N-[1,1'-Biphenyl]-4-yl-9,9-dimethyl-9H...

white powder

2 L 50.0 g biphenyl-4-amine in the reactor (330 mmol), 2-bromo-9, 9-dimethyl-9H-fluorene 43.2 g (276 mmol), palladium acetate, 1.2 g (5.6 mmol), phosphinejanteu 6.4 g (11.02 mmol), 126 g (386 mmol) of cesium carbonate, into 1000 mL of toluene was stirred under reflux for 24 hours. After completion of the reaction by cooling to room temperature, filtered and concentrated under reduced pressure with toluene. Separated by column chromatography to give the 57 g.(Yield 91percent)2-bromo-9, 9-dimethyl--9H- fluoreneAdd 27.3 g to a dry 2L three-necked flask 2-Bromo-9, 9'-dimethylhydrazine and 4-aminobiphenyl 18.6 g, Then dry and degassed 600 mL of toluene was added as a solvent. Add 28.8 g of sodium tert-butoxide, 0.45 g of palladium acetate catalyst (2percent mol) And 2.5g Ligand 1, 1'-binaphthyl-2, 2'-bisdiphenylphosphine (BINAP, 4percent mol). The temperature was raised to 110°C and the reaction was completed overnight. Cooled to room temperature, add activated carbon adsorption, suction filtration, Solvent was removed and recrystallized from toluene and ethanol. 33 g of intermediate E are obtained (yield 91percent).4-amino-Biphenyl 38g (224.55 mmol), 2- bromo-9, 9-dimethyl-fluorene 40.89g (149.70 mmol), cesium carbonate 107.30g (329.33 mmol), palladium (II) acetate, 3.36g (14.97 mmmol) to insert the tree -tert- butylphosphine 14.53mL (29.94 mmol) were suspended in 600 ml of toluene was stirred under reflux for 12 hours. Extracted with dichloromethane and distilled water, and the organic layer was purified by silica gel filter. The organic solution was removed and hexane: dichloromethane = 7: 3 (v / v) subjected to silica gel column in the intermediate product (A) 50.0g (yield: 90percent).Synthesis of Intermediate C-4 A 500 mL 2-necked round-bottomed flask was charged with 4-aminobiphenyl (50.0 mmol, 8.45 g) Bromo-9, 9-dimethyl-9H-fluorene (50.0 mmol, 13.7 g), Pd2 (dba) 3 (1.5 mmol, 1.35 g), t-BuONa (100.0 mmol, 9.6 g) 150 mL of toluene was added as a solvent, and P (t-Bu) 3 (1.5 mmol, 0.3 g) was added thereto, followed by stirring at 90 ° C. for 3 hours. When the reaction was completed, the temperature of the reaction solution was extracted with dichloromethane to room temperature. The obtained extract was dried over MgSO4 and dried under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain 14.1 g (yield: 78percent) of Intermediate 6-11 as a yellow solidIn a 500 mL two-neck round bottom flask4-aminobiphenyl (50.0 mmol, 8.45 g), Bromo-9, 9-dimethyl-9H-fluorene (50.0 mmol, 13.7 g), Pd2 (dba) 3 (1.5 mmol, 1.35 g), t-BuONa (100.0 mmol, 9.6 g)And filled with nitrogen.To this was added 150 mL of toluene as a solventP (t-Bu) 3 (1.5 mmol, 0.3 g) was added thereto, followed by stirring at 90 ° C for 3 hours.When the reaction was completed, the temperature of the reaction solution was extracted with dichloromethane to room temperature. The obtained extract was dried over MgSO4 and dried under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain 14.1 g (yield: 78percent) of Intermediate 6-11 as a yellow solid.4-Amino-biphenyl 20g (118.2mmol) and 2-bromo-9, 9-dimethyl-fluorene 29.1g (106.4mmol), sodium t- butoxide 15.3g (159.6mmol) and tri -tert- butylphosphine dissolving 0.65g (3.19mmol) in 590ml of toluene and, after inserting the Pd (dba) 2 0.61g (1.06mmol) and the mixture was stirred under reflux for 6 hours under a nitrogen atmosphere. After the reaction the organic layer was then extracted with ethyl ahseteyiteugwa dry distilled over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The