Structure of 1077-01-6
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CAS No. : | 1077-01-6 |
Formula : | C7H4F4O |
M.W : | 180.10 |
SMILES Code : | FC(F)(F)OC1=CC(F)=CC=C1 |
MDL No. : | MFCD00236323 |
Boiling Point : | No data available |
InChI Key : | AUKDFDQPJWJEDH-UHFFFAOYSA-N |
Pubchem ID : | 2777286 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 33.08 |
TPSA ? Topological Polar Surface Area: Calculated from |
9.23 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.12 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.57 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.41 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.72 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.81 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.12 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.44 |
Solubility | 0.0648 mg/ml ; 0.00036 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.45 |
Solubility | 0.064 mg/ml ; 0.000355 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.3 |
Solubility | 0.0898 mg/ml ; 0.000499 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-4.86 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.63 |
* 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 |
---|---|---|
...presented by the following formula (4) which can respectively correspond to the formula (1) can be obtained. (D) Fluorine substituted aromatic compound represented by the formula (4) corresponding to the hydroxy compound wherein X1 is a substituent of the group (a) in the formula(1): ... 2-fluorobenzophenone, 3-fluorobenzophenone, 4-fluorobenzophenone, 2-trifluoromethylfluorobenzene, 3-trifluoromethylfluorobenzene, 4-trifluoromethylfluorobenzene, 2-trichloromethylfluorobenzene, 3-trichloromethylfluorobenzene, 4-trichloromethylfluorobenzene, 2-trifluoromethoxyfluorobenzene, 3-trifluoromethoxyfluorobenzene, 4-trifluoromethoxyfluorobenzene, 2-trichloromethoxyfluorobenzene, 3-trichloromethoxyfluorobenzene, 4-trichloromethoxyfluorobenzene, 2-fluorophenylmethylsulfone, 3-fluorophenylmethylsulfone, ... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To the solution of 3- (trifluoromethoxy)fluorobenzen(1g, 5.5 mmol) in lOmL THF at -78C, n-BuLi (1.6M, 3.75mL) was added dropwise. The resulting solution was stirred at -78C for 30 min. 12 (2.1g, 8.25 mmol) in THF (5mL) was added. The mixture was warmed to room temperature and then quenched with Na2C03 in saturated Na2S203 (1: 10) (30mL). The crude product was extracted with ether. The ether layer was dried over Na2S04 and filtered through a short silica gel column to give the desired iodide as an oil. ¹H NMR (CDC13): 7.39 (m, 1H), 7.12 (d, J=9.0 Hz, 1H), 7.05 (t, J=6.0 Hz, 1H) MS (ESI): m/e 307 (M+1)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of l-fluoro-3-trifluoromethoxy-benzene (1.73g, 9.6 mmol) inTHF (20 mL) at -78 0C was added nBuLi (1.2eq, 4.6 mL of 2.5M in hexanes). The mixture was stirred for 180 minutes and quenched with DMF (2 mL) and allowed to warm to room temperature. Solvents were removed, the reaction was washed with H2O (10 mL) and the organics concentrated giving the crude product. | ||
4-Fluoro-2-trifluoromethoxy-benzaldehyde To a solution of <strong>[1077-01-6]1-fluoro-3-trifluoromethoxy-benzene</strong> (1.73g, 9.6 mmol) in THF (20 mL) at -78 C. was added nBuLi (1.2 eq, 4.6 mL of 2.5M in hexanes). The mixture was stirred for 180 minutes and quenched with DMF (2 mL) and allowed to warm to room temperature. Solvents were removed, the reaction was washed with H2O (10 mL) and the organics concentrated giving the crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sulfuric acid; potassium nitrate; at 0 - 5℃; for 2h;Inert atmosphere; | <strong>[1077-01-6]1-fluoro-3-(trifluoromethoxy)benzene</strong> (7.5 g, 41.6 mmol) was dissolved in concentrated sulfuric acid (30 mL),and the mixuture was cooled to 0 C. KNO3 (1.04 g, 10.25 mmol) was added slowly in batches. The internal temperatureis keeped below 5 C. Upon completion of the addition, the mixture was stirred for 2 hours. An eice-water mixture (about50 mL) was added. The reaction solution was extracted with methyl tert-butyl ether (2033 mL), and the organic phaseswere combined, dried and filtered. The filtrate was concentrated and purified by flash silica gel column chromatographyto obtain 4-fluoro-1-nitro-2-(trifluoromethoxy)benzene (4.0 g, 42%). |
