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According to the synthetic scheme shown above, compound (T-2) (129.5 g) obtained as an intermediate of Example 1 was dissolved in DryTHF (500 ml), and the resultant solution was cooled to -70C. In a nitrogen atmosphere, n-BuLi (500 ml) was added dropwise, and agitation was carried out at -70C for 2 hours. Then, a DryTHF solution of trimethyl borate (129.5 g) was slowly added dropwise at -70C, and the resultant solution was heated to room temperature and agitated for 16 hours. After completion of the reaction, 2N-HCl (200 ml) was added, and then extraction was carried out with toluene, an organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then the resultant solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and thus a light brown solid was obtained. The resultant material was subjected to recrystallization (heptane: toluene = 4 : 1 in a volume ratio), and thus (T-20) was obtained as a colorless crystal (117.2 g, yield: 71%).
71%
The compound (T-2) obtained in the above step(129.5 g) was dissolved in Dry THF (500 ml)It was cooled to -70 C.N-BuLi (500 ml) was added dropwise under a nitrogen atmosphere, and the mixture was stirred at -70 C. for 2 hours. Thereafter, a Dry THF solution of trimethyl borate (129.5 g) was slowly added dropwise at -70 C., the temperature was raised to room temperature, and the mixture was stirred for 16 hours.After completion of the reaction, 2N HCl (200 ml) was added and the mixture was extracted with toluene, washed with water and saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a light brown solid.This product was recrystallized (heptane: toluene = 4: 1 by volume ratio) to obtain (T-20) as colorless crystals (117.2 g, yield 71%).
In a reactor under nitrogen atmosphere, 50 ml of tetrahydrofuran (THF) was added to 6.15g of magnesium (Mg), followed by stirring at 44 C. 60.0 g of 1-bromo-4-etoxy-2,3-difluorobenzene (a1) dissolved in 130 ml of THF was added dropwise thereto in the temperature range of 38 C. to 49 C. for 1 hour. The resulting solution was added dropwise to a solution of 200 ml of THF and 39.5 g of trimethyl boratein the temperature range of -50 C. to -30 C. The reaction solution was injected into a mixture of 500 ml of 1N hydrochloric acid and 600 ml of ethyl acetate. The mixture was separated into organic layer and aqueous layer, and the organic layer was extracted. The resulting organic layer was washed with saturated chloride aqueous solution and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to provide the residue. The resulting residue was purified by re-crystallization from a heptane, dried to provide 41.6 g of 4-ethoxy-2,3-difluorophenylboronic acid (a2) as a yellew solid.
With sodium carbonate;palladium on activated charcoal; In isopropyl alcohol; for 10h;Reflux; Inert atmosphere;
In a reactor under nitrogen atmosphere, 20.0 g of compound (a2)17.2 g of 4-bromo-2,3-difluorophenol (a3), 30.6 g of sodium carbonate, 0.54 g of palladium on carbon catalyst (Pd/C) were dissolved in 120 mL of 2-propanol (IPA). After stirring by refluxing for 10 hours, the reaction mixture was cooled to room temperature, and injected into a mixture of 500 ml of 1N hydrochloric acid and 300 ml of toluene which was cooled into 0 C. The mixture was separated into organic layer and aqueous layer and the organic layer was extracted. The resulting organic layer was washed with saturated chloride aqueous solution and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to provide the residue. The resulting residue was purified by recrystallization from heptan, dried to provide 13.2 g of 4'-ethoxy-2,3,2',3'-tetrafluorobiphenyl-4-ol (a4) as a white solid.
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In Solmix A-11; water; toluene; for 2h;Inert atmosphere; Reflux;
First Step: 4-Bromoiodobenzene (1) (20.0 g), <strong>[212386-71-5]4-ethoxy-2,3-difluorophenylboronic acid</strong> (2)(14.4 g), potassium carbonate (29.3 g), Pd(Ph3P)2Cl2 (1.49 g), toluene (100 ml) , Solmix A-11 (100 ml), and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25 C, and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by means of recrystallization from Solmix A-11 and dried, giving 20.8 g of 4-ethoxy-4'-bromo-2,3-difluoro-1,1'-biphenyl (3). The yield based on the compound (1) was 94.0%.