product n- hexane / dichloromethane (7: 3 by volume) to yield a column of silica gel 28.5 g (yield 74percent) of intermediate M-8 and chromatographed to give the desired compound as a white solid.20 g (118.2 mmol) of 4-aminobiphenyl, 29.1 g (106.4 mmol) of 2-bromo-9, 9-dimethylfluorene, 15.3 g (159.6 mmol) of sodium t-butoxide, and 0.65 g (3.19 mmol) of tri-tert-butylphosphine were dissolved in 590 ml of toluene, 0.61 g (1.06 mmol) of Pd(dba)2 was added thereto, and the mixture was agitated for 6 hours under a nitrogen atmosphere while being refluxed. When the reaction was complete, the resultant was extracted with ethyl acetate and distilled water, an organic layer obtained therefrom was dried with magnesium sulfate and filtered, and the filtered solution was concentrated under a reduced pressure. The concentrated product was purified with n-hexane/dichloromethane (7:3 of a volume ratio) through silica gel column chromatography, obtaining 28.5 g of a white solid compound, an intermediate M-8 (74percent of a yield).Synthesis of Intermediate 14 (0113) (0114) Under a nitrogen atmosphere, Intermediate 13 (1.69 g, 10 mmol) and 2-bromo-9, 9-dimethyl-9H-fluorene (2.73 g, 10 mmol) were mixed and dissolved in toluene (30 mL). PdUnder a nitrogen atmosphere, Intermediate 9 (1.69g, 10 mmol) and 2-bromo-9, 9-dimethyl-9H-fluorene (2.73 g, 10 mmol) were mixed and dissolved in toluene (30 mE).Pd2dba3 (0.18 g, 0.2 mmol), t-13u3P (1 M, 0.4 ml, 0.4 mmol), and t-l3uONa (2.88 g, 30 mmol) were added and refluxed for5 hrs.10090] After the reaction was terminated, the reactants were cooled to normal temperature, and MC (200 mE) andH20 (200 mE) were added. After extraction, the organiclayer was dried over anhydrous magnesium sulfate to remove a small amount of water contained therein, suc17tioned, and concentrated. The resultant compound was pun-fled by column chromatography eluting with Hex:MC=5:1, to obtain Intermediate 10 (2.57 g, 71percent).10091] Intermediate 10 MS(FAI3): 361(M)In a nitrogen environment 2-Bromo-9, 9-dimethyl-9 hydrogen-fluorene(100 g, 366 mmol)After dissolving in 900 mL of toluene, To this was added biphenyl-4-amine (74.3 g, 439 mmol), Tris (diphenylideneacetone) dipalladium (0) (3.35 g, 3.66 mmol), Tris-tert-butylphosphine (3.7 g, 18.3 mmol) And sodium tert-butoxide (42.2 g, 439 mmol) And the mixture was refluxed by heating at room temperature for 5 hours.After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with dichloromethane. Then, water was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure.The residue thus obtained was separated and purified by flash column chromatography to obtain Compound I-11 (93.9 g, 71percent).General procedure: In a 250 ml reactor, (7.9 g, 24.6 mmol), 4-bromoiodobenzene (8.3 g, 30 mmol)Palladium acetate (0.4 g, 0.3 mmol), Sodium tertiary butoxide (4.2 g, 43 mmol), Tertiary butyl phosphine (0.1 g, 0.3 mmol), 100 ml of toluene was added and the mixture was stirred under reflux for 13 hours.After completion of the reaction, the filtrate is concentrated and the filtrate is concentrated. The reaction mixture was separated by column chromatography to obtain (4.0 g, 34percent).24.0 g (142 mmol, 1.2 eq.) of 4-amino biphenyl (CAS 92-67-1) and 32.0 g (117 mmol, 1.0 eq.) of 2-bromo -9, 9'-dimethyl aminofluorene (CAS 28320-31-2) 950 ml of the toluene is introduced into a first, the 30 saturate the argon minutes. 