December 2007
1687
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2.38 (3H, s), 2.39 (3H, s), 2.47 (1H, dd, Jꢀ9.3, 16.0 Hz), 2.85 (1H, dd, 33b (0.37 g, 71%). mp 125.5—126.5 °C; ESI-MS m/z: 325.4 [MꢄH]ꢄ; H-
Jꢀ3.4, 16.0 Hz), 3.21—3.32 (2H, m), 3.62—3.75 (2H, m), 5.84—5.88 (1H, NMR (CDCl3) d: 1.19 (3H, t, Jꢀ7.3 Hz), 2.37 (3H, s), 2.39 (3H, s), 2.54
m), 7.40 (1H, s), 7.61 (1H, dd, Jꢀ8.2, 8.2 Hz), 7.69 (1H, s), 7.99 (1H, dd, (1H, dd, Jꢀ8.1, 16.1 Hz), 2.91 (1H, dd, Jꢀ3.9, 16.1 Hz), 4.06—4.12 (2H,
Jꢀ8.2, 8.2 Hz), 7.97—8.07 (2H, m), 8.65 (1H, dd, Jꢀ2.1, 2.1 Hz).
m), 5.56—5.59 (1H, m), 7.31 (1H, s), 7.40 (1H, dd, Jꢀ4.9, 8.3 Hz), 7.69
14: mp 145—146 °C (hydrochloride salt); ESI-MS m/z: 414.2 [MꢄH]ꢄ; (1H, s), 8.08—8.11 (1H, m), 8.48 (1H, dd, Jꢀ1.4, 4.6 Hz), 8.78 (1H, d,
1H-NMR (CDCl3) d: 2.23—2.26 (2H, m), 2.28 (3H, s), 2.36 (3H, s), 2.37 Jꢀ2.7 Hz).
(3H, s), 2.40—2.44 (3H, m), 2.93 (1H, dd, Jꢀ2.6, 16.0 Hz), 3.22—3.34 (2H,
m), 3.66—3.79 (2H, m), 5.70—5.73 (1H, m), 6.62—6.67 (1H, m), 7.31— 1-yl]acetate (16) Using 5,6-dimethyl-2-benzofuran-1,3-dione 30 and 4-
7.36 (2H, m), 7.38 (1H, s), 7.67 (1H, s). aminopyridine, it was obtained in a similar manner as that for 33b. mp
22: mp 137—138 °C (hydrochloride salt); ESI-MS m/z: 406.2 [MꢄH]ꢄ; 140—144.5 °C; ESI-MS m/z: 325.2 [MꢄH]ꢄ; 1H-NMR (CDCl3) d: 1.24
(3H, t, Jꢀ7.1 Hz), 2.37 (3H, s), 2.39 (3H, s), 2.51 (1H, dd, Jꢀ9.0, 16.0 Hz),
Ethyl 2-[5,6-Dimethyl-3-oxo-2-(4-pyridinyl)-2,3-dihydro-1H-isoindol-
1H-NMR (CDCl3) d: 0.89 (3H, t, Jꢀ7.3 Hz), 1.49 (2H, sext, Jꢀ7.3 Hz),
2.22—2.46 (7H, m), 2.36 (3H, s), 2.37 (3H, s), 2.87 (1H, dd, Jꢀ3.4, 3.05 (1H, dd, Jꢀ3.2, 16.0 Hz), 4.11—4.24 (2H, m), 5.54—5.57 (1H, m),
16.0 Hz), 3.17—3.34 (2H, m), 3.60—3.78 (2H, m), 5.78—5.82 (1H, m), 7.29 (1H, s), 7.68—7.69 (3H, m), 8.63 (2H, d, Jꢀ6.1 Hz).
7.19—7.23 (1H, m), 7.37 (1H, s), 7.42—7.46 (2H, m), 7.64—7.68 (3H, m).
In Chart 1, when R1 is 3-pyridinyl, the carboxylic acid 34 is 34b.
