* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene at 110℃; Inert atmosphere
20.4 g (100 mmol, 1.0 eq.) of 5-phenyl-2-thiophenolboronic acid and 31.1 g (110 mmol, 1.1 eq.) of p-bromoiodobenzene were added to a 2 L three-necked flask and 1000 ml of toluene and 100 ml of ethanol were added. Dissolve, purge with nitrogen for 15 minutes, add 150 ml of 2M aqueous solution containing 41.5 g (300 mmol, 3.0 eq.) of K2CO3, and finally add 2.3 g of Pd(PPh3)4 (2 molpercent). The temperature was raised to 110°C and the reaction was completed overnight. Activated carbon adsorption was added, suction filtration, solvent removal, drying and recrystallization from toluene and ethanol gave 26.2 g of intermediate-9 with a yield of 83percent.
78%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene at 100℃;
20.4 g (100 mmol, 1.0 eq.) of 5-phenyl-2-thiophene boric acid and 31.1 g (110 mmol, 1.1 eq.)P-bromo-iodobenzene was added to a 2L three-necked flask was charged with 1000ml of toluene and 100ml of ethanol were dissolved,After nitrogen was passed for 15 minutes, 150 ml of a 2M aqueous solution containing 41.5 g (300 mmol, 3.0 eq.) of K2CO3 was added, and finally 2.3 g of Pd(PPh3)4 (2 mol percent) was added.The temperature was raised to 100°C and the reaction ended overnight. Add activated carbon adsorption, suction filtration, remove the solvent,It was dried and recrystallized from toluene and ethanol to give 19.6 g of Intermediate-17 with a yield of 78percent.
75%
With potassium carbonate In tetrahydrofuran; water for 3 h; Heating / reflux
2-Thiophene boronic acid (10 g, 78.1 mmol) and bromo benzene (7.48 mL, 70.3 mmol) were dissolved in anhydrous THF (300 mL), and then Pd(PPh ) (4.51 g, 3.913 4 mmol) and a K CO aqueous solution (156 mL, 312.4 mmol) were added thereto,2 3 refluxed for 3 hrs. The organic layer was extracted with ethyl acetate, and dried over magnesium sulfate. The organic layer was filtered under reduced pressure, and concentrated to remove the solvent. The residue was purified by column chromatography, and then recrystallized in THF and ethanol to obtain a white solid compound (1O g, 83percent).[125] MS: [M+H] = 161.[126] The prepared white solid compound (5 g, 31.3 mmol) were dissolved in anhydrous THF (200 mL), and then cooled to -1O0C. Then, n-butyllithium (15 mL, 37.5 mmol) was slowly added dropwise, and stirred for 1 hr. Subsequently, the reaction temperature was decreased to -780C, and then boronic acid trimethylester (10.5 mL, 93.75 mmol) was slowly added, stirred for 12 hrs. After the temperature was decreased to O0C, a 2 N hydrochloric acid aqueous solution (16 mL) was added thereto, and stirred to obtain a white precipitate. The organic layer was extracted with THF, dried over magnesium sulfate, and then filtered under reduced pressure. The filtrate was concentrated to remove the solvent, and the resultant was dissolved in THF. An excessive amount of aqueous solution was added thereto, and the organic layer was separated with dimethylchloromethane. A hydrochloric acid aqueous solution was added to the separated aqueous layer, precipitated, filtered to obtain a compound (2.7 g, 42percent).[127] 3-Bromoiodobenzene (3.5 g, 12.3 mmol) and the above prepared compound (2.5 g, 12.3 mmol) were dissolved in anhydrous THF (100 mL), and Pd(PPh ) (0.71 g, 0.61 mmol) were added thereto. K CO (3.4 g, 24.6 mmol) dissolved in H O (50 mL) was added thereto, and then refluxed under stirring. After 3 hrs, the resultant was washed with brine, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered under reduced pressure, and concentrated to remove the solvent. The residue was purified by column chromatography to obtain a compound H (2.9 g, 75percent).[128] MS: [M+H]+ = 315.
