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CAS No. : | 13671-00-6 | MDL No. : | MFCD00051778 |
Formula : | C8H6F2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QNPFLTKQLFSKBY-UHFFFAOYSA-N |
M.W : | 172.13 | Pubchem ID : | 518798 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 37.64 |
TPSA : | 26.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.96 cm/s |
Log Po/w (iLOGP) : | 2.0 |
Log Po/w (XLOGP3) : | 1.96 |
Log Po/w (WLOGP) : | 2.59 |
Log Po/w (MLOGP) : | 2.79 |
Log Po/w (SILICOS-IT) : | 2.54 |
Consensus Log Po/w : | 2.37 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.38 |
Solubility : | 0.718 mg/ml ; 0.00417 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.14 |
Solubility : | 1.25 mg/ml ; 0.00729 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.03 |
Solubility : | 0.162 mg/ml ; 0.00094 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.27 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
58% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at -78 - 20℃; for 2 h; |
General procedure: n-BuLi (1.67 M solution in hexane, 1.3 mL, 2.2 mmol) was added dropwise into a solution of p-bromoanisole (383 mg, 2.0 mmol) in THF (3 mL) at -78 °C for 30 min. Then, DMF (0.22 mL, 2.2 mmol) was added to the mixture and the obtained mixture was stirred at rt. After 2 h at the same temperature, THF was removed. Then, MeOH (3 mL) was added to the residue and the mixture was stirred at room temperature. After 30 min, I2 (1523 mg, 6 mmol) and K2CO3 (829 mg, 6 mmol) were added at 0 °C and the obtained mixture was stirred for 22 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (5 mL) and was extracted with CHCl3 (3.x.20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide methyl 4-methoxy-1-benzoate in 82percent yield. If necessary, the product was purified by short column chromatography (SiO2:hexane:EtOAc=9:1) to give pure methyl 4-methoxybenzoate as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | for 6 h; Reflux | General procedure: A catalytic amount of concentrated H2SO4 wasadded to a solution of carboxylic acids 16(a–j) (1.0 mmol)in 50 mL of methanol, and the mixture was refluxed for 6 h. It was allowed to cool. The saturated solution ofNaHCO3 was added to the reaction mixture, and it wasextracted with EtOAc (2 X 50 mL). The combined organiclayer was dried Na2SO4 and concentrated to obtain puremethyl esters 17(a–j). |
75.9% | Inert atmosphere; Reflux | To a suspension of 2,6-difluorobenzoic acid (50 g, 316 mmol) in MeOH (800 mL) was added TsOH ( 6 g, 10percent), the mixture was heated to reflux overnight. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with saturated NaHCO3 and brinesuccessively. The organic layer was separated, dried over Na2SO and concentrated under reduced pressure to give methyl 2,6-difluorobenzoate. 41 g (75.9percent yield) 1 H NMR (400 MHz, CDCI3) δ ppm 7.37-7.46 (m, 1 H), 6.91 - 6.98 (m, 2H), 3.95 (s, 3H). |
73% | Stage #1: for 2 h; Reflux Stage #2: at 20℃; for 2 h; |
Step 2: methyl 2,6-difluorobenzoateTo a solution of 2,6-difluorobenzoic acid (100 g, 0.63 mol) in sulfurous dichloride (150 mL) and the resulting reaction mixture was heated to refluxing for 2 hrs. Sulfurous dichloride was removed in vacuo, the residue in pyridine (100 ml) was added MeOH (100 mL) slowly and stirred at room temperature for 2 hrs. The solvent was removed in vacuo, the residue was dissolved in EtOAc (200 mL) and washed with aqueous NaOH (IN), HC1 (IN) and brine. The solution was dried over Na2S04, filtered and concentrated to afford the desired product (78.8 g, 73percent).1H NMR (CDCI3): ? 7.46-7.38 (1H, m), 6.98-9.93 (2H, m), 3.95 (3H, d, J = 2.0 Hz). |
73% | Stage #1: for 2 h; Reflux Stage #2: for 2 h; Reflux |
2,6-difluorobenzoic acid (10 (^, 0.63111001) was dissolved in thionyl chloride (1501 ^), and the resulting mixture was heated under reflux for 2 hours. The excess sodium sulfoxide was distilled off and the resulting residue (100 mL) was added dropwise and the methanol was slowly added dropwise (100 mL). The reaction was stirred at room temperature for 2 hours and the solvent was removed in vacuo to remove the solvent. The resulting oil was dissolved in 200 mL of ethyl acetate and treated with IN sodium hydroxide solution, IN hydrochloric acid , Water and saturated salt water. After evaporation of the solvent in vacuo, the title compound (78.8 g, 73percent) was obtained as an oil. |
