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26th September 2011 @ 07:44
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Conversion of carboxylic acid PMY 8-2 to the acid chloride using thionyl chloride and its subsequent coupling with side chain PMY 9-1 to give TCMDC-123794.

Reaction Scheme

Reaction start time: 16.20 EST 26/09/11
PMY 8-2 (104 mg, 0.45 mmol, 1 equiv.) was dissolved in dry PhMe (5 mL). 1 drop DMF added followed by thionyl chloride (0.2 mL, 2.74 mmol, 6 equiv.). After 2 hours, TLC does not show product consistant with PMY 10/11-1. Mixture concentrated under reduced pressure, redissolved in toluene and concentrated twice more.

Residue dissolved in MeCN (5 mL). Side chain PMY 9-1 (131 mg, 0.50 mmol, 1.1 equiv.) in MecN (2 mL) and triethylamine (0.2 mL) was added and the reaction heated to 60 °C overnight. After 15 hours, TLC shows formation of products and starting materials and impurity consistant with PMY 10/11-1 (suspect anhydride of acid SM). Reaction cooled and then concentrated under reduced pressure. The residue was purified by chromatography on silica (10-50% EtOAc/petrol, then 3-10% MeOH/DCM) to obtain a brown glassy oil after drying under vacuum (49 mg, 23% of theory, not clean). Recovered SM mixed with "anhydride" (60 mg) and a polar gum (110-140 mg, side chain by TLC). The gum was subjected to high vacuum with gentle heating to drive off solvent. A white material sublimed onto the flask, NMR attached). glassy oil repurified by chromatography (0-3% MeOH/DCM) to obtain a clear glass (17 mg)

TLC (25% EtOAc/petrol) visualised with UV and vanillin:
TLC, acid chloride stage

TLC at 15 hours in various solvents

Left to right: 1:1, 3:1 EtOAc/petrol, 10% MeOH/DCM, 10% MeOH/DCM. Plate on far right spots as follows: PMY 8-2, reaction mix (RM)/PMY 8-2, RM, RM/PMY 9-1, PMY 9-1. A bit sideways on the final plate too, due to a drop of solvent high up on the plate.

NMR:
1H NMR post column
1H NMR recov \"SM\"
1H NMR recovered polar gum
1H NMR sublimed material

400 MHz NMR 1H and 13C
300 MHz, 1H, 19F, partial 13C


IR:
IR spectra
IR JCAMP-DX


Mass Spectrometry:
m/z (ESI+) 477 [M+H]+

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

See also:
Synthesis of TCMDC-123794 via acid chloride (PMY 11-1)
Synthesis of TCMDC-123812 via acid chloride (PMY 10-2)
Linked Posts
Attached Files
TLC at 15 hours in various solvents
1H NMR post column
1H NMR recovered polar gum
1H NMR sublimed material
1H NMR recov \"SM\"
IR spectra
IR JCAMP-DX
400 MHz NMR 1H and 13C
300 MHz, 1H, 19F, partial 13C
Comments