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CAS No. : | 61090-37-7 | MDL No. : | MFCD06659470 |
Formula : | C8H9NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RWPLKRGISDOAAG-UHFFFAOYSA-N |
M.W : | 135.16 | Pubchem ID : | 11701043 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 40.19 |
TPSA : | 35.25 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) : | -6.24 cm/s |
Log Po/w (iLOGP) : | 1.55 |
Log Po/w (XLOGP3) : | 1.25 |
Log Po/w (WLOGP) : | 1.21 |
Log Po/w (MLOGP) : | 1.09 |
Log Po/w (SILICOS-IT) : | 1.82 |
Consensus Log Po/w : | 1.38 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.91 |
Solubility : | 1.66 mg/ml ; 0.0123 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.59 |
Solubility : | 3.49 mg/ml ; 0.0258 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.3 |
Solubility : | 0.682 mg/ml ; 0.00505 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.66 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | 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 |
---|---|---|
67.7% | With hydrogen bromide In water at 110℃; for 16 h; | Synthesis of 4-amino-2,3-dihydrobenzofuran (1c) The compound 1b (4.10 g, 16.3 mmol) was dissolved in hydrobromic acid (HBr) (48percent aqueous, 20.0 mL, commercial product), and the mixed solution was stirred by heating at 110°C for 16 hours. After the mixed solution was allowed to cool to room temperature, sodium hydroxide granules were gradually added at 0°C so that the pH was adjusted to about 9. Subsequently, the mixture was extracted with ethyl acetate (EtOAc) (50 mL * 4). The combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by a medium-pressure column chromatography (Smart Flash EPCLC W-Prep 2XY system) (n-hexane/EtOAc =1/1), and thus 4-amino-2,3-dihydrobenzofuran (compound 1c) (1.49 g, 11.0 mmol, 67.7percent) was obtained as a colorless solid. TLC Rf = 0.30 (n-hexane/EtOAc = 1/1) 1H NMR (400 MHz, CDCl3) δ 6.94 (dd, J = 8.4, 8.4 Hz, 1H), 6.28 (dd, J = 0.4, 7.6 Hz, 1H), 6.23 (dd, J = 0.4, 7.6 Hz, 1H), 4.59 (t, J = 8.4 Hz, 2H), 3.60 (brs, 2H), 3.02 (t, J = 8.4 Hz, 2H) |
67.6% | With water; hydrogen bromide In neat (no solvent) at 20 - 110℃; for 16 h; | Synthesis of 4-amino-2,3-dihydrobenzofuran (1c) The compound 1b (4.10 g, 16.3 mmol) was dissolved in hydrobromic acid (HBr) (48percent aqueous, 20.0 mL, commercial product), and the mixed solution was stirred by heating at 110° C. for 16 hours. After the mixed solution was allowed to cool to room temperature, sodium hydroxide granules were gradually added at 0° C. so that the pH was adjusted to about 9. Subsequently, the mixture was extracted with ethyl acetate (EtOAc) (50 mL*4). The combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by a medium-pressure column chromatography (Smart Flash EPCLC W-Prep 2XY system) (n-hexane/EtOAc=1/1), and thus 4-amino-2,3-dihydrobenzofuran (compound 1c) (1.49 g, 11.0 mmol, 67.6percent) was obtained as a colorless solid. TLC Rf=0.30 (n-hexane/EtOAc=1/1) 1H NMR (400 MHz, CDCCl3) δ (6.94 (dd, J=8.4, 8.4 Hz, 1H), 6.28 (dd, J=0.4, 7.6 Hz, 1H), 6.23 (dd, J=0.4, 7.6 Hz, 1H), 4.59 (t, J=8.4 Hz, 2H), 3.60 (brs, 2H), 3.02 (t, J=8.4 Hz, 2H) |
40% | Stage #1: With hydrogen bromide In water at 100℃; Stage #2: With sodium hydroxide In water |
Synthesis of 2,3-dihydrobenzofuran-4-amine Into a 210 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide (10.5 g, 41.83 mmol, 1.00 equiv). To the mixture was added HBr (48percent) (100 mL). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 100° C. in a bath of oil. The reaction progress was monitored by TLC (EtOAc/PE=1:2). Adjustment of the pH to 9 was accomplished by the addition of NaOH. The resulting solution was extracted with EtOAc and the organic layers combined. The resulting mixture was washed with H2O. The mixture was dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 2.5 g (40percent) of 2,3-dihydrobenzofuran-4-amine as yellow oil. |
40% | Stage #1: With hydrogen bromide In water at 100℃; for 16 h; Stage #2: With sodium hydroxide In water |
Concentrated hydrobromic acid (100 mL) was added to N-(2-(2-hydroxyethyl)-3- methoxyphenyl)pivalamide (41.8 mmol) and the reaction mixture was heated at 100 °C for 16 h. The pH of the solution was adjusted to 9 with solid sodium hydroxide and the solution was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were was washed with water (50 mL), dried (sodium sulfate), and concentrated to provide 2,3-dihydrobenzofuran-4-amine in 40percent yield as yellow oil. |
40% | Stage #1: With hydrogen bromide In water at 100℃; Stage #2: With sodium hydroxide In water |
