3596 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 18
Grunewald et al.
1
1133, 1000 cm-1; H NMR (CDCl3) δ 8.66 (d, J ) 2.0 Hz, 1H,
anhydrous Na2SO4. The solvent was removed under reduced
pressure and the residue recrystallized from EtOH/hexanes
to yield 34 as white crystals (90.6 mg, 93%): mp 178-179 °C;
IR (KBr) 3600, 3400, 3280-3190, 1680, 1160, 1000, 840, 640
cm-1; 1H NMR (acetone-d6) δ 8.38 (d, J ) 2.0 Hz, 1H, ArH-8),
7.93 (dd, J ) 8.0, 2.0 Hz, 1H, ArH-6), 7.58 (d, J ) 8.0 Hz, 1H,
ArH-5), 7.40 (br ex s, 1H, NH), 6.48 (br ex s, 1H, NH), 4.65-
4.46 (m, 2H, CH2F), 4.15-4.05 (m, 1H, H-3), 3.30-3.15 (m,
2H, H-4), 2.59 (d, J ) 2.5 Hz, 3H, CH3); CIMS m/z (relative
intensity) 273 (MH+, 15), 239 (100), 145 (25), 144 (20), 89 (20),
63 (20). Anal. (C11H13N2O3S) C, H, N.
(()-3-Flu or om eth yl-7-(N-m eth yla m in osu lfon yl)-1,2,3,4-
tetr a h yd r oisoqu in olin e Hyd r och lor id e (16‚HCl). Lactam
34 (1.062 g, 3.87 mmol) was reduced to THIQ 16 using the
same procedures described previously for the synthesis of
THIQ 14 from lactam 32. The hydrochloride salt of 16 was
prepared in dry EtOH using dry HCl(g). The solvent was
removed and the residue was recrystallized from EtOH/
hexanes to yield 16‚HCl as white crystals (989 mg, 99%): mp
204-206 °C; IR (KBr) 3160, 2900, 2750, 2500, 1420, 1320,
1170, 1050, 1000, 720 cm-1; 1H NMR (DMSO-d6) δ 10.5 (br ex
s, 2H, NH2+), 7.38-7.65 (m, 2H, ArH-8, SO2NH), 7.56-7.48
(m, 2H, ArH-5,6), 5.01-4.70 (m, 2H, CH2F), 4.44 (s, 2H, H-1),
3.92-3.87 (m, 1H, H-3), 3.18-3.05 (m, 2H, H-4), 2.43 (s, 3H,
NCH3); 13C NMR (DMSO-d6) δ 138.7, 136.9, 130.7, 130.8, 126.3,
126.0, 83.0 (d, J ) 683 Hz, CH2F), 52.6 (d, J ) 76 Hz, C-3),
44.5, 29.5, 27.0 (d, J ) 22 Hz, C-4); CIMS m/z (relative
intensity) 275 (M + NH4+, 6), 259 (MH+, 100), 239 (30), 225
(40). Anal. (C11H15N2FO2S‚HCl) C, H, N.
ArH-8), 8.07 (dd, J ) 7.9, 2.0 Hz, 1H, ArH-6), 7.47 (d, J ) 7.9
Hz, 1H, ArH-5), 6.33 (br ex s, 1H, NH), 4.58-4.37 (m, 2H,
CH2F), 4.15-4.04 (m, 1H, H-3), 3.15-3.00 (m, 2H, H-4), 3.10
(s, 3H, CH3); EIMS m/z (relative intensity) 258 (MH+, 100),
224 (95), 145 (60). Anal. (C11H12FNO3S‚0.5H2O) C, H, N.
