Novel estrogen receptor ligands
A halogen and alkyl technology, applied in the field of new estrogen receptor ligands, can solve the problem of undisclosed compound biological activity and so on
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Embodiment 1
[0194] 2-(4-Hydroxy-phenyl)-7-methyl-3-phenyl-benzofuran-5-ol (E1)
[0195] plan 1
[0196]
[0197] (a) NaOAc, Ac 2 O; (b)Br 2 , CHCl 3 ; (c) KOH, EtOH; (d) PhB(OH) 2 , Pd(OAc) 2 , 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, K 2 CO 3 , toluene
[0198] (a) 2-(4-Acetoxy-phenyl)-7-methyl-benzofuran-5-yl acetate
[0199] 2-(4-Hydroxy-phenyl)-7-methyl-benzofuran-5-ol (prepared according to WO03 / 51860; 16 mg, 0.067 mmol) and sodium acetate (8 mg, 0.13 mmol) were mixed with acetic anhydride (1 mL ) were mixed and stirred overnight at room temperature. Methanol (1 mL) was added, and the mixture was stirred for 30 min, then saturated aqueous sodium bicarbonate (3 mL) was added and washed with CH 2 Cl 2 The mixture was extracted and filtered through an isolute phase separator. Evaporation of the organic phase gave the title compound in quantitative yield.
[0200] (b) 2-(4-Acetoxy-phenyl)-3-bromo-7-methyl-benzofuran-5-yl acetate
[0201] 2-(4-Acetoxy-phenyl...
Embodiment 2
[0206] Example 2: 5-Hydroxy-2-(4-hydroxy-phenyl)-3-phenyl-benzofuran-7-carbonitrile (E2)
[0207] Scenario 2
[0208]
[0209] (a)Br 2 , CHCl 3 ; (b) 1,8-diazabicyclo[5.4.0]undec-7-ene, CH 3 I, acetone; (c) 1-ethynyl-4-methoxybenzene, X-Phos, Pd(AcCN) 2 Cl 2 , Cs 2 CO 3 , EtCN; (d) I 2 , CH 2 Cl 2 ;(e) PhB(OH) 2 , 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, Pd(OAc) 2 , K 2 CO 3 , toluene, ethanol; (f)BBr 3 , CH 2 Cl 2 ;
[0210] (a) 3-Bromo-2-hydroxy-5-methoxy-benzonitrile
[0211] To ice-cooled 2-hydroxy-5-methoxy-benzonitrile (1.00 g, 6.71 mmol) in CHCl over a period of 30 minutes 3 (50 mL) was added dropwise bromine (345 μL, 6.71 mmol) in CHCl 3 (50 mL), and the mixture was further stirred at 0°C for 30 minutes. The mixture was washed with excess aqueous sodium bisulfite until the orange-yellow bromine color faded, then filtered through a phase separator. Evaporation of the organic phase gave 1.53 g (100%) of the title compound.
[0212] ...
Embodiment 3
[0222] Example 3: 2-(2-Fluoro-4-hydroxy-phenyl)-7-methyl-3-phenyl-benzofuran-5-ol (E3)
[0223] Option 3
[0224]
[0225] (a) 1. EtOCOCl, Et 3 N,THF2.NaBH4(aq); (b) Trimethylsilylacetylene, X-Phos, Pd(AcCN) 2 Cl 2 , Cs 2 CO 3 , EtCN; (c) tetrabutylammonium fluoride, THF; (d) 4-bromo-3-fluoroanisole, X-Phos, Pd(AcCN) 2 Cl 2 , Cs 2 CO 3 , EtCN
[0226] Ex.: Example
[0227] (a) 4-methoxy-2-methyl-phenol
[0228] The title compound was obtained from 2-hydroxy-5-methoxy-benzaldehyde using the method described in Chem Pharm Bull 27(6), 1979, pages 1490-1494: ethyl chloroformate (571 μL, 6.0mmol) was added dropwise to an ice-cooled solution of 2-hydroxy-5-methoxy-benzaldehyde (624 μL, 5.0mmol) and triethylamine (832 μL, 6.0mmol) in THF (5mL), and heated at °C The mixture was stirred for an additional 30 minutes. The precipitate was filtered off and the filtrate was added dropwise to ice-cold NaBH over a period of 45 min 4 (756 mg, 20 mmol) in solution in water (7.5...
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