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8th February 2012 @ 06:27
Synthesis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (JRC 1-1) on a larger scale, based on PMY 6-1, and LMW 7-1.

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Experiment start time: ~11:30am, 9/2/2012.
Ethyl acetoacetate (8.2 mL, 62.8 mmol, 1 equiv.), K2CO3 (11.4 g, 82.4 mmol, 1.3 equiv.) and sodium iodide (10.3 g, 68.9 mmol, 1.1 equiv.) were dissolved in acetonitrile (120 mL) and cooled in ice water. A yellow colour was observed in the mixture. Chloroacetone (6.4 mL, 79.9 mmol, 1.3 equiv.) was added dropwise. After 5 minutes the reaction mixture was heated to reflux, at which time the mixture began to slowly turn white. At 2pm, TLC showed some starting material remaining. By 3pm, TLC showed very little starting material remaining. The reaction mixture was thus cooled to rt, filtered and concentrated under reduced pressure to leave an orange liquid. This liquid was dissolved in 90 mL ethyl acetate and washed with water (2 x 20 mL), brine/water (20 mL; 1:1) and brine (20 mL). The organic layer containing the intermediate was concentrated under reduced pressure to a brown liquid and left in a freezer overnight (19.5 g, 103.6 mmol).

The intermediate was warmed to room temperature before 4-fluoroaniline (8.2 mL, 63.8 mmol, ~0.6 equiv.) was added. This mixture was heated to 90 °C. After 3.5 hr TLC showed very little starting material remaining, so the black reaction mixture was cooled, dissolved in EtOAc (40mL) and washed with water (3 × 20 mL) and brine (20 mL). This black organic layer was left in a freezer over the weekend, before a recrystallisation from ethanol was attempted. The ethanol was removed under pressure and a 13.6 g (52 mmol) of crude product was obtained in 83.8% yield.

TLC (35% ethyl acetate/hexane in vanillin)
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TLC (25% ethyl acetate/hexane in vanillin) 3PM
anilineTLC


Risk Assessment
Risk Assessment


Linked Posts
Synthesis of ethyl 2-acetyl-4-oxopentanoate intermediate. (LMW 7-1)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-3)
Synthesis of Glycolic Acid Acetonide (PMY 7-1)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (JRC 2-1)
Linked Posts
Attached Files
Risk Assessment
JRC1-1.png
TLC1-JRC1-1
anilineTLC