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CAS No. : | 2357-52-0 | MDL No. : | MFCD00011710 |
Formula : | C7H6BrFO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DWNXGZBXFDNKOR-UHFFFAOYSA-N |
M.W : | 205.02 | Pubchem ID : | 75378 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 40.59 |
TPSA : | 9.23 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.65 cm/s |
Log Po/w (iLOGP) : | 2.29 |
Log Po/w (XLOGP3) : | 2.68 |
Log Po/w (WLOGP) : | 3.02 |
Log Po/w (MLOGP) : | 2.99 |
Log Po/w (SILICOS-IT) : | 2.92 |
Consensus Log Po/w : | 2.78 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.18 |
Solubility : | 0.136 mg/ml ; 0.000664 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.53 |
Solubility : | 0.611 mg/ml ; 0.00298 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.66 |
Solubility : | 0.0446 mg/ml ; 0.000218 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.39 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
91% | at 120℃; | A mixture of 4-bromo-2-fluoro-l-methoxybenzene (30.0 g, 146 mmol) and CuCN (15.6 g, 174 mmol) in dry DMF (45 mL) was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract was washed with water and brine, dried, and concentrated to give 20.0 g (91percent yield) of the product as a yellow solid. :H NMR (400 MHz, CDC13) δ 7.44 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.36 (dd, J = 10.8 Hz, 2.0 Hz, 1H), 7.02 (dd, J = 8.8 Hz, 8.4 Hz, 1H), 3.96 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With iron(III) chloride; sodium carbonate In water; ethyl acetate; N,N-dimethyl-formamide | 20 g of the 2-fluoro-4-bromoanisole thus obtained and 9.8 g of copper cyanide were dissolved in 100 ml of dimethyl formamide and heated under reflux for ten hours. To the reaction mixture, was added an aqueous solution of 20 g of ferric chloride in 100 ml of water. The reaction mixture was allowed to cool to room temperature and the reaction product was extracted with toluene. The organic layer was successively washed with water, a saturated aqueous solution of sodium carbonate and a saturated aqueous solution of common salt. Then the organic layer was separated. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate 10:1) and further recrystallized from ethanol. Thus 10.0 g of 3-fluoro-4-methoxybenzonitrile was obtained. Yield: 68percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: With magnesium; ethylene dibromide In tetrahydrofuranInert atmosphere Stage #2: With C17H23NO In tetrahydrofuran at 0℃; Inert atmosphere |
General procedure: To a flame-dried 25 mL round bottom flask was charged Activated Mg (7.5 mmol, 1.5 eq.) and 5 mL anhydrous THF. To this suspension was added 2 drops of 1,2-dibromoethane. After 5 min, a solution of Aryl bromide (5 mmol, 1.0 eq.) in 5 mL anhydrous THF was slowly added to the suspension of Mg at room temperature. The reaction was mildly exothermic. The Grignard reagent was titrated and 1 mmol of this reagent was added to a flame-dried reaction vial. The solution was diluted with 3 mL anhydrous THF and after cooling to 0° C. in an ice bath, a solution of oxaziridine (1.5 mmol, 1.5 eq.) in 1 mL anhydrous THF was added. The ice bath was removed and the reaction was allowed to reach room temperature. After time t, the reaction was quenched with saturated aqueous NH4Cl. The reaction mixture was diluted with 20 mL saturated aqueous NaCl and 20 mL EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified with flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium bicarbonate; bromine; sodium hydrogensulfite In chloroform; water | Synthesis of 3-fluoro-4-methoxybromobenzene Into a flask of 5 l were charged 384 g (3.04 mol) of 2-fluoroanisole and 2.5 l of chloroform, to which was added dropwise 504 g (3.16 mol) of bromine over about 3 hours while cooling on an ice water bath at 10° C. The resulting mixture was stirred at room temperature over a night and heated under reflux for 8 hours. After the air cooling, the product was added with 1 l of water and 50 g of sodium bisulfite and sufficiently shaken to separate into two layers. The resulting organic layer was washed with an aqueous solution of 5percent sodium hydrogen carbonate and further with 1 l of water and dried on magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated and distilled under a reduced pressure (4 mmHg, bp: 93-°96° C.) to obtain 585 g (yield: 94percent) of 3-fluoro-4-methoxybromobenzene. |