1.0 g (1.8 mmol, 0.02 eq.) of 1, 1'-bis ([...]) pherocene (CAS 12150-46-8), 350 mg (1.6 mmol, 0.01 eq.) its optical isomer or pharmaceutically acceptable salt (II) acetate (CAS 3375-31-3) and 29 g (300 mmol, 2.6 eq.) sodium tert-butoxide (CAS 865-48-5) adding for later, the heating night in the reflux mixture. When reaction is completed, arrangement 300 ml of the toluene in dilution and, extracted water. Sodium organic phase [...] dry, rotating evaporator to the remove the solvent. 50 ml of ethyl acetate, are added to the brown oil, mixture of 20:1 ethyl acetate/heptane mixture added to. Wherein the filtration of the slurry suspension the solid for sucking, heptane and washing was. The drying desired product purity of 99.1percent HPLC 29 g (80 mmol, 69percent)was calculates a.irst, 24.0 g (142 mmol, 1.2 equiv)of4-aminobiphenyl 1a (CAS 92-67-1)Was added to a solution of 32.0 g (117 mmol, 1.0 eq.)2-Bromo-9, 9'-dimethylfluorene2a (CAS 28320-31-2) in 950 ml of toluene and saturated with argon for 30 minutes.After that, A solution of 1.0 g (1.8 mmol, 0.02 eq.) Of 1, 1'-bis (diphenylphosphino) ferrocene (CAS 12150-46-8), 350 mg (1.6 mmol, 0.01 eq.) Palladium (II) acetate CAS 3375-31-3) and 29 g (300 mmol, 2.6 eq.) Of sodium tert-butoxide (CAS 865-48-5) are added and the mixture is heated under reflux overnight.When the reaction is complete, the batch is diluted with 300 mL of toluene, And extracted with water. Is added, and the organic phase is dried with sodium sulfate, The solvent is removed from the rotary evaporator.50 ml of ethyl acetate is added to the brown oil, This mixture is added to a mixture of heptane / ethyl acetate 20: 1.The obtained solid is filtered by suction, Was added., Yielding the desired product 3a of 29 g (80 mmol, 69percent), having an HPLC purity of 99.1percent.24.0 g (142 mmol, 1.2 eq.) of 4-aminobiphenyl 1a (CAS 92-67-1) are initially charged together with 32.0 g (117 mmol, 1.0 eq) of 2-bromo-9, 9'-dimethylfluorene 2a (CAS 28320-31-2) in 950 ml of toluene, and the mixture is saturated with argon for 30 minutes. According to the preparation method of compound 66 in Example 3, the difference is, The synthetic route used is the above route, That is, using 4-aminobiphenyl instead of carbazole, 2-bromo-9, 9-dimethylfluorene was used in place of compounds 1-5, To give compound 329-1 (yield 61percent): 8.46 g of 4-Aminobiphenyl and 15.02 g of 2-Bromo-9, 9-dimethyl-fluorene were placed in a three-necked flask under nitrogen, After stirring with 200 ml of toluene, 11.22 g of potassium tert-butoxide was added, 0.56 g of palladium acetate, 1.32 g of Tri-tert-butylphosphine, and heated under reflux for 2 hours.After cooling, the filtrate was concentrated and the column was separated (Hex: EA = 10: 1). The product was 9.5 g and the yield was 53percent.To a 250 mL round bottom flask was added R1 (3.00 g, 12.23 mmol), G5 (3.22 g, 11.80 mmol), Tris (dibenzylideneacetone) dipalladium (0) (0.17 g, 0.18 mmol)(±) -2, 2'-Bis (diphenylphosphino) -1, 1'-binaphthalene (BINAP) (0.23 g, 0.37 mmol)And sodium tert-butoxide (1.65 g, 17.12 mmol) were dissolved in toluene (120 mL), stirred at 100 ° C. in a bath for 24 hours, After removing the toluene, it was extracted with dichloromethane and water and then distilled under reduced pressure.After the silica gel column, the solvent was distilled off under reduced pressure to obtain Compound G6 (3.80 g, 8.68 mmol)250 ml round bottom cap to 4 a-phenylaniline (2. 00G, 11. 82 Mmol), 2 a-bromodibenzothiophene (3. 42G, 13. 00 Mmol), Tris (dibenzylideneacetone) dipalladium (0) (0. 16G, 0. 18 Mmol), (±) - (diphenylphosphino) - 2, 2 'a-Bis' 1, 1 provided binaphthalene (BINAP) (0. 22G, 0. 35 Mmol) and Sodium tert-a butoxide (1. 59G, 16. 