4-BROMOMETHYL-3-FLUOROBENZOIC ACID METHYL ESTER

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 KGeneral 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 KGeneral 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 gradientEXAMPLE 185 4-Bromomethyl-3-fluorobenzoic acid methyl ester 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. 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.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.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).To a stirred solution of 3-fluoro-4-methylbenzoic acid (308 mg, 2 mmol) in DMF (3 mL) were added KMethyl 4-(bromomethyl)-3-fluorobenzoate. Step 2: Synthesis of methyl 4-(bromomethyl)-3-fluorobenzoate: To a solution of the above product (21 g, 125 mmol) in CC1

Molecular Weight:247.06
XLogP3:2.4
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:245.96917
Monoisotopic Mass:245.96917
Topological Polar Surface Area:26.3
Heavy Atom Count:13
Complexity:187
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes