Structure of 1192813-41-4
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CAS No. : | 1192813-41-4 |
Formula : | C6H4F2N2O3 |
M.W : | 190.10 |
SMILES Code : | O=[N+](C1=CN=C(OC(F)F)C=C1)[O-] |
MDL No. : | MFCD11847317 |
InChI Key : | WLHADOSXRICWAB-UHFFFAOYSA-N |
Pubchem ID : | 53403752 |
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 | 0.17 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 6.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 39.65 |
TPSA ? Topological Polar Surface Area: Calculated from |
67.94 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.76 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.5 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.43 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.61 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.32 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.2 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.74 |
Solubility | 0.348 mg/ml ; 0.00183 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.57 |
Solubility | 0.0509 mg/ml ; 0.000268 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.76 |
Solubility | 3.33 mg/ml ; 0.0175 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 |
-5.68 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) |
2.06 |
* 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% | With hydrogen;palladium 10% on activated carbon; In methanol; under 760.051 Torr; for 1.0h; | Step B: 6-(Difluoromethoxy)pyridin-3-amine To <strong>[1192813-41-4]2-(difluoromethoxy)-5-nitropyridine</strong> (4.7 g, 24.7 mmol) in degassed methanol (100 mL) was added 10% palladium on carbon (500 mg, 0.47 mmol) and the reaction was hydrogenated at atmospheric pressure for 1 hour. To this was added acetic acid (2.83 mL, 49.4 mmol) and the reaction was filtered through Celite and concentrated in vacuo to afford 6-(difluoromethoxy)pyridin-3-amine (6.33 g, 25.9 mmol, 105% yield) as an olive green liquid. 1H NMR (400 MHz, MeOD-d4) delta ppm 7.60 (d, J=2.76 Hz, 1H), 7.37 (s, 0.5H), 7.15 (dd, J=8.66, 2.89 Hz, 1H), 7.00 (s, 0.5H), 6.71 (d, J=8.78 Hz, 1H). |
With hydrogenchloride; iron; In ethanol; water; at 80℃; for 20.0h; | 2-Difluoromethoxy-5-nitro-pyridine obtained in Step A (1.6 g) was treated with iron (5 g) and concentrated hydrochloric acid (0.23 ml) in ethanol (15 ml) and water (2.5 ml) at 800C for 20 minutes. Filtration over Celite and evaporation of the solvent afforded 6- difluoromethoxy-pyridin-3-yl-amine (1.4 g) as an orange solid. IH NMR (400 MHz, CDCI3) 3.51 (br s, 2H), 6.89 (d, IH), 7.23 (d, IH), 7.44 (dd, IH), 7.80 (d, IH). | |
With hydrogenchloride; iron; In ethanol; water; at 80℃; for 0.333333h; | Step B: 2-Difluoromethoxy-5-nitro-pyridine obtained in Step A (1.6 g) was treated with iron (5 g) and concentrated hydrochloric acid (0.23 ml) in ethanol (15 ml) and water (2.5 ml) at 800C for 20 minutes. Filtration over Celite and evaporation of the solvent afforded 6- difluoromethoxy-pyridin-3-yl-amine (1.4 g) as an orange solid. IH NMR (400 MHz, CDCl3) 3.51 (br s, 2H), 6.89 (d, IH), 7.23 (d, IH), 7.44 (dd, IH), 7.80 (d, IH). |
With hydrogen;palladium 10% on activated carbon; In methanol; under 760.051 Torr; for 1.0h; | Step B: 6-(difluoromethoxy)pyridin-3-amine To <strong>[1192813-41-4]2-(difluoromethoxy)-5-nitropyridine</strong> (4.7 g, 24.7 mmol) in degassed methanol (100 mL) was added 10% palladium on carbon (500 mg, 0.47 mmol) and the reaction was hydrogenated at atmospheric pressure for 1 hour. To this was added acetic acid (2.83 mL, 49.4 mmol) and the reaction was filtered through Celite and concentrated in vacuo to afford 6-(difluoromethoxy)pyridin-3-amine (6.33 g, 25.9 mmol, 105 % yield) as an olive green liquid. XH NMR (400 MHz, MeOD-d4) delta ppm 7.60 (d, J=2.76 Hz, 1 H), 7.37 (s, 0.5 H), 7.15 (dd, J=8.66, 2.89 Hz, 1 H), 7.00 (s, 0.5 H), 6.71 (d, J=8.78 Hz, 1 H). | |
