Structure of 88675-31-4
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CAS No. : | 88675-31-4 |
Formula : | C14H10BrFO |
M.W : | 293.13 |
SMILES Code : | FC1=CC=C(C(C(Br)C2=CC=CC=C2)=O)C=C1 |
MDL No. : | MFCD00699290 |
InChI Key : | DYTDDALWSRMTDA-UHFFFAOYSA-N |
Pubchem ID : | 11300837 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 17 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.07 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 68.95 |
TPSA ? Topological Polar Surface Area: Calculated from |
17.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.55 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
4.19 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.24 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
4.03 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
4.53 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.91 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.62 |
Solubility | 0.00701 mg/ml ; 0.0000239 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.26 |
Solubility | 0.0162 mg/ml ; 0.0000553 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-6.04 |
Solubility | 0.00027 mg/ml ; 0.000000923 mol/l |
Class? Solubility class: Log S scale |
Poorly 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) |
No |
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) |
Yes |
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 |
-5.11 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) |
2.61 |
* 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 |
---|---|---|
94.8% | With hydrogen bromide; bromine; acetic acid; In dichloromethane; at 26℃;Product distribution / selectivity; | EXAMPLE-2; 2-Bromo- 1 -(4-fluorophenyl)-2-phenylethanone; Methylene chloride (1L) is taken in a 4 necked RB flask equipped with mechanical strring rod, pressure equalization funnel and a CaCl2 guard tube. 100 g (0.466 mol) of l-(4-Fluorophenyl)-2-phenyl ethanone is introduced in to the above flask and stirred for 5 minutes to obtain a clear solution.2ml of a 30% hydrobromic acid in acetic acid is then added , followed by gradual addition of a cold solution of bromine (73 g, 0.456 mole) in 200ml of methylene chloride at 26+/-2C. Bromine solution is added in such a manner that it is consumed instantly as indicated by colouration of reaction mixture. After addition of bromine solution the reaction mixture is cooled to 19+/-1C , treated with 5%» aqueous sodium sulphite ( 200 ml) and stirred for about lhr at 21.5+/-3.5C. The organic layer is then separated and is subjected to the above operation twice with 5% aqueous sodium sulphite (2 x 200ml).The organic layer is then stirred with 5% aqueous sodium bicarbonate (200 ml) for about 1 hr at 21.5+/-3.5 C and separated.. The organic layer is finally stirred with 5% aqueous sodium chloride(200ml) and separated. The organic layer is dried over sodium sulphate and filtered. Methylene chloride is removed by distillation and the syrup thus obtained solidified on standing in to a pale orange coloured solid. Yield 129 g ( 94.8%) |
93% | With hydrogen bromide; bromine; In dichloromethane; at 0 - 5℃; | HBr (2.88 ml, 0.01 eq) was added dropwise to the reaction solution of 1- (4-fluorophenyl) -2-phenylethan-1-one (144 g, 1 eq) obtained in step 1 in CH 2 Cl 2 (1.4 L). After cooling to 0-5 .Br 2 (34.56 ml, 2 eq) was diluted with CH 2 Cl 2 (0.29 L) and added dropwise to 1- (4-fluorophenyl) -2-phenylethan-1-one solution.next,5% Na 2 SO 3 (0.29 L) was added to the reaction solution, and the mixture was stirred at 20 to 25 C. for 1 hour.The CH2Cl2 layer was separated and washed twice more with 5% Na2SO3 (0.29 L). 5% NaHCO 3 (0.29 L) was added and stirred at 20-25 C. for 1 hour. The CH 2 Cl 2 layer was separated and washed with 5% NaCl (0.29 L). MgSO 4 (30 g) was added to the organic layer, and dried and filtered.The filtrate was concentrated under reduced pressure, hexane (0.4 L) was added thereto, and stirred at 20 to 30 C. for 1 hour and 0 to 5 C. for 2 hours to form a solid. The resulting solid was filtered, washed with hexane (0.2 L) and vacuum dried at 25-30 C. for 12 hours to afford the title compound.184 g of solids (yield 93%); |
92% | With copper(II) nitrate trihydrate; hydrogen bromide; oxygen; In acetic acid; at 60℃; for 4.5h;Green chemistry; | The representative example of oxidative bromination is described as follows: A mixture of 1.2 g acetophenone 1a (10 mmol) and 0.121 g Cu(NO3)2?3H2O (0.5mmol) was stirred and an oxygen balloon (about 0.5-1 L) was attached to the reaction system. Then 8mol/L aqueous solution of hydrobromic acid (1.5mL, 12mmol) was added dropwise to the mixture. The reaction mixture was then stirred at 70C and monitored by TLC or GC. After the completion of the reaction, the mixture was extracted with CH2Cl2. The organic extract was first washed with 5% sodium sulfite, saturated sodium bicarbonate solution, and then water and finally dried over anhydrous magnesium sulfate. The solvent was removed under vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/dichloromethane 3:1) to afford the product, alpha-bromoacetophenone (2a) in 1.81 g, yield: 91%. |
