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23rd January 2012 @ 00:48
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Synthesis of the amide analogue of TCMDC-123812 by coupling of glycinamide and acid PMY 8-3 using DCC/HOBt conditions following tip from Bill Jackson (Creative Chemistry)

Reaction Scheme

Reaction start time: 13.47 23/01/12
PMY 8-3 (100 mg, 0.43 mmol, 1 equiv.), Glycinamide.HCl (52 mg, 0.47 mmol, 1.1 equiv.) and pyridine (0.04 mL, 0.48 mmol, 1.1 equiv.) were stirred in DCM (15 mL) and dry DMF (3 mL) at 0 °C. Anhydrous HOBt (87 mg, 0.64 mmol, 1.5 equiv.) was added followed by DCC (0.10 mL, 0.64, 1.5 equiv.). After 3 hours, TLC shows formation of a new product, SM remains. Reaction left overnight. After 19 hours, TLC shows only a small trace of SM and a new product. Mixture was poured into brine (20 mL) and the layers separated. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue (brown oil with precipitate) was adsorbed onto a short silica column and purified by chromatography (30%-50% EtOAc/hexane). 2 spots collected. Top spot (red stain), PMY 31-3-A and almost baseline spot (UV, no vanillin stain) PMY 31-3-B. PMY 31-3-A contains 1H NMR signals associated with pyrrole component, no expected methylene signal for coupled product. Also contains dicyclohexylurea (DCU) type signals. 31-3-B contains DCU and HOBt type signals, no pyrrole.

TLC visualised with UV and vanillin:
TLC 3 hrs
TLC 19 hrs

3 hrs: left plate, 10% MeOH/DCM; Rightplate, 50% EtOAc/hexane. 19hrs (50% EtOAc/hexane).

NMR:
1H NMR 31-3-B
1H NMR 31-3-A


Mass Spec:
PMY 31-3-A MassSpec

ESI+, not consistent with expected product. 462 [M+Na] (consistent with PMY 12-1-A, urea-by product.

Risk and Hazard Assessment:
RA
Linked Posts
Attached Files
Scheme
RA
TLC 3 hours
TLC 3 hrs
TLC 19 hrs
1H NMR 31-1-B
1H NMR 31-3-B
1H NMR 31-3-A
PMY 31-3-A MassSpec
Comments
Re: Coupling of pyrrole carboxylic acid PMY 8-3 and glycinamide (PMY 31-3) by Matthew Todd
23rd January 2012 @ 02:47
HOBt now classified as potentially explosive, and taken here as class 3, though danger of explosion low. To be handled with this risk in mind. Reaction cleared to proceed.