Structure of 116419-94-4
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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. : | 116419-94-4 |
Formula : | C10H9F3O2 |
M.W : | 218.17 |
SMILES Code : | O=C(OC)C1=CC=C(C)C(C(F)(F)F)=C1 |
MDL No. : | MFCD14698074 |
InChI Key : | LXUTXZRWQVCTTR-UHFFFAOYSA-N |
Pubchem ID : | 11952921 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.3 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 47.69 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.43 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.02 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.95 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.25 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.23 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.18 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.19 |
Solubility | 0.14 mg/ml ; 0.000641 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.24 |
Solubility | 0.126 mg/ml ; 0.000579 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.75 |
Solubility | 0.0384 mg/ml ; 0.000176 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 |
-5.49 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) |
1.78 |
* 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 |
---|---|---|
100% | Stage #1: With potassium hydroxide In dimethyl sulfoxide at 25℃; for 0.75 h; Stage #2: at 25℃; for 2 h; |
A solution of KOH (84 tug, 1.5 mmol) in DMSO (5 ml) was stilled fot- 30 min at 25 0C. The above slurry was then treated with 4-methyl-3-trifluoromethyl-benzoic acid (306 mg, 1.5 mmol) in H)MSO (5 ml) and the resulting mixture was stirred for 15 min, and iodottiethane (426 mg, 3 mmol) was then added to the mixture. The reaction was stirred for 2 h at 25 °C and then quenched with water. The resulting solution was extracted with βtOAc. The organic layer was washed with NaCl(sat) and dried with lsfa2Sψ4(S). The organics were removed under reduced pressure to give the title compound as an oil 327 mg (100percent). NMR: 8.10 (m, 214), 7.60 (s, IH), 3.86 (s, 3H), 2.45 (s, 3H); tn/z 218. |
100% | Stage #1: With potassium hydroxide In dimethyl sulfoxide at 25℃; for 0.75 h; Stage #2: at 25℃; for 2 h; |
Method 22; 4-Methyl-3-trifluoromethyl-benzoic acid methyl ester; A solution of KOH (84 mg, 1.5 mmol) in DMSO (5 ml) was stirred for 30 min at25 °C. The above slurry was treated with 4-methyl-3-trifluoromethyl-benzoic acid (306 mg, 1.5 mmol) in DMSO (5 ml) and the resulting mixture was stirred for 15 min, and iodomethane (426 mg, 3 mmol) was added to the mixture. The reaction was stirred for 2 h at 25 °C and then quenched with water. The resulting solution was extracted with EtOAc. The organic layer was washed with NaCl(sat) and dried with Na2SO4(S). The organics were removed under reduced pressure to give the title compound as an oil 327 mg (100percent). NMR: 8.10 (m, 2H), 7.60 (s, IH), 3.86 (s, 3H), 2.45 (s, 3H); m/z 218 |
100% | Stage #1: With potassium hydroxide In dimethyl sulfoxide for 0.25 h; Stage #2: at 0 - 25℃; for 2 h; |
Method 57; 4-Methyl-3-trifluoromethyl-benzoic acid methyl ester; A slurry of potassium hydroxide (84 mg, 1.5 mmol) in DMSO was treated with a solution of 4-methyl-3-trifluoromethyl-benzoic acid (306 mg, 1.5 mmol) in DMSO (5 ml). The resulting mixture was stirred for 15 min and cooled with an ice bath. After the addition of methyl iodide (426 mg, 3 mmol), the mixture was stirred for 2 h at 25 °C. The reaction mixture was quenched with water and extracted with EtOAc. The organics were washed with NaCl(sat), dried with Na2SO4(s) and concentrated under reduced pressure to give 327 mg (100percent). NMR: 8.10 (m, 2H), 7.60 (s, IH), 3.86 (s, 3H), 2.45 (s, 3H); m/z 218 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In acetone at 20℃; for 24 h; | To a mixture of 4-methyl-3-(trifluoromethyl) benzoic acid (1 equiv), K2C03 (1.5 equiv) in acetone (15 times) was added Mel (1.5 equiv) at room temperature. Stirring was continued for 24h. Reaction was monitored by thin layer chromatography. The salts were filtered and resulting filtrate was concentrated, diluted with water, extracted with ethyl acetate. Concentration of organic layer afforded the pale yellow oil (95percent yield). ESI MS m/z -219 (M+H l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Reflux | 20 mmol of 3-trifluoromethyl-4-methyl-benzoic acid was dissolved in a round-bottomed flask containing 60 mL of methanol.A catalytic amount (3percent mmol) of concentrated sulfuric acid was added and the reaction was stirred at reflux overnight.The solvent was removed on a rotary evaporator, and 30 ml of a saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate (2×50 ml) and drying over anhydrous sodium sulfate.The solvent was removed on a rotary evaporator to give 3-trifluoromethyl-4-methyl-benzoic acid methyl ester compound a (yield: 96percent). |
95% | for 6 h; Reflux | Example 88: preparation of methyl 5-(5-(4~((3-(dimethylamino)pyrrolidin~1-yl)methyl)-3- (trifluoro-methyl)benzamido)-2-methylbenzamido)-1H~pyrrolof2,3-b]pyridine-2- carboxylate (ND0119); Step 1: preparation of methyl 3-(trifluoromethyl)-4-methylbenzoate; A reactor is charged with 1q (4.9mmol) of 3-(trifluoromethylH-methylbenzoic acid in 10ml methanol in the presence of a catalytic amount of sulphuric acid. The mixture is heated for 6 hours at reflux. The solvent is then evaporated under reduced pressure and 100ml of a saturated sodium bicarbonate solution is added to the mixture. The solution is extracted by 3*30ml ethyl acetate. The organic phases are combined, dried on sodium sulphate and evaporated under reduced pressure to give the expected product (1α. 95percent). |
95% | Reflux | General procedure: General procedure for esterification: 4-methyl-3 -substituted benzoic acid (24 mmol) in methanol (50 mL) with H2SO4 (0.260 mL, 4.8 mmol) are stirred and heated to reflux for one night. Methanol is evaporated and product is extracted at pH = 7 with EtOAc. |
88.4% | Stage #1: at 0 - 20℃; for 1 h; Stage #2: at 80℃; for 5 h; |
To a stirred methanol (300 mL) was added dropwisely sulfurous dichloride (30 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. To this stirred solution was added 4-methyl-3-(trifluoromethyl)benzoic acid (30 g, 0.15 mol) in one portion at room temperature. The mixture was stirred at 80 °C for 5 hrs. The solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate and brine. The organic phase was dried over sodium sulfate anhydrous and concentrated. The residue (28.3 g, yield: 88.4percent) was used into next step directly. 1H NMR (400 MHz, CDC13) δ 8.24 (s, 1H), 8.03 (d, J= 8.0 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 3.90 (s, 3H), 2.50 (s, 3H)ppm. |
84.8% | for 24 h; Reflux | 4-methyl-3-(trifluoromethyl) benzoic acid (2.04 g, 10 mmol, 1.0 eq) in 25 mL of MeOH was added 2 mL of concentrated sulfuric acid. And the reaction monitored by TLC was completed after 24 hours under reflux with stirring. MeOH was distilled off and DCM was added to dissolved the residue. The solution was washed successively with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution and water. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give the product (1.85 g, 84.8percent yield) for the next step. |
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