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30th January 2012 @ 23:01
Product not isolated, "lost" on silica. Repeated successfully PMY 31-5

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Synthesis of the amide analogue of TCMDC-123812 by coupling of glycinamide and acid PMY 8-4 via the acid chloride.

Reaction Scheme

Reaction start time: 10.55 31/01/12
PMY 8-4 (100 mg, 0.43 mmol, 1 equiv.) was stirred in dry PhMe (2 mL) and cooled in ice. Thionyl chloride (50 μL, 0.67 mmol, 1.6 equiv.) was added followed by DMF (20 μL). After 50 minutes, the reaction was allowed to warm to room temperature. After 2 hour 40 mins at room temperature, reaction was concentrated under reduced pressure. Further PhMe (4 mL) was added and concentrated again. Hexane (3 mL) was added and the residue stirred for 15 mins at room temperature, then filtered (syringe filter). The pale yellow solution was dropped spilling approx half before being concentrated under reduced pressure to a yellow gum which was dissolved in dry THF (2 mL). Glycinamide.HCl (57 mg, 0.51 mmol, 1.2 equiv.) and DIPEA (0.13 mL, 0.99 mmol, 2.3 equiv.) were stirred for 15 minutes (did not dissolve). THF solution of acid chloride was added and the mixture heated to 80 °C. After overnight heating, TLC shows 2 new products and a small amount of SM. Reaction was a white precipitate in a slightly yellow oil. Reaction concentrated. Mass spec of crude (MeOH then filtered) does not show expected product. Anhydride observed ([M+Na] 471, [2M+Na] 919.00) and an unknown ([M+Na] 553, [2M+Na] 1083). Residue was purified by chromatography (10-45% EtOAc/hexane), two fractions, early running 31-4-A and later running 31-4-B. The red spot on the TLC should have come off the column but didn't. Column obviously not flushed thoroughly enough.

Note: Glycinamide.HCl (57 mg) DIPEA (0.13 ml) mix (attempted freebase) is not fully soluble in THF, nor DMF (4 mL).

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


Reference:
Patent:WO2006076202

See also:
Coupling of pyrrole carboxylic acid PMY 8-3 and glycinamide (PMY 31-3)

Risk and Hazard Assessment:
See: Synthesis of TCMDC-123812 via acid chloride (PMY 10-1)
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Scheme
Scheme updated
TLC