2-[5,6-Dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-
1
23: mp 79—84 °C; ESI-MS m/z: 406.3 [MꢄH]ꢄ; H-NMR (CDCl3) d:
1.00 (6H, d, Jꢀ6.5 Hz), 2.29—2.32 (2H, m), 2.36 (3H, s), 2.37 (3H, s), yl]acetic Acid (34b) A solution of 33b (0.20 g, 0.59 mmol) in MeOH
2.38—2.43 (1H, m), 2.46—2.49 (2H, m), 2.67 (1H, sept, Jꢀ6.5 Hz), 2.87
(1.5 ml) and 15% aqueous K2CO3 (0.46 ml) was stirred at 75 °C for 4 h. The
(1H, dd, Jꢀ3.6, 16.0 Hz), 3.17—3.30 (2H, m), 3.61—3.73 (2H, m), 5.79— reaction mixture was concentrated under reduced pressure and H2O was
5.82 (1H, m), 7.19—7.25 (1H, m), 7.38 (1H, s), 7.42—7.46 (2H, m), 7.64— added to the residue before the mixture was extracted with diethyl ether. The
7.68 (3H, m).
aqueous layer was acidified with concentrated hydrochloric acid and the re-
24: mp 112.5—119 °C (hydrochloride salt); ESI-MS m/z: 466.2 [MꢄH]ꢄ; sulting precipitate was collected by filtration, washed with water, and dried
1H-NMR (CDCl3) d: 0.83 (6H, t, Jꢀ7.3 Hz), 1.22—1.41 (5H, m), 2.11— to afford 34b (0.12 g, 69%). 1H-NMR (DMSO-d6) d: 2.34 (3H, s), 2.36 (3H,
2.21 (4H, m), 2.36—2.42 (9H, m), 2.90 (1H, dd, Jꢀ3.3, 16.0 Hz), 3.19— s), 2.61 (1H, dd, Jꢀ6.8, 16.4 Hz), 2.86 (1H, dd, Jꢀ4.2, 16.4 Hz), 5.67—5.70
3.28 (2H, m), 3.62—3.74 (2H, m), 5.76—5.79 (1H, m), 6.88—6.93 (1H, m), (1H, m), 7.49—7.63 (3H, m), 8.00—8.03 (1H, m), 8.44 (1H, dd, Jꢀ1.5,
7.37—7.42 (3H, m), 7.59—7.63 (1H, m), 7.67 (1H, s).
4.6 Hz), 8.84 (1H, d, Jꢀ2.2 Hz), 12.34 (1H, br s).
Propyl 2-[5,6-Dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-
25: mp 142.5—144 °C (hydrochloride salt); ESI-MS m/z: 464.3 [MꢄH]ꢄ;
1H-NMR (CDCl3) d: 1.01—1.30 (5H, m), 1.60—1.63 (1H, m), 1.77—1.80 1-yl]acetate (18) 34b (74 mg, 0.25 mmol), 1-propanol (16 mg, 0.27
(4H, m), 2.22—2.27 (1H, m), 2.36 (6H, s), 2.36—2.43 (3H, m), 2.49—2.58 mmol), and 4-dimethylaminopyridine (3 mg, 0.025 mmol) were dissolved
(2H, m), 2.89 (1H, dd, Jꢀ3.7, 16.0 Hz), 3.17—3.29 (2H, m), 3.62—3.73 in dichloromethane, and at 5 °C, N-(3-dimethylaminopropyl)-Nꢁ-ethyl-
(2H, m), 5.75—5.79 (1H, m), 6.87—6.94 (1H, m), 7.37—7.42 (3H, m), carbodiimide hydrochloride (53 mg, 0.27 mmol) was added then the solution
7.58—7.63 (1H, m), 7.67 (1H, s).
was warmed to 25 °C over 1.5 h. The reaction mixture was concentrated
under reduced pressure and H2O was added to the residue, which was then
26: mp 135—142 °C (hydrochloride salt); ESI-MS m/z: 478.2 [MꢄH]ꢄ;
1H-NMR (CDCl3) d: 1.33—1.88 (12H, m), 2.25—2.60 (6H, m), 2.36 (3H, extracted with EtOAc. The organic layer was washed with saturated aqueous
s), 2.37 (3H, s), 2.90 (1H, dd, Jꢀ3.2, 16.0 Hz), 3.23 (2H, br s), 3.67 (2H,
br s), 5.75—5.78 (1H, m), 6.88—6.93 (1H, m), 7.35—7.42 (3H, m), 7.60 under reduced pressure to afford 18 (34 mg, 40%). mp 123—127 °C; ESI-
(1H, d, Jꢀ10.8 Hz), 7.67 (1H, s).