94%
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In Solmix A-11; water; toluene; for 2h;Reflux; Inert atmosphere;
4-Ethoxy-2,3-difluorophenylboronic acid (7) (14.4 g), 4-bromoiodobenzene (8) (20.0 g), potassium carbonate (29.3 g), Pd (Ph3P)2Cl2 (1.49g), toluene (100ml), Solmix A-11 (100ml) and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25 C, and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to separate into organic and aqueous phases. The extraction into an organic phase was carried out. The organic phase obtained was washed with water and dried over anhydrous magnesium sulfate. Then, the solution was concentrated under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel; toluene). The product was further purified by means of recrystallization (Solmix A-11), giving 20.8 g of 4-ethoxy-4'-bromo-2,3-difluoro-1,1'-biphenyl (9). The yield based on the compound (8) was 94.0%.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 20h;Reflux;
Method B (from 2-bromoselenophene): A mixture of 45.0 g (0.21 mol) of 2-bromoselenophene, 52.0 g (0.26 mol) of <strong>[212386-71-5]4-ethoxy-2,3-difluorophenylboronic acid</strong>, 20.0 g (17.3 mmol) of tetrakis(triphenylphosphine)palladium(0) and 600 ml of 2 N sodium carbonate soln. in 1100 ml of toluene/ethanol (1:1) is heated under reflux for 20 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with sat. sodium hydrogencarbonate soln., 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=3:2). Further purification is carried out by recrystallisation from ethanol; 2-(4-ethoxy-2,3-difluorophenyl)selenophene is obtained as a beige solid.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 1.5h;Reflux;
Example 30; 2-(4-Ethoxy-2,3-difluorophenyl)-5-propyltellurophene; 30.1 Preparation of 2-(4-ethoxy-2,3-difluorophenyl)tellurophene; A mixture of 10.0 g (38.7 mmol) of 2-bromotellurophene, 8.0 g (39.6 mmol) of <strong>[212386-71-5]4-ethoxy-2,3-difluorophenylboronic acid</strong>, 3.5 g (3.0 mmol) of tetrakis-(triphenylphosphine)palladium(0) and 100 ml of 2 N sodium carbonate soln. in 200 ml of toluene/ethanol (1:1) is heated under reflux for 1.5 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with sat. sodium hydrogencarbonate soln., 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=3:2). Further purification is carried out by recrystallisation from ethanol; 2-(4-ethoxy-2,3-difluorophenyl)tellurophene is obtained as a yellow solid.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 23h;Reflux;
Example 4; 2-(4-Ethoxy-2,3-difluorophenyl)-5-methylselenophene; 4.1 Preparation of 2-(4-ethoxy-2,3-difluorophenyl)selenophene; Method A (from 2-iodoselenophene): A mixture of 34.8 g (0.14 mol) of 2-iodoselenophene, 32.8 g (0.16 mol) of <strong>[212386-71-5]4-ethoxy-2,3-difluorophenylboronic acid</strong>, 8.10 g (77.01 mmol) of tetrakis -(triphenylphosphine)palladium(0) and 300 ml of 2 N sodium carbonate soln. in 800 ml of toluene/ethanol (1:1) is heated under reflux for 23 h. The mixture is diluted with MTBE and washed with water. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with 2 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:EtOAc=15:1-10:1?5:1). Further purification is carried out by recrystallisation from n-heptane; 2-(4-ethoxy-2,3-difluorophenyl)selenophene is obtained as a beige solid.
With potassium carbonate;palladium on carbon; In ethanol; water; toluene; for 2h;Reflux; Inert atmosphere;
Ethyl 4-iodoethylbenzoate (1) (25.0 g), <strong>[212386-71-5]4-ethoxy-2,3-difluorophenylboronic acid</strong> (2) (20.1 g), potassium carbonate (25.0 g), Pd/C (0.25 g), toluene (100 ml), ethanol (100 ml) and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25 C, and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases. The extraction to an organic phase was carried out. The organic phase obtained was washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel; toluene). The product was further purified by means of recrystallization from ethanol and dried, giving 18.8 g of ethyl 4-ethoxy-2,3-difluoro-4'-biphenylcarboxylate (3). The yield based on the compound (1) was 67.9%.
