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With potassium <i>tert</i>-butylate In tetrahydrofuran for 3 h; Reflux
5-Bromo-3-methyl-pyridine-2-carboxylic acid 1-dimethylamino-meth-(E)-ylideneamide (2.5 g, 9.25 mmol) was dissolved in THF (20 ml). KOtBu (1 .565 g, 13.05 mmol) in THF (30 ml) was added dropwise and the reaction mixture was heated to reflux for 3h and then cooled to rt.The pH was adjusted to 7 with concentrated HCI. The reaction mixture was concentrated.The brown solid obtained was titruated with water (10 ml). The solid thus obtained was collected by filtration (2 g, 8 mmol).HPLC: RtH9= 0.56 min; ESIMS [M+H]+ = 224.8, 226.8 (1 Br);1H-NMR (400 MHz, DMSO-d6): δ 1 1 .90 (s, 1 H), 8.85 (s, 1 H), 8.50 (s, 1 H), 7.43 (d, 1 H), 6.67(d, 1 H).
With potassium tert-butylate; In tetrahydrofuran; for 3.0h;Reflux;
5-Bromo-3-methyl-pyridine-2-carboxylic acid 1-dimethylamino-meth-(E)-ylideneamide (2.5 g, 9.25 mmol) was dissolved in THF (20 ml). KOtBu (1 .565 g, 13.05 mmol) in THF (30 ml) was added dropwise and the reaction mixture was heated to reflux for 3h and then cooled to rt.The pH was adjusted to 7 with concentrated HCI. The reaction mixture was concentrated.The brown solid obtained was titruated with water (10 ml). The solid thus obtained was collected by filtration (2 g, 8 mmol).HPLC: RtH9= 0.56 min; ESIMS [M+H]+ = 224.8, 226.8 (1 Br);1H-NMR (400 MHz, DMSO-d6): delta 1 1 .90 (s, 1 H), 8.85 (s, 1 H), 8.50 (s, 1 H), 7.43 (d, 1 H), 6.67(d, 1 H).
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; In toluene; at 130.0℃; for 36.0h;
3-Bromo-7H-[1 ,7]naphthyridin-8-one (1.5 g, 6.67 mmol) was suspended in toluene (20 ml). DIPEA (3.5 ml, 20 mmol) and POCI3 (1.8 ml, 20 mmol) were added and the reaction mixture was heated to 130 C for 36 h. The reaction mixture was cooled to rt and partitioned between water (75 ml) and EtOAc (150 ml). The phases were separated and the aq phase was extracted twice with EtOAc (25 ml). The combined organic layer was washed with NaHC03 solution and brine, treated with MgS04 and filtered. The filtrated was concentrated to give the desired product as a beige solid (1 .1 g, 4.52 mmol).HPLC: RtH9= 0.86 min; ESIMS [M+H]+ = 242.8, 244.8, 246.8 (1 Br,1 CI);1H-NMR (400 MHz, DMSO-d6): delta 9.22 (d, 1 H), 8.95 (2, 1 H), 8.49 (d, 1 H), 7.99 (d, 1 H).
5-bromo-3-(2-(dimethylamino)vinyl)picolinonitrile[ No CAS ]
[ 1375301-90-8 ]
Yield
Reaction Conditions
Operation in experiment
With water; hydrogen bromide; In ethanol; for 4.0h;Reflux;
To a mixture of compound E2 (1.1 g, 4.4 mmol) in EtOH (9 mL) was added HBr (9 mL, 40% aq.) dropwise at room temperature. The mixture was stirred at reflux temperature for 4 h and cooled to room temperature. The precipitated solid was filtered and the filter cake was neutralized with sat. Na2C03 until the evolved gas ceased. Then the mixture was filtered and the filter cake was dried to give compound E3. MS (M+H+): 225.
With hydrogen bromide; In ethanol; water; for 4.0h;Reflux;
To a mixture of compound E2 (1.1 g, 4.4 mmol) in EtOH (9 mL) was added HBr (9 mL, 40% aq.) dropwise at room temperature. The mixture was stirred at reflux temperature for 4 h and cooled to room temperature. The precipitated solid was filtered and the filter cake wasneutralized with sat. Na2CO3 until the evolved gas ceased. Then the mixture was filtered and the filter cake was dried to give compound E3. MS (M+H): 225.
With copper(l) iodide; In N,N-dimethyl-formamide; at 100.0℃; for 16.0h;Inert atmosphere;
A mixture of compound E3 (2.0 g, 8.89 mmol), sodium methanolate (2.40 g, 44.4 mmol) and copper(I) iodide (846 mg, 4.44 mmol) in DMF (20 mL) was stirred at 100 C for 16 h under N2. Then mixture was concentrated to give crude E4 which was used in the next step without further purification.
With copper(l) iodide; In N,N-dimethyl-formamide; at 100.0℃; for 16.0h;Inert atmosphere;
A mixture of compound E3 (2.0 g, 8.89 mmol), sodium methanolate (2.40 g, 44.4mmol) and copper(I) iodide (846 mg, 4.44 mmol) in DMF (20 mL) was stirred at 100 C for 16 hunder N2. Then mixture was concentrated to give cmde E4 which was used in the next stepwithout further purification.
(4aR,7aR)-4a-(2-fluoro-5-((3-methoxy-1,7-naphthyridin-8-yl)amino)phenyl)-3-imino-2-methyloctahydrocyclopenta[e][1,2,4]thiadiazine 1,1-dioxide[ No CAS ]
Chemistry
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