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Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 3 h; Stage #2: With hydrogenchloride In tetrahydrofuran; hexane; water
2.04 g (10 mmol) of intermediate I-3 and 37.5 mL (60 mmol) of n-BuLi (1.60M hexane solution) was gradually reacted with THF at about −78° C. 3.8 ml (60 mmol) of CH3I was added into the reaction solution, and was then stirred at room temperature for about 3 hours, followed by adding 5 ml of a 1N HCl aqueous solution into the mixture. The organic phase was separated from the reaction solution, and the aqueous phase was extracted with dichloromethane (2×100 ml). The collected organic phase was dried using magnesium sulfate to evaporate the solvent. The residue was separated and purified using silica gel column chromatography to obtain 2.03 g of Intermediate I-4 (Yield: 78percent). This compound was identified using MS/FAB. C20H20: calc. 260.37. found 260.45
78%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667 h; Stage #2: at 20℃; for 3 h;
In -78 THF intermediate I- 3s (2.04g, 10mmol) and n-BuLi (1.60M hexane solution) (37.5, 60mmol), it reacted for 10 minutes at the slowly. After the CH 3 I (3.8, 60mmol) was put into the reaction solution and it mixed at a room temperature for 3hours 1N HCl (aq) (5)was added. The layer of water was extracted in the dichloromethane (2×100) to separate the organic layeramong the reaction solution. The residue which was dry to the magnesium sulfate and disappeared the solvent and was the collected organic layer obtained was refined to the silica gel pipe chromatography after dividingand the intermediate I-4 2.03g (the yield 78percent) was obtained. The generated compound was confirmed through the MS / FAB. C20H20: the calculation value 260.37,and the measured value 260.45.
78%
With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane; water at -78 - 20℃; for 3 h;
2.04 g (10 mmol) of Intermediate 3-6 and 37.5 ml (60 mmol) of n-BuLi (1.60M hexane solution) were mixed in THF at -78° C. to induce a reaction therebetween. Subsequently, 3.8 ml (60 mmol) of iodomethane was added to the reaction solution, the resulting solution was stirred at room temperature for 3 hours, and 5 ml of 1N HCl (aq) was added thereto. An organic layer was separated from the reaction solution and the remaining water layer was extracted twice with 100 ml of dichloromethane. The obtained organic layer was dried with magnesium sulfate and a solvent was evaporated therefrom to obtain a crude product. The crude product was purified with silicagel column chromatography to obtain 2.03 g of Intermediate 4-6 (yield: 78percent). The obtained compound was confirmed by MS/FAB. C20H20: calc. 260.15. found 260.21.
78%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667 h; Stage #2: at 20℃; for 3 h;
Synthesis of Intermediate I-4 2.04 g (10 mmol) of Intermediate I-3 and 37.5 mL (60 mmol) of n-BuLi (1.60 M hexane solution) were slowly reacted in THF at a temperature of -78° C. for 10 minutes. 3.8 mL (60 mmol) of iodomethane was added to the reaction solution, stirred at room temperature for 3 hours, and 5 mL of 1N HCl (aq) was added thereto. From the reaction solution, the organic layer was separated, and the remaining water layer was extracted twice with 100 mL of dichloromethane to collect an organic layer. The organic layer thus collected was dried with magnesium sulfate, and the residue obtained after filtering and evaporating the solvent was separated and purified using silica gel column chromatography to obtain 2.03 g of Intermediate I-4 (yield: 78percent). The compound thus produced was confirmed by MS/FAB. C20H20: calc. 260.15. found 260.21.