MS m/z: 339.2 [MꢄH]ꢄ; 1H-NMR (CDCl3) d: 0.88 (3H, t, Jꢀ7.6 Hz),
Using 43a, 43b, and 43c, compounds 27, 28, and 29, respectively, were 1.53—1.62 (2H, m), 2.37 (3H, s), 2.39 (3H, s), 2.55 (1H, dd, Jꢀ8.2,
NaHCO3 and water, then dried over anhydrous Na2SO4 and concentrated
obtained in a similar manner as that for 5.
16.0 Hz), 2.93 (1H, dd, Jꢀ4.1, 16.1 Hz), 3.96—4.04 (2H, m), 5.57—5.60
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27: mp 182—184 °C; ESI-MS m/z: 408.2 [MꢄH]ꢄ; H-NMR (CDCl3) d: (1H, m), 7.30 (1H, s), 7.39 (1H, dd, Jꢀ4.9, 8.3 Hz), 7.69 (1H, s), 8.09—8.12
2.14 (2H, quin, Jꢀ7.5 Hz), 2.21—2.26 (5H, m), 2.37—2.45 (3H, m), 2.96 (1H, m), 8.48 (1H, dd, Jꢀ1.3, 4.9 Hz), 8.79 (1H, d, Jꢀ2.4 Hz).
(1H, dd, Jꢀ3.3, 16.0 Hz), 2.98 (4H, t, Jꢀ7.5 Hz), 3.21—3.31 (2H, m),
Methyl 2-[5,6-Dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoin-
3.64—3.74 (2H, m), 5.76—5.79 (1H, m), 6.87—6.92 (1H, m), 7.35—7.41 dol-1-yl]acetate (17) Using 34b and methanol, it was obtained in a similar
(2H, m), 7.44 (1H, s), 7.59 (1H, dt, Jꢀ10.9, 2.0 Hz), 7.71 (1H, s).
manner as that for 18. mp 162.5—169.5 °C (hydrochloride salt); ESI-MS
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1
28: mp 172—175 °C; ESI-MS m/z: 422.2 [MꢄH]ꢄ; H-NMR (CDCl3) d: m/z: 311.2 [MꢄH]ꢄ; H-NMR (CDCl3) d: 2.37 (3H, s), 2.39 (3H, s), 2.55
1.82—1.84 (4H, m), 2.19—2.27 (5H, m), 2.34—2.45 (3H, m), 2.87—2.93 (1H, dd, Jꢀ8.3, 16.4 Hz), 2.92 (1H, dd, Jꢀ4.2, 16.4 Hz), 3.65 (3H, s),
(5H, m), 3.20—3.31 (2H, m), 3.63—3.76 (2H, m), 5.75—5.78 (1H, m), 5.56—5.59 (1H, m), 7.29 (1H, s), 7.40 (1H, dd, Jꢀ4.6, 8.3 Hz), 7.69 (1H, s),
6.87—6.92 (1H, m), 7.29 (1H, s), 7.35—7.41 (2H, m), 7.58—7.61 (1H, m), 8.06—8.11 (1H, m), 8.48 (1H, dd, Jꢀ1.3, 4.6 Hz), 8.79 (1H, d, Jꢀ2.7 Hz).
7.59 (1H, s).
29: mp 185—187 °C; ESI-MS m/z: 410.2 [MꢄH]ꢄ; H-NMR (CDCl3) d: 32b (150 mg, 0.59 mmol) and acetylmethylene triphenylphosphorane
2.24—2.28 (5H, m), 2.39—2.45 (3H, m), 2.95 (1H, dd, Jꢀ3.1, 16.2 Hz), (188 mg, 0.59 mmol) in toluene (12 ml) were heated under reflux for 24 h
5,6-Dimethyl-3-(2-oxopropyl)-2-(3-pyridinyl)isoindolin-1-one
(19)
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3.22—3.31 (2H, m), 3.69—3.71 (2H, m), 5.17 (4H, s), 5.81—5.84 (1H, m), under an argon atmosphere and the reaction mixture was then concentrated
6.93 (1H, td, Jꢀ7.8, 2.4 Hz), 7.35—7.44 (2H, m), 7.52 (1H, s), 7.58 (1H, dt, under reduced pressure. The resulting residue was chromatographed on a sil-
Jꢀ10.6, 2.3 Hz), 7.74 (1H, s).
In Chart 1, when R1 is 3-pyridinyl, the hemiacetal 32 is 32b.