92.3% | With sodium hydroxide; bromine In chloroform | (a) Synthesis of STR7 A reaction vessel was charged with 128 g (1.016 mol) of 2-fluoroanisole and 250 ml of chloroform. To this mixture was added dropwise under agitation at room temperature 177 g (1.106 mol) of bromine over the period of at least 3 hours. The reaction liquid was poured into a diluted aqueous solution of NaOH, and the chloroform layer was separated, washed with a solution of edible salt and dried over Glauber's salt. The solvent was distilled off and the residue was distilled under reduced pressure to obtain 2-fluoro-4-bromoanisole. Yield 192 g (yield rate: 92.3percent) b.p. 107°-116° C./25-31 mmHg |
91% | With sodium hydroxide; bromine In chloroform | (a) Synthesis of 3-fluoro-4-methoxybenzamidine hydrochloride: 306 g of 2-fluoroanisole was dissolved in 750 ml of chloroform. To the resulting solution, was added dropwise 389 g of bromine under stirring at room temperature. After the completion of the addition, the reaction mixture was heated under reflux for nine hours and then allowed to cool to room temperature. The mixture was washed with 500 ml of a 5percent aqueous solution of sodium hydroxide and then the organic layer was washed with 500 ml portions of water thrice. The organic layer was separated and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by distillation (main fraction: 14 mmHg, 98°-100° C.) to thereby give 454 g of 2-fluoro-4-bromoanisole. Yield: 91percent. |
86% | With N-Bromosuccinimide In acetonitrile at 70℃; for 3 h; | The crude product (1.0 g, 7.9 mmol) was dissolved in acetonitrile (15 mL) and N-bromosuccinimide (1.4 g, 8.7 mmol) was added and reacted at 70 ° C for 3 h. After the reaction was completed, most of the acetonitrile was distilled off, 30 mL of water was added, the mixture was stirred for 10 min and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over anhydrous magnesium sulfate and separated by column chromatography (pure petroleum ether as eluent) The brominated product (intermediate A_2c) was obtained as a light yellow oily liquid (1.4 g, yield 86percent) oA-2c: SH (300 MHz; CDCl 3) 7.23-7.16 (2H, m), 6.82 (D, J = 8.7Hz), 3.86 (3H, s); δ (75ΜΗζ; CDC13) 152.3 (d, Jc, F = 249.0Hz), 147.1 (d, 119.6 (d, J = 21.1 Hz), 114.6 (d, J = 2.2 Hz), 111.9 (d, J = 8.2 Hz), 56.4 |
73.4% | With sodium hydroxide; bromine In chloroform; water | Example 21 [Synthesis of 3'-fluoro-4'-dodecyloxybiphenyl-4-carboxylic acid] 2-Fluoroanisole (266 g) was dissolved in 700 ml of chloroform and 337 g of bromine was added dropwise to the solution. The mixture was reacted under reflux at 67° to 68° C. for 1 hour, subsequently left to cool, washed with a 5percent aqueous solution of sodium hydroxide and then with water, and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was distilled (95° to 96° C./12 mmHg) to obtain 317 g of 4-bromo-2-fluoroanisole (yield 73.4percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | [000274] To a solution of 4-bromo-2-fluorophenol (15 g, 78.5 mmol) in DMF (200 mL) was added K2CO3 (32.25 g, 235.6 mmol), CH3I (12.3 mL, 96.3 mmol). The mixture was stirred at rt overnight. Water (500 mL) was added to the mixture and the mixture was extracted with ethyl acetate (200 mL x 3), dried over anhydrous Na2S04, and purified by column chromatography on silica gel (petroleum 100percent) to obtain Compound 4A (11.3 g, 70percent)) as a colorless oil. 1H-NMR (CDCI3, 400 MHz) major characteristic peaks: δ (ppm) 3.86 (s, 3H), 6.83 (t, J= 8.8 Hz, 1H), 7.20 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.2% | With n-butyllithium In hexane | 3-Fluoro-4-methoxyphenylboronic Acid The title compound was prepared by reacting 4-bromo-2-fluoroanisole (10 g, 0.049 mol) with n-butyl lithium (23.4 mL of 2.5 M solution in hexane, 0.059 mol) followed by triisopropyl borate (45.2 mL, 36.9 g, 0.196 mol) according to method F to yield 7.1 g (85.2percent) of a white solid-MS (ESI) m/z 169 (M-H)-: 1H NMR (DMSO-d6): δ 3.84 (3H, s), 7.10-7.16 (1H, m), 7.51-7.60 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 0.666667 h; Stage #2: at -78 - 20℃; for 1 h; |