70%
With potassium carbonate In tetrahydrofuran; water for 5 h; Reflux
After 1-bromo-4-iodobenzene (2.82 g, 10 mmol) and 2-phenyl-cyophenboronic acid (2.04 g, 10 mmol) were dissolved in tetrahydrofuran (30 mL), 2M potassium carbonate aqueous solution (20 mL) was added thereto, and tetrakistriphenylphosphino palladium (Pd(PPh3)4 (231 mg, 2 molpercent) was put thereinto, agitated and refluxed for 5 hours. The temperature was lowered to normal temperature, the water layer was removed, and the organic layer was dried with anhydrous magnesium sulfate and filtered. The filtered solution was concentrated under the reduced pressure and recrystallized with ethylether to prepare the compound B-17 (2.2 g, 70percent). MS: [M]+=315
70%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water for 5 h; Reflux
1-bromo-4-iodobenzene (2.82g, 10mmol) and 2-phenyl-5-thiophenyl boronic acid (2.04g, 10mmol) were dissolved in THF (30mL), 2M K2CO3 aqueous solution (20mL) was added, Pd (PPh3)4 (0.231g, 2molpercent) was added and stirred under reflux for 5 hours. The reaction mixture was cooled to room temperature, aqueous layer was removed, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The solution was filtered, concentrated under reduced pressure, and recrystallized with ethyl ether to obtain compound B-17(2.2g, 70percent yield).
Reference：
[1] Patent: CN108101896, 2018, A, . Location in patent: Paragraph 0082; 0091-0094; 0178
[2] Patent: CN108101898, 2018, A, . Location in patent: Paragraph 0111; 0137-0140
[3] Patent: WO2008/133459, 2008, A1, . Location in patent: Page/Page column 52
[4] Patent: EP2311826, 2011, A2, . Location in patent: Page/Page column 70
[5] Patent: KR101567610, 2015, B1, . Location in patent: Paragraph 0254-0257
[6] Patent: US2008/108832, 2008, A1, . Location in patent: Page/Page column 51
[7] Patent: EP2177516, 2010, A1, . Location in patent: Page/Page column 46-47
2
[ 29488-24-2 ]
[ 306934-95-2 ]
Yield
Reaction Conditions
Operation in experiment
48.8%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: With Trimethyl borate In tetrahydrofuran; hexane at -78 - 20℃; for 3.5 h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexane
Synthesis of Compound 112To a solution of Compound 111 (2.50 g, 10.4 mmol) in dry THF (50 ml) was added dropwise n-BuLi (8.4 mL of a 2.5 M solution in hexane) at -78° C. under nitrogen atmosphere. After the mixture had been stirred for about 1 hour, trimethylborate (2.40 mL, 20.9 mmol) was added dropwise at -78° C. After about 30 minutes, the cooling bath was removed, and the mixture then was stirred for about 3 hours at room temperature. The mixture was quenched with 1 N HCl (100 ml) and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was slurried in petroleum ether, filtered off with suction, and dried to obtain of Compound 112 (1.04 g, 48.8percent).