16% | With sulfuric acid; nitric acid; at -10℃; | (Comparative Example 6); 4-Fluoro-l-nitro-2- (trifluoromethoxy) benzeneFuming nitric acid (20 mL) was added dropwise to concentrated sulfuric acid (40 ml) under cooling (-100C), and subsequently, 1- fluoro-3- (trifluoromethoxy) benzene (15 g, 83 mmol) was added to the mixture at -100C, and the mixture was stirred for 0.5 hours. After the mixture was added into ice-water to stop the reaction, it was extracted with dichloromethane . After the obtained organic layer was washed with a IN aqueous sodium hydroxide solution and water, it was dried with anhydrous sodium sulfate. After filtration, the solution was concentrated and the residue was purified by silica gel column chromatography (100:0-97:3, hexane : ethyl acetate) to give the title compound (3.1 g, 16%) as an oil.1H-NMR (400 MHz, CDCl3) delta: 8.10 (IH, dd, J = 5.5, 9.4 Hz) , 7.23-7.15 (2H, m) . |
12 g | With sulfuric acid; potassium nitrate; at 0℃; for 3h;Cooling with ice; | Under ice cooling mixture of 3-fluoro - trifluoromethoxyphenyl (20g) was dissolved in 40 ml of concentrated sulfuric acid, with rapid stirringWas added portionwise potassium nitrate (28g), was stirred at 0oC 3 hours and stirred at room temperature overnight, the reaction solution was carefullyGo on into 1 kg ice, stirred for 30 minutes, extracted with ethyl acetate, dried over sodium sulfate, filtered, and the filtrate was evaporated, the residue was purified by column chromatography to give 12 g pale yellow liquid. |
0.5 g | With sulfuric acid; nitric acid; at -10 - 20℃; for 0.5h; | To a 100 mL round-bottomed flask were added concentrated H2SO4 (25 mL), fuming HNO3 (25 mL), and <strong>[1077-01-6]1-fluoro-3-(trifluoromethoxy)benzene</strong> (9.0 g, 50 mmol) at -10 C. in sequence. The mixture was stirred at rt for 30 min then poured onto ice and extracted with EtOAc (3*20 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (30 mL), brine (30 mL), dried over anhydrous Na2SO4, concentrated to dryness, and purified by FCC to give the title compound as a pale-yellow oil (0.50 g). 1H NMR (300 MHz, CDCl3): delta 8.21-8.14 (m, 1H), 7.21-7.12 (m, 2H). |
8.5 g | With sulfuric acid; potassium nitrate; at -5 - 0℃; for 1h; | Add 20 mL of concentrated sulfuric acid to a 250 mL three-necked flask.The ice salt bath is cooled to -5-0 C,Adding m-fluorotrifluoromethoxybenzene(10 g, 60 mmol), then potassium nitrate (5.9 g, 60 mmol) was added portionwise.The reaction was stirred at 0 C for 1 h.Slowly pour the reaction into the iceIn water, extracted with ethyl acetate (40 mL×3) three times, and the organic phases were combined.Wash 3 times with saturated saline (20mL × 3),Dry over anhydrous sodium sulfate for 0.5 h, suction filtration under reduced pressure.The filtrate was concentrated under reduced pressure at 45 C to give 8.5 g of pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; nitric acid; at 0 - 20℃; | 11A) 4-Fluoro-1-nitro-2-trifluoromethoxy-benzene To 1-fluoro-3-trifluoromethoxybenzene (1 mL) was added concentrated sulfuric acid (1 mL) at 0 C. To the cold solution was added dropwise (0.7 mL) of a solution made from concentrated nitric acid (1 mL) and concentrated sulfuric acid (1 mL). The reaction was slowly allowed to warm to room temperature then poured onto ice and extracted with ether. The organic layer was separated and washed with sodium hydroxide 1N, then brined and dried over magnesium sulfate. The solvent was removed under reduce pressure at room temperature. A pale yellow oil (1 g) was recovered and used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | General procedure: To reactant 1 or 3 (1 g, 8.76 mmol) in THF (50 ml), was added LDA (condition A) or n-BuLi (condition B) (4.82 ml, 9.64 mmol) at -78 C slowly, after 30 min, added EtO-13CHO/DMF-13CHO (0.736 ml, 9.64 mmol) and left for stirring at -78 C for 30 min. Quenched with a few drops of dil H2SO4 (aq) and satd NH4Cl (aq 50 mL), extracted with Et2O (3 × 50 mL), dried, purified by column chromatography on silica gel eluting with a solution of EtOAc/hexane(1:9) to give products 2 or 4 (0.860 g, 69% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54%Spectr. | With phosphoric acid; silver trifluoromethanesulfonate; Selectfluor; In dichloromethane; water; at 55℃; for 1h;Inert atmosphere; Glovebox; | General procedure: A microwave vial (5 mL) was sealed under an inert atmosphere (Argon glovebox) with a stir bar, Selectfluor (177.1 mg, 0.5 mmol, 2 equiv), silver trifluoromethanesulfonate (12.8 mg, 0.05 mmol, 20 mol%) and aryloxydifluoroacetic acids (0.25 mmol, 1.0 equiv). To this vial DCM (1.8 mL), trifluoroacetic acid (76.5 