55 Mmol) a, Toluene (110 ml) after melting, 100 °C bath after a stirring time of the reaction end is 24 in number are extracted using a stand-alone Toluene Dichloromethane and water after vacuum distilling, after silica gel column solvent distilled at a reduced pressure, compound E1 (3. 05G, 8. 68 Mmol) by Congress.Biphenyl-4-amine (2.00 g, 11.82 mmol), 3-Bromo-9, 9-Dimethylfluorene (3.23 g, 11.82 mmol), sodium tert-butoxide (5.26 g, 26.0 mmol) Tris (dibenzylideneacetone) dipalladium (0) (0.43 g, 0.47 mmol) and tert-butylphosphine (0.07 g, 0.71 mmol) were dissolved in Toluene (130 mL)After completion of the reaction, toluene was removed, and dichloromethane and water were used for extraction.After the silica gel column, the solvent was distilled off under reduced pressure to obtain Compound A4 (2.56 g, 7.09 mmol).To a 250 mL round bottom flask was added 4-aminobiphenyl (3.00 g, 17.73 mmol) 2-bromo-9, 9-dimethyl-9H-fluorene (4.68 g, 17.13 mmol), Tris (dibenzylideneacetone)dipalladium (0) (0.24 g, 0.27 mmol) (0.33 g, 0.53 mmol) and sodium tert-butoxide (2.39 g, 24.82 mmol) were added to a solution of (±) -2, 2'-Bis (diphenylphosphino) -1, 1'- binaphthaleneAfter dissolving in toluene (140 mL)The reaction mixture was stirred at 100 ° C for 24 hours. After the reaction was completed, toluene was removed, and the residue was extracted with dichloromethane and water. The residue was subjected to vacuum distillation, After silica gel column, the solvent was distilled off under reduced pressure to obtain Compound H1 (3.05 g, 7.41 mmol).General procedure: A glassvial was charged with [Pd(IPr*me)(acac)Cl], neat amine (1.1 mmol), and the arylhalide (1 mmol) in dry 1, 4-dioxane (1 mL) under an atmosphere of argonand sealed with a screw cap fitted with aseptum. LiHMDS (1.1 mmol) was subsequently injected at roomtemperature under argon, the reaction mixture was then refluxed at 110 for 3 h, After this time, dioxane was evaporated, the crude product wasdissolved in CHA solution of 9, 9-dimethyl-7-aminofluorene 49 mmol was added4-bromobiphenyl was dissolved in 400 mL of toluene, The solution was degassed and saturated with nitrogen, Then 2.43 mmol of 1M tri-tert-butylphosphine solution and 1.21 mmol were addedOf palladium (II) acetate, And then 146 mmol of sodium tert-butoxide was added. The reaction mixture was heated under boiling in a protective atmosphere for 6 hours, The mixture was then partitioned between toluene and water, the organic phase was washed three times with water and dried over sodium sulfate, and the mixture was stirred on a rotary evaporator, The residual residue was recrystallized from heptane / toluene after the crude product was filtered through silica gel using toluene and finallyDegassed in a high vacuum to give compound C-1. The yield was 20 g (81percent of the theoretical value).9, 9-dimethyl-9H-fluoren-2-amine (15.0 g, 71.67 mmol) 18.4 g of 4-bromo-1, 1'-biphenyl(1.43 mmmol) of tris (dibenzylideneacetone) dipalladium (0) was suspended in 239 ml of toluene, followed by addition of tri-tert-butylphosphine 1.4 mL (5.73 mmol) was added thereto, followed by reflux stirring for 12 hours. Extracted with dichloromethane and distilled water, and the organic layer is subjected to silica gel filtration. The organic solution was removed and recrystallized from dichloromethane and hexane to obtain 18.6 g (yield: 72percent) of the intermediate product (O).

Molecular Weight:361.5
XLogP3:7.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:3
Exact Mass:361.183049738
Monoisotopic Mass:361.183049738
Topological Polar Surface Area:12
Heavy Atom Count:28
Complexity:510
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes