Structure of 177420-64-3
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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. : | 177420-64-3 |
Formula : | C8H4BrF3O2 |
M.W : | 269.02 |
SMILES Code : | O=C(O)C1=C(C(F)(F)F)C=CC=C1Br |
MDL No. : | MFCD06253757 |
InChI Key : | AZERNJLIPMDNFQ-UHFFFAOYSA-N |
Pubchem ID : | 4737630 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 46.1 |
TPSA ? Topological Polar Surface Area: Calculated from |
37.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.4 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.02 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.32 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.38 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.95 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.01 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.6 |
Solubility | 0.0683 mg/ml ; 0.000254 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.47 |
Solubility | 0.0915 mg/ml ; 0.00034 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.51 |
Solubility | 0.0831 mg/ml ; 0.000309 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 |
-5.8 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 |
0.56 |
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) |
1.68 |
* 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 |
---|---|---|
With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; at 21℃; for 0.5h; | <strong>[177420-64-3]2-bromo-6-(trifluoromethyl)benzoic acid</strong> (70% pure, 60mg) was dissolved in anhydrous tetrahydrofuran (2ml). To this was added anhydrous dimethylformamide (5mul) and 0.25ml of a solution of oxalyl chloride (87mul) in anhydrous tetrahydrofuran (0.9ml). It was then stirred under nitrogen at 210C for 30 minutes and then a solution of 5-amino-lambda/-[2- (aminomethyl)-3,3,3-trifluoro-2-hydroxypropy|]-1-(4-fluorophenyl)-1/-/-pyrazole-4- carboxamide (72mg) in anhydrous tetrahydrofuran (2ml) and diisopropylethylamine (130mul) was added. It was stirred under nitrogen for 2 hours to give a suspension before being partitioned between ethyl acetate (20ml) and 2M hydrochloric acid (10ml), washed <n="124"/>with water (10ml) and saturated brine (10ml), dried over MgSO4 and evaporated to give a gum (128mg). Purification of this gum via the Flashmaster 2 on SiO2 (2Og) using 0-100% ethyl acetate in cyclohexane for 30 minutes gave the title compound (39.5mg). 1H NMR (400 MHz, CHLOROFORM-d) d ppm 9.0 (t, 1 H), 8.03 (m, 2H), 7.91 (s, 1 H), 7.83 (d, 1 H), 7.58 (m, 3H), 7.36 (m, 2H), 6.65 (s, 1 H), 6.35 (br. s., 2H), 3.75 (m, 2H), 3.52 (m, 2H). LC-MS Retention Time 3.32 mins, MH+ 612, 614.Example 45 was further preparatively separated into its enantiomers (Isomers A and B) using a Chiralpak AD column eluting with 40% propan-2-ol in heptane at a flow rate of 15ml/min.Enantiomer 1 (Isomer A)Analytical Chiral HPLC (25 x 0.46cm Chiralpak AD column, 40% propan-2-ol in heptane eluting at 1 ml/min) - Retention time 4.80mins.Enantiomer 2 (Isomer B)Analytical Chiral HPLC (25 x 0.46cm Chiralpak AD column, 40% propan-2-ol in heptane eluting at 1 ml/min) - Retention time 7.49mins. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.15 g | 2-Bromo-6- (trifluoromethyl) benzoic acid (0.203 g)Was dissolved in dichloromethane (3 mL)Under ice cooling, oxalyl chloride (0.0710 mL)And a catalytic amount of N, N-dimethylformamide were added, followed by stirring at room temperature for 3 hours.The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (1.5 mL)Under ice cooling, a solution of zirconium (IV) chloride (0.264 g) and the compound obtained in Example 1a (0.200 g) in dichloromethane (2 mL) was added.After stirring the reaction mixture at room temperature for 2 hours, water was added and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography(Ethyl acetate / hexane) to give the title compoundThe title compound (0.150 g) was obtained as a colorless amorphous solid. |
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