Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
a technology of glucocorticoid mimetics and ligands, applied in the field of glucocorticoid mimetics or ligands, can solve the problems of increased transcription rate, severe and life-threatening, and number of adverse side effects
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example 1
Synthesis of 2-methylpropane-2-sulfinic acid [3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-trifluoromethylbut-(Z)-ylidene]-amide (Methods A and B)
[0284]
[0285] To a mixture of 8.5 g (49.9 mmol) of ethyl trifluoromethylpyruvate, 6.6 g (120 mmol) of manganese, and 0.65 g (4.8 mmol) of zinc chloride in 40 mL of THF warmed at reflux, was added 200 microL (2 mmol) of 1-bromo-2-methylpropene. After 30 min, 9.13 mL (90.5 mmol) of 1-bromo-2-methylpropene in 30 mL of THF was added dropwise over a 1 hour period. The mixture was refluxed for 1 hour after the addition, and was then cooled to 0° C. and diluted with 150 mL of saturated aqueous ammonium chloride and 100 mL of EtOAc. The organic phase was separated and the aqueous layer extracted with three 100 mL portions of EtOAc. The combined organic layers were washed with two 50 mL portions of saturated aqueous ammonium chloride, two 50 mL portions of brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuo. The crude residu...
example 2
Synthesis of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentanoic acid ethyl ester (Method C)
[0291]
[0292] To a room temperature solution of 45 mL (22.5 mmol) of a 0.5 M solution of 2-methyl-2-phenylpropylmagnesium chloride in diethyl ether was added 38 g (22.5 mmol) of ethyl trifluoropyruvate in 10 mL of anhydrous THF. The reaction became slightly warm to the touch and a white precipitate quickly developed. After 2 hours, the reaction was diluted with diethyl ether and quenched with 1 N aqueous HCl. The aqueous layer was separated and extracted with ether. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a brown oil. Chromatography on silica gel eluting with hexanes-EtOAc (98:2), afforded the title compound as a clear, colorless oil (4.6 g, 67%).
[0293] This intermediate may then be used as described in Example 1 and Scheme I of the General Synthetic Methods section to produce compounds of the invention.
example 3
Synthesis of 1,1,1-trifluoro-4-(4-fluorophenyl)-4-methylpentan-2-one (Method D)
[0294]
[0295] To a mixture of 15.8 g of N,O-dimethylhydroxylamine hydrochloride and 21.7 mL of trifluoroacetic anhydride in 400 mL of CH2Cl2 was added 37 mL of pyridine dropwise at 0° C. The resulting mixture was allowed to stir at 0° C. for 30 min and then quenched with water. The organic layer was washed with water, 1 N HCl, water, and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residual colorless oil was placed under vacuum for 5 min, providing 2,2,2-trifluoro-N-methoxy-N-methylacetamide which was used for the next reaction without further purification.
[0296] A mixture of 3 g of the above 2,2,2-trifluoro-N-methoxy-N-methylacetamide in 30 mL of anhydrous ether was cooled to 0° C. and treated with 42 mL of 0.5 M solution of 2-methylpropenylmagnesium bromide in THF. The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to room temperature. The res...
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