67.9%
With potassium carbonate;5% Pd(II)/C(eggshell); In ethanol; water; toluene; for 2h;Inert atmosphere; Reflux;
Example 1; Synthesis of 4-ethoxy-2,3-difluoro-4'-[2,3-difluoro-4-(4-pentylcyclohexyl)phenoxymethyl]-1,1'-biphenyl (No. 1123) [Show Image] First Step: 4-Iodoethyl benzoate (1) (25.0 g), <strong>[212386-71-5]4-ethoxy-2,3-difluorophenylboronic acid</strong> (2) (20.1 g), potassium carbonate (25.0 g), palladium on carbon (NX type of 5%Pd/C; 50% wet; made by N. E. Chemcat; hereinafter referred to as Pd/C) (0.25 g), toluene (100 ml), ethanol (100 ml) and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25 C, and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by means of recrystallization from ethanol and dried, giving 18.8 g of ethyl 4-ethoxy-2,3-difluoro-4'-biphenylbenzoate (3). The yield based on the compound (1) was 67.9%.
250 mL three flask was added 15.8g (0.1mol) 2,3-difluorophenyl ether,tetrahydrofuran, 100ml, with nitrogen replacement air, cooled to -60 C, wasadded dropwise 2.5M n-butyllithium 44ml (0.11mol), After the addition stirring.The reaction for half an hour, a solution of trimethyl borate 11.5g (0.11mol),plus after any of its natural warming, rising to -10 C, the The reactionsolution was poured into a mass percent concentration of 5% hydrochloric acidin water hydrolysis reaction, pH value of the system 1, liquid separation, Theaqueous phase was extracted 100ml of toluene, and the combined organic phases,100ml × 2 brine, net solvent was distilled off under reduced pressure, add 50mloil Ethers boil, cooled to room temperature, freezing in the refrigerator, awhite solid was filtered to give 16.2g (3-a), in 80% yield
71%
Preparation of 1-ethoxy-2,3-difluorophenylboronic acid (T-3) The compound (T-2) (129.5 g) obtained in the above procedure was dissolved in dried tetrahydrofuran (hereinafter, abbreviated to dried THF) (500 ml), and the solution was cooled to -70 C. n-BuLi (500 ml) was added dropwise under an atmosphere of nitrogen, and the stirring was continued at -70 C for 2 another hours. Then, trimethyl borate (129.5 g) in a dried THF solution was added dropwise slowly at -70 C, and warmed up to room temperature. The stirring was continued for another 16 hours. After the completion of the reaction, 2N-HCl (200 ml) was added to the mixture. The mixture was extracted with toluene, and washed with water and brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to leave pale brown solids. Recrystallization (heptane: toluene= 4:1 by volume) gave the compound (T-3) as colorless powders (117.2 g) in 71% yield.
With sodium carbonate;palladium on activated charcoal; In solmix; for 6h;Reflux; Inert atmosphere;
Preparation of 4'-ethoxy-2',3,3'-trifluorobiphenyl-4-ol (T-5) The compound (T-3) (88.8 g) obtained in the above procedure, 4-bromo-2-fluorophenol (T-4) (76.4 g), sodium carbonate (50.8 g) and Pd-C (NX type) (0. 21 g) were dissolved in Solmix (400 ml) and the mixture was heated to reflux for 6 hours under an atmosphere of nitrogen. After the completion of the reaction, the reaction mixture was filtered through Celite, and the filtrate was extracted with toluene. The organic layer was washed with an aqueous 2N-sodium hydroxide solution, a saturated aqueous solution of sodium hydrogencarbonate, water and brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to leave pale brown solids. Recrystallization (heptane:toluene= 4:1 by volume) gave 4'-ethoxy-2',3,3'-trifluorobiphenyl-4-ol (T-5) as colorless powders (72.0 g) in 67% yield.
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