Reference：
[1] Patent: US7485733, 2009, B2, . Location in patent: Page/Page column 77
[2] Chemistry - A European Journal, 2002, vol. 8, # 10, p. 2384 - 2396
[3] Patent: US2008/108832, 2008, A1, . Location in patent: Page/Page column 51
[4] Patent: EP2177516, 2010, A1, . Location in patent: Page/Page column 46-47
3
[ 825-55-8 ]
[ 5419-55-6 ]
[ 306934-95-2 ]
Yield
Reaction Conditions
Operation in experiment
63.6%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: at -78 - 25℃; Inert atmosphere Stage #3: With hydrogenchloride In tetrahydrofuran; water for 1 h; Inert atmosphere
2-Phenylthiophene (1.0 g, 6.24 mmol) was dissolvedin THF (20 mL) and this reaction mixture was cooledto −78 C under N2 atmosphere. Then n-BuLi (1.6M,3.9 mL, 6.42 mmol) was added over 15 min to the solutionand stirred for 1 h at the same temperature. Triisopropylborate (1.44 mL, 6.24 mmol) was added dropwise at−78 C to the cooled solution for the duration of 10min, and the resulting mixture was allowed to warm upto room temperature for overnight. The reaction mixturewas acidified with 10percent HCl, and stirred for 1 h.The aqueous mixture was extracted with diethyl ether for three times (50 mL) and the organic layer was washedwith water. The resulting solution was concentrated underreduced pressure. The crude product was recrystallizedfrom ethanol:water (1:20) to afford compound 2 as lightblue solid (810 mg, 63.6percent).13 1H NMR (400 MHz,DMSO-d6) 8.25 (s, 2H), 7.68–7.64 (m, 3H), 7.52(d, 3.7 Hz, 1H), 7.41 (t, 8.1 Hz, 2H), 7.32 (t, 7.3 Hz, 1H).
Reference：
[1] Journal of Nanoscience and Nanotechnology, 2017, vol. 17, # 8, p. 5530 - 5538
[2] ChemPlusChem, 2017, vol. 82, # 5, p. 742 - 749
4
[ 825-55-8 ]
[ 306934-95-2 ]
Yield
Reaction Conditions
Operation in experiment
35%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.333333 h; Reflux Stage #2: With Trimethyl borate In tetrahydrofuran; hexane at -78 - 20℃; Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water for 1 h;
5-Phenyl-2-thiopheneboronic acid n-Butyllithium (1.6M in hexanes) (24 ml, 38.1 mmol) was added drop wise to a solution of 2-phenylthiophene (6.1 g, 38.1 mmol) in anhydrous THF (150 ml), at 0°C, under nitrogen. The ice-bath was removed, and the mixture heated to reflux for 20 min. After cooling, the reaction mixture was added drop wise to a solution of trimethyl borate (8.7 ml, 76.25 mmol) in anhydrous THF (100 ml), at -78°C, under nitrogen. This was allowed to warm to room temperature overnight, then was acidified with concentred HCl, stirred for 1 h, then extracted with Et2O (3 x 100 ml). The combined extracts were washed with water (2 x 100 ml), dried (Na2SO4), and the solvent removed. The resulting grey solid was recrystallized from ethanol / water (50: 50), then dissolved in aqueous NaOH (2M, 500 ml), Et2O (250 ml) added, the aqueous layer precipitated with concentred HCl, extracted with Et2O (300 ml), dried (Na2SO4) and the solvent removed under pressure to give the title compound (2.72 g, 35 percent) as an off white solid.
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at -78 - 20℃; for 3.5 h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water
To a solution of Compound 111 (2.50 g, 10.4 mmol) in dry THF (50 ml) was added dropwise n-BuLi (8.4 mL of a 2.5 M solution in hexane) at-78 °C under nitrogen atmosphere. After the mixture had been stirred for about 1 hour, trimethylborate (2.40 mL, 20.9 mmol) was added dropwise at-78 °C. After about 30 minutes, the cooling bath was removed, and the mixture then was stirred for about 3 hours at room temperature. The mixture was quenched with 1 N HCl (100 ml) and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was slurried in petroleum ether, filtered off with suction, and dried to obtain of Compound 112 (1.04 g, 48.8percent).
