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With potassium carbonate; In N,N-dimethyl-formamide; at 25 - 30℃;
A mixture of 3-bromo-1H-pyrazolo[3,4-djpyrimidin-4-amine (Formula III, when X is bromo, 10 g), potassium carbonate (12.9 g), and tert-butyl (3S)-3-[(methylsulfonyl)oxyjpiperidine-1-carboxylate (Formula IV, when Pr? is Boc and Pr2 ismethylsulfonyl, 14.35 g) was added to dimethylformamide (100 mL) at 25°C to 30°C.The reaction mixture was stirred at 120°C for 5 hours to 6 hours. The remaining tert-butyl(3S)-3-[(methylsulfonyl)oxyjpiperidine-1-carboxylate (Formula IV, when Pr? is Boc andPr2 is methylsulfonyl, 6.5 g) was added to the mixture, and then the reaction mixture wasstirred overnight at 120°C, and then cooled to 25°C to 30°C. Water (1.25 L) was added tothe mixture, and the product was extracted with ethyl acetate (2 x 500 mL) at 25°C to3 0°C. Excess ethyl acetate was recovered under vacuum at a temperature not exceeding5 0°C. Hexane (250 mL) was added to the mixture, and the reaction mixture was stirredovernight at 25°C to 3 0°C. A sticky mass was obtained and used as such for the nextreaction.
7.52 g
With potassium carbonate; In dimethyl sulfoxide; at 120℃;
Example 5: Preparation of tert-butyl (3R)-3-(4-amino-3-bromo-lH-pyrazolo[3.4- dlpyrimidin-l-vDpiperidine-l-carboxylate (Formula V. when X is bromine and Pr1 is Boc) A mixture of 3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (Formula III, when X is bromine, Example 2, 10 g), potassium carbonate (12.9 g), and tert-butyl (3S)-3- [(methylsulfonyl)oxy]piperidine-l-carboxylate (Formula IV, when Pr1 is Boc and Pr2 is mesyl, Example 3, 13.7 g) in dimethylsulfoxide (110 mL) was stirred at 120°C for 12 hours. tert-Butyl (3S)-3-[(methylsulfonyl)oxy]piperidine-l-carboxylate (Formula IV, when Pr1 is Boc and Pr2 is mesyl, Example 3, 3 g) was added to the reaction mixture, and the reaction mixture was heated with stirring overnight at 120°C. The reaction mixture was cooled to room temperature, and then water (1 L) was added to it. The product was extracted with ethyl acetate (2 chi 500 mL) at room temperature. The solvent was recovered under vacuum at a temperature not more than 50°C. Hexane (250 mL) was added to the crude product, and then the mixture was stirred overnight at room temperature. The mixture was filtered off, and then dried under vacuum at 50°C for 8 hours to obtain the title compound. Yield: 7.52 g
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;
Synthesis of intermediate 15-b: oc Scheme 15 To a solution of intermediate 1-c' (300 mg, 1.4 mmol), intermediate 29-a (344 mg, 1.6 mmol) and triphenylphosphine (404 mg, 1.5 mmol) in THF cooled to 0°C was added DIAD (300 muIota, 1.5 mmol) dropwise. After the addition was completed, the reaction was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride and ethyl acetate were added, th organic layer was separated, washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. Purification by silica gel chromatography provided intermediate 15-b as yellow solid.
3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 12h;Inert atmosphere;
General procedure: To a mixture of S2 (10 g, 47.0 mmol) and 1,4-dioxane/H2O (150mL, v/v, 5/1) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14.7 g, 70.4mmol), K2CO3 (13.0 g,93.9 mmol), and Pd(PPh3)4 (2.7 g, 2.3 mmol). The reaction mixture was placed into an oil bath preheated to 100 °C, with stirring at this temperature for 12 h under argon. TLC showed the completion of the reactin. The reaction mixture was filtered through a Celitebed, and the filtrate was concentrated and purified by silica gel column chromatography (eluting with 0?10percent MeOH in DCM) to afford S3 as a white solid (8.0 g, 79percent)
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