|
Stage #1: 2‐bromo‐3‐methoxynaphthalene; isopropylmagnesium bromide With tris-(dibenzylideneacetone)dipalladium(0); XPhos In tetrahydrofuran at 70℃; for 6h; Inert atmosphere;
Stage #2: With boron tribromide In dichloromethane at 0 - 20℃; for 15h; Inert atmosphere;
Stage #3: o-fluorobromobenzene; aniline Overall yield = 1.1 g; Further stages; |
3.3.1; 3.3.2; 3.3.3; 3.3.4; 3.3.5 Step 1 : Synthesis of 3-isopropyl-2-methoxynaphthalene
Into a 1 L three-neck flask were put 3.5 g (15 mmol) of 2-bromo-3-methoxynaphthalene and 0.21 g (0.44 mmol) of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (abbreviation: XPhos), and the air in the flask was replaced with nitrogen. Then, 60 mL of tetrahydrofuran (abbreviation: THF) was added, and the resulting mixture was degassed under reduced pressure and then stirred at 70 °C. To this mixture was added 0.20 g (0.22 mmol) of tris(dibenzylideneacetone)dipalladium(0) (abbreviation: Pd2(dba)3), and 22 mL of cyclohexylmagnesium bromide (a 2.0 mol/L tetrahydrofuran solution, 44 mmol) was dropped into the mixture; then, this mixture was stirred for 6 hours at 70 °C under a nitrogen stream. After the stirring, this mixture was dropped into 0 °C hydrochloric acid (1 mol/L), and an aqueous layer of the resulting mixture was subjected to extraction using toluene. The obtained solution of the extract and an organic layer were combined, and the mixture was washed with water and saturated brine. Then, the mixture was dried with magnesium sulfate. The mixture was separated by gravity filtration, and the obtained filtrate was concentrated to give a yellow oily substance. The obtained oily substance was purified by silica gel column chromatography (a developing solvent: hexane) to give 2.5 g of a white solid in a yield of 75 %. A synthesis scheme of Step 1 is shown in (b-1). Step 2: Synthesis of 3-isopropyl-2-naphthol and 3-normalpropyl-2-naphthol Into a 300 mL three-neck flask were put 2.5 g (13 mmol) of a mixture of 3-isopropyl-2-methoxynaphthalene and 3-normalpropyl-2-methoxynaphthalene, and the air in the flask was replaced with nitrogen. Then, 65 mL of dichloromethane was added, and the resulting solution was stirred at 0 °C. Into the solution, 26 mL of boron tribromide (a 1.0 mol/L dichloromethane solution, 26 mmol) was dropped; then, the resulting solution was stirred for 15 hours while the temperature was returned to room temperature. After the stirring, this mixture was dropped into a 0 °C saturated aqueous solution of sodium hydrogencarbonate, and an aqueous layer of the resulting mixture was subjected to extraction using dichloromethane. The obtained solution of the extract and an organic layer were combined, and the mixture was washed with water and saturated brine. Then, the mixture was dried with magnesium sulfate. The mixture was separated by gravity filtration, and the obtained filtrate was concentrated to give 2.3 g of a target yellowish white solid in a yield of 98 %. A synthesis scheme of Step 2 is shown in (b-2). Step 3 : Synthesis of 6-isopropylbenzo[b]naphtho[1,2-d]furan and 6-normalpropylbenzo[b]naphtho[1,2-d]furan Into a 200 mL three-neck flask were put 2.3 g (12 mmol) of a mixture of 3-isopropyl-2-naphthol and 3-normalpropyl-2-naphthol, 4.3 g (25 mmol) of 2-bromofluorobenzene, and 8.0 g (25 mmol) of cesium carbonate, and the air in the flask was replaced with nitrogen. Then, 62 mL of N-methyl-2-pyrrolidone (abbreviation: NMP) was added and the resulting solution was degassed under reduced pressure and then stirred for 7 hours at 180 °C under a nitrogen stream. After the stirring, 7.2 g (22 mmol) of cesium carbonate and 0.30 g (1.1 mmol) of triphenylphosphine were added to this mixture. The resulting mixture was degassed by being stirred under reduced pressure. To this mixture was added 0.13 g (0.58 mmol) of palladium(II) acetate, and the resulting mixture was stirred for 7 hours at 180 °C under a nitrogen stream. After the stirring, water was added to this mixture, and an aqueous layer was subjected to extraction using ethyl acetate. The obtained solution of the extract and an organic layer were combined, and the mixture was washed with water and saturated brine. Then, the