71% | at 20℃; Reflux | To a solution of 2,6-difluorobenzoic acid (30.0 g, 190.0 mmol) in MeOH (100 mL) was added concentrated sulfuric acid (5 mL) dropwise at room temperature. The reaction mixture was heated under reflux overnight. The solvent was removed in vacuo. The residue was dissolved in EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 1 (23.2 g, 71percent) as a yellow oil. 1H NMR (CDCl3): δ 7.45–7.39 (m, 1H), 6.98–6.93 (m, 2H), 3.96 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at -78 - 20℃; for 2 h; |
General procedure: n-BuLi (1.67 M solution in hexane, 1.3 mL, 2.2 mmol) was added dropwise into a solution of p-bromoanisole (383 mg, 2.0 mmol) in THF (3 mL) at -78 °C for 30 min. Then, DMF (0.22 mL, 2.2 mmol) was added to the mixture and the obtained mixture was stirred at rt. After 2 h at the same temperature, THF was removed. Then, MeOH (3 mL) was added to the residue and the mixture was stirred at room temperature. After 30 min, I2 (1523 mg, 6 mmol) and K2CO3 (829 mg, 6 mmol) were added at 0 °C and the obtained mixture was stirred for 22 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (5 mL) and was extracted with CHCl3 (3.x.20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide methyl 4-methoxy-1-benzoate in 82percent yield. If necessary, the product was purified by short column chromatography (SiO2:hexane:EtOAc=9:1) to give pure methyl 4-methoxybenzoate as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 20℃; for 2 h; | Step 3: methyl 2,6-difluoro-3-nitrobenzoateTo a solution of methyl 2,6-difluorobenzoate (68.8 g, 0.4 mol) in con. H2SO4 (300 mL) was added potassium nitroperoxous acid (48.5 g, 0.48 mol) for three times and the resulting reaction mixture was stirred at room temperature for 2 hrs. The mixture was droped into ice-water (500 mL) and filtered. The solid was washed with water and dried to afford the desired product (89 g, 100percent).1H NMR (DMSC i): ? 8.49-8.43 (1H, m), 7.56-7.51 (1H, m), 3.95 (3H, s). |
100% | at 20℃; for 2 h; | The 2, 6 - difluoro-benzoic acid methyl ester (68.8g, 0.4 µM) dissolved in concentrated sulfuric acid (300 ml) in, addition of potassium nitrate (48.5g, 0 . 48 µM), continuing stirring at room temperature 2 hours. The resulting reaction solution is poured into crushed ice in slow, filtering, the resulting solid with a large number of washing and drying can be obtained as shown in the title compound (89g, 100percent) |
98% | at 0℃; for 1 h; | To a solution of compound 1 (21.0 g, 122.0 mmol) in concentrated sulfuric acid (50 mL) was added fuming nitric acid (8 mL) dropwise at 0 °C. After the reaction mixture was stirred at 0 °C for 1 h, it was poured into ice-water. The precipitate was collected by filtration and rinsed with water to give 2 (26.0 g, 98percent) as a white solid, mp 58–60 °C. 1H NMR (CDCl3): δ 8.25–8.22 (m, 1H), 7.15–7.11 (m, 1H), 4.01 (s, 3H). |
80.6% | at 0℃; for 0.5 h; | Fuming nitric acid (1 1 g, 174 mmol) was added to a solution of methyl 2,6- difluorobenzoate (25 g, 145 mmol) in concentrated sulfuric acid (50 ml_) at 0 °C, and the reaction was stirred for 30 min at 0°C. The reaction mixture was poured over ice-water. The precipitate was filtered to give the title compound 25.1 g (80.6 percent yield) 1H NMR (400 MHz, CDCI3) δ ppm 8.13-8.20 (m, 1 H), 7.02-7.10 (m, 1 H), 3.93 (s, 3H). |
64% | at 20℃; for 1 h; Cooling with ice | Sulfuric acid (37 mL) was slowly added to nitric acid (20 mL) under ice-cooling, and added methyl 2,6-difluorobenzoate (25.7 g,149 mmol), The reaction was gradually warmed to room temperature and stirring was continued for 1 hour. The reaction system was poured into ice-water and filtered to obtain a white solid compound P'(20.7 g, yield 64percent). |
64% | at 20℃; for 1 h; Cooling with ice | Sulfuric acid (37 mL) was slowly added to nitric acid (20 mL) under ice-cooling, and methyl 2,6-difluorobenzoate (25.7 g, 149 mmol) and the reaction was gradually allowed to warm to room temperature. Stirring was continued for 1 hour, The reaction system was poured into ice-water and filtered to give a white solid compound d (20.7g, yield 64percent) |
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