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Stage #1: With sodium methylate In methanol at 10 - 35℃; for 0.416667 h; Stage #2: With acetic acid In methanol at 50℃; for 1 h; Stage #3: With hydrogenchloride In methanolReflux
Step 1: 2-(1H-Imidazol-2-yl)pyrazine 2,2-Diethoxyethanamine (3 g, 2.25 mmol) was dissolved in dry methanol (20 mL). To this was added sodium methoxide (1.22 g, 22.5 mmol, as a 25percent solution in methanol). After stirring for 25 minutes at room temperature, pyrazine-2-carbonitrile (2.37 g, 22.5 mmol) and acetic acid (1.35 g, 22.5 mmol) were added and the subsequent solution was stirred at 50° C. for 1 hour. MeOH (40 mL) and 6N HCl (12 mL) were added and the reaction was stirred at reflux overnight. The reaction mixture was cooled to room temperature and partitioned between 1:1 Et2O and water (60 mL) and the layers were separated. The aqueous layer was basified to pH 9/10 and extracted with 10percent MeOH in DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated to give the desired compound (1.49 g yellow solid). 1H NMR (400 MHz, MeOH-d4) δ ppm: 7.67 (s, 1H), 7.09 (d, J=1.8 Hz, 1H), 6.99 (d, J=2.5 Hz, 1H), 5.72 (s, 2H)
Example 3 :f4aS RJaS)-7a-f2-fluoro-5-f2-fpyrazin-2-yl)-lH-imidazol-5-vDphenvn-5-methYl- 4a. .7.7a -t etrah ydro-4 H - f tiro Gamma3 ,4-d] f 1.3]thiazin-2-amineStep 1 : 2-(lH midazol-2-yl)py 2,2-Diethoxyethanamine (3 g, 2.25 mmol) was dissolved in dry methanol (20 mL). To this was added sodium methoxide (1.22 g, 22.5 mmol, as a 25% solution in methanol). After stirring for 25 minutes at room temperature,, pyrazine-2-carbonitrile (2.37 g, 22.5 mmol) and acetic acid (1.35 g, 22.5 mmol) were added and the subsequent solution was stirred at 50C for 1 hour. MeOH (40 mL) and 6N HC1 (12 mL) were added and the reaction was stirred at reflux overnight. The reaction mixture was cooled to room temperature and partitioned between 1 : 1 Et20 and water (60 mL) and the layers were separated. The aqueous layer was basified to pH 9/10 and extracted with 10% MeOH in DCM. The combined organic extracts were dried (MgSOa), filtered and concentrated to give the desired compound ( 1.49 g yellow solid). 1 H NMR (400 MHz, eOH-d,) delta ppm: 7.67 (s, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 6.99 (d, J=2.5 Hz, 1 H), 5.72 (s, 2 H)
1.49 g
Step 1: 2-(1H-Imidazol-2-yl)pyrazine 2,2-Diethoxyethanamine (3 g, 2.25 mmol) was dissolved in dry methanol (20 mL). To this was added sodium methoxide (1.22 g, 22.5 mmol, as a 25% solution in methanol). After stirring for 25 minutes at room temperature, pyrazine-2-carbonitrile (2.37 g, 22.5 mmol) and acetic acid (1.35 g, 22.5 mmol) were added and the subsequent solution was stirred at 50 C. for 1 hour. MeOH (40 mL) and 6N HCl (12 mL) were added and the reaction was stirred at reflux overnight. The reaction mixture was cooled to room temperature and partitioned between 1:1 Et2O and water (60 mL) and the layers were separated. The aqueous layer was basified to pH 9/10 and extracted with 10% MeOH in DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated to give the desired compound (1.49 g yellow solid). 1H NMR (400 MHz, MeOH-d4) delta ppm: 7.67 (s, 1H), 7.09 (d, J=1.8 Hz, 1H), 6.99 (d, J=2.5 Hz, 1H), 5.72 (s, 2H)
Step 2: 2-( l -{ [2-(Trimethylsilyl ethoxy1methyl}-l H-imidazol-2-yI)pyrazineTo a solution of 2-(lH-imidazol-2-yl)pyrazine (0.75 g, 5.1 mmol) in DMF (7 mL) was added sodium hydride (60% dispersion in oil, 0.42 g, 10.3 mmol) and the reaction stirred at 40C for 2 hours. [2-(chloromethoxy)ethyl](trimethyl)silane ( 1.71 g, 10.3 mmol) was added and the reaction was stirred at 40C for a further 3 hours The reaction mixture was partitioned between EtOAc and water and the layers separated. The aqueous layers was extracted with EtOAc (x2) and the combined organic layers were dried (MgS04), filtered and concentrated in vacuo. The residue was purified using column chromatography (gradient 20-60% EtOAc in hexane) to give the title compound (0.88 g, yellow oil). NMR (400 MHz, CDC13) delta ppm: 9.47 (d. J=1.0 Hz, 1 H), 8.36 - 8.59 (m, 2 H), 7.26 - 7.28 (m, 1 H), 7.24 (d, J=1.3 Hz, 1 H), 5.96 - 6.00 (m, 2 H), 3.53 - 3.61 (m, 2 H), 0.86 - 0.94 (m, 2 H), -0.10 - -0.05 (m, 9 H).
0.88 g
Step 2: 2-(1-[2-(Trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)pyrazine To a solution of 2-(4H-imidazol-2-yl)pyrazine (0.75 g, 5.1 mmol) in DMF (7 mL) was added sodium hydride (60% dispersion in oil, 0.42 g, 10.3 mmol) and the reaction stirred at 40 C. for 2 hours. [2-(chloromethoxy)ethyl](trimethyl)silane (1.71 g, 10.3 mmol) was added and the reaction was stirred at 40 C. for a further 3 hours The reaction mixture was partitioned between EtOAc and water and the layers separated. The aqueous layers was extracted with EtOAc (*2) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified using column chromatography (gradient 20-60% EtOAc in hexane) to give the title compound (0.88 g, yellow oil). 1H NMR (400 MHz, CDCl3) delta ppm: 9.47 (d, J=1.0 Hz, 1H), 8.36-8.59 (m, 2H), 7.26-7.28 (m, 1H), 7.24 (d, J=1.3 Hz, 1H), 5.96-6.00 (m, 2H), 3.53-3.61 (m, 2H), 0.86-0.94 (m, 2H), -0.10-0.05 (m, 9H).
A methanolic solution containing 0.5 mmol of impz in 5 mL was slowly added to a solution of 0.5 mmol of CuCl2-2H2O in 5 mL of methanol under stirring for 4 h and at room temperature.A green solid precipitated and the powder was collected by filtration, washed with a small amount of cold methanol and dried under vacuum. The yield was 38%. This complex is soluble in water, DMSO and DMF and slightly soluble in methanol and ethanol. Anal. Calc. for CuCl2C7H6N4 (%): C 30.0; H 2.16; N 20.0.Found: C 30.2; H 2.46; N 19.8. Molar conductivity in deionized water (Scm2mol1): 206.9.
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