Structure of 191478-99-6
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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. : | 191478-99-6 |
Formula : | C8H7F2NO2 |
M.W : | 187.14 |
SMILES Code : | COC(=O)C1=C(F)C=C(N)C=C1F |
MDL No. : | MFCD16038807 |
InChI Key : | UWPLTCWTTVMXCM-UHFFFAOYSA-N |
Pubchem ID : | 23001755 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H317-H319 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 42.04 |
TPSA ? Topological Polar Surface Area: Calculated from |
52.32 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.56 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.28 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.18 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.17 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.84 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.81 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.02 |
Solubility | 1.8 mg/ml ; 0.00963 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.98 |
Solubility | 1.97 mg/ml ; 0.0105 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.67 |
Solubility | 0.396 mg/ml ; 0.00211 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) |
No |
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 |
-6.53 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 |
1.0 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) |
1.33 |
* 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 dmap; In dichloromethane; | Methyl 2,6-difluoro-4-[(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-benzoate (Compound A) To a solution of 3-methoxymethoxy-5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid (Compound K, as described in U.S. Pat. No. 5,856,490, 112mg, 0.38 mmol) in 6 ml of anhydrous methylene chloride was added 4-(dimethylamino)pyridine (DMAP, 100 mg, 0.46mmol), <strong>[191478-99-6]methyl 2,6-difluoro-4-aminobenzoate</strong> (Compound H1, as described in U.S. Pat. No. 5,856,490, 77mg, 0.38mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 110 mg, 0.57 mmol). The reaction mixture was stirred at room temperature for overnight then concentrated to dryness. The residue was purified by column chromatography with ethyl acetate: hexane (1:9) to yield the title compound as a clear oil. 1H NMR CDCl3 delta 8.18 (s, 1H), 7.38 (s, 1H), 7.35 (s, 1H), 7.10 (s, 1H), 5.39 (s, 2H), 3.94 (s, 3H), 3.59 (s, 3H), 1.70 (s, 4H), 1.31 (s, 3H), 1.30 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
This oil was then dissolved in 1 ml of CH3 CN, then a solution of NaN3 (100 mg, 1.54 mmol) in 0.5 ml of water was added. The reaction mixture was refluxed for two days. Salt was removed by filtration and the remaining solution was concentrated to an oil. This oil was then dissolved in 1 ml of methanol, followed by a catalytic amount of Pd/C (10%, w/w). The reaction mixture was hydrogenated for 12 hours. Catalyst was removed and the solution was concentrated to an oil. After column chromatography (ethyl acetate/hexane 1/3), the title compound was obtained as colorless crystals. 1 H NMR delta 6.17 (d, J=10.44 Hz, 2H), 4.2 (b, 2H), 3.87 (s, 3H). | ||
This oil was then dissolved in 1 ml of CH3 CN, then a solution of NaN3 (100 mg, 1.54 mmol) in 0.5 ml of water was added. The reaction mixture was refluxed for two days. Salt was filtered and the remaining solution was concentrated to an oil. This oil was then dissolved in 1 ml of methanol, followed by a catalytic amount of Pd/C (10%, w/w). The reaction mixture was hydrogenated under a hydrogen balloon for 12 h. Catalyst was removed and the solution was concentrated to an oil. After column chromatography (ethyl acetate/hexane 1/3), the title product was obtained as colorless crystals. 1 H NMR delta 6.17 (d, J=10.44 Hz, 2H), 4.2 (b, 2H), 3.87 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With pyridine; In dichloromethane; at 80℃; for 12.0h; | Methyl 4-amino-2,6-difluorobenzoate (3.60 g, 19.2 mmol) was suspended in methylene chloride (1.5 L), and 4-iodobenzenesulfonyl chloride (7.50 g, 25.0 mmol) and pyridine (6.0 ml) were added thereto, followed by stirring at 80 C. for 12 hours. After the reaction solution was concentrated under reduced pressure, 4 N hydrochloric acid was added. After stirring for 10 minutes, the obtained suspension was filtered. The obtained solid was stirred in a mixture solvent of petroleum ether/ ethyl acetate (8:1) for 1 hour, and then filtered and dried under reduced pressure to obtain the title compound (7.4 g, 85%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With pyridine; In dichloromethane; at 20℃; for 12.0h; | 6-Chloropyridine-3-sulfonyl chloride (10.0 g, 47.0 mmol) was dissolved in methylene