Stage #1: 4-bromo-p-terphenyl With tetrakis(triphenylphosphine) palladium(0) In 1,2-dimethoxyethane at 20℃; for 0.166667h;
Stage #2: 2-phenylthiophen-5-ylboronic acid With sodium carbonate In 1,2-dimethoxyethane for 24h; Heating; Further stages.;
Synthesis of Compound 112To a solution of Compound 111 (2.50 g, 10.4 mmol) in dry THF (50 ml) was added dropwise n-BuLi (8.4 mL of a 2.5 M solution in hexane) at -78 C. under nitrogen atmosphere. After the mixture had been stirred for about 1 hour, trimethylborate (2.40 mL, 20.9 mmol) was added dropwise at -78 C. After about 30 minutes, the cooling bath was removed, and the mixture then was stirred for about 3 hours at room temperature. The mixture was quenched with 1 N HCl (100 ml) and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was slurried in petroleum ether, filtered off with suction, and dried to obtain of Compound 112 (1.04 g, 48.8%).
Synthetic Example 4 Synthesis of Intermediate 4 A reaction vessel of 20 L was charged with 703 g of Intermediate 3 and 7 L of anhydrous THF (tetrahydrofuran) under argon flow and cooled down to -30 C. n-Butyhllithium (n-BuLi, 1.6 M hexane solution) 2.3 L was added thereto to carry out reaction for one hour. After cooled down to -70 C., 1658 g of triisopropyl borate (manufactured by Tokyo Kasei Kogyo Co., Ltd.) was added thereto. The solution was slowly heated and stirred at room temperature for one hour. A 10% hydrochloric acid solution 1.7 L was added thereto and stirred. The reaction solution was extracted with ethyl acetate and water, and the organic layer was washed with water. The organic layer was dried on anhydrous sodium sulfate, and the solvent was removed by distillation. The residue was washed with hexane, whereby 359 g of a white powder was obtained.
Synthesis Example 3 (synthesis of Intermediate 3); Under an argon stream, to a 20-L reaction container, 703 g of Intermediate 2 and 7 L of dehydrated tetrahydrofuran (THF) were charged, and the mixture was cooled to -30C. 2.3 L of n-BuLi (1.6 M hexane solution) was added thereto, and the mixture was reacted for 1 hour. After the resultant was cooled to -70C, 1,658 g of Boric Acid Triisopropyl Ester (manufactured by Tokyo Chemical Industry Co . , Ltd.) wasaddedthereto. The temperature of the mixture was raised slowly, and the mixture was stirred at room temperature for 1 hour. 1. 7 L of 10%-hydrochloric acid solution was added thereto and the mixture was stirred. The mixture was extracted with ethyl acetate and water, and an organic layer was washed with water. The resultant was dried with anhydrous sodium sulfate to thereby distill off the solvent. The resultant was washed with hexane, whereby 359 g of white powder was obtained. Under an argon stream, to a 20-L reaction container, 506 g of 5-phenyl-2-thiopheneboronic acid obtained above, 600 g of 4-iodobromobenzene, 41 g of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), 2.6 L of 2 M sodium carbonate (Na2CO3) solution, and 10 L of dimethoxyethane were charged, and the mixture was reacted at 80C for 8 hours. The reactant was extracted with toluene and water, followed by drying with anhydrous sodium sulfate. The resultant was concentrated under reduced pressure, and the obtained crude product was subjected to column purification, whereby 277 g of white powder was obtained. By an FD-MS analysis, the white powder was identified as Intermediate 3.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 110.0℃;Inert atmosphere;
20.4 g (100 mmol, 1.0 eq.) of 5-phenyl-2-thiophenolboronic acid and 31.1 g (110 mmol, 1.1 eq.) of p-bromoiodobenzene were added to a 2 L three-necked flask and 1000 ml of toluene and 100 ml of ethanol were added. Dissolve, purge with nitrogen for 15 minutes, add 150 ml of 2M aqueous solution containing 41.5 g (300 mmol, 3.0 eq.) of K2CO3, and finally add 2.3 g of Pd(PPh3)4 (2 mol%). The temperature was raised to 110C and the reaction was completed overnight. Activated carbon adsorption was added, suction filtration, solvent removal, drying and recrystallization from toluene and ethanol gave 26.2 g of intermediate-9 with a yield of 83%.
