Structure of 139911-28-7
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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. : | 139911-28-7 |
Formula : | C9H8BrFO2 |
M.W : | 247.06 |
SMILES Code : | CCOC(=O)C1=C(Br)C=CC(F)=C1 |
MDL No. : | MFCD06204688 |
InChI Key : | ODFAIHQRCRQZGM-UHFFFAOYSA-N |
Pubchem ID : | 15037299 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.22 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 50.19 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.2 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.93 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.19 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.38 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.14 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.97 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.36 |
Solubility | 0.108 mg/ml ; 0.000435 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.14 |
Solubility | 0.177 mg/ml ; 0.000718 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.02 |
Solubility | 0.0238 mg/ml ; 0.0000964 mol/l |
Class? Solubility class: Log S scale |
Moderately 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 |
-5.73 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 |
0.0 |
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<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.82 |
* 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 |
---|---|---|
3.4 g (92%) | tetrakis(triphenylphosphine)palladium (0); In ethanol; toluene; | Ethyl 2-(2-Methyl-4-fluorophenyl)-5-fluorobenzoate Tetrakis(triphenylphosphine)palladium(0) (0.02 eq, 0.31 g) was added to a vigorously stirred solution of <strong>[139911-28-7]ethyl 2-bromo-5-fluorobenzoate</strong> (1.0 eq, 3.3 g, 0.013 mol) and 2-methyl-4-fluorophenylboronic acid (1.2 eq, 0.016 mol, 2.4 g) in 45 mL of toluene, 22 mL of 2M aqueous sodium carbonate, and 11 mL of ethanol and the mixture was refluxed for 9 h. The cooled reaction mixture was poured into 50 mL each of water, ammonium hydroxide, and 2M aqueous sodium bicarbonate and then filtered through Celite. The filtrate was extracted with ethyl acetate and the organics were dried (MgSO4) and concentrated to yield 3.9 g of a yellow oil. Chromatography (silica gel, 20% ethyl acetate/hexane) gave 3.4 g (92%) of product as a light colored oil. 1 H NMR (CDCl3, 60 mHz) delta 7.7 (dd, 1 H), 7.5 (m, 1 H), 7.25- 6.75 (m, 4 H), 4.0 (q, 2 H), 2.0 (s, 3 H), 1.0 (t, 3 H); IR (CDCl3 solution) 3130, 2220, 1700, 1450, 1080 cm-1; MS m/z 276 (M+), 201 (base peak). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.4 g (92%) | In ethanol; toluene; | Ethyl 2-(2-Methyl-4-fluorophenyl)-5-fluorobenzoate Tetrakis(triphenylphosphine)palladium(O) (0.02 eq, 0.31 g) was added to a vigorously stirred solution of <strong>[139911-28-7]ethyl 2-bromo-5-fluorobenzoate</strong> (1.0 eq, 3.3 g, 0.013 mol) and 2-methyl-4-fluorophenylboronic acid (1.2 eq, 0.016 mol, 2.4 g) in 45 mL of toluene, 22 mL of 2M aqueous sodium carbonate, and 11 mL of ethanol and the mixture was refluxed for 9 h. The cooled reaction mixture was poured into 50 mLeach of water, ammonium hydroxide, and 2M aqueous sodium bicarbonate and then filtered through Celite. The filtrate was extracted with ethyl acetate an the organics were dried (MgSO4) and concentrated to yield 3.9 g of a yellow oil. Chromatography (silica gel, 20% ethyl acetate/hexane) gave 3.4 g (92%) of product as a light colored oil. 1 H NMR (CDCl3, 60 mHz) delta7.7 (dd, 1H), 7.5 (m, 1H), 7.25-6.75 (m, 4H), 4.0 (q, 2H), 2.0 (s, 3H), 1.0 (t, 3H); IR (CDCl3 solution) 3130, 2220, 1700, 1450, 1080 cm-1; MS m/z 276 (M+), 201 (base peak). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | tris-(dibenzylideneacetone)dipalladium(0); triphenylphosphine; In N,N-dimethyl-formamide; at 130.0℃; for 4.0h;Inert atmosphere; | Example 2 - ethyl 2-cyano-5-fluorobenzoateZinc cyanide (26.5 g; 0.225 mol) and Pd2(dba)3 (1.9 g; 3.4 mmol) were added to a solution of <strong>[139911-28-7]ethyl 2-bromo-5-fluorobenzoate</strong> (27.9 g; 0.112 mol) in DMF (71 ml).Triphenyl phosphine (2.9 g; 11 mmol) was added and then the reaction mixture was stirred at 130C under nitrogen atmosphere for 4 hours. The mixture was poured out into H20 (300 ml) and then extracted with EtOAc (200 ml). The organic layer was separated, washed with H20 (2 x 100 ml), brine (100 ml), dried (MgSC^), filtered and the solvent was evaporated.The residue was purified by column chromatography over silica gel (eluent: hexanes/ EtOAc (5/1, v/v)). The product fractions were collected and the solvent was evaporated.Yield: 20 g (93%; orange solid). |