3-Hydroxy-5,6-dimethyl-2-(3-pyridinyl)isoindolin-1-one (32b) 5,6-
ica gel column (CHCl3/MeOHꢀ25/1) to give 19 (20 mg, 12%). mp 141.5—
144 °C; ESI-MS m/z: 295.2 [MꢄH]ꢄ; 1H-NMR (CDCl3) d: 2.14 (3H, s),
2.37 (6H, s), 2.64 (1H, dd, Jꢀ9.5, 16.0 Hz), 3.04 (1H, dd, Jꢀ2.9, 16.0 Hz),
Dimethyl-2-benzofuran-1,3-dione 30 (2.0 g, 11 mmol) and 3-aminopyridine 5.68—5.71 (1H, m), 7.24 (1H, s), 7.39 (1H, dd, Jꢀ4.6, 8.3 Hz), 7.68 (1H, s),
(1.0 g, 11 mmol) in CH3COOH (30 ml) were heated under reflux for 1.5 h.
After cooling, H2O was added and the precipitate was collected by filtration,
8.10—8.13 (1H, m), 8.47 (1H, d, Jꢀ4.1 Hz), 8.77 (1H, d, Jꢀ1.7 Hz).
2-[5,6-Dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-
washed with water, and dried to afford 5,6-dimethyl-2-(3-pyridinyl)-1H- yl]ethyl Methanesulfonate (42) To a solution of 33b (8.4 g, 26 mmol) in
isoindole-1,3(2H)-dione 31b (2.3 g, 83%). The obtained 31b (0.5 g, MeOH (250 ml), NaBH4 (11 g, 0.52 mol) was added portionwise, followed
2.0 mmol) was suspended in MeOH (10 ml) and tetrahydrofuran (10 ml), and by stirring at 80 °C for 3 h. Ice-water was added to the reaction mixture and
under ice-cooling NaBH4 (75 mg, 2.0 mmol) was added portionwise then the resulting precipitate was collected by filtration, washed with water, and
stirred at the same temperature for 30 min. To the reaction mixture, H2O was dried to afford 3-(2-hydroxyethyl)-5,6-dimethyl-2-(3-pyridinyl)isoindolin-1-
added then the precipitate was collected by filtration, washed with water, and one 41 (6.0 g, 82%). After the obtained 41 (5.5 g, 20 mmol) was dissolved in
1
dried to afford 32b (0.4 g, 79%). H-NMR (CDCl3) d: 2.39 (3H, s), 2.42 dichloromethane (140 ml), triethylamine (5.4 ml, 29 mmol) and methanesul-
(3H, s), 6.36 (1H, s), 7.43 (2H, dd, Jꢀ4.6, 8.2 Hz), 7.45 (1H, s), 7.62 (1H, fonyl chloride (2.4 ml, 21 mmol) were added to it and the mixture was
s), 8.28—8.31 (1H, m), 8.36 (1H, d, Jꢀ3.6 Hz), 8.97 (1H, d, Jꢀ2.0 Hz).
In Chart 1, when R1 is 3-pyridinyl, the ethyl ester 33 is 33b.
stirred at 25 °C for 2 h then concentrated under reduced pressure. The result-
ing residue was chromatographed on a silica gel column (CHCl3/MeOHꢀ
Ethyl 2-[5,6-Dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol- 20/1) to give 42 (5.5 g, 76%). 1H-NMR (CDCl3) d: 2.31—2.50 (2H, m),
1-yl]acetate (33b) A solution of 32b (0.4 g, 1.6 mmol) and ethyl 2-(tri- 2.38 (3H, s), 2.42 (3H, s), 2.80 (3H, s), 3.88—3.94 (1H, m), 4.02—4.08
phenylphosphoranylidene)acetate (0.66 g, 1.9 mmol) in toluene (10 ml) was (1H, m), 5.41—5.43 (1H, m), 7.33 (1H, s), 7.42 (1H, dd, Jꢀ4.6, 8.3 Hz),
heated under reflux for 4 h under an argon atmosphere and the reaction mix-
ture was then concentrated under reduced pressure. The resulting residue
7.71 (1H, s), 8.14 (1H, d, Jꢀ8.3 Hz), 8.49 (1H, d, Jꢀ4.8 Hz), 8.80 (1H, s).
3-(2-Ethoxyethyl)-5,6-dimethyl-2-(3-pyridinyl)isoindolin-1-one (21)
was chromatographed on a silica gel column (CHCl3/acetoneꢀ5/1) to give NaOEt (38 mg, 0.55 mmol) and 42 (100 mg, 0.28 mmol) in EtOH (15 ml)