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CAS No. : | 867288-00-4 | MDL No. : | MFCD14585527 |
Formula : | C13H11F2NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BFAMMODYWZEGDM-UHFFFAOYSA-N |
M.W : | 235.23 | Pubchem ID : | 53375439 |
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 : | 62.69 |
TPSA : | 35.25 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) : | -5.58 cm/s |
Log Po/w (iLOGP) : | 2.47 |
Log Po/w (XLOGP3) : | 3.04 |
Log Po/w (WLOGP) : | 4.07 |
Log Po/w (MLOGP) : | 3.48 |
Log Po/w (SILICOS-IT) : | 3.61 |
Consensus Log Po/w : | 3.33 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.6 |
Solubility : | 0.0585 mg/ml ; 0.000249 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.45 |
Solubility : | 0.0842 mg/ml ; 0.000358 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -5.25 |
Solubility : | 0.00133 mg/ml ; 0.00000564 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.69 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
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 |
---|---|---|
61% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; for 3.5h;Inert atmosphere; | 4-bromo-2.6-difluoro-aniline 1 g (4.81 mmol) and m-methoxyphenylboronic acid 730 mg (4.81 mmol. 1 eq)Potassium carbonate (4.82 g 24.88 mmol 6 eq) [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (425.35 mg481 mmol 6 eq) was placed in a 100 ml two-necked flask, and 30 ml (dioxane: water = 3:1) was injected with nitrogen to protect the solution, and 80 was allowed to react for 3.5 h. After the TLC monitoring reaction is completed, the post-treatment distillation is carried out under reduced pressure to about 10 ml, and the solution is poured into a separating funnel, extracted with dichloromethane for 2-3 times, dried over anhydrous Na 2 SO 4 , filtered, and evaporated to dryness to give a black oily drop. Separated and purified by petroleum ether: ethyl acetate = 6:1 silica gel column chromatography to obtain a pale yellow oily liquid about 690 mg, yield 61percent. |
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In methanol; water; toluene; at 72℃; for 4h;Industry scale; Inert atmosphere;Product distribution / selectivity; | 10 kg of <strong>[67567-26-4]4-bromo-2,6-difluoroaniline</strong> (48.08 mol) and 67 L of toluene were charged into a reactor under nitrogen atmosphere and stirred at 20 °C until complete dissolution. 1.67 kg of Pd(PPh3)4 (1.44 mol) were charged and stirred for 10 min. 48 L of a 20 wt. percent aqueous solution of Na2C03 were then charged, followed by the addition of a solution of 3- methoxyboronic acid (8.77 kg, 57.7 mol) in methanol (32 L) over 20 minutes. The mixture was heated at 72 °C for 4 hours and then cooled to 20 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; sodium carbonate; In Isopropyl acetate; water;Industry scale;Purification / work up; | A solution of 123 L of a 10% aqueous solution of Na2C03, 1.5 L of a 25 wt. % aqueous solution of ammonia and 2.0 kg of a filtration resin (Dicalite) were charged to the reactor and the mixture stirred for 5 minutes. The mixture was recirculated through a filter until clarification of the liquors (35 min) and charged into a reactor. 60 L of isopropyl acetate were added and the mixture was stirred for 10 minutes and the phases (A1 +01 ) were allowed to separate. The aqueous phase (A1 ) was transferred to a different reactor and 60 L of isopropyl acetate were charged. The mixture was stirred and the phases (A2 + 02) were allowed to separate. Both organic phases (01+02) were charged into a reactor and 108 L of a 10 wt. % aqueous solution of Na2C03 were added. The mixture was stirred and the phases (A3+03) were allowed to separate. The organic phase (03) was stirred with 108 L of a 10 wt. % aqueous solution of Na2C03 and the phases (A4+04) were allowed to separate. The organic phase (04) was stirred with 100 L demineralised water and the phases (A5+05) were allowed to separate. The organic phase (05) was filtered over a filtration resin (Dicalite) in a filter and charged in to a reactor. 2.2. Distillation: The organic phase (05) was distilled during 2 hours under reduced pressure (approx. 750 mm Hg) keeping the distilled mixture at temperature below 65 C. | |
