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14th February 2012 @ 00:41
1581.png

Reaction start time: ~11am 13/02/2012
350 mg (1.5 mmol, 1 equiv.) of PMY 8-4 was dissolved in 3mL chilled toluene under a nitrogen atmosphere. The reaction vessel was cooled in an ice bath whilst thionyl chloride (0.3 mL, 4 mmol, 2.5 equiv.) and 1 drop of DMF as a catalyst were added. The reaction vessel was then raised from the ice bath and the mixture was allowed to react for 3 hr, before the toluene was removed in vacuo.

Paul Ylioja (PMY) took over the experiment from this point, r e-addingtoluene (dried with mol. sieves, 3 mL) and removing it once more in vacuo, before adding hexane (6 mL). The hexane layer, containing the acid chloride, was triturated from the mixture, filtered and concentrated to give a yellow solid (160 mg, xx%). This was dissolved in THF (6 mL).

A day later (16/02/2012, 2:30 pm) I resumed the experiment. Glycolamide (0.025 g, 0.33 mmol), N,N-diisoproylethylamine (0.25 mL, 1.43 mmol) and 4-dimethylaminopyridine (0.0075, 0.06 mmol) were dissolved in dry THF (6 mL) before the yellow acid chloride (80 mg, x mmol, x equiv.) from the previous paragraph was added to the dry reaction vessel under an atmosphere of nitrogen. The reaction mixture was heated to reflux. TLC at 5:45pm showed much starting material remaining, and the reaction was left overnight. The following day had TLC at 1:30pm and 4:15 showed some starting material remaining. Reflux was halted, and the reaction vessel was cooled and left under a nitrogenous atmosphere over the weekend. TLC on Monday morning showed roughly the same amount of starting material remaining. Reaction vessel was removed from nitrogenous atmosphere and the solvent removed in vacuo, before being dissolved in DCM and purified by flash chromatography. Eluent used was EtOAc/petrol in increasing polarity (50%, 70%, 80%, 90%: EtOAc). Suspected product came out using 90%EtOAc/petrol. Solvent was removed to give 28.2 mg (0.09 mmol) in % yield.

TLC: 10%MeOH/DCM, 5:30pm (16/02/2012)
jrc 3-1 (530pm).png


TLC: 10%MeOH/DCM, 1:30pm (17/02/2012)
JRC3-1(midday).JPG


TLC: 10%MeOH/DCM, 4:15pm (17/02/2012)
JRC3-1(4PM).JPG


TLC: 10%MeOH/DCM, 10:00am (20/02/2012)
JRC3-1 20/2/2012 10am


Risk Assessment:
JRC 3-1 RA.docx
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14th February 2012 @ 00:16
This procedure details the hydrolysis of the ester (Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate) into the carboxylic acid ((1-(4-Fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid), as shown below diagrammatically.

1577.png

The crude product JRC 1-1 (13.6g, 58.3 mmol, 1 equiv.), was dissolved in EtOH (20mL) and added to an excess of 20% sodium hydroxide (170 mL, 875 mmol, 15 equiv.). The mixture was stirred at rt for 10 min before being heated to 60 °C at 3PM and left overnight. TLC at 11am the following morning showed some starting material remaining, so the mixture was heated to reflux for another 2 hours before being cooled, filtered and washed with water (2 x 20 mL). The solid obtained was dissolved in water (50 mL). Sodium hydroxide (1.5g, 38 mmol, 0.65 equiv) and sodium bicarbonate (2.2 g, 26 mmol, 0.44 equiv.) were added for the purpose of making the solution basic again. Water (100 mL) was added to the basic solution, and the mixture was heated to ensure all product was dissolved before the mixture was washed with ethyl acetate (3 x 30 mL). The inorganic layer was re-acidified (checked with universal indicator papers, pH 2) and vacuum dried to give 9.565 g (41 mmol) of product in 70.32% yield.

TLC: 25% ethyl acetate/hexane. Visualised with UV/vanillin (11am; 14/2/2012)
JRC 2-1 (11AM).JPG


Risk assessment:
JRC 2-1 RA.pdf


See also:
Upscaled Synthesis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (JRC 1-1) - previous experiment
Synthesis of TCMDC-123812 via acid chloride (JRC 3-1) - next experiment
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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.

1547.png

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)
1573.png

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)
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