| 26.9 g |
With potassium carbonate; In N,N-dimethyl acetamide; at 100℃; for 10h; |
A suspension solution of 14.6 g of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine synthesized by the method described in WO 2007/126841, 25 g of (S)-tert-butyl 3-(methylsulfonyloxy)piperidine-1-carboxylate obtained in Step 1, and 69 g of potassium carbonate in 150 ml of DMA was heated to 100°C, and was stirred for 10 hours. The suspension solution was cooled to room temperature, and then 300 ml of water was added thereto. A solid thus obtained was collected by filtration and washed with water, and the solid was dried. Thus, 26.9 g of the title compound was obtained as a yellow solid. Physical property value: m/z [M+H]+ 446.2 |
| 13.8 g |
|
A mixture of 3-iodo-1H-pyrazolo[3,4-djpyrimidin-4-amine (Formula III, when X is iodo, 18 g), cesium carbonate (51.8 g), and dimethylaminopyridine (0.88 g) was addedto N-methylpyrrolidinone (400 mL) under nitrogen at room temperature. The temperature of the reaction mixture was raised to 70°C. A solution of tert-butyl (3S)-3- [(methylsulfonyl)oxyjpiperidine-1-carboxylate (Formula IV, when Pr? is Boc and Pr2 is methylsulfonyl, 29 g) in N-methylpyrrolidone (150 mL) was added drop-wise to thesolution over a period of one hour at 70°C. The reaction mixture was stirred overnight at70°C. Water (1.7 L) was added to the reaction mixture, then the mixture was stirred at5°C for 3 hours, and then stirred overnight at room temperature. The yellowish solidproduct was filtered, then washed with water (100 mL). The resulting solid was dried at45°C under vacuum for 9 hours to obtain the title compound.Yield: 13.8g |
| 13.8 g |
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 70℃;Inert atmosphere; |
Example 4: Preparation oftert-butyl (3R)-3-(4-amino-3-iodo-lH-pyrazolor3.4- dlpyrimidin-l-vDpiperidine-l-carboxylate (Formula V. when X is iodine and Pr1 is Boc) A mixture of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (Formula III, when X is iodine, Example 1, 18 g), cesium carbonate (51.8 g), and dimethylaminopyridine (0.88 g) was added to N-methylpyrrolidone (400 mL) under nitrogen at room temperature. The temperature of the reaction mixture was raised to 70°C. A solution of tert-butyl (3S)-3- [(methylsulfonyl)oxy]piperidine-l-carboxylate (Formula IV, when Pr1 is Boc and Pr2 is mesyl, Example 3, 29 g) in N-methylpyrrolidone (150 mL) was added drop-wise over a period of 1 hour at 70°C. The reaction mixture was stirred overnight at 70°C. Water (1.7 L) was added to the reaction mixture, then the mixture was stirred at 5°C for 3 hours, and then stirred overnight at room temperature. The yellowish solid product was filtered, then washed with water (100 mL). The resulting solid was dried at 45 °C under vacuum for 9 hours to obtain the title compound. Yield: 13.8 g |
|
With di-isopropyl azodicarboxylate; triethylphosphine; In tetrahydrofuran; at 5 - 200℃; for 12.5h; |
A solution of diisopropyl azodicarboxylate in tetrahydrofuran (30 mL) was added drop wise tostined solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (Formula III, 5.9 g), (S)-tertbutyl-3-hydroxypiperidine-1-carboxylate (Formula IV, L=H; 10 g), triethylphosphine (11.8 g), and tetrahydrofuran (300 mL) at 5-10 °C over 30 mm. The resulting mixture was stined at room temperature for 12 h and then concentrated under vacuum. The residue was purified on silica gel column then eluted with dichloromethane and methanol (10:1) to give (R)-tert-butyl-3-(4-amino- 3 -iodo- 1 H-pyrazolo[3 ,4-d]pyrimidine- 1 -yl)piperidine- 1 -carboxylate |
| 26.9 g |
With potassium carbonate; In N,N-dimethyl acetamide; at 100℃; for 10h; |
(Step 2) Synthesis of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (0188) A suspension solution of 14.6 g of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine synthesized by the method described in WO 2007/126841, 25 g of (S)-tert-butyl 3-(methylsulfonyloxy)piperidine-1-carboxylate obtained in Step 1, and 69 g of potassium carbonate in 150 mL of DMA was heated to 100° C., and was stirred for 10 hours. The suspension solution was cooled to room temperature, and then 300 mL of water was added thereto. A solid thus obtained was collected by filtration and washed with water, and the solid was dried. Thus, 26.9 g of the title compound was obtained as a yellow solid. |
| 26.9 g |
With potassium carbonate; In N,N-dimethyl acetamide; at 100℃; for 10h; |
(Step 2) Synthesis of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl) piperidine-1-carboxylate 3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (14.6 g) synthesized by the method described in the pamphlet of International Publication No. WO 2007/126841, (S)-tert-butyl 3-(methylsulfonyloxy) piperidine-1-carboxylate (25 g) obtained in (Step 1), and potassium carbonate (69 g) were suspended in DMA (150 mL), and the suspension was heated to 100° C. and stirred for 10 hours. After the mixture was cooled to room temperature, water (300 mL) was added thereto, and the precipitated solid was collected by filtration, washed with water, and then dried to obtain 26.9 g of the title compound as a yellow solid. Physical property value: m/z [M+H]+ 446.2 |
| 26.9 g |
With potassium carbonate; In N,N-dimethyl acetamide; at 100℃; for 10h; |
A suspension solution of 14.6 g of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine synthesized by the method described in WO 2007/126841, 25 g of (S)-tert-butyl 3-(methylsulfonyloxy)piperidine-1-carboxylate obtained in Step 1, and 69 g of potassium carbonate in 150 mL of DMA was heated to 100° C., and was stirred for 10 hours. The suspension solution was cooled to room temperature, and then 300 mL of water was added thereto. A solid thus obtained was collected by filtration and washed with water, and the solid was dried. Thus, 26.9 g of the title compound was obtained as a yellow solid. Physical property value: m/z [M+H]+ 446.2 |
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