Step-2 -Preparation of 6-(difluoromethoxy)pyridin-3-amine To a solution of <strong>[1192813-41-4]2-(difluoromethoxy)-5-nitropyridine</strong> (0.900 g, 2.35 mmol) in ethanol (5.0 mL), was added iron powder (0.400 g, 7.14 mmol) and conc. HCl (0.2 mL). The reaction mass was refluxed for 1/2 h. Ethanol was removed under vacuum. To the reaction mass, water was added, basified with NaHCO3 and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.400 g of the desired product. 1HNMR (DMSO-d6): delta 7.65 (s, 1H), 7.52-7.03 (t, J=72.0 Hz, 1H), 7.27 (s, 1H), 6.73 (d, J=8.4 Hz, 1H); MS [M-H]-: 159.14. | ||
6.33 g | With palladium 10% on activated carbon; hydrogen; In methanol; under 760.051 Torr; for 1.0h; | To <strong>[1192813-41-4]2-(difluoromethoxy)-5-nitropyridine</strong> (4.7 g, 24.7mmol) in degassed methanol (100 mL) was added 10% palladium on carbon (500 mg, 0.47 mmol) and the reaction was hydrogenated at atmospheric pressure for 1 hour. To this was added acetic acid (2.83 ml., 49.4 mmol) and the reaction wasfiltered through Celite and concentrated in vacuo to afford6-(difluoromethoxy)pyridin-3-amine (6.33 g, 25.9 mmol,105% yield) as an olive green liquid. |
With hydrogenchloride; iron; In ethanol; water; at 80℃; for 0.333333h; | Step B: 2-Difluoromethoxy-5-nitro-pyridine obtained in Step A (1.6 g) was treated with iron (5 g) and concentrated hydrochloric acid (0.23 ml) in ethanol (15 ml) and water (2.5 ml) at 800C for 20 minutes. Filtration over Celite and evaporation of the solvent afforded 6-difluoromethoxy-pyridin-3-yl-amine (1.4 g) as an orange solid. IH NMR (400 MHz, CDCl3) 3.51 (br s, 2H), 6.89 (d, IH), 7.23 (d, IH), 7.44 (dd, IH), 7.80 (d, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.4% | With sodium carbonate; In acetonitrile; at 0 - 20℃; for 16.0h; | To a solution of 5-nitropyridin-2-ol (XCVIII) (1 g, 7.14 mmol) in acetonitrile (10 mL) at 0 C. was added sodium carbonate (1.513 g, 14.28 mmol), and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (XCIX) (1.107 mL, 10.71 mmol). The reaction was allowed to stir from 0 C. to room temperature over 16 h. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on a silica gel column (0%?10% EtOAc/hexane) to give 2-(difluoromethoxy)-5-nitropyridine (C) as a light brown oil (1.01 g, 5.31 mmol, 74.4% yield). 1H NMR (DMSO-d6, 500 MHz) delta ppm 7.36 (d, J=9.61 Hz, 1H), 7.82 (t, J=71.70 Hz, 1H), 8.70 (dd, J=9.06, 2.74 Hz, 1H), 9.15 (d, J=2.74 Hz, 1H); ESIMS found for C6H4F2N2O3 m/z 191.0 (M+H). |
49% | With sodium sulfate; In acetonitrile; at 20℃; for 16.0h; | Step A: 2-(Difluoromethoxy)-5-nitropyridine To 2-hydroxy-5-nitropyridine (7 g, 50 mmol) in acetonitrile (500 mL) was added sodium sulfate (1.5 g, 10.6 mmol), and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (6.2 mL, 60 mmol) and the reaction was allowed to stir at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and the acetonitrile was removed in vacuo. The remaining aqueous component was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The pale brown oily solid was triturated with ether/hexanes, filtered and the filtrate concentrated to afford 2-(difluoromethoxy)-5-nitropyridine (4.7 g, 24.7 mmol, 49% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) delta ppm 9.14 (d, J=2.76 Hz, 1H), 8.68 (dd, J=9.03, 2.76 Hz, 1H), 7.98 (s, 0.5H), 7.62 (s, 0.5H), 7.34 (d, J=9.03 Hz, 1H). |
49% | With sodium sulfate; In acetonitrile; at 20℃; for 16.0h; | Step A: 2-(Difluoromethoxy)-5-nitropyridineTo 2-hydroxy-5-nitropyridine (7 g, 50 mmol) in acetonitrile (500 niL) was added sodium sulfate (1.5 g, 10.6 mmol), and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (6.2 mL, 60 mmol) and the reaction was allowed to stir at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and the acetonitrile was removed in vacuo. The remaining aqueous component was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The pale brown oily solid was triturated withether/hexanes, filtered and the filtrate concentrated to afford 2-(difluoromethoxy)-5- nitropyridine (4.7 g, 24.7 mmol, 49 % yield) as a yellow oil. XH NMR (400 MHz, DMSO-de) delta ppm 9.14 (d, J=2.76 Hz, 1 H), 8.68 (dd, J=9.03, 2.76 Hz, 1 H), 7.98 (s, 0.5 H), 7.62 (s, 0.5 H), 7.34 (d, J=9.03 Hz, 1 H). |
