Heterocyclic compounds as agonists for the thyroid receptor
A technology of compounds, solvates, applied in the field of heterocyclic compounds as thyroid receptor agonists
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[0493] The following compounds illustrate compounds of the invention or, if appropriate, compounds for use in the invention.
[0494] general experimental conditions
[0495] Compounds were analyzed on HPLC-MS with alternating + / - API and equipped with different brands of 50mm*2.1mm, 5μ C8 columns. Elute with 0.05% formic acid / acetonitrile or 0.05% ammonium acetate / acetonitrile.
[0496] Calculated MW is the average of the isotopes and "observed" represents the most abundant isotope detected in LC-MS.
[0497] Intermediate 1
[0498] Methyl 3-[4-(4-aminophenoxy)-3,5-dibromophenyl]propionate
[0499]
[0500] p-Fluoronitrobenzene (210 mg, 1.5 mmol), methyl 3-(4-hydroxy-3,5-dibromophenyl)propionate (500 mg, 1.5 mmol) and potassium carbonate (410 mg, 3 mmol) were purged with nitrogen Solution in dimethylsulfoxide (3ml) and heated at 130°C for 17h. The mixture was diluted with ethyl acetate and washed with sodium bicarbonate (sat), water and brine. The combined organic ph...
Embodiment 29～30
[0538] The preparation of embodiment 29~30
[0539] Dissolve ethyl {3,5-dibromo-4-[(2,4-dichloroquinolin-6-yl)oxy]phenoxy}acetate in methanol (0.5 mL), and add sodium methoxide (100 mg ). The mixture was stirred overnight at reflux in a closed valve. The crude product was purified by semi-preparative HPLC (Zorbax CombiHT (SB-C8) mobile phase: solvent A: water with 0.5% formic acid; 5 solvent B: acetonitrile. Gradient: 80% of A to 5% of A) to give { 3,5-dibromo-4-[(2,4-dimethoxyquinolin-6-yl)oxy]phenoxy}acetic acid and {3,5-dibromo-4-[(4-chloro -2-methoxyquinolin-6-yl)oxy]phenoxy}acetic acid.
[0540] General Procedure B for the Preparation of Examples 31-33
[0541] Potassium carbonate (3 equiv), a suitable quinoline (1 equiv) (eg 6-hydroxy-quinoline) (commercially available or prepared from p-aminophenol) and a suitable iodobenzene (eg 3, A stirred mixture of 5-dibromo-4-iodo-nitrobenzene) (1 equiv) in dimethylformamide (14 mL / mmol) was heated for 18 h. After diluting wi...
Embodiment 34
[0547] ({3,5-Dibromo-4-[(4-methyl-2-propylquinolin-6-yl)methyl]benzyl}oxy)acetic acid
[0548]
[0549] Lithium diisopropylamide (1.2 mL, 1.2 mmol, 1 M) was added to a solution of 1,3-dibromo-5-methyl-benzene (0.25 g, 1 mmol) in THF (2 mL) at -78 °C , the mixture was stirred for 30 minutes. Add p-nitrobenzyl chloride (0.26 g, 1.2 mmol) in tetrahydrofuran (1 mL). The reaction was stirred for 16 h and allowed to come to room temperature. Water and diethyl ether were added and the mixture was extracted with diethyl ether (3 x 10 mL). The organic phase was collected and dried. The solvent was evaporated and the product was purified by flash chromatography (diethyl ether / heptane 1:3) to give 0.15 g (40% yield) of pure 1,3-dibromo-5-methyl-2-(4 -nitrobenzyl)-benzene.
[0550] Add N-bromosuccinimide (23 mg, 0.13 mmol) to 1,3-dibromo-5-methyl-2-(4-nitro-benzyl)-benzene (50 mg, 0.13 mmol) in tetrahydrofuran (2 mL) in the mixture. The mixture was stirred at reflux for 1 h. Fi...
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