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1st August 2012 @ 03:22
Desired product obtained in 40% yield (product lost during recrystallisation step) according to 1H NMR. Progressed to hydrolysis.

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Synthesis of ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate for conversion to TCMDC-123812 analogues.

MD1-1.png

Reaction Start time: 2:30 PM EST 1/8/12
Potassium carbonate (11.3 g, 82 mmol, 1.3 equiv.) and sodium iodide (10.3g, 69 mmol, 1.1 equiv.) were stirred in acetonitrile (100 mL) and cooled in an ice bath. Ethyl acetoacetone (8.2 mL, 64 mmol, 1 equiv.) followed by chloroacetone (6.4 mL, 80 mmol, 1.2 equiv.) were added dropwise. The mixture was heated to 90 °C. TLC at 2:50 PM showed starting material and minor products. TLC at 4:40 PM showed main product forming with starting product still present. 5:10 PM TLC showed that starting material was present. The reaction was left over night. TLC at 9:20 AM showed minor traces of starting material. The mixture was filtered then concentrated under reduced pressure. The concentrated mixture was then washed with water (2 × 20 mL) and with brine (2 × 20 mL). The product was dried then concentrated under reduced atmosphere giving (11.06 g, 59.4 mmol, 92% yield) a brown oil which was used in the second step without further purification.

4-fluoroaniline was added at 1:25 PM and the reaction was heated to 90 °C. TLC at 4:35 PM showed the starting materials were present. Reaction was left over night. TLC at 10:15 AM showed minor amounts of starting material. The reaction was cooled and dissolved with ethyl acetate (50 mL) then washed with water (2 × 20 mL), followed by brine (1 × 20 mL). The mixture was then concentrated under reduced pressure to give a brown liquid that was stored in the fridge over the weekend.

The mixture was washed with 1 M HCl (2 × 20 mL) and water (2 × 20 mL) then neutralised with KCO3 followed by drying with MgSO4. TLC at 3:08 PM showed the absence of 4-fluoroaniline. Product was filtered then concentrated under reduced atmosphere followed by recrystallisation from EtOH (37 mL) and 40% EtOH (aq) (20 mL). The brown crystals (6.6 g, 25 mmol, 40% yield, product was present in the filtrate and was thrown away accidentally) were filtered and dried.

The product was characterised by HNMR and the spectra was compared to PMY 6-1 and JRC 1-1.

TLC (25% ethyl acetate/hexane in vanilin):
1st TLC @ 2;50 PM MD 1-1.jpg
2nd TLC @ 4;40 PM MD 1-1 PNG.png
3rd TLC @5;10 PM MD 1-1 PNG.png

From left to right: ethyl acetoacetate, ethyl acetoacetate and reaction mixture, reaction mixture.

TLC (25% ethyl acetate/hexane in vanilin) 2/8/12
2nd Reaction TLC at 10:15 AM, 3/8/12
2nd Reaction TLC at 4:35 PM, 2/8/12

From left to right: ketoester intermediate, intermediate + reaction mixture, mixture, aniline + mixture, aniline.

TLC (25% ethyl acetate/hexane in vanilin) 6/8/12
TLC at 3:08 PM after acid wash at

From left to right: ketoester intermediate, intermediate + reaction mixture, mixture, aniline + mixture, aniline.

See also:
Upscaled Synthesis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (JRC 1-1)
Synthesis of ethyl 2-acetyl-4-oxopentanoate intermediate. (LMW 7-1)
Synthesis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 6-1)

Risk and Hazard Assessment:
RA
Linked Posts
Attached Files
RA
Scheme
1st TLC @ 2;50 PM MD 1-1.jpg
1st TLC @ 2;50 PM MD 1-1.jpg
2nd TLC @ 4;40 PM MD 1-1.jpg
3rd TLC @5;10 PM MD 1-1.jpg
1st TLC @ 2;50 PM MD 1-1 PNG.png
2nd TLC @ 4;40 PM MD 1-1 PNG.png
3rd TLC @5;10 PM MD 1-1 PNG.png
2nd Reaction TLC at 4:35 PM, 2/8/12
2nd Reaction TLC at 10:15 AM, 3/8/12
TLC at 3:08 PM after acid wash at
Comments
Re: Synthesis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (MD 1-1) by Matthew Todd
1st August 2012 @ 13:17
Risk assessment looks good. If you have done a TLC, upload it so we can see...