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With sodium hydroxide; n-butyllithium; carbon dioxide; In tetrahydrofuran; diethyl ether; hexane;
EXAMPLE 1 2,6-difluoro-m-toluic acid Into a flask equipped with stirrer, dropping funnel, carbon dioxide condenser and gas inlet tube are charged 100 g. (0.78 mole) of 2,4-difluoro-toluene and 500 ml. of dry tetrahydrofuran. The system is flushed with dry nitrogen and cooled (carbon dioxide-acetone bath) to an internal temperature of -50C. A 585 ml. solution of 15% n-butyllithium (0.935 mole n-butyl-lithium) in hexane is added dropwise into a flask. The resulting dark red-purple solution is maintained at -50C. for about one hour, and then poured onto a slurry of about 1000 g. of powdered carbon dioxide and about 100 ml. of diethyl ether. After standing for about 20 hours at room temperature the residue is treated with 250 ml. of 2N sodium hydroxide. The caustic layer is washed with toluene, acidified with concentrated HCl, and the white precipitate which forms is recrystallized from hot chloroform to give 2,6-difluoro-m-toluic acid; m.p. 139-140C.
To a 0 "C solution of 2,6-difluoro-3- methylbenzoic acid (10.0 g, 58.1 mrnol, 1.0 equiv) in dry methanol (100 mL) was added dropwise thionyl chloride (4.64 mL, 63.9 mmol, 1.1 equiv). The resulting solution was refluxed overnight. After the reaction mixture was allowed to cool to room temperature, the solvent was removed in vacuo. The product was dissolved in ethyl acetate and washed with aq. satd. NaHCO3. The EtOAc layer was dried over sodium sulfate, filtered and concentrated in vacuo to provide the desired ester (9.35 g, 86%).
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; for 2h;
To a stirred solution of <strong>[32890-88-3]2,6-difluoro-3-methylbenzoic acid</strong> (8.75 mmol, 1.5 g), 2-methylpropan-2-amine (9.43 mmol, 1 mL, 0.690 g) and triethylamine (28.7 mmol, 4 mL, 2.90 g) in dichloromethane (20 mL) was added 1-propanephosphonic acid cyclic anhydride (13.50 mmol, 8 mL, 8.59 g, 50% solution In ethyl acetate). The reaction was stirred for 2 hours before being diluted with dichloromethane and aqueous sodium hydrogen carbonate. The organic layer was separated, dried and concentrated under vacuum to yield the title compound (1.1 g). MS (ESI) m/z 228.4 [M+H]+
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; for 2h;
To a stirred solution of <strong>[32890-88-3]2,6-difluoro-3-methylbenzoic acid</strong> (8.75mmol, 1.5g), 2- methylpropan-2-amine (9.43mmol, 1 mL, 0.69Og) and triethylamine (28.7mmol, 4ml_, 2.9Og) in dichloromethane (2OmL) was added 1-propanephosphonic acid cyclic anhydride (13.50mmol, 8mL, 8.59g, 50% solution in ethyl acetate). The reaction was stirred for 2 hours before being diluted with dichloromethane and aqueous sodium hydrogen carbonate. The organic layer was separated, dried and concentrated under vacuum to yield the title compound (1.1g). MS (ESI) m/z 228.4 [M+H]+
ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate[ No CAS ]
N-(2,6-difluoro-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide[ No CAS ]
ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate[ No CAS ]
ethyl 5-[(2,6-difluoro-3-methylphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 341 mg (1.98 mmol) of 2,6- difluoro-3-methylbenzoic acid [purchased from Aurum Pharmatech EEC] in 8 ml of toluene, 0.39 1 ml (2.24 mmol) of DIPEA and 0.44 ml (2.0 mmol) of DPPA were added at room temperature in an argon atmosphere and reacted at room temperature for 0.5 hours and subsequently at 100 C. for 1 hour with stirring. The reaction solution was cooled, and then, a solution of 500 mg (1.32 mmol) of ethyl 6,6-dimethyl-3-[1 -(trimethylsilyl)cyclobutanecarboxamido] -5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxy-late synthesized in the same way as in Reference Example 3 in 2 ml of toluene was added thereto at room temperature and reacted at room temperature for 2 hours with stirring. 10866] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate=90:10-70:30 (v/v)), and a fraction containing ethyl 5-[(2,6- difluoro-3-methylphenyl)carbamoyl] -6,6-dimethyl-3-[ 1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate was concentrated under reduced pressure.
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