With a filtration resin (Dicalite); In water; ethyl acetate;Purification / work up; | 2) Purification of <strong>[867288-00-4]3,5-difluoro-3'-methoxybiphenyl-4-amine</strong> 2.1. 600 mL of isopropyl acetate were added and the mixture was stirred for 10 minutes and the phases (A1 +O1) were allowed to separate. The aqueous phase (A1) was stirred with 600 mL of isopropyl acetate for 10 minutes and the phases (A2 + 02) were allowed to separate. Both organic phases (O1+O2) were stirred with 600 mL demineralised water and the phases (A3+O3) were allowed to separate. The organic phase (03) was filtered over a filtration resin (Dicalite) in a filter. 2.2. Distillation: The organic phase (03) was distilled under reduced pressure (approx. 750 mm Hg) keeping the distilled mixture at temperature below 65C to yield a dark coloured oil residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With hydrogenchloride; In Isopropyl acetate; water; at 0 - 5℃; for 2h;pH < 2;Product distribution / selectivity; | The distillation residue was dissolved in 800 L of isopropyl acetate (8 vol/w) , the mixture was cooled to 0-5 C and 50 mL of a 35 wt. % aqueous solution of HCI were added drop- wise until the pH was lower than 2. The aminium salt precipitated as a white solid from the dark brown coloured solution. The slurry was stirred for 2 hours at 0-5 C, filtered and the cake washed twice with 50 mL of previously cooled isopropyl acetate. The cake was pulled dry under reduced pressure and dried at 60 C under reduced pressure (approx. 750 mm Hg) to constant weight. A total of 1 17 g (0.431 mmol, 89 % yield) of 3,5-difluoro- 3'-methoxybiphenyl-4-aminium chloride were isolated as beige solid |
89% | With hydrogenchloride; In Isopropyl acetate; water; at 0 - 5℃;pH 2;Product distribution / selectivity; | 3) Preparation of the aminium salt (step b) The distillation residue was dissolved in 800 L of isopropyl acetate (8 vol/w) , the mixture was cooled to 0-5 C and 50 mL of a 35 wt. % aqueous solution of HCl were added drop-wise until the pH was lower than 2. The aminium salt precipitated as a white solid from the dark brown coloured solution. The slurry was stirred for 2 hours at 0-5 C, filtered and the cake washed twice with 50 mL of previously cooled isopropyl acetate. The cake was pulled dry under reduced pressure and dried at 60 C under reduced pressure (approx. 750 mm Hg) to constant weight. A total of 117 g (0.431 mmol, 89 % yield) of 3,5-difluoro-3'-methoxybiphenyl-4-aminium chloride were isolated as beige solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane;Reflux; | Procedure-1A solution of an anhydride (1.3 eq.) and an amine (1 eq) were dissolved in dioxane and refluxed overnight. Dioxane was evaporated and the resultant residue dissolved in AcOEt and extracted into aq. 2N NaHCO3 solution. The aqueous layer was acidified with aq. 2N HCl to obtain a solid, which was filtered and dried to give the desired amide.Examples 1-11, 14, 16-17 and 20 were synthesized using general procedure-1. EXAMPLE 1 2-(3,5-Difluoro-3'-methoxybiphenyl-4-ylcarbamoyl)benzoic acid The title compound (52 mg) was obtained from intermediate 1 (150 mg, 0.64 mmol) and phthalic anhydride (189 mg) as a white solid. M.P.: 168-173 C. 1H-NMR (delta ppm, DMSO-d6, 400 MHz): 13.05 (s, 1H), 10.19 (s, 1H), 7.83 (d, J7.4, 1H), 7.69-7.63 (m, 1H), 7.62-7.52 (m, 4H), 7.39 (t, J 7.9, 1H), 7.34-7.27 (m, 2H), 6.98 (d, J 6.8, 1H), 3.83 (s, 3H). MS (m/z): 381.55 ([M-H]-). | |
In 1,4-dioxane;Reflux; | Procedure -1A solution of an anhydride (1.3 eq.) and an amine (1 eq) were dissolved in dioxane and refluxed overnight. Dioxane was evaporated and the resultant residue dissolved in AcOEt and extracted into aq. 2N NaHC03 solution. The aqueous layer was acidified with aq. 2 HC1 to obtain a solid, which was filtered and dried to give the desired amide.Example 12-(3^-Difluoro-3'-methoxybiphenyl-4-yIcarbainoyI)berizoic acid:The title compound (52 mg) was obtained from intermediate 1 (150 mg, 0.64 mmol) and phthalic anhydride (189 mg) as a white solid. MJ: 168-173G te-NMR (delta ppm, DUSO- k, 400 MHz): 13.05 (s, 1H), 10.19 (s, 1H), 7.83 (d, J 7.4, 1H), 7.69-7.63 (m, 1H), 7.62-7.52 (m, 4H), 7.39 (t, / 7.9, 1H), 7.34-7.27 (m, 2H), 6.98 (d, / 6.8, 1H), 3.83 (s, 3H). MS (m z): 381.55 ([itf-H]"). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | The product of the previous step of 300m 4-(3-pyridyl))-phenylamine (Intermediate 1m) was dissolved in analytically pure tetrahydrofuran.(10 ml), slowly dropped into a reaction flask containing (1.5 ml) boron trifluoride diethyl ether solution at minus 15 times. After reacting for 5 min, 0.9 ml of isobutyl tert-butoxide was added dropwise, and the reaction was carried out for 2 h. Observe the precipitation, the reaction was warmed to minus 5 temperature and 10 ml of n-pentane was added. Then, the temperature was raised to 25 C, 10 ml of n-pentane was added, and the filter cake was added to the filter to be placed in a new reaction flask, followed by 294 mg of sodium azide. 30ml (acetonitrile: water = 3:1), reacted at 80 C for 1 h. After TLC monitoring reaction was completed, the post-treatment was distilled under reduced pressure to about 10 ml, and the solution was poured into a separating funnel and extracted with dichloromethane for 2-3 times. The water was dried over Na 2 SO 4 , filtered, and evaporated to dryness to give a white oily oily residue, which was purified by petroleum ether: ethyl acetate = 15:1 silica gel column chromatography to give a pale yellow oily liquid about 180 mg, yield 54%. |
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