Substituted benzofurans and benzothiophenes, methods of making and methods of use as integrin antagonists
a technology of benzofura and benzothiophene, which is applied in the field of substitution of benzofurans and benzothiophenes, can solve the problems of increased mortality, incapacitation, and increased bone fractures
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example 1
Synthesis of 3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]thiophen-3-yl)propanoic acid
a) Synthesis of 3-Iodophenyl acetate
[0169] A solution of 3-iodophenol (3 g, 13.6 mmol), acetyl chloride (2.9 ml, 40.9 mmol) and potassium carbonate (9.42 g,68.2 mmol) in N,N-dimethylforrnamide (75 ml) was stirred for 16 h at room temperature. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with 1N NaOH, dried over magnesium sulfate, and evaporated under vacuum. The crude product was chromatographed over silica gel, eluting with 20% ethyl acetate / hexanes to yield 2.3 g (65%) of 3-iodophenyl acetate.
[0170] NMR 1H Cl3CD δ: 7.57 (1H, m), 7.46 (1H, m), 7.08 92H, m) 2.29 (3H, s).
b) Synthesis of 3-[1,1-bis(Methylethyl)-2-methyl-1-silapropylthio]phenyl acetate
[0171] Triisopropylsilanethiol (2.91 ml, 13.5 mmol) was added dropwise to a suspension of sodium hydride (325 mg, 13.5 mmol) in THF (10 ml). After the evolution of hydrogen ceased, a solution of 3-io...
example 2
Synthesis of 3-{6-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-benzo[b]thiophen-3-yl}-propionic acid
a) 7-(2-Hydroxy-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester
[0188] 7-Ethoxycarbonylmethyl-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (synthetic methodology described in WO 00 / 33838) (6.11 g, 19.0 mmol) was dissolved in tetrahydrofuran (40 ml) at room temperature. The solution was place under argon. Lithium borohydride [2M in tetrahydrofuran] (22.8 mmol, 11.43 mL) was carefully added and the reaction was refluxed overnight (16 h). The mixture was poured into a solution of saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated under vacuum to give a crude mixture, which was purified via column chromatography to give 7-(2-hydroxy-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (49% yield). 1H NMR (Cl3CD), δ: 7.30 (d, 1H,...
example 3
Synthesis of 3-(6-{2-[6-(Methylamino)-2-pyridyl]ethoxy}benzo[b]furan-3-yl)propanoic acid
a) Synthesis of 3-[1,1-bis(Methylethyl)-2-methyl-1-silapropoxy]phenyl acetate
[0192] Lithium bis(trimethylsilyl)amide (73 ml, 73 ml, 1M solution in THF) was added dropwise to a solution of resorcinol monoacetate (10 g, 65.7 mmol) in THF (100 ml) at 78° C. under argon. The solution was stirred for 10 minutes and then triisopropylsilyl chloride (15.5 ml, 73 mmol) was added via syringe. After stirring at room temperature overnight, the mixture was partitioned between water and ethyl acetate. The organic layer was dried, filtered and evaporated under vacuum to yield 13 g of crude 3-[1,1-bis(Methylethyl)-2-methyl-1-silapropoxy]phenyl acetate which was used in the next step without further purification. NMR 1H Cl3CD δ: 7.19 (t, 1H, J=8 Hz), 6.75 (m, 1H), 6.68 (m, 1H), 6.63 (t, 1H, J=4 Hz), 2.29 (s, 3H), 1.25 (m, 3H), 1.11 (d, 18H, J=7.0 Hz).
b) Synthesis of 3-[1,1 -bis(Methylethyl)-2-methyl-1-silaprop...
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