chloride (300 ml), and <strong>[191478-99-6]methyl 4-amino-2,6-difluorobenzoate</strong> (7.5 g, 40 mmol) and pyridine (9.0 ml, 102 mmol) were added thereto, followed by stirring at room temperature for 12 hours. The reaction solution was washed with water and 2 N hydrochloric acid, followed by extraction with methylene chloride. The extraction liquids were combined, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Then, the solvent was removed. The obtained residue was recrystallized from a mixture solvent of petroleum ether/ ethyl acetate (1:2). The precipitated solid was filtered and then dried under reduced pressure to obtain the title compound (12.0 g, 83%) as a white solid. [0204] 1H NMR (CD3OD, 300 MHz): delta 8.82 (d, J=2.4 Hz, 1H), 8.20 (dd, J=2.4 Hz, 8.7 Hz 1H), 7.86-7.82 (t, 1H), 7.04 (d, J=10 Hz, 2H), 3.86 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With pyridine; In dichloromethane; at 20℃; for 12.0h; | 4-(Chlorosulfonyl)benzoic acid (25.0 g, 113 mmol) and <strong>[191478-99-6]methyl 4-amino-2,6-difluorobenzoate</strong> (19.0 g, 101 mmol) were dissolved in methylene chloride (500 ml), and pyridine (25.0 ml, 285 mmol) was added thereto, followed by stirring at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. The obtained residue was diluted with water, and then the pH was adjusted to 1.0 by adding 6 N hydrochloric acid. The precipitated solid was filtered, and washed with water. The obtained solid was resuspended in water, and washed with a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate (100 ml×2). The pH of the obtained aqueous layer was adjusted to 6.0 by adding 6 N hydrochloric acid thereto, followed by extraction with ethyl acetate (100 ml×2). The extraction liquids were combined, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Then, the solvent was removed to obtain the title compound (15.0 g, 36%). [0213] 1H NMR (d-DMSO, 400 MHz): delta 11.50 (s, 1H), 8.14 (d, J=8.4 Hz, 2H), 8.01 (d, J=8.4 Hz, 2H), 6.67 (d, J=10.4 Hz, 2H), 3.87 (s, 3H); MS (ESI) m/z 372 (M+H)+ |
36% | With pyridine; In dichloromethane; at 20℃; for 12.0h; | (Step 1) 4-([3,5-Difluoro-4-(methoxycarbonyl)phenyl]amino}sulfonyl)benzoic acid (0430) (0431) 4-(Chlorosulfonyl)benzoic acid (25.0 g, 113 mmol) and <strong>[191478-99-6]methyl 4-amino-2,6-difluorobenzoate</strong> (19.0 g, 101 mmol) were dissolved in methylene chloride (500 ml), pyridine (25.0 ml, 285 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was diluted with water, a 6 N aqueous solution of hydrochloric acid was added for adjustment of the pH to 1.0, and the precipitated solid was filtered and washed with water. The obtained solid was suspended in water again, washed with a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with ethyl acetate (100 ml×2). A 6 N aqueous solution of hydrochloric acid was added to the obtained aqueous layer for adjustment of the pH to 6.0, and ethyl acetate was added (100 ml×2) for extraction. The extracts were combined, washed with a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was removed to obtain the title compound (15.0 g, 36%). (0432) 1H NMR (d-DMSO, 400 MHz): delta 11.50 (s, 1H), 8.14 (d, J=8.4 Hz, H), 8.01 (d, J=8.4 Hz, 2H), 6.67 (d, J=10.4 Hz, 2H), 3.87 (s, 3H); MS (ESI) m/z 372 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With pyridine; In dichloromethane; at 20℃; for 12.0h; | 5-Iodopyridine-2-sulfonyl chloride (5.1 g, 17 mmol) and <strong>[191478-99-6]methyl 4-amino-2,6-difluorobenzoate</strong> (2.5 g, 13 mmol) were dissolved in methylene chloride (25 ml), and pyridine (5.0 ml) was added thereto, followed by stirring at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. To the obtained residue, 6 N hydrochloric acid (100 ml) was added. The precipitated solid was filtered, and dried under reduced pressure to obtain the title compound (3.0 g, 69%). [0261] 1H NMR (d-DMSO, 400 MHz): delta 11.58 (br, 1H), 9.00 (d, J=2.0 Hz, 1H), 8.54-8.51 (dd, J=8.4, 2.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 6.94 (d, J=10.4 Hz, 2H), 3.81 (s, 3H).; MS (ESI) m/z 455 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With pyridine; In dichloromethane; at 20℃; for 12.0h; | Methyl 4-amino-2,6-difluorobenzoate (5.00 g, 26.7 mmol) was dissolved in dichloromethane (100 ml), and p-bromobenzenesulfonyl chloride (7.50 g, 29.4 mmol) and pyridine (6.5 ml, 80 mmol) were added, followed by stirring at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and purification was conducted by silica gel column chromatography (dichloromethane/methanol=95:5) to obtain the title compound (8.50 g, 21.0 mmol, 79%). [0301] MS (ESI) m/z 406 (M+H)+ |
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