13) a n d Its Z-Isom er (14). To a
stirred solution of the mixture of 10l and 12l (8.83 g, 19.2
mmol) which were obtained (64% yield) from the reaction of 7
(9.00 g, 32.0 mmol) and 5l (7.24 g, 30.0 mmol), in CH2Cl2 (150
mL), was added TiCl4 (4.10 mL, 37.4 mmol) with ice-cooling,
and the mixture was stirred for 30 min at 0 °C. The mixture
was poured into ice water (200 mL) and extracted with AcOEt