ethyl 4-bromo-2,2-dimethylbutanoate

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-1H-indazole (commercially available from Insight Chemical Solutions Ltd., 826 mg, 4.19 mmol) in DMF (10 ml) at room temperature were added Cs2CO3 (1.37 g, 4.19 mmol) and ethyl 4-bromo-2,2-dimethylbutanoate (D99) (1.40 g, 6.29 mmol) and the resulting mixture was stirred at 80° C. for 24 h then cooled to room temperature and diluted with AcOEt. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [15-25% EtOAc/cyclohexane] gave the title compound (600 mg, 40%) as orange oil. MS (ES) C15H1981BrN2O2 requires 340, found 341 [M+H]+ then cooled to room temperature The organic phase was washed with water dried over MgSO4 concentrated in vacuo Purification of the residue by flash chromatography on silica gel [15-25% EtOAc/cyclohexane]

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hydrogen bromide was bubbled through 3,3-dimethyldihydro-2(3H)-furanone (1 g, 8.76 mmol) at room temperature for ca. 5 h and the resulting mixture was left at room temperature overnight. Nitrogen was then bubbled through the mixture. The crude acid was dissolved in DCM (10 ml) and treated with oxalyl chloride (2.3 ml, 26.3 mmol) and DMF (1 drop) and the resulting mixture was stirred at room temperature over the weekend then concentrated in vacuo. The residue was treated with ethanol (10 ml) and the resulting mixture stirred at room temperature for 1 hour then poured into water. The aqueous phase was extracted twice with diethyl ether and the ethereal solution was washed with brine, dried and concentrated in vacuo to give the title compound (949 mg, 49%) as a very pale yellow oil which was used in the next step without further purification. Nitrogen was then bubbled through the mixture The crude acid was dissolved in DCM (10 ml) then concentrated in vacuo The residue was treated with ethanol (10 ml) the resulting mixture stirred at room temperature for 1 hour then poured into water The aqueous phase was extracted twice with diethyl ether the ethereal solution was washed with brine dried concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 4-[(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]-2,2-dimethylbutanoate was prepared following the procedure for N-(4-chlorophenyl)-N-{(2S,4R)-1-[(1-isopropyl-1H-pyrazol-4-yl)carbonyl]-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl}acetamide, substituting ethyl 4-{[5-(chlorocarbonyl)isoxazol-3-yl]oxy}-2,2-dimethylbutanoate for 1-isopropyl-1H-pyrazole-4-carbonyl chloride. (Ethyl 4-{[5-(chlorocarbonyl)isoxazol-3-yl]oxy}-2,2-dimethylbutanoate was prepared in three steps from methyl 3-hydroxy 5-isoxazole carboxylate. Methyl 3-hydroxy 5-isoxazole carboxylate (1.00 g, 6.94 mmol) was alkylated using ethyl 4-bromo-2,2-dimethylbutanoate (1.59 g, 7.63 mmol) in the presence of potassium carbonate (1.05 g, 7.64 mmol) and catalytic potassium iodide in DMF (5.00 mL) at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified on silica gel by flash chromatography using hexane/ethyl acetate (10-50% gradient) to afford methyl 3-(4-ethoxy-3,3-dimethyl-4-oxobutoxy)isoxazole-5-carboxylate in 35% yield. Selective hydrolysis of the methyl ester by subsequent treatment with lithium hydroxide (aq) (1.50 equiv.) in methanol at room temperature afforded 3-(4-ethoxy-3,3-dimethyl-4-oxobutoxy)isoxazole-5-carboxylic acid which was then treated with oxalyl chloride and catalytic DMF in dichloromethane to yield the desired ethyl 4-{[5-(chlorocarbonyl)isoxazol-3-yl]oxy}-2,2-dimethylbutanoate). at room temperature overnight the mixture was extracted with ethyl acetate The organics were washed with brine dried over anhydrous sodium sulfate filtered concentrated in vacuo purified on silica gel by flash chromatography