Beta-amyloid protein production/secretion inhibitors
a technology of protein production and secretion, which is applied in the direction of biocide, heterocyclic compound active ingredients, drug compositions, etc., can solve the problems that there is no effective method of treating or preventing this disease, and achieve excellent inhibitory effect against production
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referential example 1
1-(2,5-Difluorophenyl)-1-pentanol
[0208]
[0209] At −78° C. under an argon atmosphere, n-butyl lithium (a 1.52M hexane solution, 14.5 ml, 22.0 mmol) was added dropwise to a solution of 1,4-difluorobenzaldehyde (2.84 g, 20.0 mmol) in tetrahydrofuran (40 ml). While stirring, the temperature of the reaction mixture was raised to −20° C. over 2 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The extracts were combined, washed successively with water and brine, dried over MgSO4, and then concentrated. The residue thus obtained was purified by chromatography on a silica gel column (9% ethyl acetate-hexane), whereby the title compound (2.62 g, 66%) was obtained as a pale yellow oil.
[0210]1H-NMR (400 MHz, CDCl3) δ: 0.90 (3H, t, J=7.3 Hz), 1.28-1.50 (4H, m), 1.70-1.82 (2H, m), 1.91-1.95 (1H, br m), 4.98 (1H, dd, J=11.7, 5.9 Hz), 6.88-7.00 (2H, m), 7.18 (1H, ddd, J=8.8, 5.6, 3.2 Hz).
example 1
2-[1-[(4-Chlorophenyl)thio]pentyl]-1,4-difluorobenzene
[0211]
[0212] At 0° C., 4-chlorobenzenethiol (435 mg, 3.00 mmol), triphenylphosphine (798 mg, 3.00 mmol), and diisopropyl azodicarboxylate (588 μl, 3.00 mmol) were successively added to a solution of 1-(2,5-difluorophenyl)-1-pentanol (300 mg, 1.50 mmol) in methylene chloride (6 ml). The reaction mixture was stirred at room temperature for 15 hours, diluted with methylene chloride, and then washed successively with a 1N aqueous solution of sodium hydroxide and brine. After drying over MgSO4, the mixture was concentrated. The residue thus obtained was purified twice by medium-pressure chromatography on a silica gel column (first time with 1% ethyl acetate-hexane, and second time with hexane), whereby the title compound (266 mg, 54%) was obtained as a colorless oil.
[0213] IR (ATR) ν: 2958, 2931, 1624, 1595, 1574, 1493, 1475, 1425, 1389, 1234, 1215, 1171, 1095, 1012, 874, 814 cm−1.
[0214]1H-NMR (400 MHz, CDCl3) δ: 0.86 (3H, t, J=7.3...
example 2
2-[1-[(4-Chlorophenyl)sulfinyl]pentyl]-1,4-difluorobenzene (Isomer 2-A and Isomer 2-B)
[0219]
[0220] After addition of 3-chloroperbenzoic acid (301 mg, 1.74 mmol) to a solution of 2-[1-[(4-chlorophenyl)thio]pentyl]-1,4-difluorobenzene (515 mg, 1.58 mmol) in methylene chloride (10 ml) at 0° C., the mixture was stirred for 18 hours at room temperature. After further addition of 3-chloroperbenzoic acid (100 mg, 0.578 mmol), the mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with methylene chloride, washed successively with a 1N aqueous solution of sodium hydroxide, water, and brine, dried over MgSO4, and concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (10% ethyl acetate-hexane), whereby the title Isomer 2-A (low-polarity) and the title Isomer 2-B (high-polarity) (230 mg, 43%) were obtained each as a colorless oil. The resulting title Isomer 2-A was then recrystallized from hexane and obt...
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