Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 57688-34-3 | MDL No. : | MFCD03424687 |
Formula : | C13H10F3N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PDKIAMYXBRKPBW-UHFFFAOYSA-N |
M.W : | 237.22 | Pubchem ID : | 2782709 |
Synonyms : |
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.08 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 61.28 |
TPSA : | 26.02 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -4.89 cm/s |
Log Po/w (iLOGP) : | 2.16 |
Log Po/w (XLOGP3) : | 4.02 |
Log Po/w (WLOGP) : | 5.11 |
Log Po/w (MLOGP) : | 4.01 |
Log Po/w (SILICOS-IT) : | 3.77 |
Consensus Log Po/w : | 3.81 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.23 |
Solubility : | 0.0138 mg/ml ; 0.0000584 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.27 |
Solubility : | 0.0128 mg/ml ; 0.0000538 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -5.45 |
Solubility : | 0.000846 mg/ml ; 0.00000356 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 1.54 |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With C22H24Cl2N6O2Pd2; potassium carbonate In ethanol; water for 4h; Reflux; | General Procedure for the Suzuki-Miyaura cross-coupling reaction: General procedure: In a 10 mL glass tube containing a Teflon-coated stir bar was placed p-bromobenzaldehyde 2e (0.05 g, 0.27 mmol, 1 equiv), phenylboronic acid 1a (0.05 g, 0.40 mmol, 1.5 equiv), 2M K2CO3 (0.33 mL, 0.67 mmol, 2.5 equiv), 4-AAP-Pd(II) (0.28 mg, 0.3 mol % Pd) and EtOH (2 mL). The mixture was stirred at reflux for 4 h. After cooling, the mixture was diluted with ether Et2O (5 mL), washed with sat. aq. NaHCO3 (3 mL), brine (3 mL) and dried over Na2SO4. Evaporation of the solvent and purification of the residue over a silica gel column (Hex: AcOEt 90:10), furnished the biphenyl 3q. |
70% | With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 17h; | |
70% | With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 17h; | 1 A solution of 4-bromoaniline (29 mmol), 4-trifluoromethylphenyl boronic acid (35 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.4 mmol) in 2M aqueous potassium carbonate solution (50 mL) and Λ/,Λ/-dimethylformamide (50 ml.) was heated at 100 0C for 17 h. The reaction mixture was cooled, poured into half-saturated aqueous sodium bicarbonate solution (400 mL), and extracted with (3 x 400 mL) diethyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography (10-30% ethyl acetate/hexanes) provided the title product as a white powder (70%). ESMS [M+H]+: 238.2. |
70% | With potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 17h; | 1 4'-(trifluoromethyl)-4-biphenylamine PREPARATION 1 4'-(trifluoromethyl)-4-biphenylamine A solution of 4-bromoaniline (29 mmol), 4-trifluoromethylphenyl boronic acid (35 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.4 mmol) in 2M aqueous potassium carbonate solution (50 mL) and N,N-dimethylformamide (50 mL) was heated at 100° C. for 17 h. The reaction mixture was cooled, poured into half-saturated aqueous sodium bicarbonate solution (400 mL), and extracted with (3*400 mL) diethyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography (10-30% ethyl acetate/hexanes) provided the title product as a white powder (70%). ESMS [M+H]+: 238.2. |
70% | With potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 17h; | 1 Preparation 1 4'-(trifluoromethyl)-4-biphenylamine A solution of 4-bromoaniline (29 mmol), 4-trifluoromethylphenyl boronic acid (35 mmol), and tetrakis(triphenylphosphine)palladium(O) (1.4 mmol) in 2M aqueous potassium carbonate solution (50 mL) and N,N-dimethylformamide (50 mL) was heated at 100° C. for 17 h. The reaction mixture was cooled, poured into half-saturated aqueous sodium bicarbonate solution (400 mL), and extracted with (3*400 mL) diethyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography (10-30% ethyl acetate/hexanes) provided the title product as a white powder (70%). ESMS [M+H]+: 238.2. |