78%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 100.0℃;
20.4 g (100 mmol, 1.0 eq.) of 5-phenyl-2-thiophene boric acid and 31.1 g (110 mmol, 1.1 eq.)P-bromo-iodobenzene was added to a 2L three-necked flask was charged with 1000ml of toluene and 100ml of ethanol were dissolved,After nitrogen was passed for 15 minutes, 150 ml of a 2M aqueous solution containing 41.5 g (300 mmol, 3.0 eq.) of K2CO3 was added, and finally 2.3 g of Pd(PPh3)4 (2 mol %) was added.The temperature was raised to 100C and the reaction ended overnight. Add activated carbon adsorption, suction filtration, remove the solvent,It was dried and recrystallized from toluene and ethanol to give 19.6 g of Intermediate-17 with a yield of 78%.
75%
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; for 3.0h;Heating / reflux;
2-Thiophene boronic acid (10 g, 78.1 mmol) and bromo benzene (7.48 mL, 70.3 mmol) were dissolved in anhydrous THF (300 mL), and then Pd(PPh ) (4.51 g, 3.913 4 mmol) and a K CO aqueous solution (156 mL, 312.4 mmol) were added thereto,2 3 refluxed for 3 hrs. The organic layer was extracted with ethyl acetate, and dried over magnesium sulfate. The organic layer was filtered under reduced pressure, and concentrated to remove the solvent. The residue was purified by column chromatography, and then recrystallized in THF and ethanol to obtain a white solid compound (1O g, 83%).[125] MS: [M+H] = 161.[126] The prepared white solid compound (5 g, 31.3 mmol) were dissolved in anhydrous THF (200 mL), and then cooled to -1O0C. Then, n-butyllithium (15 mL, 37.5 mmol) was slowly added dropwise, and stirred for 1 hr. Subsequently, the reaction temperature was decreased to -780C, and then boronic acid trimethylester (10.5 mL, 93.75 mmol) was slowly added, stirred for 12 hrs. After the temperature was decreased to O0C, a 2 N hydrochloric acid aqueous solution (16 mL) was added thereto, and stirred to obtain a white precipitate. The organic layer was extracted with THF, dried over magnesium sulfate, and then filtered under reduced pressure. The filtrate was concentrated to remove the solvent, and the resultant was dissolved in THF. An excessive amount of aqueous solution was added thereto, and the organic layer was separated with dimethylchloromethane. A hydrochloric acid aqueous solution was added to the separated aqueous layer, precipitated, filtered to obtain a compound (2.7 g, 42%).[127] 3-Bromoiodobenzene (3.5 g, 12.3 mmol) and the above prepared compound (2.5 g, 12.3 mmol) were dissolved in anhydrous THF (100 mL), and Pd(PPh ) (0.71 g, 0.61 mmol) were added thereto. K CO (3.4 g, 24.6 mmol) dissolved in H O (50 mL) was added thereto, and then refluxed under stirring. After 3 hrs, the resultant was washed with brine, and the organic layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered under reduced pressure, and concentrated to remove the solvent. The residue was purified by column chromatography to obtain a compound H (2.9 g, 75%).[128] MS: [M+H]+ = 315.
70%
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; for 5.0h;Reflux;
After 1-bromo-4-iodobenzene (2.82 g, 10 mmol) and 2-phenyl-cyophenboronic acid (2.04 g, 10 mmol) were dissolved in tetrahydrofuran (30 mL), 2M potassium carbonate aqueous solution (20 mL) was added thereto, and tetrakistriphenylphosphino palladium (Pd(PPh3)4 (231 mg, 2 mol%) was put thereinto, agitated and refluxed for 5 hours. The temperature was lowered to normal temperature, the water layer was removed, and the organic layer was dried with anhydrous magnesium sulfate and filtered. The filtered solution was concentrated under the reduced pressure and recrystallized with ethylether to prepare the compound B-17 (2.2 g, 70%). MS: [M]+=315
70%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; for 5.0h;Reflux;
1-bromo-4-iodobenzene (2.82g, 10mmol) and 2-phenyl-5-thiophenyl boronic acid (2.04g, 10mmol) were dissolved in THF (30mL), 2M K2CO3 aqueous solution (20mL) was added, Pd (PPh3)4 (0.231g, 2mol%) was added and stirred under reflux for 5 hours. The reaction mixture was cooled to room temperature, aqueous layer was removed, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The solution was filtered, concentrated under reduced pressure, and recrystallized with ethyl ether to obtain compound B-17(2.2g, 70% yield).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80.0℃; for 8.0h;
A reaction vessel of 20 L was charged with 506 g of 5-phenyl-2-thiopheneboronic acid obtained above, 600 g of 4-iodobromobenzene, 41 g of tetrakis(triphenylphosphine)-palladium (Pd(PPh3)4), 2.6 L of a 2 M solution of sodium carbonate (Na2CO3) and 10 L of dimethoxyethane under argon flow, and then they were reacted at 80 C. for 8 hours. The reaction solution was extracted with toluene/water, and the extract was dried on anhydrous sodium sulfate. This was concentrated under reduced pressure, and a crude product obtained was refined through a column, whereby 277 g of a white powder was obtained. It was identified as Intermediate 4 by analysis of FD-MS.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 80.0℃; for 8.0h;Inert atmosphere;
Synthesis Example 3 (synthesis of Intermediate 3); Under an argon stream, to a 20-L reaction container, 703 g of Intermediate 2 and 7 L of dehydrated tetrahydrofuran (THF) were charged, and the mixture was cooled to -30C. 2.3 L of n-BuLi (1.6 M hexane solution) was added thereto, and the mixture was reacted for 1 hour. After the resultant was cooled to -70C, 1,658 g of Boric Acid Triisopropyl Ester (manufactured by Tokyo Chemical Industry Co . , Ltd.) wasaddedthereto. The temperature of the mixture was raised slowly, and the mixture was stirred at room temperature for 1 hour. 1. 7 L of 10%-hydrochloric acid solution was added thereto and the mixture was stirred. The mixture was extracted with ethyl acetate and water, and an organic layer was washed with water. The resultant was dried with anhydrous sodium sulfate to thereby distill off the solvent. The resultant was washed with hexane, whereby 359 g of white powder was obtained. Under an argon stream, to a 20-L reaction container, 506 g of 5-phenyl-2-thiopheneboronic acid obtained above, 600 g of 4-iodobromobenzene, 41 g of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), 2.6 L of 2 M sodium carbonate (Na2CO3) solution, and 10 L of dimethoxyethane were charged, and the mixture was reacted at 80C for 8 hours. The reactant was extracted with toluene and water, followed by drying with anhydrous sodium sulfate. The resultant was concentrated under reduced pressure, and the obtained crude product was subjected to column purification, whereby 277 g of white powder was obtained. By an FD-MS analysis, the white powder was identified as Intermediate 3.
Stage #1: 2-phenylthiophene With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.333333h; Reflux;
Stage #2: With Trimethyl borate In tetrahydrofuran; hexane at -78 - 20℃;
Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water for 1h;
5-Phenyl-2-thiopheneboronic acid n-Butyllithium (1.6M in hexanes) (24 ml, 38.1 mmol) was added drop wise to a solution of 2-phenylthiophene (6.1 g, 38.1 mmol) in anhydrous THF (150 ml), at 0°C, under nitrogen. The ice-bath was removed, and the mixture heated to reflux for 20 min. After cooling, the reaction mixture was added drop wise to a solution of trimethyl borate (8.7 ml, 76.25 mmol) in anhydrous THF (100 ml), at -78°C, under nitrogen. This was allowed to warm to room temperature overnight, then was acidified with concentred HCl, stirred for 1 h, then extracted with Et2O (3 x 100 ml). The combined extracts were washed with water (2 x 100 ml), dried (Na2SO4), and the solvent removed. The resulting grey solid was recrystallized from ethanol / water (50: 50), then dissolved in aqueous NaOH (2M, 500 ml), Et2O (250 ml) added, the aqueous layer precipitated with concentred HCl, extracted with Et2O (300 ml), dried (Na2SO4) and the solvent removed under pressure to give the title compound (2.72 g, 35 %) as an off white solid.