muL, 1.0 mmol, 4.0 equiv) and water (0.2 mL) were injected. This mixture was heated for an hour at 55 C. The resulting mixture was cooled down to room temperature, diluted with dichloromethane (4 mL), washed with water (3×5 mL), brine (5 mL), dried over anhydrous MgSO4 and filtered. The dried extract was concentrated on a rotary evaporator. The resulting crude product was dissolved in a small quantity of dichloromethane and loaded on to a silica cartridge (10 g, Biotage), airdried and eluted with pentane. The pure fractions were combined and the solvent was evaporated to obtain the pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; potassium nitrate; at 0℃; for 1h; | To a solution of <strong>[1077-01-6]1-fluoro-3-(trifluoromethoxy)benzene</strong> (2.Og, 11.lmmol) in H2504 (5.OmL) was added KNO3 (1.34g, 13.3mmol) at 0C. The reaction mixture was stirred at 0 O for 1 h. TLC showed the reaction to be complete. The reaction mixture was diluted with H20 (5OmL) and extracted with EtOAc (3x50m1). The organic layer was dried over Na2504 and concentrated under reduced pressure. The residue was triturated with 10% EtOAc in hexane to afford 2-fluoro-1-nitro-4- (trifluoromethoxy)benzene as a yellow liquid. Yield: 1.8g (crude). The crude data showed product and it was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; In acetonitrile; at 20℃; for 16h;Glovebox; Irradiation; Sealed tube; Inert atmosphere; | General procedure: In a glovebox, to an oven-dried 20 mL screw cap vial was added 2- (3, 5-bis (trifluoromethyl) phenyl) -4-nitro-l- (trifluoromethoxy) -6- (trifluoromethyl) -lii-benzo [d] imidazole (1) (105 mg, 0.200 mmol, 1.00 equiv) , arene (2.00 mmol, 10.0 equiv) and Ru (bpy) 3 ( REe) 2, (0.0516 mg, 0.0600 pmol, 0.0300 moll) . Then MeCN (1.00 mL, 0.200 M) and a magnetic stir bar were added. The vial was capped and taken out of the glovebox. The reaction mixture was then stirred and irradiated with a 10 W LED (402 nm) at room temperature. After 16 h, an internal standard PhCF3 (5.84 mg, 4.95 pL, 0.04 mmol, 0.200 equiv) was added to the reaction vial, 0.200 mL of the resulting mixture was transferred to a 2 mL vial containing 0.500 mL of CDCI3. After the yield was determined using 19F NMR, the NMR sample was combined with the rest of the reaction mixture and the solvent was removed in vacuo. The crude material was purified by HPLC under noted conditions. The fractions containing the desired product were combined and extracted with CDCI3 (3 1 mL) , dried with magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to furnish the desired product of trifluoromethoxylation . For volatile compounds, after purification by HPLC, the desired product was extracted with 1 mL CDC13 and then directly characterized. The NMR peaks are referring to CH3CN residue signal ^H-NMR: d 1.94, 13C~NMR: 5 118.26, 1.32).2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; In acetonitrile; at 20℃; for 16h;Glovebox; Irradiation; Sealed tube; Inert atmosphere; | General procedure: In a glovebox, to an oven-dried 20 mL screw cap vial was added 3- methyl-4-nitro-l- ( trifluoromethoxy) -6- (trifluoromethyl ) -1H- benzo[d] [1, 2, 3] triazol-3-ium trifluoromethanesulfonate (lb) (98.0 mg, 0.200 mmol, 1.00 equiv), arene (2.00 mmol, 10.0 equiv) and Ru (bpy) 3 (PFe) 2, (1.72 mg, 2.00 pmol, 1.00 mol%). Then MeCN (1.00 mL, 0.200 M) and a magnetic stir bar were added. The vial was capped and taken out of the glovebox. The reaction mixture was then stirred and irradiated with 2 of 10 W LED (Xmax = 447 nm) at room temperature. After 16 h, an internal standard PhCF3 (24.6 pL, 0.200 mmol, 1.00 equiv) was added to the reaction vial, 0.200 mL of the resulting mixture was transferred to a 2 mL vial containing 0.500 mL of CDC13. After the yield was determined using 19F NMR, the NMR sample was combined with the rest of the reaction mixture and the solvent was removed in vacuo. The crude material was purified by HPLC under noted conditions. The fractions containing the desired product were combined and extracted with CDC13 (3 x 10.0 mL) , dried with magnesium sulfate, and filtered unless otherwise noted. The filtrate was concentrated in vacuo to furnish the desired product of trifluoromethoxylation . For volatile compounds, after purification by HPLC, the desired product was extracted with 1 mL CDCI3 and then directly characterized. The NMR peaks are referring to CCN residue signal (1H-NMR : d 1.94, 13C-NMR: d 118.26, 1.32).2 |
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