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sBuLi (97 mL, 126 mmol) was dissolved in tetrahydrofuran (THF) (200 ml.) at -78 0C and TMEDA (19.02 mL, 126 mmol) was added. 3-chloro-4-fluorobenzoic acid (10 g, 57.3 mmol, commercially available from e.g. Sigma-Aldrich, Fluorochem or Apollo) dissolved in tetrahydrofuran (THF) (50 mL) was added dropwise at -78 0C and the solution stired at this temperature for 30 minutes. Hexachloroethane (54.2 g, 229 mmol) dissolved in tetrahydrofuran (THF) (200 mL) was added dropwise and the solution stirred to room temperature over 4 hours. Water (25 mL) was added and the solution concentrated in vacuo. The residue was partitioned between diethyl ether (300 mL) and saturated sodium bicarbonate solution (50 mL) and extracted with saturated sodium bicarbonate solution (3 x 50 mL). The aqueous phase was acidified to pH1 with 5N hydrochloric acid, extracted with diethyl ether (3 x 200 mL), combined extracts dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a crude solid (9.21 g). The crude solid was recrystalised from heptane/diethyl ether to afford the desired product in 4.91 g. LC/MS = 207/209/211 (M-H)-, retention time = 0.88 minutes (2 minute method). The mother liquors were concentrated in vacuo, washed with heptane and dried to afford a second batch of desired product in 2.62 g LC/MS = 207/209/211 (M-H)-, retention time = 0.88 minutes (2 minute method).
With toluene-4-sulfonic acid; for 48.0h;Heating / reflux;
To a solution of 3-chloro-4-fluoro-benzoic acid (11.75 g, 67.3 [MMOL)] in [ETOH] was added PTSA (1.2 g) and the resulting mixture was heated under reflux for 2 days. On cooling the mixture was poured into water and the aqueous phase was basified with a solution of NaOH 1 N. The product was extracted with CH2CI2 and the organic phase was dried over [NA2SO4] and concentrated under reduced pressure to give the title compound as an oil (13.08g, 96%); [APCI MS] [M/Z] 203 (MH+).
96%
With toluene-4-sulfonic acid; for 48.0h;Heating / reflux;
To a solution of 3-chloro-4-fluoro-benzoic acid (11.75 g, 67.3 [MMOL)] in EtOH was added PTS (1.2 g) and the resulting mixture was heated under reflux for 2 days. On cooling the mixture was poured into water. The aqueous phase was basified with a solution of [NAOH] 1 N. The product was extracted with [CH2CI2] and the organic phase was dried over [NA2SO4] and concentrated under reduced pressure to give the title compound as an oil (13.08g, 96%); [APCI MS] m/z 203 (MH+).
Preparative Example 29.; A round bottomed flask was charged with 3-chloro-4-fluorobenzoic acid (5.0 g, 28.6 mmol), sulfuric acid (0.84 g, 8.6 mmol), and methanol (60 mL). The solution was heated at reflux overnight. The methanol was removed in vacuo. The residue was extracted with ethyl acetate (5 x), dried over sodium sulfate, filtered and concentrated in vacuo to yield 4.73 g (88%).A round bottomed flask was charged with the ester intermediate (4.73 g, 25 mmol), potassium carbonate (3.45 g, 25 mmol), piperazine-1-carboxylic acid tert-butyl ester (5.59 g, 30 mmol) and acetonitrile (6 mL). The mixture was heated at 650C overnight and the solvent removed in vacuo. The residue was dissolved in ethyl acetate and washed with 0.5 N HCI, 0.5 N NaOH, and brine. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. There was obtained 4.79 g of intermediate 34 which was not purified further.
A round bottomed flask was charged with 3-chloro-4-fluoro-benzoic acid (2.0 g, 11.4 mmol),sulfuric acid (0.33 g, 3.4 mmol), MeOH (20 mL) and refluxed for 16 h (TLC indicatedcomplete consumption of starting material). The volatiles were removed under reducedpressure; the residue was diluted with water (15 mL) and extracted with EtOAc (3 x 50 mL).The combined organic extracts were washed with brine (50 mL), dried over Na2S04 andconcentrated in vacuo to give the crude residue which was purified by columnchromatography (100-200 silica gel, 40 g, 10% EtOAc-hexane) to afford methyl3-chloro-4-fluoro-benzoate ( 1.5 g, 69%) as a light yellow oil. 1H NMR [300 MHz, CDCh]: J 8.08 (dd, J = 6.9, 2.1 Hz, 1H), 7.94-7.89 (m, 1H), 7.18 (t, J =8.7 Hz, 1H), 3.90 (s, 3H).
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