40% | With potassium carbonate In 1,2-dimethoxyethane; water at 30 - 50℃; | 2.4.C Step C: 4'-(trifluoromethyl)biphenyl-4-amine A solution of 4-bromoaniline (20 g, 116 mmol), 4-(trifluoromethyl)phenylboronic acid (15 g, 79 mmol), potassium carbonate (36.3 g, 263 mmol), and palladium(II) acetate (946 mg, 4.21 mmol) in 1,2-dimethoxyethane (80 mL) and water (80 mL) was stirred at 30° C. overnight. The reaction was then heated to 50° C. for 7 hours. The reaction was filtered through Celite and extracted with ethyl acetate (3*200 mL). The combined organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0.5-1.7% petroleum ether/ethyl acetate) gave 4'-(trifluoromethyl)biphenyl-4-amine (10 g, 40%) as an off white solid. 1H NMR (400 MHz, (CD3)2SO, δ): 7.73-7.82 (m, 4H), 7.55 (dd, 2H), 6.72 (d, 2H), 5.47 (s, 2H). MS (M+1): 238.2. |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; benzene Heating; | ||
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 15h; Inert atmosphere; | 1. 1,1'-Biphenyl-4-amines 3a-x General procedure: 4-Bromobenzenamines 1a-c (6.4 mmol) were dissolved in the mixed solvents (2M K2CO3:DMF = 1:1, 24 mL), and then added corresponding 4-substituent phenylboronic acids 2a-h (7.7 mmol) and Pd (PPh3)4 (0.22 mmol) under argon. The reaction mixture was refluxed at 100 for 15 h (TLC monitored the reaction). The reaction was then cooled to room temperature and filtered. The filtrate was added 10 times the amount of water and extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution, concentrated under reduced pressure, and dried to give a crude product. The crude product was purified by flash column chromatography (ethyl acetate/petroleum ether, 1:8-1:5) to afford 1,1'-biphenyl-4-amines 3a-x, yield: 77-95%. | |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 183 Reference Example 4 [00515] Synthesis of 4-((4'-bromo-[l,l'-biphenyl]-4-yl)thio)-lH-l,2,3-triazole-5- carboxylic acid (4) General procedure: A mixture of (4-iodophenyl)(methyl)sulfane (Compound 4A) (500 mg, 2 mmol), 4-bromophenylboronic acid (400 mg, 2 mmol), Na2CCh (636 mg, 6 mmol), and Pd(PPh3)4 (115 mg, 0.1 mmol) in toluene/EtOH/H20 (20/10/4 mL) was stirred at 80 °C under nitrogen overnight The mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 4B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. - NMR (CDCb, 500 MHz): d (ppm) 2.52 (s, 3H), 7.32 (d, J= 8.5 Hz, 2H), 7.43 (d, J= 8.5 Hz, 2H), 7.48 (d, J= 8.5 Hz, 2H), 7.55 (d, J= 8.5 Hz, 2H). | |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 183 Synthesis of 4-((4'-bromo-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (4) General procedure: A mixture of (4-iodophenyl)(methyl)sulfane (Compound 4A) (500 mg, 2 mmol), 4-bromophenylboronic acid (400 mg, 2 mmol), Na2CO3 (636 mg, 6 mmol), and Pd(PPh3)4 (115 mg, 0.1 mmol) in toluene/EtOH/H2O (20/10/4 mL) was stirred at 80 oC under nitrogen overnight. The mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 4B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H- NMR (CDCl3, 500 MHz): d (ppm) 2.52 (s, 3H), 7.32 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide; sulfuric acid; sodium nitrite 1.) AcOH, 5 deg C, 1 h, 2.) AcOH, 0 deg C, 1 h; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With tin(ll) chloride In ethanol; ethyl acetate Heating; | |
With iron; ammonium chloride In ethanol Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With hydrogenchloride In water at 110℃; for 2h; | 8 A solution of 4'-(trifluoromethyl)-4-biphenylamine (0.84 mmol) in water (1 mL) and 1 M hydrochloric acid solution (0.84 mL) was treated with ammonium thiocyanate (0.84 mmol). The reaction mixture was heated at 110 0C for 2 h. The homogeneous reaction solution was cooled and poured onto ice (4 g). A white precipitate formed and was collected by filtration. Purification of the residue by Gilson reverse phase HPLC yielded the title product (21%). ESMS [M+H]+: 297. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In dichloromethane at 0℃; for 0.5h; | 2 EXAMPLE 2 1,1,1-trifluoro-N-[4'-(trifluoromethyl)-4-biphenylyl]methanesulfonamide Triflic anhydride (0.36 mmol) was added dropwise to an ice-cooled solution of 4'-(trifluoromethyl)-4-biphenylamine (0.32 mmol) in dichloromethane (1.5 mL). The reaction mixture was stirred at 0° C. for 30 min, then diluted with water (35 mL) and extracted with (3*35 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (20-50% ethyl acetate/hexanes) provided the title compound as a tan solid (60%). 1H NMR (400 MHz, DMSO-d6) δ 12.15 (br,1H), 7.90 (d, 2H, J=8.4 Hz), 7.82 (m, 4H), 7.39 (d, 2H, J=8.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With pyridine In dichloromethane at 20℃; for 18h; | |
85% | In pyridine; dichloromethane at 20℃; for 18h; | 10 To a solution of 4'-(trifluoromethyl)-4-biphenylamine (4.21 mmol) and pyridine (6.31 mmol) in dichloromethane (30 mL) was added 4-nitrophenyl formate (4.21 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was dissolved in ethyl acetate (150 mL) and washed with water (3 x 100 mL) and brine (1 x 100 mL). The organic layer was dried over sodium sulfate and was concetrated in vacuo. Purification of the residue by Gilson reverse phase HPLC afforded the title product as a white solid (85%). ESMS [M+H]+: 266.2. |
In pyridine; dichloromethane at 20℃; for 18h; | 22 To a solution of 4'-(trifluoromethyl)-4-biphenylamine (4.21 mmol) in dichloromethane (30 mL) and pyridine (6.31 mmol) was added 4-nitrophenyl formate (4.21 mmol). The reaction mixture was stirred at room temperature for 18 h, then diluted with ethyl acetate (150 mL) and washed with water (3 x 100 mL) and brine (1 x 100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide the crude [4'-(trifluoromethyl)-4-biphenylyl]formamide intermediate. ESMS [M+H]+: 266.2. Crude [4'-(trifluoromethyl)-4-biphenylyl]formamide (2.1 mmol) was dissolved in a solution of 1 M lithium aluminum hydride in THF (20 mL). The reaction mixture was stirred at room temperature for 18 h and then quenched with 0.5N aqueous sodium hydroxide solution (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Recrystallization of the residue with hot isopropyl alcohol provided the title product as a white solid (60%). ESMS [M+H]+: 252.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With pyridine In dichloromethane at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Stage #1: isocyanate de chlorosulfonyle; 4'-(trifluoromethyl)-[1,1'-biphenyl]-4-amine In dichloromethane at 20℃; for 3h; Stage #2: With water In dichloromethane at 20℃; for 18h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With hydrogenchloride at 110℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine at 20 - 100℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With hydrogenchloride at 60℃; for 5.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | In dichloromethane at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With pyridine; isocyanate de chlorosulfonyle; water In acetonitrile at 0 - 20℃; for 15h; | |
57% | With pyridine; isocyanate de chlorosulfonyle In water; acetonitrile at 0 - 20℃; for 18.0333h; | 1a Ex 1a N-[4'-(trifluoromethyl)-4-biphenylyl]sulfamide EXAMPLE 1 Ex 1a N-[4'-(trifluoromethyl)-4-biphenylyl]sulfamide To an ice-cooled solution of chlorosulfonylisocyanate (0.47 mmol) in acetonitrile (1.0 mL) was added water (0.47 mmol). The reaction mixture was stirred at 0° C. for 1 min and then allowed to warm to room temperature slowly. After 3 h, the reaction mixture was cooled to 0° C., at which point a solution of 4'-(trifluoromethyl)-4-biphenylamine (0.43 mmol), pyridine (0.86 mmol), and acetonitrile (1.0 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1 min and then allowed to warm to room temperature slowly. After 15 h, the reaction mixture was diluted with water (60 mL) and brine (10 mL), and extracted with (3*50 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate and then concentrated in vacuo. Purification by silica gel chromatography (Isco Combi-Flash, 20-50% ethyl acetate/hexanes) afforded the title compound as a white solid (57%). ESMS [M+H]+: 317.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With triethylamine In dichloromethane at 20℃; for 18h; | |
35% | With triethylamine In dichloromethane at 20℃; for 18h; | 2 N,N-dimethyl-N'-[4'-(trifluoromethyl)-4-biphenylyl]sulfamide EXAMPLE 2 N,N-dimethyl-N'-[4'-(trifluoromethyl)-4-biphenylyl]sulfamide To a solution of 4'-(trifluoromethyl)-4-biphenylamine (0.42 mmol) in dichloromethane (2.0 mL) was sequentially added triethylamine (1.26 mmol) and dimethylaminesulfamoyl chloride (0.63 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. Purification by Gilson reverse phase HPLC afforded the title product as a white solid (35%). ESMS [M+H]+: 345.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With pyridine In dichloromethane at 20℃; for 18h; | |
47% | With pyridine In dichloromethane at 20℃; for 18h; | 1a EXAMPLE 1 Ex 1a N-[4'-(trifluoromethyl)-4-biphenylyl]methanesulfonamide To a solution of 4'-(trifluoromethyl)-4-biphenylamine (0.42 mmol) in dichloromethane (2.0 mL) was sequentially added pyridine (0.84 mmol) and methanesulfonylchloride (0.63 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. Purification by Gilson reverse phase HPLC afforded the title product as a white solid (47%). ESMS [M+H]+: 316.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-BuLi / hexane; tetrahydrofuran / 1 h / -100 - -78 °C 1.2: ZnCl2 / tetrahydrofuran; hexane / 1 h 1.3: 85 percent / Pd(PPh3)4 / tetrahydrofuran; hexane / 18 h 2.1: 62 percent / SnCl2*2H2O / ethanol; ethyl acetate / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-BuLi / hexane; tetrahydrofuran / 1 h / -100 - -78 °C 1.2: ZnCl2 / tetrahydrofuran; hexane / 1 h 1.3: 85 percent / Pd(PPh3)4 / tetrahydrofuran; hexane / 18 h 2.1: 62 percent / SnCl2*2H2O / ethanol; ethyl acetate / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: N-methylsulfamic acid With pyridine; oxalyl dichloride In dichloromethane at 0 - 20℃; for 0.166667h; Stage #2: 4'-(trifluoromethyl)-[1,1'-biphenyl]-4-amine With pyridine In dichloromethane at 0 - 20℃; for 18h; | 9 N-methyl-N'-[4'-(trifluoromethyl)-4-biphenylyl]sulfamide EXAMPLE 9 N-methyl-N'-[4'-(trifluoromethyl)-4-biphenylyl]sulfamide To a solution of oxalyl chloride (0.59 mmol) in dichloromethane (2.0 mL) was added methylsulfamic acid (0.55 mmol). The reaction mixture was stirred at room temperature for 10 min and was cooled to 0° C. before the addition of 4'-(trifluoromethyl)-4-biphenylamine (0.42 mmol) and pyridine (0.84 mmol) in dichloromethane (2 mL). After stirring at room temperature for 18 h, the reaction mixture was diluted with water (10 mL) and brine (10 mL) and the organics were extracted with (3*20 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate and then concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC afforded the title compound as a white solid (57%). ESMS [M+H]+: 331.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide for 6h; Inert atmosphere; | 6.1.2.1. Method A (from 8) General procedure: To a stirred solution of 8 (1 mmol), kept under inert atmosphere, and the appropriate substituted aniline (1 mmol) in dry DMF (25 mL), HBTU (2 mmol) was added portionwise. The resulting suspension was stirred for 6 h, then poured into chilled 2 M HCl (20 mL). The mixture was extracted exhaustively with Et2O, and the collected organic layers were dried and concentrated under reduced pressure. The residue was purified by flash chromatography, obtaining the title compound. For details about the purification of the crude product, see the specific method. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 6 h / Inert atmosphere 2: palladium on activated charcoal; hydrogen / tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In N,N-dimethyl-formamide for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In N,N-dimethyl-formamide for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: toluene-4-sulfonic acid / 1,2-dimethoxyethane / 5 h / 120 °C / Molecular sieve; Sealed tube 2.1: sodium cyanoborohydride; acetic acid; methanol / 1,2-dimethoxyethane / 20 °C 3.1: water; lithium hydroxide / tetrahydrofuran / 2 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide; water / 0.5 h / 80 °C 4.2: 80 °C | ||