mixture was dried with magnesium sulfate. The mixture was separated by gravity filtration, and the obtained filtrate was concentrated to give a brown oily substance. The obtained oily substance was purified by silica gel column chromatography (a developing solvent: hexane) to give 2.7 g of a target white solid in a yield of 84 %. A synthesis scheme of Step 3 is shown in (b-3). Step 4: Synthesis of 6-isopropyl-8-iodobenzo[b]naphtho[1,2-d]furan and 6-normalpropyl-8-iodobenzo[b]naphtho[1,2-d]furan Into a 300 mL three-neck flask was put 2.7 g (10 mmol) of a mixture of 6-isopropylbenzo[b]naphtho[1,2-d]furan, and the air in the flask was replaced with nitrogen. Then, 75 mL of tetrahydrofuran was added, and the mixture was stirred at -80 °C. Into this solution was dropped 7.2 mL (12 mmol) of -butyllithium (a 1.6 mol/L -hexane solution), the temperature was returned to room temperature, and the mixture was stirred for 2 hours under a nitrogen stream. After the stirring, the temperature of the resulting mixture was reduced to -80 °C; then, a solution of 5.3 g (21 mmol) of iodine in 20 mL of tetrahydrofuran was added to the mixture, and stirring was performed for 15 hours while the temperature was gradually returned to room temperature. After the stirring, an aqueous solution of sodium thiosulfate was added to this mixture, and an aqueous layer was subjected to extraction using ethyl acetate. The obtained solution of the extract and an organic layer were combined, and the mixture was washed with water and saturated brine. Then, the mixture was dried with magnesium sulfate. The mixture was separated by gravity filtration, and the obtained filtrate was concentrated to give a brown oily substance. The obtained compound was purified by silica gel column chromatography (a developing solvent: hexane) to give 3.2 g of a target white solid. A synthesis scheme of Step 4 is shown in (b-4). Step 5: Synthesis of N-phenyl-6-isopropylbenzo[b]naphtho[1,2-d]furan-8-amine and N-phenyl-6-normalpropyl[b]naphtho[1,2-d]furan-8-amine Into a 100 mL three-neck flask were put 1.6 g (4.1 mmol) of a mixture of 6-isopropyl-8-iodobenzo[b]naphtho[1,2-d]furan and 6-normalpropyl-8-iodobenzo[b]naphtho[1,2-d]furan, 0.47 g (5.1 mmol) of aniline, and 1.2 g (13 mmol) of sodium t-butoxide, and the air in the flask was replaced with nitrogen. To this mixture was added 21 mL of toluene, and the resulting mixture was degassed under reduced pressure. To this mixture were added 0.30 mL (0.35 mmol) of tri(tert-butyl)phosphine (a 10 wt% hexane solution) and 40 mg (70 μιηο) of bis(dibenzylideneacetone)palladium(0) and then, stirring was performed for 5.5 hours at 80 °C under a nitrogen stream. After the stirring, 300 mL of toluene was added to the resulting mixture and then, suction filtration was performed through Florisil (Catalog No. 066-05265 produced by Wako Pure Chemical Industries, Ltd.), Celite (Catalog No. 537-02305 produced by Wako Pure Chemical Industries, Ltd.), and alumina to give a filtrate. The obtained filtrate was concentrated to give a brown oily substance. This oily substance was purified by silica gel column chromatography (a developing solvent was a mixed solvent of hexane: toluene = 4: 1) to give 1.1 g of a target colorless oily substance in a yield of 78 %. A synthesis scheme of Step 5 is shown in (b-5). The colorless oily substance obtained in Step 5 was analyzed by nuclear magnetic resonance (1H NMR) spectroscopy. In addition, 1H NMR charts are shown in FIGS. 15A to 15C. Note that FIG. 15B is an enlarged chart showing the range of 6.5 ppm to 9.0 ppm in FIG. 15 A. FIG. 15C is an enlarged chart showing the range of 0.5 ppm to 4.0 ppm in FIG. 15 A The results reveal that a mixture of N-phenyl-6-isopropylbenzo[b]naphtho[1,2-d]furan-8-amine and N-phenyl-6-normalpropylbenzo[b]naphtho[1,2-d]furan-8-amine was obtained. 1H NMR (CDC13, 300 MHz): σ = 8.60-8.58 (m, 1H), 8.00-7.92 (m, 2H), 7.75-7.63 (m, 2H), 7.55-7.50 (m, 1H), 7.42-7.27 (m, 6H), 7.65-7.01 (m, 1H), 3.72-3.68 (m, 1H (iPr)), 3.13 (t, J= 7.6 Hz, 2H (nPr)), 1.93 (sext, J= 7.4 Hz, 2H (nPr)), 1.52 (d, J= 6.8 Hz, 6H (iPr)), 1.08 (t, J = 7.6 Hz, 3H (nPr)). |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