Synthesis of 2,3-dihydrobenzofuran-4-amine Into a 210 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide (10.5 g, 41.83 mmol, 1.00 equiv). To the mixture was added HBr (48percent) (100 mL). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 100° C. in a bath of oil. The reaction progress was monitored by TLC (EtOAc/PE=1:2). Adjustment of the pH to 9 was accomplished by the addition of NaOH. The resulting solution was extracted with EtOAc and the organic layers combined. The resulting mixture was washed with H2O. The mixture was dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator This resulted in 2.5 g (40percent) of 2,3-dihydrobenzofuran-4-amine as yellow oil. |
40% | Stage #1: at 100℃; for 16 h; Stage #2: With sodium hydroxide In water |
4. Synthesis of 2,3-dihydrobenzofuran-4-amine; Concentrated hydrobromic acid (100 mL) was added to N-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide (41.8 mmol) and the reaction mixture was heated at 100° C. for 16 h. The pH of the solution was adjusted to 9 with solid sodium hydroxide and the solution was extracted with ethyl acetate (3.x.100 mL). The combined organic layers were was washed with water (50 mL), dried (sodium sulfate), and concentrated to provide 2,3-dihydrobenzofuran-4-amine in 40percent yield as yellow oil. |
40% | Stage #1: With hydrogen bromide In water at 100℃; for 16 h; Stage #2: With sodium hydroxide In water |
4. Synthesis of 2,3-dihydrobenzofuran-4-amine.Concentrated hydrobromic acid (100 mL) was added to iV-(2-(2-hydroxyethyl)-3- methoxyphenyl)pivalamide (41.8 mmol) and the reaction mixture was heated at 100 0C for 16 h. The pH of the solution was adjusted to 9 with solid sodium hydroxide and the solution was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were was washed with water (50 mL), dried (sodium sulfate), and concentrated to provide 2,3-dihydrobenzofuran-4- amine in 40percent yield as yellow oil. |
40% | Stage #1: at 100℃; for 16 h; |
Concentrated hydrobromic acid (100 mL) was added to N-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide (41.8 mmol) and the reaction mixture was heated at 100° C. for 16 h. The pH of the solution was adjusted to 9 with solid sodium hydroxide and the solution was extracted with ethyl acetate (3.x.100 mL). The combined organic layers were was washed with water (50 mL), dried (sodium sulfate), and concentrated to provide 2,3-dihydrobenzofuran-4-amine in 40percent yield as yellow oil. |
40% | Stage #1: at 100℃; for 16 h; |
4. Synthesis of 2,3-dihvdrobenzofuran-4-amine.Concentrated hydrobromic acid (100 mL) was added to 7v~-(2-(2-hydroxyethyl)-3- methoxyphenyl)pivalamide (41.8 mmol) and the reaction mixture was heated at 100 °C for 16 h. The pH of the solution was adjusted to 9 with solid sodium hydroxide and the solution was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were was washed with water (50 mL), dried (sodium sulfate), and concentrated to provide 2,3-dihydrobenzofuran-4- amine in 40percent yield as yellow oil. |
40% | Stage #1: With hydrogen bromide In water at 100℃; for 16 h; Stage #2: With sodium hydroxide In water |
Concentrated hydrobromic acid (100 mL) was added to N-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide (41.8 mmol) and the reaction mixture was heated at 100° C. for 16 h. The pH of the solution was adjusted to 9 with solid sodium hydroxide and the solution was extracted with ethyl acetate (3*100 mL). The combined organic layers were was washed with water (50 mL), dried (sodium sulfate), and concentrated to provide 2,3-dihydrobenzofuran-4-amine in 40percent yield as yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: With hydrogen bromide In water; acetic acid at 20℃; for 4 h; Heating / reflux Stage #2: With sodium hydroxide In water; acetic acid |
2-(2'-Hydroxyethyl)-3-methoxy-N-tert-butoxycarbonyl-aniline (158 g, 0.59 mol) was added portionwise to a stirred solution of hydrogen bromide in acetic acid (30percent, 1.7 L) at room temperature. The reaction was then heated to reflux for 4 h. The reaction mixture was cooled to room temperature, basified to pH 14 with aqueous sodium hydroxide solution (6 N) and extracted with dichloromethane (3*2 L). The organic extracts were combined, dried (magnesium sulphate) and evaporated to give the title compound as an orange oil (78 g, 92percent); NMR (400 MHz, CDCl3) δH 2.99 (2H, t, J 8.5 Hz), 3.55 (2H, br s), 4.57 (2H, t, J 8.5 Hz), 6.19 (1H, d, J 7.5 Hz), 6.25 (2H, d, J 7.5 Hz), 6.92 (1H, t, J 8.0 Hz); IR νmax (Nujol)/cm-1 2853, 2610, 1544, 1462, 1262, 1234, 986 and 761. |