92% | With dihydrogen peroxide; acetic acid; potassium bromide; In dichloromethane; water; at 0 - 5℃; for 2h; | The bromination reaction using the bromide prepared above, specifically, 8.7 g of 4'-fluorophenyl-2-phenylethanone,80 mL of dichloromethane and 10 mL of water were added to a 250 mL three-necked flask, and then 8.6 g of the above-mentioned dried potassium bromide-containing solid was added.Stir and lower the temperature to 0-5 C, then add 3 mL of acetic acid dropwise. After the addition is completed, continue to maintain the temperature of 0-5 C and add 30% hydrogen peroxide 2.44 g.After the completion of the dropwise addition, the reaction was kept for 2 hours, and then liquid separation was carried out.18 mL of a 5% aqueous solution of sodium sulfite was added dropwise to the organic phase, and the mixture was stirred for 1 hour, and then separated.The organic phase was washed once with 18 mL of 5% aqueous sodium sulfite solution and then with 18 mL of 5% carbon.The aqueous sodium hydrogencarbonate solution and the 18 mL saturated saline solution were each washed once.The organic phase was dried over sodium sulfate, concentrated by filtration and solidified to give 10.9 g of pale yellow solid.2-bromo-1-(4'-fluorophenyl)-2-phenylethanone (Compound I), yield 92%, HPLC purity97.4%. |
90% | With hydrogen bromide; dihydrogen peroxide; acetic acid; at 40℃; for 16h; | The third step, 10.7g 4-fluorophenylacetophenone was dissolved in 100ml of glacial acetic acid, 40% hydrobromic acid was added 15ml, stirred,Slowly dropping 30% mass fraction of hydrogen peroxide 9ml, 40 reaction 16h, TLC trace showed the end of the reaction.Unreacted bromine was removed by adding saturated aqueous sodium sulfite to the reaction mixture.The reaction mixture was extracted with 200 ml of ethyl acetate and an appropriate amount of aqueous sodium carbonate. The organic layer was separated and the organic layer was washed twice with aqueous sodium carbonate solution and dried over anhydrous magnesium sulfate.After filtration and spin drying, 13.25 g of 2-bromo-1- (4-fluorophenyl) -acetophenone was obtained as a yellow thick liquid in a yield of 90%. |
88% | With copper(ll) bromide; In dichloromethane; ethyl acetate; for 18h;Reflux; Inert atmosphere; | General procedure: Copper(II) bromide (CuBr2, 268 mg, 1.2 mmol) was added to a solution of skeleton 5 (1.0 mmol) in the co-solvent of EtOAc and CH2Cl2 (1:1, 20 mL), at 25 C. The reaction mixture was stirred at reflux for 18 h. The reaction mixture was cooled to 25 C. Saturated NaHCO3 (5 mL) was added to the reaction mixture and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product. Purification on silica gel (hexanes/EtOAc = 10/1-6/1) afforded skeletons 3 and 6. |
85% | Compound 4 (5.00 g, 23.34 mmol) was suspended in water (15 mL) in a flaskcovered with aluminum foil. Five drops of 40 % aqueous solution of HBr was added.The mixture was stirred at room temperature for 5 min, Br2 (2.05 g, 12.84 mmol) wasadded dropwise. The reaction mixture was stirred at room temperature for 5 h, and30 % aqueous solution of H2O2 (6.5 mL, 25.70 mmol) was slowly added. After 12 h,dichloromethane (30 mL) was added and the organic layer was washed with 5 %aqueous sodium sulfite (10 mL) and 5 % aqueous sodium chloride (2×20 mL) andthen dried over anhydrous magnesium sulfate. The organic mixture was concentrated to give a light yellow oil 5 (5.82 g, 85 % yield). 1H NMR (600 MHz, CDCl3) delta: 8.01-7.98 (m,2H), 7.49 (d, J=7.2 Hz,2H), 7.36-7.30 (m,3H), 7.07 (t, J=8.6 Hz,2H), 6.32 (s,1H). 13C NMR (150 MHz, CDCl3) delta: 189.33, 166.29, 164.59,135.52, 131.69, 131.63, 130.04, 128.89, 128.74, 115.71, 115.57, 51.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In acetone; at 20℃; for 5h;Darkness; | To a mixture of compound 3 (3.50 g, 17.06 mmol) and potassium carbonate (3.54 g, 25.61 mmol) in acetone (20 mL), a solution of compound 5 (5.00 g, 17.06 mmol) in acetone (5 mL)was added dropwise, and then the mixture was stirred at room temperature for 5 h. During the whole process, the flask was covered with aluminum foil. The mixture was filtered and the filter cake was washed with acetone (20 mL). The combined filtrate was evaporated to give the crude product. Isopropyl alcohol (30 mL) was added and the mixture was heated to 85-90 C. After cooling to 0-5 C, the resulting suspension was filtered, washed with isopropyl alcohol(5 mL), and dried in vacuum oven at 50 C toafford 1 (5.70 g, 80 % yield) as white solid with a purity of 99.8 %. Mp 203-205 C (lit. 206-209 C). 1H NMR (600 MHz, DMSO-d6) delta: 10.20 (s,1H), 8.13(t, J=7.2 Hz,2H), 7.36-7.01 (m,12H), 5.42 (d, J=11.4 Hz,1H), 4.87 (d, J=11.4 Hz,1H), 2.90 (m,1H), 1.16(d, J=7.2 Hz,3H), 0.93 (d, J=3.6Hz, 3H). 13C NMR (150 MHz, DMSO-d6) delta: 208.08, 196.42, 165.82, 165.01, 164.14, 138.11, 135.09, 132.15, 131.75, 131.69, 128.83, 128.67, 128.61, 127.52, 123.91, 119.63, 115.83, 115.69, 63.02, 51.75, 39.42, 18.80, 17.86. HRMS (ESI), calcd.: C26H24FNO3 [M-H]- m/z: 416.1740; found: 416.1716 |
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