TCMDC_ArylPyrrole

Attempted synthesis of side chain in greater purity. See also

13 μL of conc. HCl was added to a suspension of glycolic acid (1.0 g, 13.2 mmol, 1 equiv.) in 3,4-dihydro-2H-pyran (3.6 mL, 39 mmol, 3 equiv.) and the reaction mixture was heated to 80 ˚C  for 30 minutes.

Volatiles were evaporated, and the resulting residue was purified by flash column chromatography over silica (Ethyl acetate/Petrol 3:7). Two major fractions collected - very streaky TLC plates with elution of all spots. I think that the material deteriorated on storage in the fridge - should have purified immediately. Second fraction cleaner than first - to be used in next reaction AEW 84-1.

http://www.jbc.org/content/276/45/41638.full.pdf+html

Data:

¹H NMR:

Fraction A:

Fraction B:

Hazard and Risk Assessment:

Repeat synthesis see PMY 9-1 to make side-chain of TCMDC-123794 4-aminoantipyrine.

Crude (AEW 75-1) ("27.0 mmol") was stirred in toluene (40 mL). The material crystallised and was dissolved by heating. 4-aminoantipyrine (5.73 g, 28.2 mmol, 1.05 equiv.) was added and the reaction heated to reflux. 

NMR:

Risk and Hazard Assessment:

See also:
Synthesis of Glycolic Acid Acetonide (PMY 7-1)

AEW 73-1 (80 mg, 0.26 mmol, 1 equiv.) was dissolved in CH₂Cl₂ (2.6 mL), EDCI (60 mg, 0.31 mmol, 1.2 equiv.) and HOBt (3.5 mg, 0.03 mmol, 0.1 equiv.) were added and the mixture stirred for 20 minutes. Ammnonia (28% aq. soln., 0.24 mL, 0.39 mmol, 1.5 equiv.) was added and the reaction mixture stirred at room temperature. Reaction mixture stirred for 4 hours, still SM. Stirred o/n still SM by TLC. Reaction quenched by addition of an aqueous solution of sodium hydrogen carbonate and then extracted with CH₂Cl₂, washed with brine, dried (MgSO₄), filtered and evaporated to yield a yellow oil with white/yellow crystals. Purified by column using 1-10% MeOH in DCM. Gave desired poduct as white semi-solid (52 mg, 0.17 mmol, 66% yield).

Data:

TLC 5% MeOH in CH₂Cl₂ (20 h)

500 MHz

Hazard and Risk Assessment:

Total yield: 3.34 g, 73% yield. Better yield on 2 g scale.

DMF (10.0 mL) was stirred under a nitrogen atmosphere in an ice-bath. Phosphoryl chloride (2.36 mL, 25.4 mmol, 1.2 equiv.) was added and the reaction stirred for 25 minutes. Reaction still colourless. A solution of pyrrole AEW 10-2 (4.00 g, 21.0 mmol, 1 equiv.) in DMF (10 mL) was added dropwise over 10 minutes. The reaction was removed from the ice-bath and allowed to warm to room temperature. 

After 1 h 20 mins, reaction was complete by TLC. Poured over ice (200 ml). pH adjusted to 9 (meant to be 6) (approx. 20% NaOH) and left stirring overnight. In the morning pH was 1. 20% NaOH added until pH 11 and the reaction mixture was left to stir for a further 40 minutes. The solid was filtered and washed with water to form a wet beige paste. Recrystallised from (MeCN/water) to give a free-flowing pale brown solid (2.36 g, 10.9 mmol, 52% yield). Second crop of crystals was still paste-like, they were dissolved in EtOAc and combined with the mother liquor. MeCN and EtOAc was removed under reduced pressure and the aqueous layer was extracted with EtOAC, washed with brine, dried (MgSO₄) filtered and evaporated to yield a brown solid (976 mg, 4.49 mmol, 21% yield). Both fractions = good by ¹H NMR. 

Data:

Original Experiment:
Scale up (11 mmol): Formylation of 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole (PMY 2-4)

Starting material synthesis:
Repeat Preparation of 1-(4-Fluoro-phenyl)-2,5-dimethyl-1H-pyrrole (AEW 1-1)

References:

1. Gangjee, A.; Patel, J.; Kisliuk, R. L.; Gaumont, Y; J. Med. Chem., 1992, 35 (20), 3678–3685. doi:10.1021/jm00098a013

• Manetti, F.; Magnani, M.; Castagnolo, D.; Passalacqua, L.; Botta, M.; Corelli, F.; Saddi, M.; Deidda, D; De Logu, A. ChemMedChem, 2006, 1, 973–989. doi: 10.1002/cmdc.200600026
  

InChI=1S/C12H12FN/c1-9-3-4-10(2)14(9)12-7-5-11(13)6-8-12/h3-8H,1-2H3
gave
InChI=1S/C13H12FNO/c1-9-7-11(8-16)10(2)15(9)13-5-3-12(14)4-6-13/h3-8H,1-2H3

Hazard and Risk Assessment:

Resynthesis of glycolic acid acetonide. See also Synthesis of Glycolic Acid Acetonide (PMY 7-1).

Started 11.30 am Thursday 15th August

Condensation of acetone and glycolic acid to give the protected/activated glycolic acid acetonide for further side chain elaboration.

Glycolic acid (2.05 g, 27.0 mmol, 1 equiv.) was stirred in acetone (40 mL) with a few crystals of p-TSA for 1 hour. NaHCO₃ (approx 1 g) was added and dried (MgSO₄) before filtration and partially concentration to a colourless oil. 

NMR:

References:

• doi: 10.1016/j.ejmech.2008.02.022
• doi: 10.1016/0040-4039(90)80091-Y

Risk and Hazard Assessment
See: