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CAS No. : | 128577-47-9 | MDL No. : | MFCD00273345 |
Formula : | C9H8BrFO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OJBQAHZJVDWSFD-UHFFFAOYSA-N |
M.W : | 247.06 | Pubchem ID : | 18766370 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 50.52 |
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) : | -6.08 cm/s |
Log Po/w (iLOGP) : | 2.47 |
Log Po/w (XLOGP3) : | 2.43 |
Log Po/w (WLOGP) : | 2.78 |
Log Po/w (MLOGP) : | 3.11 |
Log Po/w (SILICOS-IT) : | 3.14 |
Consensus Log Po/w : | 2.79 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.05 |
Solubility : | 0.222 mg/ml ; 0.000899 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.63 |
Solubility : | 0.586 mg/ml ; 0.00237 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.02 |
Solubility : | 0.0238 mg/ml ; 0.0000964 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.92 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501 | UN#: | 3261 |
Hazard Statements: | H302-H314 | Packing Group: | Ⅱ |
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 |
---|---|---|
100% | With N-Bromosuccinimide; Perbenzoic acid In tetrachloromethane; water for 6 h; Reflux | Procedure for bromination: 4-methyl-3-fluoro-benzoic acid methyl ester (18.3 mmol) in CC (40 mL) with NBS (3.9 g, 22 mmol) and benzoylperoxide with 25percent of water (0.55 g, 1.7 mmole) are stirred and heated to reflux for 6 h. Solvent is evaporated, a water solution of K2C03 is added and product is extracted with EtOAc to obtain a pale yellow solid. 4-(bromomethyl)-3-fluoro benzoic acid methyl ester Yield = quant (5.9g), ESI-MS: [M+H]+= 247 Da. |
100% | With N-Bromosuccinimide; Perbenzoic acid In tetrachloromethane; water for 6 h; Reflux | General procedure for bromination: 4-Methyl-3-fluoro benzoic acid methyl ester (18.3 mmol) in CCL, (40 mL) with NBS (3.9 g, 22 mmol) and benzoylperoxide with 25percent of water (0.55 g, 1.7 mmole) are stirred and heated to reflux for 6 h. Solvent is evaporated, a water solution of K2CO3 is added and product is extracted with EtOAc to obtain a pale yellow solid. 4-(Bromomethyl)-3-fluoro benzoic acid methyl ester Yield = quant (5.9g), ESI-MS: [M+H]+= 247 Da. |
93% | With tert.-butylhydroperoxide; cetyltrimethylammonim bromide; potassium bromide In water at 120℃; Microwave irradiation | General procedure: The reaction mixture was treated in a controlled microwavesynthesizer (Biotage Initiator+SP Wave model, 0–200 W at2.45 GHz, capped at 60 W during steady state) for severalminutes (the reaction attained 120 °C at 1 bar pressure). Thefinal products were isolated by column chromatographyusing an EtOAc–hexane gradient |
75% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 5 h; Heating / reflux | EXAMPLE 185 4-[(4-Chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid methyl ester; 4-Bromomethyl-3-fluoro-benzoic acid methyl ester 3-Fluoromethyl benzoic acid methyl ester (4.2 g, 25 mmol), N-bromosuccinimide (4.90 g, 27.50 mmol) and dibenzoyl peroxide (0.18 g, 0.75 mmol) were dissolved in CCl4 (100 ml) and the mixture was irradiated with a 150 W lamp and refluxed under an argon atmosphere for 5 h. The reaction mixture was allowed to cool to r.t. and then filtered. The concentrated filtrate was purified over silica gel (isopropyl ether/n-heptane 1:10 v/v): colourless oil 4.6 g (75percent); MS: m/e=248.0 (M), 167.1 (M-Br, 100percent). |
68% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 18 h; Heating / reflux | 4-Bromomethyl-3-fluorobenzoic acid methyl ester N-Bromosuccinimide (2.4g, 13.5mmol) and 2,2'-azobisisobutyronitrile (213mg, 1.3mmol) were added to a solution of 3-fluoro-4-methylbenzoic acid methyl ester (2.1g, 12.5mmol) in carbon tetrachloride (60ml) and heated at reflux for 18h. The mixture was cooled, filtered and reduced in vacuo. The residue was purified by flash column chromatography on silica gel (eluant EtOAc:hexanes, 10:90) to afford a colourless oil identified as 4-bromomethyl-3-fluorobenzoic acid methyl ester, yield 2.1g, 68percent. |
60.9% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In dichloromethane for 18 h; Reflux | Methyl 3-fluoro-4-methylbenzoate (8.500 g, 50.544 mmol), 1-bromopyrolidin-2,5-one (NBS, 9.446 g, 53.071 mmol) and azobisisobutyronitrile (AIBN, 0.415 g, 2.527 mmol) were mixed in dichloromethane (150 mL) at room temperature, and the mixture was heated under reflux for 18 hours, and then cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate anhydrous, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate/hexane = from 0percent to 50percent) and concentrated to give the title compound (7.600 g, 60.9percent) as a white solid. |
48% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 18 h; Reflux | INTERMEDIATE 33 - PREPARATION of Methyl 4-(bromomethyl)-3-fluorobenzoate. To a mixture of methyl 3-fluoro-4-methylbenzoate (0.630 g; 3.75 mmol) in carbon tetrachloride (30 mL) was added N-bromosuccinimide (0.840 g, 4.67 mmol) and benzoyl peroxide (0.094g; 0.375 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 1 to 12percent ethyl acetate in heptane) to give 0.444 g (48percent) of methyl 4-(bromomethyl)-3-fluorobenzoate as an oily residue which was directly used in the next step. |
48% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 18 h; Reflux | To a mixture of methyl 3-fluoro-4-methylbenzoate (0.630 g; 3.75 mmol) in carbon tetrachloride (30 mL) was added N-bromosuccinimide (0.840 g, 4.67 mmol) and benzoyl peroxide (0.094 g; 0.375 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 1 to 12percent ethyl acetate in heptane) to give 0.444 g (48percent) of methyl 4-(bromomethyl)-3-fluorobenzoate as an oily residue which was directly used in the next step. |
41% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 74 h; Heating / reflux | 3-Fluoro-4-methylbenzoic acid methyl ester from Example E3.1 (4.5g, 26.6mmol) was dissolved in carbon tetra;chloride (150ml). AIBN (457mg, 2.7mmol) and N-bromosuccinimide (5.2g, 29.3mmol) were added and the mixture was heated at reflux for 18h. The mixture was allowed to cool and further portions of AIBN (457mg, 2.7mmol) and W-bromosuccinimide (5.2g, 29.3mmol) were added. The mixture was heated at reflux for 56h. The mixture was allowed to cool and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10percent EtOAc:90percent pet ether) to yield the title compound (2.7g, 41percent). |
200 mg | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 80℃; | To a stirred solution of 3-fluoro-4-methylbenzoic acid (308 mg, 2 mmol) in DMF (3 mL) were added K2CO3 (552 mg, 4.0 mmol) and CH3I (0.2 mL, 3.0 mmol) at room temperature. The resulting mixture was stirred at the same temperature for 5 h. Then the reaction was quenched with water (15 mL) extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was used directly into next step (220 mg, 1.3 mmol, 65percent). The methyl ester intermediate was dissolved in CC14 (5 mL). To the solution were added NBS (278 mg, 1.56 mmol) and AIBN (21 mg, 0.13 mmol). The resulting mixture was heated at 80 °C overnight. Then the reaction was quenched with water (15 mL) extracted with DCM (3 x 15 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0 - 50percent EtOAc/hexanes) to afford as colorless solid (200 mg, 62percent). 1H NMR (400 MHz, CDC13) δ 7.81 (dd, / = 8.0, 1.3 Hz, 1H), 7.72 (dd, / = 10.2, 1.3 Hz, 1H), 7.47 (t, = 7.7 Hz, 1H), 4.52 (s, 2H), 3.99 - 3.78 (m, 3H). 13C NMR (100 MHz, CDCI3) δ 165.5 (d, = 2.7 Hz), 161.5, 159.0, 132.4 (d, = 7.7 Hz), 131.2 (d, = 3.0 Hz), 130.1 (d, = 14.7 Hz), 125.6 (d, = 3.6 Hz), 117.0, 116.8, 52.5, 24.6 (d, = 4.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With N-Bromosuccinimide; azobisisobutyronitrile In tetrachloromethane | Methyl 4-(bromomethyl)-3-fluorobenzoate. To a stirred mixture of N-bromosuccinimide (6.75 g, 37.5 mmol) in carbon tetrachloride (100 mL) was added a solution of methyl 3-fluoro-4-methylbenzoate (6.31 g, 37.5 mmol) in carbon tetrachloride (50 mL) and 2,2'-azobisisobutyronitrile [AIBN] (32 mg, 0.2 mmol). The reaction mixture was heated at 75 °C for 3 hours. To the flask was added additional AIBN (31 mg, 0.2 mmol) and the mixture was heated at reflux (~80 °C) for 2.5 hours. The solids were filtered and rinsed with carbon tetrachloride. The filtrate was washed with 10percent sodium thiosulfate (2x15 mL), saturated sodium bicarbonate (15 mL), and dried over sodium sulfate. Evaporation of the solvent on a rotary evaporator, followed by evacuation under high vacuum, gave a pale yellow oil (8.67 g). This liquid was purified by flash chromatography on a silica gel column eluted with 95:5 hexanes:ethyl acetate to afford a very pale yellow liquid (4.70 g, 51percent). (Where the term 'hexanes' is used, the term means that the solvent is a mixture of hexane isomers). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.7% | for 5 h; Reflux | Step 2: Synthesis of methyl 4-(bromomethyl)-3-fluorobenzoate: To a solution of the above product (21 g, 125 mmol) in CC14 (200 ml) was added a mixture of NBS (20 g, 113 mmol) and benzoyl peroxide (1.5 g, 6 mmol). The resulting solution was refluxed for 5 hours. Then the solvent was evaporated and the residue was dissolved in DCM (300 ml) and washed with H20 (200 ml x 3). The organic layer was dried with anhydrous Na2S04, filtered and evaporated to give the crude product as colorless oil (18 g, 64.7percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With dimethyl sulfoxide In hexane; dichloromethane; water; ethyl acetate | (1) Methyl 3-fluoro-4-bromomethylbenzoate (80 mg, 0.32 mmol), described in J. Med. Chem., 35(5) 877 (1992), was dissolved in a mixture of anhydrous dimethyl sulfoxide (4.5 ml) and anhydrous dichloromethane (3 ml). To the solution cooled to 0° C. was added dropwise with stirring triethylamine N-oxide dihydrate (180 mg, 1.62 mmol) and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and this mixture was partitioned between a mixture of ethyl acetate and hexane (1:1) and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column using ethyl acetate-hexane (1:10) as the eluant to give methyl 3-fluoro-4-formylbenzoate (29 mg, yield 48percent) as a white solid. NMR spectrum (400 MHz, CDCl3) δ ppm: 3.97 (3H, s), 7.85 (1H, d, J=11 Hz), 7.9-8.0 (2H, m), 10.43 (1H, s). Mass spectrum m/z (EI): 182 (M+, 100percent). |
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