Multi-step reaction with 4 steps 1.1: tetrahydrofuran / 90 °C / Molecular sieve 2.1: zinc(II) chloride / diethyl ether; tetrahydrofuran / 2 h / 0 °C 3.1: water; lithium hydroxide / tetrahydrofuran / 2 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide; water / 0.5 h / 80 °C 4.2: 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: toluene-4-sulfonic acid / 1,2-dimethoxyethane / 5 h / 120 °C / Molecular sieve; Sealed tube 2.1: sodium cyanoborohydride; acetic acid; methanol / 1,2-dimethoxyethane / 20 °C 3.1: water; lithium hydroxide / tetrahydrofuran / 2 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 0.5 h / 80 °C 4.2: 80 °C | ||
Multi-step reaction with 4 steps 1.1: tetrahydrofuran / 90 °C / Molecular sieve 2.1: zinc(II) chloride / diethyl ether; tetrahydrofuran / 2 h / 0 °C 3.1: water; lithium hydroxide / tetrahydrofuran / 2 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 0.5 h / 80 °C 4.2: 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / 1,2-dimethoxyethane / 5 h / 120 °C / Molecular sieve; Sealed tube 2: sodium cyanoborohydride; acetic acid; methanol / 1,2-dimethoxyethane / 20 °C 3: water; lithium hydroxide / tetrahydrofuran / 2 h / 20 °C | ||
Multi-step reaction with 3 steps 1: tetrahydrofuran / 90 °C / Molecular sieve 2: zinc(II) chloride / diethyl ether; tetrahydrofuran / 2 h / 0 °C 3: water; lithium hydroxide / tetrahydrofuran / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | In tetrahydrofuran; at 90℃;Molecular sieve; | Step A:methyl 6-(3-methyl-1-(4'-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinateTo a solution of methyl 6-formylnicotinate (0.200 g, 1.21 mmol) in tetrahydrofuran (8 mL) containing activated molecular sieves was added 4'-(trifluoromethyl)biphenyl-4-amine (316 mg, 1.33 mmol).The reaction was heated to 90° C. and stirred overnight.The reaction was concentrated to dryness and the residue was dissolved in tetrahydrofuran (8 mL).The solution was cooled to 0° C. Zinc chloride (3.52 mL, 1M in diethyl ether, 3.52 mmol) was added, followed by isobutylmagnesium bromide (1.47 mL, 2.0M in THF, 3.52 mmol).The reaction was stirred at 0° C. for 2 hours.The reaction was quenched with saturated ammonium chloride.The mixture was diluted with dichloromethane and water.The layers were separated and the aqueous was extracted again with dichloromethane.The combined organic layers were dried over sodium sulfate, filtered and concentrated.Purification by column chromatography gave methyl 6-(3-methyl-1-(4'-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinate (210 mg, 39percent) as a yellow oil. 1H NMR (400 MHz, CD3OD, delta): 9.09 (s, 1H), 8.31 (d, 1H), 7.72-7.57 (m, 5H), 7.41 (d, 2H), 6.65 (d, 2H), 4.61-4.52 (m, 1H), 3.94 (s, 3H), 1.92-1.73 (m, 2H), 1.1.72-1.61 (m, 1H), 1.05 (d, 3H), 0.91 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / 1,2-dimethoxyethane / 5 h / 120 °C / Molecular sieve; Sealed tube 2: sodium cyanoborohydride; acetic acid; methanol / 1,2-dimethoxyethane / 20 °C | ||
