Structure of 57381-62-1
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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. : | 57381-62-1 |
Formula : | C8H6BrClO2 |
M.W : | 249.49 |
SMILES Code : | O=C(OC)C1=CC=C(Cl)C=C1Br |
MDL No. : | MFCD10566822 |
InChI Key : | BIFARHLBYAKSSN-UHFFFAOYSA-N |
Pubchem ID : | 15110995 |
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 | 0.12 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 50.43 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.46 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
4.12 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.89 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.24 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.01 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.14 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.22 |
Solubility | 0.015 mg/ml ; 0.0000602 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.38 |
Solubility | 0.0104 mg/ml ; 0.0000418 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.95 |
Solubility | 0.0282 mg/ml ; 0.000113 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 |
-4.9 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<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.59 |
* 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 |
---|---|---|
In tetrahydrofuran; | REFERENCE EXAMPLE 3 Cyclopropylmethylketone (4.0 g) was added to a suspension of sodium hydride (3.2 g, 60percent oil dispersion) in dry tetrahydrofuran (10 ml). When the evolution of hydrogen had subsided, a solution of <strong>[57381-62-1]methyl 2-bromo-4-chlorobenzoate</strong> (10.0 g) in tetrahydrofuran was added dropwise. The resulting mixture was heated at reflux overnight, cooled, evaporated to dryness and poured onto dilute hydrochloric acid. The mixture was extracted (dichloromethane), dried (magnesium sulphate) and evaporated to give, after purification by chromatography, 1-(2-bromo-4-chlorophenyl)-3-cyclopropyl-propan-1,3-dione (3.07 g), m.p. 42°-45° C. as an orange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With tetrabutyl ammonium fluoride; In toluene; at -70 - 20℃; for 14h; | <strong>[57381-62-1]2-bromo-4-chloro-benzoic acid methyl ester</strong> (12.4 g, 50 mmol) in toluene (200 ml) was cooled to -70 ° C and trifluoroMethyltrimethylsilane (13 ml, 70 mmol). Tetrabutylammonium fluoride (IM, 2.5 ml) was added dropwise and the mixture was allowed to stand for 4 hoursHeated to room temperature, followed by stirring at room temperature for 10 hours. The reaction mixture was concentrated to give crude [l- (2-bromo-4-chloro-phenyl) -2,2,2-trifluoro-1-methoxy-ethoxy] -trimethyl-silane. The crude intermediate was dissolved in methanol (100 ml) and added6N HCl (100 ml). The mixture was maintained at 45-50 & lt; 0 & gt; C for 12 hours. The methanol was removed and the crude product was extracted with dichloromethane (200 ml)Extract. The combined DCM layers were washed with water (50 ml), NaHCO3 (50 ml), brine (50 ml) and dried over sodium sulfate. Removal of dissolvedThe crude product was purified by ISCO column chromatography using 1-2percent ethyl acetate in hexanes as solventTo give 1- (2-bromo-4-chloro-phenyl) -2,2,2-trifluoro-ethanone (10 g, 70percent). |
With tetrabutyl ammonium fluoride; In toluene; at -70 - 20℃; for 14h; | 2-Bromo-4-chloro-benzoic acid methyl ester (12.4 g, 50 mmol) in toluene (200 ml) was cooled to -70° C., and trifluoromethyl trimethyl silane (13 ml, 70 mmol) was added. Tetrabutylammonium fluoride (1M, 2.5 ml) was added dropwise, and the mixture was allowed to warm to room temperature over 4 h, after which it was stirred for 10 h at room temperature. The reaction mixture was concentrated to give the crude [1-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-1-methoxy-ethoxy]-trimethyl-silane. | |
In toluene; | 2-Bromo-4-chloro-benzoic acid methyl ester (12.4 g, 50 mmol) in toluene (200 ml) was cooled to -70° C., and trifluoromethyl trimethyl silane (13 ml, 70 mmol) was added. Tetrabutylamonium fluoride (1M, 2.5 ml) was added dropwise, and the mixture was allowed to warm to room temperature over 4 h, after which it was stirred for 10 h at room temperature. The reaction mixture was concentrated to give the crude [1-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-1-methoxy-ethoxy]-trimethyl-silane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Step 1: Synthesis of 1-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone. To a 500 ml 2 necked RB flask containing anhydrous methanol (300 ml) was added thionyl chloride (29.2 ml, 400 mmol) dropwise at 0-5 C. (ice water bath) over 10 min. The ice water bath was removed, and 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol) was added. The mixture was heated to mild reflux for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated. Crude product was dissolved in dichloromethane (DCM, 250 ml), washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml), dried over sodium sulfate, and concentrated to give the 2-bromo-4-chloro-benzoic acid methyl ester (26 g, 99%), which was directly used in the following step. | |
