Structure of 116369-24-5
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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. : | 116369-24-5 |
Formula : | C6H4BrClFN |
M.W : | 224.46 |
SMILES Code : | NC1=CC(Cl)=C(Br)C=C1F |
MDL No. : | MFCD09878173 |
Boiling Point : | No data available |
InChI Key : | SKJMNEFZWYBTHT-UHFFFAOYSA-N |
Pubchem ID : | 14129196 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 43.51 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.87 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.66 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.25 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.26 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.88 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.78 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.35 |
Solubility | 0.0999 mg/ml ; 0.000445 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.86 |
Solubility | 0.311 mg/ml ; 0.00139 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.79 |
Solubility | 0.0362 mg/ml ; 0.000161 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 |
-5.78 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 |
2.0 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) |
1.57 |
* 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 |
---|---|---|
60% | a) N-(4-bromo-5-chloro-2-fluorophenyl)-2-[(35)-l-(cyclopropylcarbonyl)-3- pyrrolidinyl]acetyl}hydrazinecarboxamideTo a round bottom flask was added triphosgene (2.66 mmol) and dichloromethane (20 mL) under nitrogen, and the solution was cooled to -78 C. In a separate vial, 4- bromo-5-chloro-2-fluoroaniline (6.83 mmol) was dissolved in dichloromethane (20 mL) and Hunig's base (17.1 mmol) was added. This solution was slowly added to the cooled solution and then the reaction was allowed to warm to room temperature. After 10 min, analysis by LCMS indicated desired intermediate formation. The reaction was cooled again to -78 C and 2-[(35)-l-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (3.98 mmol) in dichloromethane (5 mL) was added slowly. The reaction was allowed to warm to room temperature and stirred for 30 min. Analysis by LCMS indicated desired product formation. The reaction was poured into a separatory funnel and partitioned with saturated aq sodium bicarbonate. The aqueous layer was extracted with dichloromethane (3x) and the combined organic layers were dried over Na2S04, filtered, and concentrated to an oil. The residue was purified by silica gel chromatography (0-15%isopropanol/ethyl acetate). The desired fractions were combined and concentrated to afford the title product as an oil (1.12 g, 60%). MS(ES)+ m/e 461.1, 463.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-Bromosuccinimide; In acetonitrile; at 25℃; for 1h; | 4-Bromo-5-chloro-2-fluoroaniline To a mixture of 5-chloro-2-fluoroaniline (1 equiv.) in acetonitrile (0.5 M) was added N-bromosuccinimide (1 equiv.) at 25 C. The mixture was stirred at 25 C. for 1 h. The mixture was concentrated to a residue, the residue was purified via silica gel chromatography to give 4-bromo-5-chloro-2-fluoroaniline (91%) as a yellow oil. 1H NMR (400 MHz, CDCl3) delta ppm: 7.23 (d, J=10.2 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 3.92-2.64 (br, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-chloro-succinimide; In acetonitrile; at 90℃; for 0.5h; | 4-Bromo-2,3-dichloro-6-fluoroaniline To a mixture of <strong>[116369-24-5]4-bromo-5-chloro-2-fluoroaniline</strong> (1 equiv.) in acetonitrile (0.36 M) was added NCS (1 equiv.) portion-wise at 90 C. over 30 min. The mixture was stirred at 90 C. for 1 h. The residue was purified by chromatography to give 4-bromo-2,3-dichloro-6-fluoroaniline (76%) as a brown solid. 