Multi-step reaction with 2 steps 1: tetrahydrofuran / 90 °C / Molecular sieve 2: zinc(II) chloride / diethyl ether; tetrahydrofuran / 2 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane at 120℃; for 5h; Molecular sieve; Sealed tube; | 2.4.D Step D: methyl 6-(3-methyl-1-(4'-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinate A solution of methyl 6-(3-methylbutanoyl)nicotinate (90 mg, 0.41 mmol), 4'-(trifluoromethyl)biphenyl-4-amine (145 mg, 0.610 mmol) and p-toluenesulfonic acid monohydrate (1.5 mg, 0.008 mmol) in anhydrous 1,2-dimethoxyethane (2.5 mL) was heated to 120° C. for 5 hours over activated molecular sieves in a sealed tube. The suspension was cooled to room temperature. Sodium cyanoborohydride (12.8 mg, 0.203 mmol) in methanol (1 mL) was added dropwise, immediately followed by acetic acid (0.1 mL). The resulting mixture was stirred overnight at room temperature. The reaction was concentrated and the crude residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by preparative TLC (5:1 petroleum ether:ethyl acetate) gave methyl 6-(3-methyl-1-(4'-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinate (28 mg, 15%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 9.19 (s, 1H), 8.21-8.24 (d, 1H), 7.54-7.60 (m, 4H), 7.43-7.45 (d, 1H), 7.35-7.37 (d, 2H), 6.61-6.63 (d, 2H), 4.65 (s, 1H), 3.93 (s, 3H), 1.74-1.75 (d, 2H), 0.92-1.02 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With bis-triphenylphosphine-palladium(II) chloride In tetrahydrofuran; water at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: methanol / 1 h / Reflux 2: zinc; {NiBr2phan2} / water; acetonitrile / 18 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: methanol / 1 h / Reflux 2: zinc; {NiBr2phan2} / water; acetonitrile / 18 h / 80 °C 3: toluene-4-sulfonic acid / butan-1-ol / 18 h / 120 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: methanol / 1 h / Reflux 2: zinc; {NiBr2phan2} / water; acetonitrile / 18 h / 80 °C 3: toluene-4-sulfonic acid / butan-1-ol / 18 h / 120 °C 4: sodium hydroxide / water; tetrahydrofuran / 18 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: methanol / 1 h / Reflux 2: zinc; {NiBr2phan2} / water; acetonitrile / 18 h / 80 °C 3: toluene-4-sulfonic acid / butan-1-ol / 18 h / 120 °C 4: sodium hydroxide / water; tetrahydrofuran / 18 h / 25 °C 5: 1,2-dichloro-ethane; triethylamine; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 18 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: methanol / 1 h / Reflux 2: zinc; {NiBr2phan2} / water; acetonitrile / 18 h / 80 °C 3: toluene-4-sulfonic acid / butan-1-ol / 18 h / 120 °C 4: sodium hydroxide / water; tetrahydrofuran / 18 h / 25 °C 5: 1,2-dichloro-ethane; triethylamine; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 18 h / 25 °C 6: lithium hydroxide / water; tetrahydrofuran / 0.5 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In methanol for 1h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With bis(1,5-cyclooctadiene)nickel (0); (R)-1-[(Sp)-2-(dicyclohexylphosphanyl)ferrocenyl]ethyldicyclohexylphosphane; ammonia; sodium t-butanolate In 1,4-dioxane; toluene at 110℃; for 16h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,4-dioxane; water Inert atmosphere; Reflux; | General coupling procedure for compounds 5&6 General procedure: To 0.329 g (1.5 mmol) 4-iodoaniline, 1.8 mmol ArB(OH)2, 0.318 g (3 mmol) Na2CO3 and 75 mg (0.075 mmol) PdCl2(PPh3)2, 15 mL of a blended solution of dioxane and water (v/v = 3/1) was added under N2 atmosphere. Then the reaction was heated to reflux and monitored by TLC. Upon cooling, the reaction mixture was dilute with sat. NH4Cl solution, then extracted with EA (3×20 mL), and the organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4 and purified by flash chromatography to afford different 4-aminobiphenyl derivatives. According to the reductive amination procedure, the 4-aminobiphenyl derivative was further treated with salicylaldehyde and to afford the corresponding compound 5&6. | |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In N,N-dimethyl-formamide at 160℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: salicylaldehyde; 4'-(trifluoromethyl)-[1,1'-biphenyl]-4-amine In methanol at 20℃; Inert atmosphere; Stage #2: With sodium tetrahydroborate In methanol at 20℃; for 0.166667h; Inert atmosphere; | Reductive amination procedure General procedure: Under an atmosphere of N2, 0.175 g (1 mmol) compd. 