Structure of 53903-49-4
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 53903-49-4 |
Formula : | C8H8F3NO |
M.W : | 191.15 |
SMILES Code : | NC1=CC=C(OC)C=C1C(F)(F)F |
MDL No. : | MFCD04972660 |
Boiling Point : | No data available |
InChI Key : | BTRQZDUCUGJMPS-UHFFFAOYSA-N |
Pubchem ID : | 22601721 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 42.34 |
TPSA ? Topological Polar Surface Area: Calculated from |
35.25 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.85 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.75 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.46 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.22 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.13 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.28 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.34 |
Solubility | 0.879 mg/ml ; 0.0046 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.11 |
Solubility | 1.49 mg/ml ; 0.00781 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.06 |
Solubility | 0.168 mg/ml ; 0.000881 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 |
-6.22 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 |
1.0 |
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 |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.33 |
* 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 |
---|---|---|
100% | With nitrogen; hydrogen;palladium; In ethanol; | (b) 4-Methoxy-2-(alpha,alpha,alpha-trifluoromethyl)aniline prepared by aminating 4-methoxy-2-(alpha,alpha,alpha-trifluoromethyl)nitrobenzene as follows: In a 300 ml stainless steel autoclave was placed a solution of 25.0 g (0.11 mole) of 4-methoxy-2-(alpha,alpha, alpha-trifluoromethyl)nitrobenzene in 150 ml of 95% ethanol. After flushing with nitrogen, 1.1 g of 5% palladium on carbon was added and the autoclave sealed. After flushing with nitrogen, the reactor was charged with 60 psi (413 kPa) of hydrogen and stirred. Gas uptake began immediately and the temperature was maintained between 25 C. and 30 C. by occasional cooling with an ice bath. After approximately ninety minutes, the gas uptake had ceased. The autoclave was vented, flushed with nitrogen and opened. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to afford 22 g (100% yield) of a light yellow oil which was shown to be 4-methoxy-2-(alpha,alpha,alpha-trifluoromethyl)aniline. 1 H NMR analysis indicated: (delta, CDClz) 7.82 (dd, J= 2 and 9 Hz, 1H), 7.00 (d, J=2 Hz, 1H), 6.48 (d, J=9 Hz, 1H), 3.87 (br s, 2H) and 3.60 (s, 3H). Mass spectrum analysis indicated: (m/e) 191 (M+), 176, 156, 128 and 52. It was used directly in the next step without purification. |
99% | With palladium 10% on activated carbon; hydrogen; In methanol; water; ethyl acetate; at 20℃; | 4-methoxy-1-nitro-2-(trifluoromethyl)benzene (9.0 g, 40.7 mmol)Soluble in ethyl acetate (50 mL) and methanol (100 mL),Add 10% palladium on carbon (1.2g, 50% water),With hydrogen balloon,Stir at room temperature overnight.Filter after the reaction,The filtrate was concentrated under reduced pressure to give a yellow oil (7.7 g, 99.0%).Used directly for the next step. |
With hydrogen;5%-palladium/activated carbon; In ethanol; at 20℃; for 2.5h; | 4-Methoxy-2-trifluoromethylaniline; A mixture of 4-methoxy-1-nitro-2-trifluoromethyl-benzene (4.9 g, 22.2 mmol) and 5% palladium on carbon (210 mg) in EtOH (28 mL) is stirred for 2.5 h at RT, under a hydrogen atmosphere. The resulting suspension is filtered through a pad of celite. The filtrate is concentrated in vacuo to afford the title compound: ES-MS: 192.0 [M] + ; single peak at tR= 3.55 min (System 2) |
With hydrazine hydrate;raney Ni; In methanol; at 20℃; | Step-2:-Preperation of 4-methoxy-2-trifluoromethyl-phenylamine:-To a solution of 4-methoxy- 1 -nitro-2-trifluoromethyl-benzene (1.0 g, 4.52 mmol) in methanol (5-7 mL) was drop wise added raney Ni (cat. amount) and hydrazine hydrate (1 mL). The reaction mass was stirred at RT for 2-3 hours. The reaction mass was quenched in water and the filtrate was concentrated to afford 0.400 g of desired product. 