Biphenyloxyacetic acid derivatives for the treatment of respiratory disease
A technology of oxygen and phenyl, applied in the field of biphenyloxyacetic acid derivatives for the treatment of respiratory diseases, can solve the problems such as not specifically disclosed
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Embodiment 1
[0178] {[5-chloro-4'-(phenylsulfonyl)biphenyl-2-yl]oxy}acetic acid
[0179]
[0180] (i) 2'-(Benzyloxy)-5'-chlorobiphenyl-4-ylphenyl sulfone
[0181] A solution of 5-chloro-2-(phenylmethoxy)phenyl]-boronic acid (prepared by the method of WO2004089885A1) (0.5 g) in dioxane (20 ml) was treated with 1-bromo-4-(phenylsulfonyl ) benzene (0.57 g) (prepared by the method used in JACS (1952), 74, 394-7) was treated. Sodium carbonate (0.40 g) and palladium (diphenylphosphinoferrocene) dichloride (0.070 g) were added and the mixture was heated to 80° C. for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, dried and evaporated under reduced pressure to give an oil. The oil was purified by silica gel chromatography (eluting with isohexane / ether 2:1) to give the subtitle compound (0.9 g) as a white solid.
[0182] 1 H NMR CDCl 3 : δ8.00-7.92 (4H, m), 7.67-7.49 (5H, m), 7.30-7.19 (7H, m), 7.02-6.95 (1H, d), 5.08 (2H, s).
[0183] (ii) 5-Chloro-4'-(p...
Embodiment 2
[0194] {[3',5-Difluoro-4'-(phenylsulfonyl)biphenyl-2-yl]oxy}acetic acid
[0195]
[0196] (i) 4-bromo-2-fluoro-1-(phenylsulfonyl)benzene
[0197] 4-Bromo-2-fluoro-benzenesulfonyl chloride (2 g), benzene (1.3 ml) and iron(III) chloride (35 mg) were heated in a sealed tube using microwave at 200 watts for 15 sec. After cooling, purification by flash column chromatography (eluent: 20% EtOAc / hexanes) afforded the subtitle compound (1.8 g) as a solid.
[0198] 1 H NMR DMSO-d 6 : δ8.03-7.95 (3H, m), 7.84 (1H, dd), 7.80-7.65 (4H, m).
[0199] (ii) 3',5-difluoro-2-methoxy-4'-(phenylsulfonyl)biphenyl
[0200] To the product of step (i) (0.55g) and 5-fluoro-2-methoxy-phenylboronic acid (0.3g) in toluene (6ml), ethanol (4ml) and 2M Na 2 CO 3 The solution / suspension in (3ml) was added tetrakis(triphenylphosphine)palladium (0.05g). The mixture was heated to 85 °C for 3 h, then concentrated under reduced pressure to give crude material. The residue was suspended in water, e...
Embodiment 3
[0213] (2S)-2-{[3',5-Difluoro-4'-(phenylsulfonyl)biphenyl-2-yl]oxy}propanoic acid
[0214]
[0215] (i) (2S)-tert-butyl 2-{[3',5-difluoro-4'-(phenylsulfonyl)biphenyl-2-yl]oxy}propanoate
[0216] Diisopropyl azodicarboxylate (0.19 ml) was added to the product of Example 2 step (iii) (250 mg), (R)-(+)-tert-butyl lactate (141 mg) and triphenyl Phosphine (252mg) in tetrahydrofuran (10ml). After 20 minutes the ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then absorbed onto silica gel and purified by flash column chromatography (10% ethyl acetate / hexanes as eluent) to give the subtitle compound (140 mg) as an oil.
[0217] 1 H NMR DMSO-d 6 : δ8.09(1H, t), 8.00(2H, m), 7.81-7.66(5H, m), 7.34(1H, m), 7.24(1H, m), 7.02(1H, m), 4.91(1H , q), 1.40 (3H, d), 1.34 (9H, s).
[0218] (ii) (2S)-2-{[3',5-difluoro-4'-(phenylsulfonyl)biphenyl-2-yl]oxy}propanoic acid
[0219] The title compound was prepared by the...
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