99% | With thionyl chloride; at 0℃;Reflux; | Thionyl chloride (29.2 ml, 400 mmol) was added dropwise over 10 minutes at 0-5 C (ice-water bath) in a 500 ml 2-necked RB flask containing anhydrous methanol (300 ml).Remove the ice-water bath and add 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol).The mixture was heated to moderate reflux for 12 hours.Reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated.The crude product was dissolved in dichloromethane (DCM, 250 ml)Washed with water (50 ml), saturated aqueous NaHCO3 (50 ml), brine (50 ml)Dried over sodium sulfate,Concentration gave 2-bromo-4-chloro-benzoic acid methyl ester (26 g, 99%) which was used directly in the next step. |
98% | With sulfuric acid;Cooling with ice; Heating; Reflux; | Concentrated sulfuric acid (5 ml_) was added drop-wise to an ice-cold mixture of 2- bromo-4-chloro-benzoic acid (10.14 g, 0.0431 mol) and methanol (40 ml_). The resulting mixture was heated at reflux for 17 hours. After this time, the reaction mixture was cooled to room temperature, and then poured into ice-cold water (150 ml_), creating a white suspension. The suspension was extracted with ethyl acetate (150 ml_). The organic phase was washed with saturated aqueous NaHCO3 (I OO ml_), followed by saturated aqueous NaCI (100 ml_). The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-bromo-4-chloro-benzoic acid methyl ester (10.57 g, 98% yield) as a clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With thionyl chloride; In methanol; dichloromethane; | Step 1: Synthesis of 1-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone. To a 500 ml 2 necked RB flask containing anhydrous methanol (300 ml) was added thionyl chloride (29.2 ml, 400 mmol) dropwise at 0-5° C. (ice water bath) over 10 min. The ice water bath was removed, and 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol) was added. The mixture was heated to mild reflux for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated. Crude product was dissolved in dichloromethane (DCM, 250 ml), washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml), dried over sodium sulfate, and concentrated to give the 2-bromo-4-chloro-benzoic acid methyl ester (26 g, 99percent), which was directly used in the following step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A 1.0 M solution of diisobutylaluminum hydride in toluene (43 ml_, 0.043 mol) was added slowly drop-wise to a -78 °C solution of <strong>[57381-62-1]2-bromo-4-chloro-benzoic acid methyl ester</strong> (10.57 g, 0.042 mol) in toluene (50 ml_) and hexanes (425 ml_). The reaction mixture was stirred at -78 °C for 1.5 hours. After this time, a white solid had precipitated out of solution. The reaction mixture was quenched at -78 °C with ethyl acetate (100 ml_). Saturated aqueous sodium potassium tartrate was added, and the reaction mixture was warmed to room temperature. The organic phase was separated, dried over Na2SO4, filtered, and concentrated to a clear oil. TLC (30percent ethyl acetate/hexanes) and 1H NMR revealed a mixture with unreacted 2-bromo-4- chloro-benzoic acid methyl ester as the major component. The crude material was dissolved in toluene (300 ml_), and the resulting solution was cooled to -78 °C. A 1.0 M solution of diisobutylaluminum hydride in toluene (55 ml_, 0.055 mol) was added slowly drop-wise to the reaction mixture. The reaction mixture was warmed to - 45 °C and stirred at this temperature for 35 minutes. At this time, TLC (10percent ethyl acetate/hexanes) indicated nearly complete consumption of the starting material. The reaction mixture was quenched at -45 °C with ethyl acetate. Saturated aqueous sodium potassium tartrate was added, and the reaction mixture was warmed to room temperature and stirred at room temperature for 1 hour. The organic phase was separated, dried over Na2SO4, and concentrated to a yellow oil. A solution of this crude product and dichloromethane (200 mL) was evaporated onto silica gel, and the dry silica gel-supported product was loaded onto a 120 g silica gel column. Flash chromatography was carried out using an ISCO purification system (95:5 hexanes- ethyl acetate ramped to 4:1 hexanes-ethyl acetate). (2-Bromo-4-chloro-phenyl)- methanol was isolated as 5.57 g (60percent yield) of a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; sodium sulfate;copper; In nitrobenzene; at 220℃; for 7h;Inert atmosphere; | The following reagents and solvent were loaded into a reactor.10H-Phenoxazine: 10.0 g (54.58 mmol)Methyl 2-bromo-4-chlorobenzoate : 15.12 g (60.65 mmol) Copper: 3.85 g (60.65 mmol)Potassium carbonate: 8.38 g (60.65 mmol)Sodium sulfate: 8.61 g (60.65 mmol)Nitrobenzene: 125 ml [0110] Next, the reaction solution was stirred with heating under nitrogen at 220°C for 7 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure. To the resultant residue was added ethyl acetate, and the mixture was then washed with an aqueous solution of ammonium chloride. The organic layer was concentrated under reduced pressure to give a crude product. Next, the resultant crude product was purified by columnchromatography (silica gel) to afford 15.9 g of methyl 5-chloro-2- ( lOH-phenoxazin-10-yl ) benzoate (yield: 83percent) |
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