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With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene at 110℃; for 12h; Inert atmosphere;
6 Synthesis of intermediate-45
22.2 g (100 mmol) of 6-bromo-1-naphthylamine and 23.3 g (110 mmol)Dibenzofuran-4-boronic acid was added to a 2 L three-necked flask, 400 ml of toluene and 100 ml of ethanol were added and the nitrogen was added for 15 minutes. Then, 150 ml of an aqueous solution of K2CO3 (300 mmol, 2 M) was added, and finally 2.3 g of Pd (PPh3) 4 (2 mol%). The temperature was raised to 110 ° C and the reaction was carried out for 12 hoursbundle. Add activated carbon to adsorb, filter, remove the solvent, dry, and recrystallize from toluene and ethanol to give 27.5 g of intermediate-45Rate of 89%.
With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 110℃; for 6h;
4 Synthesis of intermediate (32)Reaction Formula 35
To a dry 2 L three-necked flask was added 28.3 g (100 mmol) of o-bromobenzene and 24.4 g (110 mmol) of 6-bromo-1-Naphthylamine, followed by drying and degassing of 600 ml of toluene as the solvent. 28.8 g (300 mmol) of sodium tert-butoxide was added and 0.45 g of catalyst was added (2% mol) and 2.5 g of the ligand 1,1'-binaphthyl-2,2'-dibenzophenylphosphine (BINAP, 4% mol). Heating up to 110 ° C, The reaction was carried out for 6 hours. After the end of the reaction, cooling to room temperature, add activated carbon adsorption, suction filtration, remove the solvent, with toluene and ethanol To give 33.6 g of intermediate (32) in 89% yield.
Multi-step reaction with 2 steps
1.1: palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate / toluene / 6 h / 110 °C
2.1: n-butyllithium / tetrahydrofuran / 1 h / -78 °C
2.2: 12 h / -78 - 28 °C
2.3: 5 h / 120 °C
6-(1-methyl-1H-pyrazol-4-yl)naphthalen-1-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane; water at 120℃; for 3h; Inert atmosphere;
36.1 Step 1: 6-(1-methyl-1H-pyrazol-4-yl)naphthalen-1-amine
To a solution of 6-bromonaphthalen-1-amine (470 mg, 2.12 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was added [1,1 ‘-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (155 mg, 0.21 mmol), Na2CO3 (449 mg, 4.24 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (528 mg, 2.54 mmol). The mixture was heated to 120 °C for 3 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (100 mL) was added and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM / MeOH = 30 : 1) to give the title compound (300 mg, 63%) asyellow solid. LCMS MIZ (M+H) 224.
4-(5-bromonaphthalen-2-yl)-1-methyl-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 2 steps
1.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / water; 1,4-dioxane / 3 h / 120 °C / Inert atmosphere
2.1: hydrogenchloride; sodium nitrite / water / 1 h / 0 °C
2.2: 1 h / 0 °C
Multi-step reaction with 2 steps
1.1: magnesium; iodine / tetrahydrofuran / 2 h / 51 °C
1.2: 15 h / 51 °C
2.1: caesium carbonate / N,N-dimethyl-formamide / 16 h / 160 °C
Stage #1: 6-bromo-1-aminonaphthalene With iodine; magnesium In tetrahydrofuran at 51℃; for 2h;
Stage #2: chloro-trimethyl-silane In tetrahydrofuran at 51℃; for 15h;
5
In a dry 2L three-necked flask, 3.6 g of Mg (150 mmol, 1.5 eq.), 15 ml of THF, and 0.36 g of I2 were added, and the reaction was initiated by heating.Then, a mixed solution of 24.4 g (110 mmol, 1.1 eq.) 6-bromo-1-aminonaphthalene and 300 ml of THF was added dropwise at room temperature. After the dropwise addition, the mixture was further reacted at 51 ° C for 2 hours, and allowed to stand for 5 minutes. The supernatant was added dropwise to a solution of 10.9 g (100 mmol, 1.0 eq.) Of trimethylsilyl chloride and 100 ml of THF, and then the temperature was raised to 51 ° C. and the reaction was carried out for 15 hours. After the reaction is completed, cool to room temperature, quench by adding water dropwise, extract with dichloromethane and water, wash with water, dry, spin off the solvent, and purify with a chromatography column to obtain 18.3 g of intermediate (44).The yield was 85%.
With dmap; triethylamine In dichloromethane at 20℃; for 3h; Industrial scale;
1 Example 1:
Add 50 kg of 6-bromonaphthylamine, 500 kg of solvent dichloromethane, 34 kg of acetic anhydride, 46 kg of triethylamine and 0.5 kg of catalyst DMAP into the reactor, and then stir at room temperature for 3 hours. The HPLC control detection is completed. The reactor Add 1.0% dilute hydrochloric acid solution to wash, collect the organic phase, then wash with 1.0% sodium hydroxide solution, collect the organic phase, concentrate under reduced pressure to obtain an oily substance of compound I 61.5 kg, yield>100%, purity 97.3%.
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