To a solution of Compound 111 (2.50 g, 10.4 mmol) in dry THF (50 ml) was added dropwise n-BuLi (8.4 mL of a 2.5 M solution in hexane) at-78 C under nitrogen atmosphere. After the mixture had been stirred for about 1 hour, trimethylborate (2.40 mL, 20.9 mmol) was added dropwise at-78 C. After about 30 minutes, the cooling bath was removed, and the mixture then was stirred for about 3 hours at room temperature. The mixture was quenched with 1 N HCl (100 ml) and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was slurried in petroleum ether, filtered off with suction, and dried to obtain of Compound 112 (1.04 g, 48.8%).
Stage #1: 2-phenylthiophene With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: Triisopropyl borate In tetrahydrofuran at -78 - 25℃; Inert atmosphere;
Stage #3: With hydrogenchloride In tetrahydrofuran; water for 1h; Inert atmosphere;
2.2.2. Synthesis of 2-phenylthiophen-2yl)boronic acid (2)
2-Phenylthiophene (1.0 g, 6.24 mmol) was dissolvedin THF (20 mL) and this reaction mixture was cooledto -78 C under N2 atmosphere. Then n-BuLi (1.6M,3.9 mL, 6.42 mmol) was added over 15 min to the solutionand stirred for 1 h at the same temperature. Triisopropylborate (1.44 mL, 6.24 mmol) was added dropwise at-78 C to the cooled solution for the duration of 10min, and the resulting mixture was allowed to warm upto room temperature for overnight. The reaction mixturewas acidified with 10% HCl, and stirred for 1 h.The aqueous mixture was extracted with diethyl ether for three times (50 mL) and the organic layer was washedwith water. The resulting solution was concentrated underreduced pressure. The crude product was recrystallizedfrom ethanol:water (1:20) to afford compound 2 as lightblue solid (810 mg, 63.6%).13 1H NMR (400 MHz,DMSO-d6) 8.25 (s, 2H), 7.68-7.64 (m, 3H), 7.52(d, 3.7 Hz, 1H), 7.41 (t, 8.1 Hz, 2H), 7.32 (t, 7.3 Hz, 1H).
Stage #1: 2-phenylthiophene; Triisopropyl borate With n-butyllithium In tetrahydrofuran at -78℃;
Stage #2: With hydrogenchloride In tetrahydrofuran; water
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene at 110℃; Inert atmosphere;
3.4 (4) Synthesis of Intermediate-18
20.4 g (100 mmol, 1.0 eq.) of 5-phenyl-2-thiophenolboronic acid and 39.5 g (110 mmol, 1.1 eq.) of 4-bromo-4'-iodobiphenyl were added to a 3 L three-necked flask and added thereto. 1200 ml of toluene and 120 ml of ethanol were dissolved, nitrogen was passed for 15 minutes, 150 ml of 2M aqueous solution containing 41.5 g (300 mmol, 3.0 eq.) of K2CO3 was added, and finally 2.3 g of Pd(PPh3)4 (2 mol %) was added. The temperature was raised to 110°C and the reaction was completed overnight. After the addition of activated carbon, suction filtration, removal of the solvent by evaporation, drying, and recrystallization from toluene and ethanol, 29.3 g of Intermediate-18 was obtained with a yield of 75%.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
