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(b) 3-cyano-5-amino-1H-pyrazole-4-carbonitrile 3-cyano-4-cyano-5-amino-1H-pyrazole-1-carboxamide (15.6 g, 0.089 mol) was added in small protions to boiling water (150 ml). Upon completion of the addition, the reaction mixture was stirred at reflux for 5 minutes, cooled and a solid was collected by filtration. The solid was washed with water and air dried to afford 10.4 g (88%) of 3-cyano-5-amino-1H-pyrazole-4-carbonitrile, m.p. 260 C. (dec.).
While keeping the internal temperature at 16 C. or less, ethanol was placed in an ice bath (700 mL) hydrazinecarboxylic acid tert-butyl ester in (129 g, 0.976 mol) to the solution, 2,3-dicyano-but-2-enedinitrile (125g, 0.976 mol) was added portionwise. After the addition was complete, the reaction mixture was heated to reflux for 4 hours, dried and concentrated under vacuum, it was subjected to 5-amino-1H-pyrazole-3,4-dicarbonitrile. MS (ES) m / z134.1 (M + H +).
In ethanol; at 20℃;Reflux;
tert-Butyl carbazate (7.5 g, 57 mmol) was dissolved in ethanol (45 mL) and the resulting solution was cooled in an ice-water bath. Tetracyanoethylene (7.27 g, 56.7 mmol) was added in portions over several minutes. The mixture was stirred in the ice-water bath for 10 min and then allowed to warm to rt and stirred until the tetracyanoethylene dissolved. Once dissolved the mixture was warmed to reflux and stired for 4h. The mixture was then cooled to rt and concentrated under reduced pressure to afford a sticky orange solid which was used as is in the following step. LCMS (AA): m/z 132 (M-H).
2-[4-amino-3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]ethanone dihydrochloride salt[ No CAS ]
N-(4,5-dicyano-2H-pyrazol-3-yl)-formimidic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
for 8.0h;Reflux;
And the 5-amino -1H- pyrazole-3,4-dicarbonitrile obtained above was refluxed for 8 h in trimethyl orthoformate (1 L). Then the mixture was concentrated in vacuo dried to c, N- (4,5- dicyano -2H- pyrazol-3-yl) - provided the Horumuimido acid methyl ester, which was dissolved in methanol (400 mL) 0 C. until then cooled and treated with 7N NEta3 in methanol (1L). The resulting mixture overnight subjected to warm to room temperature and filtered. 2 of the solid MeOH-H2O: 1 mixture (100 mL), and washed with acetone (100 mL) and ether (100 mL), followed by drying under vacuum, 4-amino--1H- pyrazolo [3,4-d] to give the pyrimidine-3-carbonitrile (79g, 50% yield). MS (ES) m / z161.0 (M + H +).
5-Amino-lH-pyrazole-3,4-dicarbonitrile (7.6 g, 57 mmol) was suspended in trimethylorthoformate (60 mL) in a round bottom flask fitted with a stirbar and reflux condenser. The flask was placed in an oil bath and the mixture was heated at reflux overnight. After cooling to rt the following morning, the reaction solution was concentrated under reduced pressure to afford an orange oil. The oil was dried under high vacuum with stirring for 2h. The residue was dissolved in MeOH (25 mL) and cooled under nitrogen in an ice-water bath. A solution of ammonia in MeOH (7.0 M, 65 mL, 460 mmol) was added. The resulting slightly opaque solution was warmed to rt and stirred overnight. The solids produced were isolated by suction filtration, washed with MeOH and dried under suction. The tan powder was transferred to a round bottom flask and dried under high vacuum and used without further purification (6.20 g, 68%, 2 steps). LCMS (AA): m/z 161 (M+H); 1H MR (300 MHz, i-DMSO) delta 8.04 (s, 1H).
4-amino-1-[(3aR,4R,6R,6aR)-6-([tert- butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile[ No CAS ]