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CAS No. : | 179232-29-2 | MDL No. : | MFCD06203731 |
Formula : | C8H6BrFO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 233.03 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 45.38 |
TPSA : | 26.3 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) : | -5.94 cm/s |
Log Po/w (iLOGP) : | 2.36 |
Log Po/w (XLOGP3) : | 2.51 |
Log Po/w (WLOGP) : | 2.8 |
Log Po/w (MLOGP) : | 3.09 |
Log Po/w (SILICOS-IT) : | 2.79 |
Consensus Log Po/w : | 2.71 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.1 |
Solubility : | 0.183 mg/ml ; 0.000787 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.71 |
Solubility : | 0.456 mg/ml ; 0.00196 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.61 |
Solubility : | 0.0569 mg/ml ; 0.000244 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.44 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
31% | Stage #1: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide for 0.5 h; Stage #2: at 20℃; for 240 h; |
Step A: 6-bromobenzo[d]isoxazol-3-ol: N-hydroxyacetamide (0.99 g, 12.9 mmol) was dissolved in DMF (20 mL). To this was added KOt-Bu (1.44 g, 12.9 mmol) and the reaction was stirred for 30 minutes before addition of methyl 4-bromo-2-fluorobenzoate (2.0 g, 8.58 mmol). The reaction mixture was stirred at ambient temperature for 10 days, then diluted with ethyl acetate (50 mL) and 1N NaOH (50 mL). The aqueous layer was washed with ethyl acetate, then acidified with 2N HCl (30 mL). The desired product was collected by filtration (570 mg, 31percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | for 20 h; Heating / reflux | EXAMPLE 9: 4- (8, 8-DIMETHYL-5-P-TOLYL-7, 8-dihydro-2- NAPHTHYLSELANYLETHYNYL)-2-FLUOROBENZOIC acid a. Methyl 4-BROMO-2-FLUOROBENZOATE 5 g (23 mmol) of 4-bromo-2-fluorobenzoic acid are dissolved in methanol with a few drops of sulphuric acid. The reaction medium is refluxed for 20 hours, hydrolysed and extracted with ethyl acetate. A white solid is obtained (5.6 g; yield = 100percent). |
96% | at 0 - 20℃; for 12 h; | To a solution of 4 (13.1 g, 60.0 mmol) in methanol (60 mL) was slowly added SOCk (12 mL) at 0 °C. After stirring overnight (ca. 12 h) at ambient temperature, the solvent was removed under reduced pressure, and the reaction mixture was basified with saturated NaHCCte at 0 °C. Ether (200 mL) was added to the crude mixture, which was washed with saturated NaHCCte (100 mL x 2) and brine (50 mL x 2). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The product mixture was purified by flash chromatography to provide the title product 8 as a white solid (13.4 g, 58 mmol, 96percent). NMR (400 MHz, CDCb) δ 7.86 - 7.78 (m, 1H), 7.39 - 7.30 (m, 2H), 3.92 (s, 2H). 13C NMR (101 MHz, CDCb) δ 164.35, 164.31, 163.06, 160.43, 133.30, 128.10, 128.00, 127.71, 127.67, 120.96, 120.71, 1 17.86, 1 17.76, 52.64. MS (ESI) m/z 233/235 [M+H]+. |
93% | at 0 - 23℃; for 12.25 h; | Step 1 : To a stirred solution of 4-bromo-2-fluorobenzoic acid (15.0 g, 68.49 mmol, 1 eq) in MeOH (150 mL), SOCI2 (23.09 mL, 136.9 mmol, 2 eq) was added at 0 <C for 15 min and the mixture was stirred at RT for 1 2h. The MeOH was evaporated and the residue was diluted with ethyl acetate (250 mL), washed with a saturated aqueous solution of NaHC03, brine (150 mL) and water (150 mL). The ethyl acetate layer was dried over Na2S04, evaporated under vacuum to get methyl 4-bromo-2-fluorobenzoate (15 g, 93percent) as an off white solid (LC-MS purity, 99percent; TLC system: EtOAc/PE (3:7), Rf: 0.8). |
