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With caesium carbonate In acetonitrile at 80℃; for 1.5h;
5.1 Example 5: (2,6-dimethyl-2H-indazol-7-yl)methanamine Step 1 : Synthesis of 7-bromo-2,6-dimethyl-2H-indazole
[0546] To a solution of 7-bromo-6-methyl-lH-indazole (1 equiv.) in acetonitrile, Cs2C03 (1.3 equiv.) and Mel (3 eq.) was added and reaction was heated at 80 oC for 1.5h. On completion, it was cooled and quenched by addition of water. Extraction was carried out using ethyl acetate. Organic layer was dried over Na2S04 and crude compound was column purified to afford the title compound. (Polar isomer confirmed as N-2-M ethyl and non-polar isomer confirmed as N-l -Methyl by NOE experimentation).
With caesium carbonate In acetonitrile at 80℃; for 1.5h;
5.1 Synthesis of 7-bromo-2,6-dimethyl-2H-indazole
To a solution of 7-bromo-6-methyl-1H-indazole (1 equiv.) in acetonitrile, Cs2CO3 (1.3 equiv.) and MeI (3 eq.) was added and reaction was heated at 80° C. for 1.5 h. On completion, it was cooled and quenched by addition of water. Extraction was carried out using ethyl acetate. Organic layer was dried over Na2SO4 and crude compound was column purified to afford the title compound. (Polar isomer confirmed as N-2-Methyl and non-polar isomer confirmed as N-1-Methyl by NOE experimentation).
Stage #1: 7-bromo-6-methyl-1H-indazole With sodium hydride In tetrahydrofuran at 0℃; for 1h;
Stage #2: (2-trimethylethylsilylethoxy)methyl chloride In tetrahydrofuran at 0 - 20℃; for 2h;
238.A Step A: 7-bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole:
A solution of 7-bromo-6-methyl-lH-indazole (200 mg, 0.948 mmol) in tetrahydrofuran (2 ml, 0.948 mmol) was cooled with stirring in an ice bath. Sodium hydride (45.5 mg, 1.14 mmol) was added portionwise to the mixture and the reaction was stirred at 0°C for lhour. (2- (chloromethoxy)ethyl)trimethylsilane (0.201 ml, 1.14 mmol) was next added and the reaction stirred for 2 hours while warming to room temperature. The mixture was divided between EtOAc (20 mL) and water (10 mL) and the layers separated. The organic layer was washed with water (2 x 10 mL), brine (10 mL), dried over Na2SC"4 and evaporated in vacuo. The product was purified by chromatography on silica gel using 20 to 40% EtOAc/hexanes as eluent to give 7- bromo-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (46 mg, 14%) along with isomer 7-bromo-6-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole (214 mg, 66%). ES+APCI MS m/z 341.1 [M]+.
Multi-step reaction with 3 steps
1.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C
1.2: 2 h / 0 - 20 °C
2.1: caesium carbonate; methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II) / 1,4-dioxane / 6 h / 70 °C
3.1: trifluoroacetic acid / neat (no solvent) / 1.5 h / 20 °C
Multi-step reaction with 4 steps
1.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C
1.2: 2 h / 0 - 20 °C
2.1: caesium carbonate; methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II) / 1,4-dioxane / 6 h / 70 °C
3.1: trifluoroacetic acid / neat (no solvent) / 1.5 h / 20 °C
4.1: hydrogen; 5%-palladium/activated carbon / tetrahydrofuran; methanol / 1 h
4.2: 0.02 h / -30 °C
With hydrazine hydrate In dimethyl sulfoxide at 60 - 130℃; for 18h;
[0461] A solution of 3-bromo-2-fluoro-4-methyl-benzaldehyde (9.2 g, 42.4 mmol, 1.0 equiv) and NH2NI2*H2q (42.4 g, 848 mmol, 41.2 mL, 20 equiv) in DMSO (150 mL) was stirred at 60 °C for 2 h and then at 130 °C for 16 h. Subsequently, the solution was cooled to 20 °C and poured into brine (600 mL) and filtered. The white solid was collected, washed with water (100 mL) and dried under reduced pressure to afford 7-bromo-6-methyl-l//-indazole (6.2 g, 29.4 mmol, 69% yield) as a light yellow solid.'H NMR (400 MHz, chloroform-d): d 10.69 (br s, lH), 8.15 (s, 1H), 7.59 (d,./ = 8.0 Hz, 1H), 7.06 (d,./= 8.4 Hz, 1H), 2.55 (s, 3H).
With caesium carbonate In acetonitrile at 80℃; for 1.5h;
[0462] A mixture of 7-bromo-6-methyl-li -indazole (7.9 g, 37.4 mmol, 1.0 equiv) in CH3CN (250 mL), CS2CO3 (15.9 g, 48.7 mmol, 1.3 equiv) and CH3I (15.9 g, 112 mmol, 6.99 mL, 3.0 equiv) was heated at 80 °C for 1.5 hour. Subsequently, the mixture was cooled to room temperature and filtered. The filtrate was concentrated to provide the crude residue. The residue was diluted with water (200 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layer was washed with brine 200 mL, dried over anh Na2SC>4, filtered and concentrated under reduced. The residue was purified by column chromatography (S1O2, petroleum ether/ethyl acetate, 10:1 to 2:1) to afford 7-bromo-l,6-dimethyl-indazole (4.9 g, 21.8 mmol, 58% yield) as a yellow solid.
52.55 %
With caesium carbonate In acetonitrile at 80℃;
17.1 Step 1: 7-Bromo-1,6-dimethyl-1H-indazole
7-Bromo-6-methyl-1H-indazole (1g, 4.74mmol, 1eq) and cesium carbonate (2.01g, 6.16mmol, 1.3eq) were dissolved in acetonitrile (30mL), iodomethane (2.02g, 14.21 g) was added mmol, 3eq), react at 80°C overnight. LCMS monitored the completion of the reaction, the reaction solution was filtered and concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 0-50%) to obtain 7-bromo-1,6-dimethyl-1H-indazole (560 mg, yield rate 52.55%), white solid.
With toluene-4-sulfonic acid In dichloromethane at 20℃;
19.1 Step 1: 7-Bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
7-Bromo-6-methyl-1H-indazole (1 g, 4.74 mmol, 1 eq) was dissolved in dichloromethane (20 mL), p-toluenesulfonic acid monohydrate (90.13 mg, 4.74 mmol, 0.1 eq) was added and 2,3-Dihydropyran (797.09 mg, 9.48 mmol, 2 eq). The reaction was left overnight at room temperature. The completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate=5:1). The reaction solution was extracted with water and dichloromethane, and the organic phase was washed with brine and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, and column purification of the residue (ethyl acetate/petroleum ether: 0-10%) yielded 7-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H - Indazole (1.35 g, yield: 96.53%), white solid.