Structure of 1214377-42-0
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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. : | 1214377-42-0 |
Formula : | C7H5BrF3NO |
M.W : | 256.02 |
SMILES Code : | BrC1=CN=C(C(=C1)C(F)(F)F)OC |
MDL No. : | MFCD13185815 |
InChI Key : | ZIOFHXRZJCIBCO-UHFFFAOYSA-N |
Pubchem ID : | 53393182 |
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 | 0.29 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 43.43 |
TPSA ? Topological Polar Surface Area: Calculated from |
22.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.35 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.73 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.02 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.38 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.05 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.91 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.36 |
Solubility | 0.113 mg/ml ; 0.00044 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.85 |
Solubility | 0.363 mg/ml ; 0.00142 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.9 |
Solubility | 0.0326 mg/ml ; 0.000127 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 |
-5.92 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<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.08 |
* 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 |
---|---|---|
74% | Intermediate 1 : 5-Bromo-<strong>[121643-44-5]2-methoxy-3-trifluoromethyl-pyridine</strong> To <strong>[121643-44-5]2-methoxy-3-(trifluoromethyl)pyridine</strong> (20.0 g, 1 13.0 mmol) and 1 ,3-dibromo-5,5- dimethylimidazolidine-2,4-dione (43.6 g, 152.0 mmol) was added TFA (80 mL) and the resulting mixture stirred at rt for 18h under argon. The TFA was removed in vacuo (50 mbar, 45C) and the residue suspended in tert-butyl methyl ether (200 mL). The resulting colourless solid was removed by filtration and washed with tert-butyl methyl ether (50 mL). The filtrate was concentrated in vacuo and suspended in EtOAc (50 mL) The insoluble colourless solid was removed by filtration and washed with EtOAc (50 mL).The filtrate was concentrated in vacuo, diluted with heptane/ tert-butyl methyl ether (5/1 , 20 mL) and the insoluble colourless solid was removed by filtration. The filtrate was purified by column chromatography on silica gel with heptane / EtOAc, 100/0 to 90/10. The crude product was filtered through a plug of NaHC03 (20g) and the filtrate evaporated in vacuo to give a golden oil (27.9 g). The oil was dissolved in heptanes (20 mL) and purified by filtered through a plug of silica gel (80 g), eluting with heptane to give 5-bromo-<strong>[121643-44-5]2-methoxy-3-(trifluoromethyl)pyridine</strong> as a colourless oil (22.5g, 74% yield). 1 H-NMR (400 MHz, DMSO-d6, 298 K): delta ppm 4.03 (s, 3H) 7.95 (d, 1 H) 8.4 (d, 1 H). | |
74% | With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; In trifluoroacetic acid; at 20℃; for 18h;Inert atmosphere; | Intermediate 1 : 5-Bromo-<strong>[121643-44-5]2-methoxy-3-trifluoromethyl-pyridine</strong>To <strong>[121643-44-5]2-methoxy-3-(trifluoromethyl)pyridine</strong> (20.0 g, 1 13.0 mmol) and 1 ,3-dibromo-5,5- dimethylimidazolidine-2,4-dione (43.6 g, 152.0 mmol) was added TFA (80 mL) and the resulting mixture stirred at rt for 18h under argon. The TFA was removed in vacuo (50 mbar, 45C) and the residue suspended in tert-butyl methyl ether (200 mL). The resulting colourless solid was removed by filtration and washed with tert-butyl methyl ether (50 mL). The filtrate was concentrated in vacuo and suspended in EtOAc (50 mL) The insoluble colourless solid was removed by filtration and washed with EtOAc (50 mL).The filtrate was concentrated in vacuo, diluted with heptane/ tert-butyl methyl ether (5/1 , 20 mL) and the insoluble colourless solid was removed by filtration. The filtrate was purified by column chromatography on silica gel with heptane / EtOAc, 100/0 to 90/10. The crude product was filtered through a plug of NaHC03 (20g) and the filtrate evaporated in vacuo to give a golden oil (27.9 g). The oil was dissolved in heptanes (20 mL) and purified by filtered through a plug of silica gel (80 g), eluting with heptane to give 5-bromo-<strong>[121643-44-5]2-methoxy-3-(trifluoromethyl)pyridine</strong> as a colourless oil (22.5g, 74% yield). 1H-NMR (400 MHz, DMSO-d6, 298 K): delta ppm 4.03 (s, 3H) 7.95 (d, 1 H) 8.4 (d, 1 H). |