Reference Example 1 6-Bromo-2-fluoro-3-methoxybenzaldehyde (Compound a) To a solution of diisopropylamine (22.2 mL, 159 mmol) in THF (10 mL) was added a solution of n-butyllithium/n-hexane (1.56 mol/L, 93.8 mL, 146 mmol) at - 78°C under an argon atmosphere, then the mixture was stirred at 0°C for 10 minutes. This LDA-THF solution was cooled to -78°C, and a solution of 4-bromo-2-fluoroanisole (25.0 g, 122 mmol) in THF (10 ml) was dropped slowly thereto. After the reaction mixture was stirred at -78°C for 30 minutes, DMF (14.2 ml, 183 mmol) was dropped thereto at the same temperature, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, then the mixture was extracted with ethyl acetate, and the resulting organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the precipitated crystal was collected by filtration, and washed with hexane/ethyl acetate (5/1) to give Compound a (22.8 g, 80 percent) as a colorless crystal. 1H NMR (CDCl3, δ): 3.91 (s, 3H), 7.04 (t, J = 8.7 Hz, 1H), 7.39 (dd, J = 1.8, 8.7 Hz, 1H), 10.32 (d, J = 1.0 Hz, 1H). |
67.4% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -70 - 0℃; for 2 h; Inert atmosphere Stage #2: at -70℃; for 2 h; |
In 1 L three-necked flask, 39.4 g diisopropylamine was dissolved in 100 mL THF and cooled to −5° C. Under nitrogen protection, 148.6 mL of 2.5M n-butyllithium solution was added into the system, and the solution was stirred at 0° C. for 1 h, and then cooled to −70° C. The solution of 69.2 g 2-fluoro-4-bromoanisole dissolved in 450 mL THF was added and then stirred for 2 h. The solution of 49.3 g DMF dissolved in 150 mL THF was dropwise added and stirred for 2 hours. The reaction had completed by checking by TLC. 4 L sodium bicarbonate solution was added, and the solution was extracted by 1 L ethyl acetate for two times. The organic phases were merged, washed with saturated saline solution, dried by anhydrous sodiumsulfate, and concentrated to remove most of ethyl acetate. 300 mL petroleum ether was added with stirring, and the system was stirred for 30 min filtered to give a white floccule which was dried to give 53 g compound B4, 67.4percent yield. 1H-NMR (400 MHz, DMSO-d6) (ppm) 3.89 (s, 3H), 7.40-7.44 (m, 1H), 7.56-7.58 (m, 1H), 10.18 (s, 1H). |
58% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 0.5 h; Inert atmosphere Stage #2: at -78 - 20℃; for 1 h; |
[0509] To a solution of diisopropylamine (11 mL) in anhydrous THF (50 mL) was cooled to 0 °C and was added 1.6 M n-butyl lithium/hexanes (47 mL) dropwise under nitrogen atmosphere. The mixture was stirred for 10 min at 0 °C and was then cooled to - 78 °C with an acetone dry ice bath. A solution of 4-bromo-2-fluoro-l- methoxybenzene (7.9 mL, 61 mmol) in anhydrous THF (50 mL) was added dropwise. The mixture was then allowed to stir for 30 min at -78°C. DMF (7.5 mL) was added dropwise at - 78 °C. The reaction was stirred for 1 h at room temperature. Half of the solvent from the solution was removed under reduced pressure and the solution was extracted using ethyl acetate, water (300 mL), and 1 M HC1 (65 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was crystallized by washing with hexanes. The solid was collected by filtration and dried under reduced pressure to give 6-bromo-2-fluoro-3-methoxybenzaldehyde (8.21 g, 58percent). |
58% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5 h; Inert atmosphere; Cooling with acetone-dry ice Stage #2: at -78 - 20℃; for 1 h; Inert atmosphere |
A solution of anhydrous tetrahydrofuran (50 mL) and diisopropylamine (11 mL) was cooled to 0° C. and had 1.6 M n-butyl lithium/hexanes (47 mL) added drop wise under nitrogen balloon. The mixture was stirred for 10 minutes at 0° C. and was then cooled to −78° C. with an acetone dry ice bath. A mixture of 4-bromo-2-fluoro-1-methoxybenzene (7.9 mL, 61 mmol) in anhydrous tetrahydrofuran (50 mL) was added drop wise, under nitrogen balloon, to the reaction. The mixture was then allowed to stir for 30 minutes at −78° C. N,N-dimethylformamide (7.5 mL) was added drop wise at −78° C. under a nitrogen balloon. The reaction was stirred for 1 hour at room temperature under a nitrogen balloon. Half of the solvent from the solution was removed under reduced pressure and the solution was extracted using ethyl acetate, water (300 mL), and 1 M HCl (65 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was crystallized by washing with hexanes. The solid was collected via filtration and dried under reduced pressure to give 6-bromo-2-fluoro-3-methoxybenzaldehyde (8.21 g, 58percent yield). |
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