Journal of Medicinal Chemistry
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Hz), 6.60 (1H, dd, J = 8.6, 2.0 Hz), 6.81 (1H, d, J = 2.0 Hz), 6.98
(1H, d, J = 8.5 Hz), 7.16 (1H, dd, J = 8.5, 6.8 Hz), 7.45−7.55 (1H, m),
7.99 (1H, s).
The following compounds (42a−42m) were prepared from 8 and
the corresponding anilines (14a−14m) by a method similar to that
described for 9.
2-(Benzylsulfanyl)-6-methoxybenzaldehyde (37). To a sus-
pension of sodium tert-butoxide (3.47 g, 36.1 mmol) in THF (50 mL)
was added benzylmercaptan (4.24 mL, 32.2 mmol) at 0 °C, and the
mixture was stirred at 0 °C for 30 min. To the reaction mixture was
added dropwise a solution of 2-fluoro-6-methoxybenzaldehyde (36,
4.64 g, 30.1 mmol) in THF (10 mL), and the mixture was stirred at
room temperature for 1 h. To the reaction mixture was added water
(150 mL), and the resulting precipitate was collected by filtration. The
collected solid was washed with water (20 mL) and Et2O (50 mL)
successively and dried in vacuo to give 37 (7.08 g, 91%) as a pale
yellow solid. 1H NMR (CDCl3) δ 3.91 (3H, s), 4.15 (2H, s), 6.72 (1H, d,
J = 8.3 Hz), 6.95 (1H, J = 8.3 Hz), 7.25 - 7.43 (6H, m), 10.59 (1H, s).
4-Methoxy-1,2-benzisothiazole (38). Compound 37 (18.8 g,
72.8 mmol) and thioanisole (18.0 g, 145 mmol) were dissolved in a
mixed solvent of acetonitrile (175 mL) and water (175 mL), and the
solution was stirred at room temperature for 30 min. To the reaction
mixture was added hydroxylamine-O-sulfonic acid (12.4 g, 109 mmol),
and the mixture was stirred at room temperature for 2 h. To the
reaction mixture was added saturated sodium hydrogen carbonate
(400 mL), and the mixture was extracted with EtOAc (500 mL). The
organic layer was washed with water (250 mL) and dried over MgSO4.
The solvent was evaporated in vacuo, and the residue was purified by
silica gel column chromatography (eluent, EtOAc/hexane = 0:10 to
6-(2-Chloro-4-{[5-(2-hydroxyethyl)-5H-pyrrolo[3,2-d]-
pyrimidin-4-yl]amino}phenoxy)-2,3-dihydro-1H-isoindol-1-
one (42a). Yield 71%, colorless crystals, mp 209 °C. 1H NMR
(DMSO-d6) δ 3.82−3.95 (2H, m), 4.34 (2H, s), 4.55 (2H, t, J = 4.4
Hz), 6.30 (1H, br s), 6.52 (1H, d, J = 3.0 Hz), 6.93 (1H, d, J = 2.4 Hz),
7.23−7.35 (2H, m), 7.53−7.71 (3H, m), 7.98 (1H, d, J = 2.4 Hz), 8.35
(1H, s), 8.64 (1H, br s), 9.89 (1H, br s). HRMS (m/z): [M + H]+
calcd for C22H18ClN5O3, 436.117; found, 436.118.
5-(2-Chloro-4-{[5-(2-hydroxyethyl)-5H-pyrrolo[3,2-d]-
pyrimidin-4-yl]amino}phenoxy)-2,3-dihydro-1H-isoindol-1-
1
one (42b). Yield 54%, colorless crystals, mp 210−212 °C. H NMR
(DMSO-d6) δ 3.85−3.90 (2H, m), 4.31 (2H, s), 4.50−4.60 (2H, m),
6.32 (1H, br s), 6.51 (1H, d, J = 3.3 Hz), 7.00−7.10 (2H, m), 7.30
(1H, d, J = 9.0 Hz), 7.60−7.70 (3H, m), 7.95−8.00 (1H, m), 8.34
(1H, s), 8.41 (1H, s), 9.89 (1H, br s). HRMS (m/z): [M + H]+ calcd
for C22H18ClN5O3, 436.117; found, 436.117.
5-(2-Chloro-4-{[5-(2-hydroxyethyl)-5H-pyrrolo[3,2-d]-
pyrimidin-4-yl]amino}phenoxy)-1,3-dihydro-2H-indol-2-one
1
(42c). Yield 45%, pale orange crystals, mp 253−256 °C. H NMR
(DMSO-d6) δ 3.47 (2H, s), 3.86 (2H, t, J = 4.5 Hz), 4.52 (2H, t, J =
4.5 Hz), 6.27 (1H, s), 6.50 (1H, d, J = 3.0 Hz), 6.75−6.80 (2H, m),
6.88 (1H, s), 7.08 (1H, d, J = 8.7 Hz), 7.52 (1H, dd, J = 9.1, 2.7 Hz),
7.65 (1H, d, J = 3.0 Hz), 7.91 (1H, d, J = 2.7 Hz), 8.31 (1H, s), 9.77
(1H, br s), 10.32 (1H, s). Anal. Calcd for C22H18ClN5O3: C, 60.62; H,
4.16; N, 16.07. Found: C, 60.36; H, 4.18; N, 15.94.
