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23rd September 2011 @ 00:21
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Conversion of carboxylic acid PMY 8-1 to the acid chloride using thionyl chloride and its subsequent coupling with glycolamide to give TCMDC-123812.

Reaction Scheme

Reaction start time: 10.23 EST 23/09/11
PMY 8-1 (113 mg, 0.48 mmol, 1 equiv.) was dissolved in dry PhMe (5 mL) by sonication. When cooled to 0 °C, partial precipitation occured. 1 drop DMF added followed by thionyl chloride (0.1 mL, 1.37 mmol, 2.9 equiv.). On addition a precipitate forms in under 60 seconds. Precipitate dissolved in approx. 5 minutes. Allowed to warm to room temperature. After 3 hours the reaction was concentrated to remove thionyl chloride.

Glycolamide not soluble in DCM. Acid chloride residue dissolved in anhydrous acetonitrile (5 mL) at room temperature. Glycolamide not soluble in MeCN. Added as a solid (40 mg, 0.53 mmol, 1.1 equiv.) followed by triethylamine (0.1 mL, 0.72 mmol, 1.5 equiv.). After 2 hours, glycolamide crystals no longer visible in reaction. Water added and stirred for 5 minutes. Then extracted with DCM (3 × 15 mL).Emulsions, but no too bad. Washed with brine, dried (MgSO4) and concentrated under reduced pressure to dark residue. Purified by chromatography on silica (0-20% EtOAc/petrol). First spot (28 mg) is very close to SM by 1H NMR. Probably the acid chloride still or anhydride? Second spot SM acid. No column flush, probably lost product there. Went after new spots too eagerly.

TLC (25% EtOAc/petrol) visualised with UV and vanillin:
PMY10_1.jpg

TLC at 2 hours.
Column TLC
Column spot comparison


NMR:
Crude 1H NMR

First spot NMR


Reference:
Patent:WO2006076202

Risk and Hazard Assessment:
Risk Assessment
Linked Posts
Attached Files
Risk Assessment
Risk Assessment
Reaction Scheme
Crude 1H NMR
PMY10_1.jpg
Column TLC
Column spot comparison
First spot NMR
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