2 was dissolved in methanol, 0.11 mL (1.05 mmol) salicylaldehyde was added and stirred overnight at room temperature. When compd. 2 disappeared, NaBH4 (61 mg, 1.6 mmol) was added. After stirring for 10 min, the reaction was quenched by sat. NH4Cl solution, then extracted with CH2Cl2 (3×20 mL), and the organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4 and purified by flash chromatography (PE:EtOAc = 15:1) to afford 0.230 g (82%) E6 as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: lithium diisopropyl amide; N,N,N,N,N,N-hexamethylphosphoric triamide / tetrahydrofuran / -78 - 20 °C 2: palladium on carbon; hydrogen / methanol / 4 h / 20 °C / 2068.65 - 2585.81 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N,N,N,N,N,N-hexamethylphosphoric triamide; lithium diisopropyl amide In tetrahydrofuran at -78 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With Pd(Cy*Phine)2Cl2 ; potassium hydroxide In butan-1-ol at 70℃; for 1.5h; Glovebox; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran at 75℃; for 12h; Inert atmosphere; Reflux; | 1.1 Synthesis of 5 '- (4- (trifluoromethyl) phenyl) - [1,1': 3 ', 1 "-terphenyl] -3,3" -diamine (1) In a three-necked flask,A solution of 11.25 g (50 mmol) of 4-bromotrifluorotoluene,9.4 g (55 mmol) of p-aminobenzeneboronic acid hydrochloride,2 mol / L potassium carbonate solution 75 ml and 250 ml of tetrahydrofuran,Magnetic stirring and argon,The oil bath was heated to 75 ° C,0.02 g of tetraphenylphenylphosphine palladium was added,Reflow 12h after standing,After removing the aqueous layer, the silica gel was spin-The product was collected and the solution was dried to obtain a white solid,Dried in a vacuum at 60 ° C for 12 h to give a white intermediate 4-Amino-4 '- (trifluoromethyl) -1,1'-biphenyl11.3g, the yield was 95%.The intermediate structure is as follows |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 2 h / 0 °C 2: sulfuric acid; sodium nitrite / ethanol / 80 °C / Reflux 3: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 12 h / 100 °C / Inert atmosphere; Reflux 4: palladium 10% on activated carbon; hydrazine hydrate / ethanol / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; for 2h; | 1.2 In a three-necked flask,4-Amino-4 '- (trifluoromethyl) -1,1'-biphenyl7.12 g (30 mmol) and 30 ml of DMF were dissolved and cooled to 0 ° C,Take N-bromosuccinimide (NBS)11.2 g (63 mmol) was treated with 30 ml of DMFDissolved and slowly dropped into the above reaction system.After dripping 0 reaction 2h after pouring into 1L cold water,After standing for 12h,70 ° C vacuum drying12h after the dissolution of methylene chloride and stir-dried silica gel after chromatography column,The product was collected and the solution was dried to obtain a white solid,Dry in a vacuum at 60 ° C for 12 h to give a white intermediate3,5-dibromo-4 '- (trifluoromethyl) - [1,1'-biphenyl] -4-amine 10.45 g,The yield was 89%. The intermediate structure is as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 2 h / 0 °C 2: sulfuric acid; sodium nitrite / ethanol / 80 °C / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 2 h / 0 °C 2: sulfuric acid; sodium nitrite / ethanol / 80 °C / Reflux 3: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 12 h / 100 °C / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 4 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 4 h / 0 - 20 °C / Inert atmosphere 3.1: sodium carbonate; palladium diacetate; triphenylphosphine / N,N-dimethyl-formamide / 5 h / 155 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 4 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 4 h / 0 - 20 °C / Inert atmosphere 3.1: sodium carbonate; palladium diacetate; triphenylphosphine / N,N-dimethyl-formamide / 5 h / 155 °C / Inert atmosphere 4.1: diisobutylaluminium hydride / tetrahydrofuran; toluene / -10 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 4 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 4 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 20℃; for 4h; | 2. Benzamides 4a-x General procedure: The 2-Bromobenzoic acid (5.7 mmol) was refluxed in SOCl2 (13 mmol) at 78 for 2 h and then superfluous SOCl2 was removed under reduced pressure. The reaction solution was diluted with dichloromethane and added dropwise to a solution of 3a-x (5.2 mmol) and triethylamine (2.25 mL). The reaction was carried out at room temperature for 4 h (TLC monitored the reaction). The reaction mixture was concentrated under reduced pressure to remove excess dichloromethane. The residue was added an appropriate amount of dichloromethane/petroleum ether (1:10), filtered, and dried to give white or faint yellow solids of benzamides 4a-x, yield: 60-98% in two steps. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 120℃; for 2h; Microwave irradiation; | 183 General procedure: To a solution of Compound 6A (138 mg, 0.32 mmol) in tolunen (4 mL) was added N-methylpiperazine (160 mg, 1.6 mmol), t-BuONa (61 mg, 0.64 mmol), Pd2(dba)3 (29 mg, 0.032 mmol), and Xantphos (37 mg, 0.064 mmol) and heated in a microwave oven at 120 °C for 2 hours. The mixture was concentrated and purified by reverse phase column chromatography to afford Compound 6B. LC-MS (ESI) m/z: 440 [M+H]+. | |
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 120℃; for 2h; Microwave irradiation; | 183 General procedure: To a solution of Compound 6A (138 mg, 0.32 mmol) in tolunen (4 mL) was added N-methylpiperazine (160 mg, 1.6 mmol), t-BuONa (61 mg, 0.64 mmol), Pd2(dba)3 (29 mg, 0.032 mmol), and Xantphos (37 mg, 0.064 mmol) and heated in a microwave oven at 120 oC for 2 hours. The mixture was concentrated and purified by reverse phase column (2208) chromatography to afford Compound 6B. LC-MS (ESI) m/z: 440 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; toluene / 100 °C / Inert atmosphere 2: iron; ammonium chloride / ethanol / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; toluene / 100 °C / Inert atmosphere 2: iron; ammonium chloride / ethanol / Reflux |
[ 444143-45-7 ]
3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-amine
Similarity: 1.00
[ 397-28-4 ]
3'-(Trifluoromethyl)-[1,1'-biphenyl]-4-amine
Similarity: 1.00
[ 174612-10-3 ]
3,3'-Diamino-5,5'-bis(trifluoromethyl)biphenyl
Similarity: 0.97
[ 3838-42-4 ]
3'-(Trifluoromethyl)-[1,1'-biphenyl]-4-amine hydrochloride
Similarity: 0.97
[ 400747-98-0 ]
4'-(Trifluoromethyl)-[1,1'-biphenyl]-3-amine
Similarity: 0.97
[ 444143-45-7 ]
3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-amine
Similarity: 1.00
[ 397-28-4 ]
3'-(Trifluoromethyl)-[1,1'-biphenyl]-4-amine
Similarity: 1.00
[ 174612-10-3 ]
3,3'-Diamino-5,5'-bis(trifluoromethyl)biphenyl
Similarity: 0.97
[ 3838-42-4 ]
3'-(Trifluoromethyl)-[1,1'-biphenyl]-4-amine hydrochloride
Similarity: 0.97
[ 400747-98-0 ]
4'-(Trifluoromethyl)-[1,1'-biphenyl]-3-amine
Similarity: 0.97
[ 444143-45-7 ]
3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-amine
Similarity: 1.00
[ 397-28-4 ]
3'-(Trifluoromethyl)-[1,1'-biphenyl]-4-amine
Similarity: 1.00
[ 174612-10-3 ]
3,3'-Diamino-5,5'-bis(trifluoromethyl)biphenyl
Similarity: 0.97
[ 3838-42-4 ]
3'-(Trifluoromethyl)-[1,1'-biphenyl]-4-amine hydrochloride
Similarity: 0.97
[ 400747-98-0 ]
4'-(Trifluoromethyl)-[1,1'-biphenyl]-3-amine
Similarity: 0.97
[ 444143-45-7 ]
3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-amine
Similarity: 1.00
[ 397-28-4 ]
3'-(Trifluoromethyl)-[1,1'-biphenyl]-4-amine
Similarity: 1.00
[ 174612-10-3 ]
3,3'-Diamino-5,5'-bis(trifluoromethyl)biphenyl
Similarity: 0.97
[ 3838-42-4 ]
3'-(Trifluoromethyl)-[1,1'-biphenyl]-4-amine hydrochloride
Similarity: 0.97
[ 400747-98-0 ]
4'-(Trifluoromethyl)-[1,1'-biphenyl]-3-amine
Similarity: 0.97