49% | With sodium sulfate; In acetonitrile; at 20℃; for 16.0h; | To 2-hydroxy-5-nitropyridine (7 g, 50 mmol) inacetonitrile (500 mL) was added sodium sulfate (1.5 g, 10.6mmol), and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (6.2ml., 60 mmol) and the reaction was allowed to stir at roomtemperature for 16 hours. The reaction was quenched withsaturated aqueous sodium bicarbonate and the acetonitrilewas removed in vacuo. The remaining aqueous componentwas extracted with ethyl acetate, washed with brine, driedover sodium sulfate, filtered and concentrated in vacuo. Thepale brown oily solid was triturated with ether/hexanes, filteredand the filtrate concentrated to afford 2-(difluoromethoxy)-5-nitropyridine (4.7 g, 24.7 mmol, 49% yield) asa yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.5%; 15% | In acetonitrile; for 48.0h;Reflux; | 2-Hydroxy-5-nitro-pyridine (5 g) was treated with sodium chlorodifluoro- acetate (11.5 g) in refluxing acetonitrile (186 ml) for 2 days. The solvent was evaporated, the residue poured into ethyl acetate, washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane / ethyl acetate 1 :1) afforded 2-difluoromethoxy-5-nitro-pyridine (1 g, 15%) and l-difluoromethyl-5-nitro-lH- pyridin-2-one (90 mg, 1.5%). 2-Difluoromethoxy-5-nitro-pyridine: MS (ES+) 191 (MEta+); IH NMR (400 MHz, CDCl3) 7.05 (d, IH), 7.51 (t, IH), 8.53 (dd, IH), 9.09 (d, IH). 1-Difluoromethyl-5-nitro-lH-pyridin-2-one: MS (ES+) 191 (MEta+); 6.65 (d, IH), 7.63 (t, IH), 8.14 (dd, IH), 8.73 (d, IH). |
1.5%; 15% | In acetonitrile; for 48.0h;Reflux; | Step A: 2-Hydroxy-5-nitro-pyridine (5 g) was treated with sodium chlorodifluoro- acetate (1 1.5 g) in refluxing acetonitrile (186 ml) for 2 days. The solvent was evaporated, the residue poured into ethyl acetate, washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane / ethyl acetate 1 :1) afforded 2-difluoromethoxy-5-nitro-pyridine (I g, 15%) and l-difluoromethyl-5-nitro-lH- pyridin-2-one (90 mg, 1.5%). 2-Difluoromethoxy-5-nitro-pyridine: MS (ES+) 191 (MH+); IH NMR (400 MHz, CDCl3) 7.05 (d, IH), 7.51 (t, IH), 8.53 (dd, IH), 9.09 (d, IH). 1-Difluoromethyl-5-nitro-l//-pyridin-2-one: MS (ES+) 191 (MH+); 6.65 (d, IH), 7.63 (t, IH), 8.14 (dd, IH), 8.73 (d, IH). |
In acetonitrile; for 48.0h;Reflux; | This example illustrates the preparation of 2-chloro-N-{r-[4-(5-chloro-pyrirnidin-2- yl)-benzyl]-6-difluoromethoxy- 1 ',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-3-yl} - isonicotinamide (Compound B6 of Table B).The title compound was obtained from 2-bromo-6-difluoromethoxy-pyridin-3-yl- amine following the procedures described in Example 5. 2-Bromo-6-difluoromethoxy-pyridin- 3-yl-amine was prepared as follows:Step A: 2-Hydroxy-5-nitro-pyridine (5 g) was treated with sodium chlorodifluoro- acetate (11.5 g) in refluxing acetonitrile (186 ml) for 2 days. The solvent was evaporated, the residue poured into ethyl acetate, washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane / ethyl acetate 1 :1) afforded 2-difluoromethoxy-5-nitro-pyridine (1 g) and l-difluoromethyl-5-nitro-lH-pyridin-2- one (90 mg). 2-Difluoromethoxy-5-nitro-pyridine: MS (ES+) 191 (MH+); IH NMR (400 MHz, CDCl3) 7.05 (d, IH), 7.51 (t, IH), 8.53 (dd, IH), 9.09 (d, IH). l-Difluoromethyl-5- nitro-lH-pyridin-2-one: MS (ES+) 191 (MEta+); IH NMR (400 MHz, CDCl3) 6.65 (d, IH), 7.63 (t, IH), 8.14 (dd, IH), 8.73 (d, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; for 72.0h;Reflux; | Step-1 -Preparation of 2-(difluoromethoxy)-5-nitropyridine To a solution of 2-hydroxy-5-nitro pyridine (10 g, 0.071 mol) in acetonitrile (100 mL) was added sodium chlorodifluoroacetate (11.5 g, 0.075 mol). The reaction mass was refluxed for 72 h. The excess of solvent was removed under vacuum and the reaction mass was diluted with ethyl acetate and water. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on neutral alumina eluting with 10% EtOAc: Pet.ether to afford 0.900 g of the desired product. 1HNMR (DMSO-d6): delta 7.05 (d, J=8.7 Hz, 1H), 7.53 (d, J=71.4 Hz, 1H), 8.54 (dd, J=8.1 Hz & 5.4 Hz, 1H), 7.91 (s, 1H); MS [M-]: 190.83. |