反应详情

4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenylamine (7.96 g) from the previous step was reacted in 0.5 g portions. Into a 50 mL round-bottomed flask with stopper and magnetic stir bar was added amine (0.5 g) and methylene chloride (7.5 mL). With good stirring Et3N (0.5 mL) was added, followed by a clear, colorless solution of triphosgene (0.22 g) in methylene chloride (2.5 mL). After 1 min at room temperature, an aliquot of the reaction mixture was diluted in MeOH to form the methyl carbamate. Analysis by HPLC indicated methyl carbamate peak with a retention time of 2.315 min (91%) and an amine starting material peak with a retention time of 1.650 (1.9%). After 8 min total reaction time ethylene glycol (1.38 mL) was added at once. The cloudy solution turned into a clear, yellow solution. Stirring at room temperature continued for 75 min, at which time HPLC analysis indicates a new peak with a retention time of 2.032 min (88%). The 32 0.5 g runs were combined and the combined product was divided into two portions. Each portion was diluted with methylene chloride (400 mL), and washed with water (4×100 mL), dried with brine (100 mL), and then dried over Na2SO4. Concentration under reduced pressure and combination of the two portions gave 8.77 g of 83.3% pure material. This was triturated with methylene chloride to give 1.2 g of {4-[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-carbamic acid 2-hydroxy-ethyl ester. Repeated chromatography of mother liquors with gradient of 0-5% MeOH in methylene chloride gave an additional 5.6 g of desired product, for a total of 6.8 g (70%).

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