(()-3-F lu or om eth yl-7-m eth a n esu lfon yl-1,2,3,4-tetr a h y-
d r oisoqu in olin e Hyd r och lor id e (14‚HCl). Lactam 32 (125
mg, 0.485 mmol) was dissolved in THF (10 mL). 1 M BH3‚
THF (3 mL, 3.00 mmol) was added dropwise to the solution
and the reaction mixture was heated at reflux for 3 h. The
solution was cooled, MeOH (10 mL) was added dropwise, and
the solvent was removed under reduced pressure. A solution
of 6 N HCl (10 mL) and MeOH (10 mL) was added slowly to
the residue. The mixture was heated to reflux for 30 min. The
solution was concentrated under reduced pressure, made basic
with 4 N NaOH, and extracted with EtOAc (4 × 25 mL). The
combined organic extracts were washed with basic brine and
dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure to yield 14 as a white solid, which was
dissolved in CHCl3. Dry HCl(g) was used to form the HCl salt,
which was collected by filtration and recrystallized from EtOH/
hexanes to yield 14‚HCl as white crystals (78.3 mg, 58%): mp
222-223 °C; IR (KBr) 3450, 2900, 2750, 1425, 1300, 1125,
1010, 770 cm-1; 1H NMR (DMSO-d6) δ 10.0 (br ex s, 2H, NH2+),
7.90 (s, 1H, ArH-8), 7.83 (d, J ) 8.1 Hz, 1H, ArH-6), 7.55 (d,
J ) 8.22 Hz, 1H, ArH-5), 4.98-4.80 (m, 2H, CH2F), 4.48 (s,
2H, H-1), 4.05-3.90 (m, 1H, H-3), 3.21-3.08 (m, 2H, H-4), 3.22
(s, 3H, CH3); EIMS m/z (relative intensity) 243 (M+, 5), 224
(100), 145 (60). Anal. (C11H14NFO2S‚HCl) C, H, N.
(()-7-Am in osu lfon yl-3-flu or om et h yl-3,4-d ih yd r oiso-
qu in olin -1(2H)-on e (33). Chlorosulfone 31 (313 mg, 1.13
mmol) was dissolved in acetonitrile (5 mL), concentrated
ammonium hydroxide (5 mL) was added, and the solution was
stirred overnight. The solvent was removed under reduced
pressure and the residue was recrystallized from EtOH to yield
33 as white crystals (252 mg, 87%): mp 240 °C dec; IR (KBr)
3250, 3190, 2910, 1680, 1325, 1150 cm-1; 1H NMR (CD3OD) δ
8.38 (s, 1H, ArH-8), 7.93 (d, J ) 7.9 Hz, 1H, ArH-6), 7.44 (d,
J ) 7.9 Hz, 1H, ArH-5), 4.47 (m, 1H, CHF), 4.30 (m, 1H, CHF),
3.90 (m, 1H, H-3), 3.13 (m, 1H, H-4), 2.98 (m, 1H, H-4); CIMS
m/z (relative intensities) 276 (M + NH4+, 25), 259 (MH+, 100),
225 (27). Anal. (C10H11N2FO3S) C, H, N.
(()-3-F lu or om et h yl-7-a m in osu lfon yl-1,2,3,4-t et r a h y-
d r oisoqu in olin e Hyd r och lor id e (15‚HCl). Lactam 33 (252
mg, 0.997 mmol) was dissolved in THF (10 mL). 1 M BH3‚
THF (6 mL, 6 mmol) was added dropwise to the solution and
the reaction mixture was heated at reflux for 4 h. The solution
was cooled in an ice bath and 3 N HCl (15 mL) was added
slowly. The solution was concentrated under vacuum (ca. 15
mL) and washed with EtOAc (25 mL). The aqueous phase was
treated with 6 N NaOH until the solution pH was ca. 9 (note
pKa of sulfonamide) and sodium chloride was added until the
solution was saturated. The aqueous solution was extracted
with EtOAc (4 × 50 mL). The combined organic extracts were
washed with brine and dried over anhydrous Na2SO4. The
solvent was removed and the residue was dissolved in dry
MeOH. Dry HCl(g) was used to form the hydrochloride salt.
The solvent was removed and the remaining white solid was
recrystallized from EtOH/hexanes to yield 15‚HCl as off-white
crystals (88.0 mg, 32%): mp 216-217 °C; IR (KBr) 3270, 3185,
2910, 1580, 1325, 1150 cm-1; 1H NMR (DMSO-d6) δ 10.08 (br
ex s, 2H, NH2+), 7.78-7.64 (m, 2H, ArH-6,8), 7.52 (d, J ) 8.0
Hz, 1H, ArH-5), 7.46 (ex s, 2H, SO2NH2), 4.98-4.68 (m, 2H,
CH2F), 4.44 (s, 2H, H-1), 3.95-3.89 (m, 1H, H-3), 3.17-3.05
(m, 2H, H-4); CIMS m/z 245 (MH+, 100), 225 (70), 211 (50).
Anal. (C10H13N2FO2S‚HCl) C, H, N.