1
7:3) to give 38 (10.2 g, 85%) as a white solid. H NMR (CDCl3) δ
4.00 (3H, s), 6.75 (1H, dd, J = 7.4, 0.9 Hz), 7.35 - 7.62 (2H, m), 9.02
(1H, d, J = 0.8 Hz).
6-(2-Chloro-4-{[5-(2-hydroxyethyl)-5H-pyrrolo[3,2-d]-
pyrimidin-4-yl]amino}phenoxy)-1,3-dihydro-2H-indol-2-one
1,2-Benzisothiazol-4-ol (39). A mixture of 38 (22.0 g, 133 mmol)
and pyridine hydrochloride (140 g, 1.21 mol) was stirred at 195 °C for
2 h. After cooling at room temperature, water (1.0 L), 1 N HCl
(12 mL), and EtOAc (1 L) were added to the mixture. After stirring at
room temperature for 2 h, the separated organic layer was washed with
water (500 mL) and brine (200 mL) successively, and the organic
layer was dried over MgSO4. Insoluble MgSO4 was filtered off, and the
filtrate was concentrated in vacuo. The residue was purified by silica gel
column chromatography (eluent, EtOAc/hexane = 0:10 to 10:0) to
give 39 (15.7 g, 78%) as a white solid. 1H NMR (CDCl3) δ 6.08 (1H, s),
6.74 (1H, dd, J = 8.0, 0.6 Hz), 7.38 (1H, t, J = 8.0 Hz), 7.51 (1H, dt, J =
8.0, 0.9 Hz), 9.06 (1H, d, J = 0.9 Hz).
4-(2-Chloro-4-nitrophenoxy)-1,2-benzisothiazole (40). To a
solution of 4 (5.70 g, 32.5 mmol) and 39 (5.40 g, 35.7 mmol) in DMF
(50 mL) was added potassium carbonate (9.40 g, 68.0 mmol), and the
mixture was stirred at room temperature for 24 h. Water (100 mL)
was added to the reaction mixture, and the mixture was extracted with
EtOAc (150 mL). The organic layer was washed with water (250 mL)
and brine (100 mL), and dried over MgSO4. Insoluble MgSO4 was
filtered off, and the filtrate was concentrated under reduced pressure to
give 40 (9.60 g, 96%) as a pale yellow solid. 1H NMR (CDCl3) δ 6.89
(1H, dd, J = 8.0, 0.6 Hz), 7.04 (1H, d, J = 9.1 Hz), 7.53 (1H, t, J = 8.0
Hz), 7.83 (1H, dd, J = 8.0, 0.8 Hz), 8.11 (1H, dd, J = 9.1, 2.6 Hz), 8.46
(1H, d, J = 2.6 Hz), 8.95 (1H, d, J = 0.9 Hz).
1
(42d). Yield 52%, pale orange crystals, mp 256−257 °C. H NMR
(DMSO-d6) δ 3.42 (2H, s), 3.87 (2H, t, J = 4.5 Hz), 4.53 (2H, t, J =
4.5 Hz), 6.29 (1H, br s), 6.31 (1H, d, J = 2.3 Hz), 6.46−6.56 (2H, m),
7.16 (1H, d, J = 8.3 Hz), 7.22 (1H, d, J = 8.7 Hz), 7.58 (1H, dd, J =
8.7, 2.7 Hz), 7.66 (1H, d, J = 3.0 Hz), 7.95 (1H, d, J = 2.7 Hz), 8.34
(1H, s), 9.85 (1H, br s), 10.29 (1H, br s). Anal. Calcd for C22H18ClN5O3:
C, 60.62; H, 4.16; N, 16.07. Found: C, 60.40; H, 4.21; N, 15.97.
4-(2-Chloro-4-{[5-(2-hydroxyethyl)-5H-pyrrolo[3,2-d]-
pyrimidin-4-yl]amino}phenoxy)-2,3-dihydro-1H-isoindol-1-
one (42e). Yield 98%, colorless crystals, mp 280 °C. 1H NMR (DMSO-
d6) δ 3.88 (2H, t, J = 4.5 Hz), 4.35 (2H, s), 4.53 (2H, t, J = 4.5 Hz), 6.32
(1H, br s), 6.51 (1H, d, J = 3.0 Hz), 6.89 (1H, dd, J = 7.0, 1.8 Hz), 7.30
(1H, d, J = 8.7 Hz), 7.39−7.48 (2H, m), 7.60 (1H, dd, J = 8.7, 2.5 Hz),
7.66 (1H, d, J = 3.0 Hz), 7.99 (1H, d, J = 2.5 Hz), 8.34 (1H, s), 8.68
(1H, br s), 9.88 (1H, br s). Anal. Calcd for C22H18ClN5O3 1.2 H2O: C,
57.76; H, 4.49; N, 15.31. Found: C, 57.73; H, 4.55; N, 15.30.