93% | With triphenylphosphine;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; In N,N-dimethyl-formamide; at 130.0℃; for 4.0h;Inert atmosphere; | Example 2 - ethyl 2-cyano-5-fluorobenzoateZinc cyanide (26.5 g; 0.225 mol) and Pd2(dba)3 (1.9 g; 3.4 mmol) were added to a solution of <strong>[139911-28-7]ethyl 2-bromo-5-fluorobenzoate</strong> (27.9 g; 0.112 mol) in DMF (71 ml). Triphenyl phosphine (2.9 g; 1 1 mmol) was added and then the reaction mixture was stirred at 130C under nitrogen atmosphere for 4 hours. The mixture was poured out into H2O (300 ml) and then extracted with EtOAc (200 ml). The organic layer was separated, washed with H2O (2 x 100 ml), brine (100 ml), dried (MgS04), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: hexanes/ EtOAc (5/1, v/v)). The product fractions were collected and the solvent was evaporated.Yield: 20 g (93%; orange solid). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium carbonate; In ethanol; at 80.0℃; for 3.0h; | Example 2a. 8-fluorophenanthridin-6-ol.A mixture of m<strong>[139911-28-7]ethyl 2-bromo-5-fluorobenzoate</strong> (0.250 g, 1.07 mmol), 2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)aniline (0.235 g, 1.07 mmol), palladium acetate (2.4 mg, 0.01 eq.), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (8.81 mg, 0.021 mmol), and sodium carbonate (0.114 g, 1.073 mmol) in ethanol (5.4 mL) was heated to 80 C for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was triturated with hexane, and isolated by vacuum filtration, washed with water, and dried to provide the title compound (0.15 g, 65% yield) which was used without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triphenylphosphine;tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 130.0℃; for 4.0h;Inert atmosphere; | Zinc cyanide (26.5 g; 0.225 mol) and Pd2(dba)3 (1.9 g; 3.4 mmol) were added to a solution of <strong>[139911-28-7]ethyl 2-bromo-5-fluorobenzoate</strong> (27.9 g; 0.112 mol) in DMF (71 ml). Triphenyl phosphine (2.9 g; 11 mmol) was added and then the reaction mixture was stirred at 130C under nitrogen atmosphere for 4 hours. The mixture was poured out into H2O (300 ml) and then extracted with EtOAc (200 ml). The organic layer was separated, washed with H2O (2 x 100 ml), brine (100 ml), dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: hexanes/EtOAc (5/1, v/v)). The product fractions were collected and the solvent was evaporated. Yield: 20 g (93%; orange solid). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium persulfate; N-chloro-succinimide; trifluorormethanesulfonic acid; palladium diacetate; In 1,2-dichloro-ethane; at 80.0℃; for 4.0h; | Compound 3 was prepared with similar procedure as compound 2. Compound 2 (1.45 g, 1.0 equiv.), NCS (0.83 g, 1.05 equiv.), Pd(OAc)2 (52.9 mg, 0.04 equiv.), Na2S2O8 (1.68 g, 1.2 equiv.), TfOH (2.6 mL, 5.0 equiv.) were used. The reaction mixture was stirred at 80 C for 4 h. Finally, compound 3 (0.78 g) was obtained in 47% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium persulfate; N-Bromosuccinimide; trifluorormethanesulfonic acid; palladium diacetate; In 1,2-dichloro-ethane; at 80.0℃; for 9.0h; | Compound 1 (1.68 g, 1.0 equiv.), NBS (1.87 g, 1.05 equiv.), Pd(OAc)2 (78.5 mg, 0.035 equiv.) and Na2S2O8 (2.86 g, 1.2 equiv.) were dissolved in commercial dichloroethane (12 mL) in a 100 mL round bottom flask. Then TfOH (2.2 mL, 2.5 equiv.) was added into the reaction solution. Then the reaction mixture was stirred at 80 C for 9 h. After completion of the reaction, the mixture was cooled to room temperature and then saturated NaHCO3 was added to quench the reaction. The reaction mixture was diluted with dichloromethane and washed once with saturated aqueous NaHCO3. Then organic layer was dried over Na2SO4 and concentrated on rotavapor under reduced pressure. Finally the residue was purified by silical gel column chromatography to give compound 2 (1.71 g) in 70% yield. |
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