(()-3-F lu or om eth yl-7-(N-ben zyla m in osu lfon yl)-3,4-d i-
h yd r oisoqu in olin -1(2H)-on e (35). Chlorosulfone 31 (100 mg,
0.361 mmol) was dissolved in a biphasic mixture of EtOAc (10
mL) and saturated Na2CO3 (10 mL). Benzylamine (0.3 mL, 3
mmol) was added and the reaction mixture was stirred for 3
h. The organic phase was removed, washed with 3 N HCl (2
× 10 mL) and brine (10 mL), and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and
the residue recrystallized from EtOH/hexanes to yield 35 as
white crystals (104 mg, 83%): mp 225-226 °C; IR (KBr) 3450,
3250, 3100-2900, 1680, 1360, 1325, 1160, 1000, 900, 750, 640
cm-1; 1H NMR (acetone-d6) δ 8.44 (d, J ) 2.0 Hz, 1H, ArH-8),
7.98 (dd, J ) 2.0 Hz, 7.8 Hz, 1H, ArH-6), 7.57 (d, J ) 7.8 Hz,
1H, ArH-5), 7.41 (br ex s, 1H, SO2NH), 7.32 (m, 5H, Ph
H-2,3,4,5,6), 7.12, (br ex s, 1H, CONH), 4.69-4.51 (m, 2H,
CH2F), 4.20 (s, 2H, PhCH2N), 4.15-4.10 (m, 1H, H-3), 3.33-
3.12 (m, 2H, H-4); CIMS m/z (relative intensity) 350 (MH+
+
1, 15), 349 (MH+, 100), 106 (75), 91 (12); HRMS (FAB) m/z [M
+ H]+ calcd for C17H18FN2O3S 349.1022, found 349.1044.
(()-3-F lu or om eth yl-7-(N-ben zyla m in osu lfon yl)-1,2,3,4-
tetr a h yd r oisoqu in olin e Hyd r och lor id e (17‚HCl). Lactam
35 (92 mg, 0.29 mmol) was reduced to THIQ 17 using the same
procedures described previously for the synthesis of THIQ 14
from lactam 32. The hydrochloride salt of 17 was prepared in
anhydrous EtOH using dry HCl(g). The solvent was removed
under reduced pressure and the crude hydrochloride salt was
recrystallized from EtOH/hexanes to yield 17‚HCl as white
crystals (73 mg, 75%): mp 220-221 °C; IR (KBr) 3450, 3280,
2900-2500, 1320, 1150, 1050, 1010, 700 cm-1 1H NMR
;
(CD3OD) δ 7.74 (d, J ) 8.2 Hz, 1H, ArH-6), 7.70 (s, 1H, ArH-
8), 7.45 (d, J ) 8.2 Hz, 1H, ArH-5), 7.23 (m, 5H, PhH-2,3,4,5,6),
4.95-4.70 (m, 2H, CH2F), 4.51 (s, 2H, H-1), 4.08 (s, 2H,
PhCH2N), 3.97-3.88 (m, 1H, H-3), 3.24-3.17 (m, 2H, H-4);
CIMS m/z (relative intensity) 335 (MH+, 100), 301 (95), 130
(45), 115 (30), 106 (75), 91 (95), 77 (50). Anal. (C17H19N2FO2S‚
HCl‚0.25H2O) C, H, N.
(()-3-F lu or om eth yl-7-[N-(4-ch lor op h en yl)a m in osu lfo-
n yl]-3,4-d ih yd r oisoqu in olin -1(2H)-on e (36). Compound 31
(500 mg, 1.80 mmol) was added to a solution of 4-chloroaniline
(260 mg, 2.05 mmol) in pyridine (15 mL). The solution was
stirred for 6 h. The pyridine was removed under reduced
pressure and the residue was dissolved in EtOAc (30 mL) and
3 N HCl (30 mL). The organic phase was separated, washed
with 3 N HCl (30 mL), 10% NaHCO3 (30 mL), and brine (30
mL), and dried over anhydrous Na2SO4. The solvent was
(()-3-Fluoromethyl-7-(N-methylaminosulfonyl)-3,4-dihydro-
isoqu in olin -1(2H)-on e (34). Chlorosulfone 31 (99.7 mg, 0.360
mmol) was dissolved in a biphasic mixture of EtOAc (10 mL)
and saturated Na2CO3 (10 mL). Methylamine hydrochloride
(200 mg, 2.96 mmol) was added to the reaction and the mixture
was stirred for 3 h. The organic phase was removed, washed
with 3 N HCl (2 × 10 mL) and brine (10 mL), and dried over