1H NMR (400 MHz, CDCl3) delta ppm: 7.35 (d, J=10.5 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.75% | With hydrogenchloride; iron; In ethanol; water; at 0℃; for 0.5h; | To a stirred solution of 99 (23 g, 90.39 mmol) in EtOH (90 mL) and cone HC1 (90 mL) cooled to 0 C was added Fe powder (47.52 g, 848.5 mmol) in small portions over 30 min. After addition was complete, the reaction mixture was stirred at RT for another 30 min. The solvent was distilled off under reduced pressure. Water was added to the resulting residue and the mixture neutralized with NaHC03 and diluted with EtOAc. The resulting biphasic reaction mixture was filtered through Celite and washed with EtOAc. The phases of the filtrate were separated and the organic layer was washed with water and brine solution, dried over Na2S04 and concentrated to afford 100 (18 g, 88.75 %) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In N,N-dimethyl-formamide; at 150℃; for 5h; | Copper(I) cyanide (3.99 g, 44.55 mmol) was added to a mixture of <strong>[116369-24-5]4-bromo-5-chloro-2-fluoroaniline</strong> (5.0 g, 22.28 mmol) in DMF (30 mL) at room temperature, and the mixture was stirred at 150C for 5 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was filtered. The organic layer was washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 4-amino-2-chloro-5-fluorobenzonitrile (2.81 g, 16.47 mmol, 74.0%) as a grayish white solid. 1H NMR (300 MHz, CDCl3):delta 4.34(2H,brs), 6.82(1H,d,J=7.6 Hz), 7.21-7.29(1H,m). |
51.2% | In N,N-dimethyl-formamide; at 140℃; for 10h; | To a stirred solution of 100 (18 g, 80.19 mmol) in DMF (100 mL) was added cuprous cyanide (1 1.49 g, 128.2 mmol) and the resulting mixture was heated to 140 C for 10 h. The reaction mixture was cooled to RT and and DMF was evaporated under reduced pressure. The resulting residue was partitioned between DCM and water and the resulting biphasic mixture was filtered. The phases of the filtrate were separated and the organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The crude compound was purified by column chromatography (4% EtOAc/hexane) to afford 101 (7 g, 51.20%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 1h;Inert atmosphere; Irradiation; | <strong>[116369-24-5]4-bromo-5-chloro-2-fluoroaniline</strong> (100mg, 0.446mmol),Isobutyl-1H-pyrazole-4-boronic acid pinacol ester(223 mg, 0.891 mmol),Pd (dppf) Cl2 (163 mg, 0.223 mmol)And potassium carbonate (123 mg, 0.890 mmol) were stirred in 1,4-dioxane / water (10 mL / 2 mL)Under nitrogen atmosphere, the temperature was raised to 110 C for 1 hour under microwave irradiation.Cool to room temperature,add water,Dichloromethane extraction,dry,Purification by column chromatography gave 5-chloro-2-fluoro-4- (1-isobutyl-1H-pyrazol-4-yl) aniline(67.0 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 1h;Inert atmosphere; Irradiation; | <strong>[116369-24-5]4-bromo-5-chloro-2-fluoroaniline</strong> (86mg, 0.383mmol),Cyclobutylmethyl-1H-pyrazole-4-boronic acid pinacol ester (200 mg, 0.763 mmol),Pd (dppf) Cl2 (140mg, 0.191mmol) and potassium carbonate (105mg, 0.760mmol) stirring in 1,4-dioxane / water (10mL / 2mL),Under nitrogen atmosphere, the temperature was raised to 110 C for 1 hour under microwave irradiation.Cool to room temperature,add water,Dichloromethane extraction,dry,Purification by column chromatography gave 5-chloro-2-fluoro-4- (1-cyclobutylmethyl-1H-pyrazol-4-yl) benzeneAmine (47.0 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 10h;Inert atmosphere; | Add <strong>[116369-24-5]4-bromo-5-chloro-2-fluoroaniline</strong> (0.5 g, 2.24 mmol) to 1,4-dioxane (8.0 mL) and water (4.0 mL), and then add 1-isopropyl-5 in this order. -(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl) pyridine-2 (1H) -one (0.65 g, 2.46 mmol),Potassium carbonate (0.94g, 6.72mmol) and Pd (dppf) Cl2 (0.1g, 0.12mmol),After replacing with nitrogen three times, the reaction was carried out at 80 C for 10 hours.After the reaction is completed, cool to room temperature, pour the reaction solution into water, extract with ethyl acetate, combine the organic phases, dry, filter, and concentrate. The residue is purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether). = 3/1),The title compound (0.4 g, yield: 64%) was obtained in this step. |
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