'HNMR (DMSO- 6): delta 3.67 (s, 3H), 5.09 (s, 2H), 6.79-6.85 (m, 2H), 6.96 (d, / = 6.9 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydroxide; N-chloro-succinimide; In dichloromethane; | (c) 4-Methoxy-6-(methylthiomethyl)-2-(alpha,alpha,alpha-trifluoromethyl)aniline was prepared by substituting 4-methoxy-2-(alpha,alpha,alpha-trifluoromethyl)aniline as follows: In a 250 ml three-necked flask equipped with an overhead stirrer was placed 20.12 g (0.105 mol) of 4-methoxy-2-(alpha,alpha,alpha-trifluoromethyl)aniline in 100 ml of methylene chloride. To the solution was then added 15.63 g (0.117 mol) of N-chlorosuccinimide was added with vigorous stirring. After cooling to 0 C. under a nitrogen atmosphere, a solution of 9.2 ml (8.02 g, 0.129 mol) dimethylsulfide in 40 ml of methylene chloride was then added over a one hour period while maintaining the temperature below 5 C. The reaction mixture became very thick. The ice bath was removed and after stirring at room temperature for one hour, 200 ml of ice cold 5% aqueous sodium hydroxide solution was added. The methylene chloride layer was separated, dried over anhydrous potassium carbonate, filtered and the solvent removed under reduced pressure. To the residue was then added 60 ml of 1,2-dichloroethane and 1.00 g (10 mmol) of succinimide. After refluxing for twelve hours under a nitrogen atmosphere, the reaction mixture was cooled, washed twice with 100 ml of 5% sodium hydroxide solution, dried with magnesium sulfate, filtered and concentrated under reduced pressure to afford 24.9 g of a black oil. This was distilled under reduced pressure to afford 16.5 g (63% yield) of the desired product as a clear, colorless liquid (Bp 106-110 at 0.35 mm Hg) of 95% purity as assayed by gas chromatography; 1 H NMR analysis indicated: (delta, CDCl3) 6.94 (d, J=1.8 Hz, 1H), 6.78 (d, J=1.8 Hz, 1H), 4.32 (br s, 2H, NHz), 3.54 (s, 3H), 3.51 (s, 2H) and 1.82 (s, 3H). Mass spectrum analysis indicated: (m/e) 251 (M+), 204 (100%) and 181. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In toluene; at 110℃; for 20h;Inert atmosphere; | <strong>[53903-49-4]2-Amino-5-methoxy-benzotrifluoride</strong> (10.46 mmol), K3PO4 (15.7 mmol), Xphos (1.05 mmol) and Pd4(dba)3 (0.314 mmol) were added under nitrogen to a solution of 4-bromo-2-fluoro-benzonitrile (10.46 mmol) in 50 mL toluene and the mixture was stirred for 20 hours at a bath temperature of 110 C. Then the mixture was filtered through a glass fibre filter, then the filtrate was extracted with 150 mL water. The organic phase was dried on sodium sulphate and evaporated down. In this way the product was obtained in a yield of 87% of theory. C15H10F4N2O (310.2) Mass spectrum (ESI): [M+H]+=311 [M-H]-=309 Thin layer chromatograph (silica gel; petroleum ether/ethyl acetate 7:3): Rf=0.48 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In acetonitrile; at 75℃; for 6h;Schlenk technique; Inert atmosphere; | General procedure: Experimental Procedure: A dried 25 mL Schlenk tube equipped with a magnetic stir bar was charged with Togni?s Reagent 2 (0.25 mmol, 1.0 equiv), free anilines 1 (0.75 mmol, 3.0 equiv), K2CO3 (0.375 mmol, 1.5 equiv) and CH3CN (1.5 mL). The reaction mixture was then stirred at 75 C for 6 h under an argon atmosphere. The reaction progress was monitored by TLC. After cooling to room temperature, the mixture was washed with water and extracted with CH2Cl2 three times, then washed with saturated NaCl solution. The combined organic layer was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (Elutent: petroleum ether-EtOAc) to give the pure product. The products were characterized by 1H NMR, 13C NMR, 19F NMR, GC -MS. |
65% | With tris[2-phenylpyridinato-C2,N]iridium(III); In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; Irradiation; | Under nitrogen or argon, 4-methoxy-aniline 0.4 mmol,0.2 mmol, Ir (ppy) 3(2mg) were added to the reaction and DMF1 ml flask, andthen the blue LED lights (7W) irradiation conditions at room temperature until completeconversion of trivalent iodine reagent completion of the reaction. Add 10 ml ofsaturated Na 2CO 3Aqueous solution, and extracted three times with ethyl acetate, theorganic layer was washed with water and once with saturated brine, dried over anhydrousNa 2SO 4The organic layer was dried. Column chromatography (eluent: petroleum ether 60-90: ethyl acetate = 15: 1-8: 1) to give the product in 65% yield. |
57% | With potassium carbonate; nickel(II) hydroxide; In dimethyl sulfoxide; at 35℃; for 2h; | Trifluoromethyl preparation of aromatic amines of the embodiment according to the present embodiment, the aromatic amine is p-anisidine, and other reactions after the same procedures as in Example 28 treatment. The preparation method of the trifluoromethyl aromatic amine of the present embodiment, the aromatic amine is aniline, and the nickel compound is nickel hydroxide.The base is potassium carbonate, and the reaction process parameters are: 1-trifluoromethyl-1,2-phenyliodo-3(H)-one (0.5 mmol, 1.0 eq).Aromatic amine (1.5 mmol, 3.0 eq), nickel hydroxide 10 mol%, potassium carbonate (1.5 mmol, 3.0 eq),DMSO (2 mL) was reacted at 35 C for 2 h, and the other reactions and workup procedures were the same as in Example 1. |
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