Stage #1: indenoindene; methyl iodide With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 3h;
Stage #2: With hydrogenchloride In tetrahydrofuran; hexane; water
Synthesis of Intermediate I-4
2.04 g (10 mmol) of intermediate I-3 and 37.5 mL (60 mmol) of n-BuLi (1.60M hexane solution) was gradually reacted with THF at about -78° C. 3.8 ml (60 mmol) of CH3I was added into the reaction solution, and was then stirred at room temperature for about 3 hours, followed by adding 5 ml of a 1N HCl aqueous solution into the mixture. The organic phase was separated from the reaction solution, and the aqueous phase was extracted with dichloromethane (2×100 ml). The collected organic phase was dried using magnesium sulfate to evaporate the solvent. The residue was separated and purified using silica gel column chromatography to obtain 2.03 g of Intermediate I-4 (Yield: 78%). This compound was identified using MS/FAB. C20H20: calc. 260.37. found 260.45
78%
Stage #1: indenoindene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667h;
Stage #2: methyl iodide In tetrahydrofuran; hexane at 20℃; for 3h;
1 synthesis of the intermediate I-4
In -78 THF intermediate I- 3s (2.04g, 10mmol) and n-BuLi (1.60M hexane solution) (37.5, 60mmol), it reacted for 10 minutes at the slowly. After the CH 3 I (3.8, 60mmol) was put into the reaction solution and it mixed at a room temperature for 3hours 1N HCl (aq) (5)was added. The layer of water was extracted in the dichloromethane (2×100) to separate the organic layeramong the reaction solution. The residue which was dry to the magnesium sulfate and disappeared the solvent and was the collected organic layer obtained was refined to the silica gel pipe chromatography after dividingand the intermediate I-4 2.03g (the yield 78%) was obtained. The generated compound was confirmed through the MS / FAB. C20H20: the calculation value 260.37,and the measured value 260.45.
78%
With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane; water at -78 - 20℃; for 3h;
1 Synthesis of Intermediate 4-6
2.04 g (10 mmol) of Intermediate 3-6 and 37.5 ml (60 mmol) of n-BuLi (1.60M hexane solution) were mixed in THF at -78° C. to induce a reaction therebetween. Subsequently, 3.8 ml (60 mmol) of iodomethane was added to the reaction solution, the resulting solution was stirred at room temperature for 3 hours, and 5 ml of 1N HCl (aq) was added thereto. An organic layer was separated from the reaction solution and the remaining water layer was extracted twice with 100 ml of dichloromethane. The obtained organic layer was dried with magnesium sulfate and a solvent was evaporated therefrom to obtain a crude product. The crude product was purified with silicagel column chromatography to obtain 2.03 g of Intermediate 4-6 (yield: 78%). The obtained compound was confirmed by MS/FAB. C20H20: calc. 260.15. found 260.21.
78%
Stage #1: indenoindene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667h;
Stage #2: methyl iodide In tetrahydrofuran; hexane at 20℃; for 3h;
1 Synthesis of Intermediate I-4
Synthesis of Intermediate I-4 2.04 g (10 mmol) of Intermediate I-3 and 37.5 mL (60 mmol) of n-BuLi (1.60 M hexane solution) were slowly reacted in THF at a temperature of -78° C. for 10 minutes. 3.8 mL (60 mmol) of iodomethane was added to the reaction solution, stirred at room temperature for 3 hours, and 5 mL of 1N HCl (aq) was added thereto. From the reaction solution, the organic layer was separated, and the remaining water layer was extracted twice with 100 mL of dichloromethane to collect an organic layer. The organic layer thus collected was dried with magnesium sulfate, and the residue obtained after filtering and evaporating the solvent was separated and purified using silica gel column chromatography to obtain 2.03 g of Intermediate I-4 (yield: 78%). The compound thus produced was confirmed by MS/FAB. C20H20: calc. 260.15. found 260.21.
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 24h;
Synthesis of Intermediate I-5a
3.56 g (20 mmol) of N-bromosuccinimide (NBS) was completely dissolved in 50 ml of dimethylformamide (DMF) to obtain a solution. Afterward, 2.60 g (10 mmol) of Intermediate I-4 was added into the solution and was then stirred at room temperature for about 24 hours. 50 ml of water was added into the reaction solution to obtain a precipitate, which was then extracted using dichloromethane. The aqueous phase was extracted from the reaction solution using dichloromethane (2×50 ml). The collected organic layer was dried using magnesium sulfate to evaporate the solvent. The residue was separately purified using silica gel column chromatography to obtain 2.55 g of Intermediate I-5a (Yield: 75%) This compound was identified using MS/FAB. C20H19Br: calc. 339.27. found 339.87
75%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 24h;
1 Synthesis of Intermediate I-5a
NBS (N-Bromosuccinimide, N- bromosuccinimide) 3.56g (20mmol) of DMF (Dimethylformamide) and then completely dissolved in the solution into 50 intermediate I-4 (2.60g, 10mmol) at room temperature for 24 hours to It was stirred. Put the reaction solution into water and the resulting precipitate was extracted 50 with dichloromethane. The remaining aqueous layer was extracted with dichloromethane (2 × 50). The combined organic layers were dried over magnesium sulfate and purified by separating the residue obtained by evaporation of the solvent by silica jel chromatography Intermediate I-5a 2.55g (75% yield) It was obtained. The resulting compound was confirmed by MS / FAB .C20H19Br: calculated 339.27, 339.87 measure
61%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 24h;
1 Synthesis of Intermediate I-5
Synthesis of Intermediate I-5 3.56 g (20 mmol) of N-bromosuccinimide (NBS) was completely dissolved in 50 mL of dimethylformamide (DMF), and 2.60 g (10 mmol) of Intermediate I-4 was added to the solution and stirred at room temperature for 24 hours. 50 mL of water was added to the solution, and an organic layer was obtained by extracting the reaction solution twice with 50 mL of dichloromethane. The organic layer thus collected was dried with magnesium sulfate, and the residue obtained after filtering and evaporating the solvent therefrom was separated and purified using silica gel column chromatography to obtain 2.55 g of Intermediate I-5 (yield: 61%). The compound thus produced was confirmed by MS/FAB. C20H18Br: calc. 339.27. found 339.30.
Multi-step reaction with 2 steps
1: N-Bromosuccinimide / N,N-dimethyl-formamide / 24 h / 20 °C
2: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / tetrahydrofuran; water / 5 h / 70 °C
Multi-step reaction with 2 steps
1: N-Bromosuccinimide / N,N-dimethyl-formamide / 24 h / 20 °C
2: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / tetrahydrofuran; water / 5 h / 70 °C
With aluminum oxide; copper(ll) bromide In tetrachloromethane at 80℃; for 8h;
61%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 24h;
1 Synthesis of Intermediate 5-6
3.56 g (20 mmol) of N-bromosuccinimide (NBS) was completely dissolved in 50 ml of dimethylformamide (DMF), 2.60 g (10 mmol) of Intermediate 4-6 was then added thereto, and the resulting solution was stirred at room temperature for 24 hours. The reaction solution was extracted twice with 50 ml of water and 50 ml of dichloromethane. The obtained organic layer was dried with magnesium sulfate and a solvent was evaporated therefrom to obtain a crude product. The crude product was purified with silicagel column chromatography to obtain 2.55 g of Intermediate 5-6 (yield: 61%). The obtained compound was confirmed by MS/FAB. C20H18Br2: calc. 415.97. found 416.11.
Multi-step reaction with 2 steps
1: N-Bromosuccinimide / N,N-dimethyl-formamide / 24 h / 20 °C
2: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / tetrahydrofuran; water / 5 h / 70 °C
Stage #1: With magnesium; triphenylphosphine; lithium chloride; iron(II) chloride In tetrahydrofuran at 20℃; Schlenk technique; Inert atmosphere;
Stage #2: With 1,2-Dichloropropane In tetrahydrofuran at 20℃; Inert atmosphere;
4 <Example 2>
General procedure: LiCl (25.4 mg, 0.60 mmol) was added to a Schlenk tube, dried by heating, and FeCl2 (2.6 mg, 0.02 mmol), PPh3 (10.5 mg, 0.04 mmol), Mg powder (14 .6 mg, 0.60 mmol) and compound 11 (116.6 mg, 0.20 mmol) were added under a nitrogen stream. To this mixture, THF (0.4 mL) was added and stirred at room temperature for 7 hours, then 1,2-dichloropropane (39 μL, 0.40 mmol) was slowly added and further stirred at room temperature for 12 hours. The reaction solution was diluted with chloroform (20 mL), the organic layer was washed with 1M hydrochloric acid (15 mL), dried over sodium sulfate and filtered. The organic layer was concentrated under reduced pressure, and the obtained crude product was dissolved in chloroform-methanol and recrystallized to obtain the compound of Example 2 with a yield of 93%.
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