74% | With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; trifluoroacetic acid; at 20℃; for 18h;Inert atmosphere; | To <strong>[121643-44-5]2-methoxy-3-(trifluoromethyl)pyridine</strong> (20.0 g, 1 13.0 mmol) and 1 ,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (43.6 g, 152.0 mmol) was added TFA (80 ml_) and the resulting mixture stirred at rt for 8h under argon. The TFA was removed in vacuo (50 mbar, 45C) and the residue suspended in tert-butyl methyl ether (200 ml_). The resultingcolourless solid was removed by filtration and washed with tert-butyl methyl ether (50 mL). The filtrate was concentrated in vacuo and suspended in EtOAc (50 mL) The insoluble colourless solid was removed by filtration and washed with EtOAc (50 mL).The filtrate was concentrated in vacuo, diluted with heptane/ tert-butyl methyl ether (5/1 , 20 mL) and the insoluble colourless solid was removed by filtration. The filtrate was purified by column chromatography on silica gel with heptane / EtOAc, 100/0 to 90/10. The crude product was filtered through a plug of NaHC03 (20g) and the filtrate evaporated in vacuo to give a golden oil (27.9 g). The oil was dissolved in heptanes (20 mL) and purified by filtered through a plug of silica gel (80 g), eluting with heptane to give 5-bromo-<strong>[121643-44-5]2-methoxy-3-(trifluoromethyl)pyridine</strong> as a colourless oil (22.5g, 74% yield).1H-NMR (400 MHz, DMSO-d6,298 K): delta ppm 4.03 (s, 3H) 7.95 (d, 1 H) 8.4 (d, 1 H). |
74% | With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; trifluoroacetic acid; at 20℃; for 18h;Inert atmosphere; | Intermediate 1 5-Bromo-<strong>[121643-44-5]2-methoxy-3-trifluoromethyl-pyridine</strong> To <strong>[121643-44-5]2-methoxy-3-(trifluoromethyl)pyridine</strong> (20.0 g, 113.0 mmol) and 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (43.6 g, 152.0 mmol) was added TFA (80 mL) and the resulting mixture stirred at rt for 18 h under argon. The TFA was removed in vacuo (50 mbar, 45 C.) and the residue suspended in tert-butyl methyl ether (200 mL). The resulting colourless solid was removed by filtration and washed with tert-butyl methyl ether (50 mL). The filtrate was concentrated in vacuo and suspended in EtOAc (50 mL) The insoluble colourless solid was removed by filtration and washed with EtOAc (50 mL). The filtrate was concentrated in vacuo, diluted with heptane/tert-butyl methyl ether (5/1, 20 mL) and the insoluble colourless solid was removed by filtration. The filtrate was purified by column chromatography on silica gel with heptane/EtOAc, 100/0 to 90/10. The crude product was filtered through a plug of NaHCO3 (20 g) and the filtrate evaporated in vacuo to give a golden oil (27.9 g). The oil was dissolved in heptanes (20 mL) and purified by filtered through a plug of silica gel (80 g), eluting with heptane to give 5-bromo-<strong>[121643-44-5]2-methoxy-3-(trifluoromethyl)pyridine</strong> as a colourless oil (22.5 g, 74% yield). 1H-NMR (400 MHz, DMSO-d6, 298 K): delta ppm 4.03 (s, 3H) 7.95 (d, 1H) 8.4 (d, 1H). |
52% | With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; trifluoroacetic acid; at 20℃; for 16h; | 2-Methoxy-3-trifluoromethyl-pyridine (2.7 g, 14.79 mmol) and 1 ,3-dibromo-5,5- dimethylhydantoin (5.28g, 18.48 mmol) were placed in a round-bottom flask. To this mixture was slowly added 40ml TFA. The mixture was stirred overnight at ambient temperature (16h). After completion of the reaction, TFA solvent was evaporated in vacuo and the resulting residue was neutralized to pH6-7 by the addition of saturated NaHC03. The aqueous layer was extracted with DCM two times and the combined extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a mixture of oil and white solid. The residue was redissolved into 20% Ethylacetate/Heptane (50ml) and the insoluble white solid was filtered off. The filtrate was concentrated and then purified by Flash- chromatography on silica gel (EtOAc/Heptane 5/95) to give 5-Bromo-2-methoxy-3- trifluoromethyl-pyridine as a colorless liquid (2.08 g, 52% yield).1 H-NMR (400 MHz, DMSO-d6, 298 K): ? ppm 4.03 (s, 3H) 7.95 (d, 1 H) 8.4 (d, 1 H). |
9.4 g | With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; trifluoroacetic acid; at 20℃; for 22h; | Preparation Example 36 2-Methoxy-3-(trifluoromethyl)pyridine (8 g), 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (17 g), and trifluoroacetic acid (32 mL) were mixed, followed by stirring at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added diisopropyl ether. The precipitated solid was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 5-bromo-<strong>[121643-44-5]2-methoxy-3-(trifluoromethyl)pyridine</strong> (9.4 g) as an oil. |
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