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6th October 2011 @ 00:43
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Coupling of acid PMY 8-2 and 4-aminoantipyrine for a analogue of TCMDC-123794 that does not contain the ester linker.

Reaction Scheme

Reaction start time: 12.20 06/10/11
PMY 8-2 (50 mg, 0.21 mmol, 1 equiv.) was dissolved in DCM (7 mL) and cooled in ice. DCC (49 mg, 0.24 mmol, 1.1 equiv.) was added. After 5 minutes, 4-aminoantipyrine (48 mg, 0.24 mmol, 1.1 equiv.) was added as a solution in DCM (1 mL). After 40 minutes, the reaction was allowed to warm to room temperature. After 24 hours, no change. 4-DMAP (approx 10 mg) added. Stirred over w/end. 10.00 10/10/11 No new product by TLC (except DMAP spot). Concentrated under reduced pressure. Diluted with EtOAc (3 mL) and filtered. Crude NMR shows new products, SM acid is mostly consumed, antipyrine still present. Purified by chromatography (10-50% EtOAc, then 10% MeOH/DCM) to obtain less-polar fraction as a colourless glass, PMY 12-1-A, (116 mg) consistant with acylurea by-product by 1H NMR (still contains DCM and EtOAc). Mixed fractions, PMY 12-1-B, (75 mg) unknown, potentially product. submitted for MS

PMY 12-1-B repurified by chromatography (0-30% MeOH/DCM) gave:
12-1-B-A (40 mg) 4-aminoantipyrine and pyrrole impurity.
12-1-B-B (17 mg) 4-aminoantipyrine
12-1-B-C (trace)
12-1-B-D (2 mg)
None consistent with product seen on crude or 12-1-B NMR; 8.15 ppm br doublet, 6.41 br d. ?!?

Acyl-urea product: PMY 12-1-A, slightly yellow solid (59 mg) after dissolution and evaporation from CDCl3.
m/z (ESI+) 462 [M+Na]+, 45%; 901 [2M+Na]+ 100%. InChI=1S/C26H34FN3O2/c1-18-17-24(19(2)29(18)23-15-13-20(27)14-16-23)25(31)30(22-11-7-4-8-12-22)26(32)28-21-9-5-3-6-10-21/h13-17,21-22H,3-12H2,1-2H3,(H,28,32)

PMY 12-1-B, brown gum
m/z (ESI+) 419 [M+H]+.

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC 3 hours
TLC 24 hours


NMR:
1H NMR PMY 12-1-A
1H NMR PMY 12-1-B
PMY 12-1-A, 1H, 19F, 13C NMR


1H NMR 12-1-B-A
1H NMR 12-1-B-B
1H NMR 12-1-B-D


Risk and Hazard Assessment:
See Synthesis of TCMDC-123794 Side-chain (PMY 5-1)
Linked Posts
Attached Files
Reaction Scheme
TLC 3 hours
TLC 24 hours
1H NMR PMY 12-1-A
1H NMR PMY 12-1-B
PMY 12-1-A, 1H, 19F, 13C NMR
1H NMR 12-1-B-A
1H NMR 12-1-B-B
1H NMR 12-1-B-D
Comments
Re: Coupling of acid PMY 8-2 and 4-aminoantipyrine for a linker-less analogue of TCMDC-123794 (PMY 12-1) by Paul Ylioja
18th October 2011 @ 23:35
Looks like it is reacting, mostly goes toward the acylurea by-product. There's mixed fractions that could well contain the product but not entirely convinced yet.