| 90% |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; toluene at 95 - 105℃; Inert atmosphere; |
1 Synthesis of Intermediate 1c
Add 1a (240.00 g, 0.88 mol), 1b (496.32 g, 1.76 mol), Pd(PPh3)4 (20.35 g, 17.60 mmol), potassium carbonate (302.52 g, 2.20 mol), toluene (2400 mL), pure water (1200 mL) to a reaction flask. Start to heat after extracting air for three times, and when the reaction solution temperature reaches 95-105V, maintain it for 8-12 h; take samples for TLC and HPLC, to completely react. Stop heating and cool down to 20-30° C., perform suction filtration to separate the organic layer from filtrate. Extract the aqueous layer with ethyl acetate, combine the organic layer, then wash with water, dry by anhydrous magnesium sulfate, and perform suction filtration, to get the filtrate. Concentrate the filtrate to get a dark yellow solid crude product. The crude product is recrystallized from petroleum ether to get an off-white solid product, with a yield of 90% and a purity of 95%. |
| 74% |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane Reflux; |
1 The synthesis of the following IM1 is as follows
48.5 g of [1,1':3',1"-tetraphenyl]-5'-ylboronic acid, 50.0 g of 1-bromo-4-iodobenzene were dissolved in 1000 ml of 1, in a round bottom flask. 4-Dioxane, and placed in 265 ml of K2CO3 (2M) and 6.1 g of Pd(PPh3)4, and stirred under reflux.The reaction was confirmed by thin layer chromatography (TLC), and after adding water, the reaction was terminated. The organic layer was extracted with methyl cellulose (MC), and subjected to filtration under reduced pressure, followed by recrystallization to obtain 50.4 g (yield: 74%) of intermediate IM1 |
|
With sodium carbonate In 1,2-dimethoxyethane; water |
Under a stream of argon, 21.4 g of the boronic acid compound obtained above, 18.6 g of 4-iodobromobenzene, 3.8 g of Pd(PPh3)4, 100 ml of a 2 M aqueous solution of Na2CO3 and 160 ml of dimethoxyethane were placed into a 500 ml three-necked flask, and the resultant mixture was heated under the refluxing condition for 8 hours. The reaction fluid was treated by extraction with toluene/water, and the organic layer was dried with anhydrous sodium sulfate. After the dried solution was concentrated under a reduced pressure, the obtained crude product was purified in accordance with the column chromatography, and 15.0 g of Intermediate Compound 6 shown in the following was obtained as a white powder substance. |
|
With sodium carbonate In toluene for 10h; Inert atmosphere; Reflux; |
8
Preparation Example 8 (synthesis of Intermediate 8) In an argon gas stream, 400ml of anhydrous THF was added to 29.6g (100mmol) of 3-phenyl-5-iodobiphenyl, the by-product obtained in Preparation Example 4. While stirring the mixture at -40°C, 63ml (100mmol) of 1.6M n-butyllithium in hexane was added thereto. The reaction solution was stirred for 1 hour while heating it to 0°. The reaction solution was again cooled to -78°C, and 50ml of trimethyl borate in anhydrous THF, containing 26.0g (250mmol) of trimethyl borate, was added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 5 hours, and 200ml of 1N hydrochloric acid was added. After 1 hour stirring the aqueous phase was removed, the organic phase was dried over magnesium sulfate, and the solvent was removed by distillation in vacuo. The resultant solid was washed with toluene to give 19.2g of boronic acid compound, which was identified by FD-MS analysis. In an argon gas stream, 300ml of toluene and 150ml of 2M sodium carbonate aqueous solution were added to a mixture of 28.3g (100mmol) of 4-iodobromobenzene, 28.5g (105mmol) of the boronic acid compound above and 2.31 g (2.00mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was heated under reflux for 10 hours. The solution was filtrated immediately after the reaction, and then the aqueous phase was removed. The organic phase was dried over magnesium sulfate and concentrated, and the residue was purified by column chromatography on silica gel to give 26.2g of white powder. FD-MS analysis identified the powder as Intermediate 8.Preparation Example 9 (synthesis of Intermediate 9) |
|
With sodium carbonate In water; toluene for 10h; Inert atmosphere; Reflux; |
1
Under an argon atmosphere, 1,200 mL of toluene and 650 mL of a 2 mol/L aqueous solution of sodium carbonate were added to 70 g of 1,3,5-tribromobenzene, 54 g of phenylboronic acid, and 10.2 g of tetrakis(triphenylphosphine)palladium, and then the mixture was heated for 10 hours while being refluxed. Immediately after the completion of the reaction, the resultant was filtrated, and then the aqueous layer was removed. The organic layer was dried with sodium sulfate, and was then concentrated. The residue was purified by silica gel column chromatography. Thus, 23.9 g of a white crystal were obtained. The white crystal was identified as 3, 5-diphenyl-1-bromobenzene by field desorption mass spectral (hereinafter referred to as "FD-MS") analysis. Under an argon atmosphere, 250 mL of anhydrous tetrahydrofuran were added to 23.9 g of 3,5-diphenyl-1-bromobenzene, and then the mixture was stirred at -40°C. During the stirring, 60 mL of a 1.6 mol/L solution of n-butyllithium in hexane were added to the mixture. The reaction solution was stirred for 1 hour while being heated to 0°C. The reaction solution was cooled to -78°C again, and then a solution of 43.6 g of triisopropyl borate in 50 mL of anhydrous tetrahydrofuran was dropped to the solution. The reaction solution was stirredat room temperature for 5 hours. 200 mL of 1N hydrochloric acid were added to the solution, and then the mixture was stirred for 1 hour. After that, the aqueous layer was removed. The organic layer was dried with magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resultant solid was washed with toluene. Thus, 14.8 g of a solid were obtained. The solid was identified as 3,5-diphenylphenylboronic acid by FD-MS analysis. Under an argon atmosphere, 300 mL of toluene and 80 mL of an aqueous solution of sodium carbonate having a concentration of 2 M were added to 16.1 g of 4-bromoiodobenzene, 14.8 g of 3,5-diphenylphenylboronic acid, and 1.3 g of tetrakis (triphenylphosphine)palladium(0), and then the mixture was heated for 10 hours while being refluxed. Immediately after the completion of the reaction, the resultant was filtrated, and then the aqueous layer was removed. The organic layer was dried with sodium sulfate, and was then concentrated. The residue was purified by silica gel column chromatography. Thus, 12.5 g of a white crystal were obtained. The white crystal was identified as the intermediate 1 by FD-MS analysis. |
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