93% | Stage #1: With oxalyl dichloride In dichloromethane at 20℃; for 1 h; Stage #2: at 20℃; for 1 h; |
Step 1 (0320) To a solution of compound 3a (50 g, 210 mmol) in DCM (300 mL) was added oxalyl dichloride (40.38 g, 300 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for lh. Then MeOH (50 ml) was added dropwise, the solution was stirred at room temperature for another lh. The solvent was removed to afford compound 3b (48 g, 93percent). |
64% | for 20 h; Reflux | Example 109AMethyl 4-bromo-2-fluorobenzoic acid; 4-bromo-2-fluorobenzoic acid (30 g, 0.14 mol) was dissolved in methanol with a few drops of sulfuric acid. The reaction medium was refluxed for 20 hours. The cooled reaction mixture was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered and evaporated to give methyl 4-bromo-2-fluorobenzoate (20.7 g, yield 64percent) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm); 3.85 (s, 3H), 7.55-7.58 (m, 1H), 7.70-7.73 (m, 1H), 7.79-7.83 (m, 1H); LC-MS (ESI) m/z: 233 (M+1)+, 235(M+3)+ |
4851.1 g | Reflux; Large scale | 4-Bromo-2]DIFFDT_1[-FF]IDDT_21[uorobenzonic acid (2a) (5.0 kg, 22.9 mol) was charged to a 50-L round-bottom glass reaction vessel holding methanol (20.0 L). Concentrated sulfuric acid (500 mL) was added dropwise over 40 min. The reaction mixture was heated under reux for 12 h, poured into ice water (30 L) and the white solid precipitateDDIF]F_T51[ was ltered. The product was dried by heating (less than 50 °C) in an oven overnight to afford 2b as white crystals (4851.1 g, 91.2percent yield). Mp 60.0–61.0 °C; 1IFF]DDT_8[H NMR (400 Hz, DMSO-d6): d 3.85 (t, 3H, J = 8.5 Hz), 7.54–7.57 (dd, 1H, J = 8.8, 1.2 Hz), 7.68–7.71 (dd, 1H, J = 10.4, 1.2 Hz), 7.80–7.84 (t, 1H, J = 8.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; | Methyl iodide (1.49 mL, 24 mmol) was added to asuspension of 4-bromo-2-fluorobenzoic acid (4.38 g, 20 mmol) and sodium carbonate (6.36 g, 60 mmol) in dimethylformamide (50 mL), and the mixture was stirred overnight at room temperature. After completion of the reaction, ethyl acetate was added, and the mixture was washed with water and a saturated ammonium chloride aqueous solution. After drying over magnesium sulfate, concentration was carried out to obtain 4.50 g of the desired product as a colorless solid (yield 97percent). ^oH-NMR (ppm in CDC13) d 3.93 (s, 3H), 7.33-7.38 (m, 2H), 7.80-7.85 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 0 - 20℃; for 1 h; | STEP 1 : To a solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.1 mmol) in THF (24 mL) and methanol (6 mL) at 0 °C was added a solution of (trimethylsilyl)diazomethane in hexanes (2.0 M, 5.46 mL, 10.9 mmol). The yellow solution was allowed to gradually warm to room temperature over 1 h. The volatile materials were removed and the residue was treated with aqueous hydrochloric acid (1 M). The aqueous mixture was extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, filtered, and concentrated to provide crude methyl 4- bromo-2-fluorobenzoate (2.7 g, quantitative yield). This material was used in the subsequent step without further purification. 