7-(2-Chloro-4-{[5-(2-hydroxyethyl)-5H-pyrrolo[3,2-d]-
pyrimidin-4-yl]amino}phenoxy)-2,3-dihydro-1H-isoindol-1-
one (42f). Yield 36%, pale yellow crystals, mp 264−266 °C. 1H NMR
(DMSO-d6) δ 3.80−3.90 (2H, m), 4.37 (2H, s), 4.50−4.60 (2H, m),
6.30 (1H, br s), 6.50 (1H, d, J = 3.0 Hz), 6.59 (1H, d, J = 9.0 Hz), 7.14
(1H, d, J = 9.0 Hz), 7.20−7.30 (1H, m), 7.48 (1H, t, J = 7.2 Hz),
7.55−7.60 (1H, m), 7.65 (1H, d, J = 3.0 Hz), 7.95−8.00 (1H, m), 8.33
(1H, s), 8.42 (1H, s), 9.84 (1H, br s). HRMS (m/z): [M + H]+ calcd
for C22H18ClN5O3, 436.117. Found, 436.113.
7-(2-Chloro-4-{[5-(2-hydroxyethyl)-5H-pyrrolo[3,2-d]-
pyrimidin-4-yl]amino}phenoxy)-1,3-dihydro-2H-indol-2-one
(42g). Yield 50%, pale pink crystals, mp 244−246 °C. 1H NMR
(DMSO-d6) δ 3.57 (2H, s), 3.87 (2H, t, J = 4.5 Hz), 4.53 (2H, t, J =
4.5 Hz), 6.29 (1H, br s), 6.50 (1H, d, J = 3.2 Hz), 6.54 (1H, dd, J =
8.0, 0.9 Hz), 6.82−6.93 (1H, m), 6.99 (1H, dd, J = 8.0, 0.9 Hz), 7.12
(1H, d, J = 8.9 Hz), 7.54 (1H, dd, J = 8.9, 2.6 Hz), 7.66 (1H, d, J =
3.2 Hz), 7.94 (1H, d, J = 2.6 Hz), 8.32 (1H, s), 9.82 (1H, br s), 10.77
(1H, s). HRMS (m/z): [M + H]+ calcd for C22H18ClN5O3, 436.117.
Found, 436.116.
4-(1,2-Benzisothiazol-4-yloxy)-3-chloroaniline (14m). Com-
pound 40 (9.60 g, 31.3 mmol) and reduced iron (20.0 g, 358 mmol)
were suspended in EtOH (150 mL), and the suspension was heated at
80 °C. To the mixture was added 1 N HCl (5 mL), and the mixture
was refluxed at 80 °C for 5 h. The reaction mixture was allowed
to cool at room temperature. To the mixture was added 1 N NaOH
(15 mL), and the reaction mixture was filtered through a Celite pad.
The filtrate was concentrated under reduced pressure. The residue was
diluted with EtOAc (400 mL), and the mixture was washed with water
(200 mL), saturated sodium hydrogen carbonate (200 mL), 1 N
NaOH (100 mL), and brine (100 mL) successively. The separated
organic layer was dried over MgSO4. The insoluble MgSO4 was filtered
off, and the filtrate was concentrated under reduced pressure to give
4-(2-Chloro-4-{[5-(2-hydroxyethyl)-5H-pyrrolo[3,2-d]-
pyrimidin-4-yl]amino}phenoxy)-1,3-dihydro-2H-indol-2-one
(42h). Yield 27%, colorless crystals, mp 259−261 °C. 1H NMR (DMSO-
d6) δ 3.37 (2H, s), 3.87 (2H, q, J = 4.4 Hz), 4.53 (2H, t, J = 4.3 Hz), 6.26−
6.34 (2H, m), 6.50 (1H, d, J = 3.0 Hz), 6.59 (1H, d, J = 7.4 Hz), 7.13
(1H, t, J = 8.1 Hz), 7.20 (1H, d, J = 8.8 Hz), 7.56 (1H, dd, J = 8.8, 2.6 Hz),
1
14m (8.50 g, 98%) as a pale purple solid. H NMR (CDCl3) δ 3.74
(2H, br s), 6.49 (1H, dd, J = 8.0, 0.6 Hz), 6.62 (1H, dd, J = 8.6, 2.6
Hz), 6.83 (1H, d, J = 2.6 Hz), 7.01 (1H, d, J = 8.6 Hz), 7.35 (1H, t, J =
8.0 Hz), 7.57 (1H, dt, J = 8.0, 0.8 Hz), 9.15 (1H, d, J = 0.9 Hz).
3988
dx.doi.org/10.1021/jm300185p | J. Med. Chem. 2012, 55, 3975−3991