1H NMR (400 MHz, CDCl3): 7.85-7.81 (m, IH), 7.38-7.33 (m, 2H), 3.93 (s, 3H); MS (EI) for C8H6BrFO2: 232, 234 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With chloro-trimethyl-silane In methanol for 12 h; Reflux | Example 35A Methyl 4-bromo-2-fluorobenzoate A solution of 8 g (36.53 mmol) of 4-bromo-2-fluorobenzoic acid in 44 ml of methanol is mixed with 0.46 ml (3.65 mmol) of chlorotrimethylsilane and heated to reflux for 12 h. The mixture is then concentrated and the residue is taken up in cyclohexane and filtered through silica gel. 4.49 g (19.25 mmol, 52percent yield) of a white solid are obtained. Rf (cyclohexane/ethyl acetate 2:1): 0.5. 1H-NMR (200 MHz, DMSO-d6, δ/ppm): 7.84 (1H, t), 7.75 (1H, dd), 7.58 (1H, dd), 3.88 (3H, s). MS (EI): 232 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12 g | at 20℃; for 18 h; | To a suspension of compound 5-10 (12 g, 54.79 mmol) in DCM (120 mL) was added oxalyl chloride (COCl) (10.43 g, 82.19 mmol) and two drops of DMF in a catalytic quantity at 0° C. under nitrogen atmosphere, and then the reaction solution was reacted under nitrogen atmosphere at r.t. for 3 h. Then the solvent was removed, MeOH (100 mL) was added, and the resulting reaction solution was reacted at r.t. for 18 h. After TLC indicated the reaction was complete, the reaction solution was concentrated, and the residue was dissolved in EtOAc (100 mL) and washed with saturated Na2CO3 (aq., 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give purified compound 5-11 (12 g, Yield 93.97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dicyanozinc In N,N-dimethyl-formamide at 80℃; | EXAMPLE 20A methyl 4-cyano-2-fluorobenzoate A solution of methyl 4-bromo-2-fluorobenzoate (10.0 g, 43 mmol), zinc cyanide (10.0 g, 86 mmol) and palladium tetrakis(triphenylphosphine) (2.5 g, 0.64 mmol) in anhydrous N,N-dimethylformamide (100 mL) was purged with nitrogen and the mixture stirred at 80° C. overnight. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase washed with water and concentrated. The solid was purified on silica gel using 1:5 ethyl acetate/hexane to afford the title compound (6.1 g, 80percent). MS (DCI): m/z 180 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | at 100℃; for 3.5 h; | STEP 2: To a solution of methyl 4-bromo-2-fluorobenzoate (9.1 mmol) in DMF (50 mL) was added zinc cyanide (641 mg, 5.5 mmol) followed by tetrakis(triphenyphosphine)palladium(0) (1.05 g, 0.91 mmol). The mixture was heated to 100 °C and stirred for 3 h. At that point, additional tetrakis(triphenyphosphine)- palladium(O) (500 mg, 0.43 mmol) was added. The mixture was stirred a further 30 min and was then cooled to room temperature. Water and ethyl acetate were added, and insoluble solids were removed by filtration through celite. The layers were then separated. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, washed with 10percent aqueous lithium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (10percent ethyl acetate in hexanes) to provide methyl 4-cyano-2-fluorobenzoate (1.36 g, 7.6 mmol, 84percent yield). 1H NMR (400 MHz, CDCl3): 8.06 (dd, IH), 7.53 (dd, IH), 7.47 (dd, IH), 3.98 (s, 3H); MS (EI) for C9H6FNO2: 179 (M+). |
80% | at 80℃; | EXAMPLE 17A methyl 4-cyano-2-fluoro-benzoate A solution of methyl 4-bromo-2-fluorobenzoate (10.0 g, 43 mmol), zinc cyanide (10.0 g, 86 mmol) and palladium tetrakis(triphenylphosphine) (2.5 g, 0.64 mmol) in N,N-dimethylformamide (100 mL) was stirred at 80° C. overnight. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase washed with water and concentrated. The residue was purified by flash chromatography on silica gel (1:5 ethyl acetate/hexane) to afford 6.1 g (80percent) of the title compound. MS (DCI): m/z 180 (M+H)+. |
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