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7th March 2012 @ 00:45
Reagent: JRC_2-1
Yield: 34
Desired product TCMDC-123812 synthesised in 34% yield over 2 steps.


Conversion of pyrrole carboxylic acid to the acid chloride using thionyl chloride and its subsequent coupling with glycolamide to give TCMDC-123812.


Reaction Start Time: 11.45 07/03/12
JRC 2-1 (250 mg, 2.07 mmol, 1 equiv.) was stirred in dry PhMe (2 mL). Thionyl chloride (0.15 mL, 2.14 mmol, 2 equiv.) was added dropwise and the reaction stirred for 4 hours. cat. DMF not added as for usual acid chloride generation. Thionyl chloride and PhMe removed under reduced pressure. Dry PhMe (2 mL) added and concentrated again then dried hexane (8 mL) added to the residue and stirred for 20 minutes. Triturated; hexane layer filtered and concentrated under reduced pressure. Residue triturated with further hexane (4 mL). The resulting yellow solid was dissolved in THF (8 mL).

Glycolamide (dried under high vacuum, 88 mg, 1.18 mmol, 1.1 equiv.), 4-DMAP (60 mg, 0.49 mmol, 0.5 equiv.), DIPEA (400 μL, 2.30 mmol, 2.1 equiv.) were stirred in THF (2 mL) at room temperature. The acid chloride was added dropwise. Instant precipitation occurred. Reaction heated briefly to reflux. TLC (taken before reaction temp had risen above 40 °C) shows disappearance of SM and formation of product consistent with PMY 10-2. Reaction cooled after 30 minutes. Heating was probably not necessary considering the instant visual transformation. Reaction kept under nitrogen. After 15 hours, the precipitate had mostly dissolved. TLC consistent with previous. The reaction was concentrated under reduced pressure and purified by chromatography (66% EtOAc/hexane) to obtain both product spots as an almost white powder (158 mg). The powder was loaded onto silica and purified again by careful chromatography (1% MeOH/DCM) to gain the more polar product as a white crystalline solid PMY 10-6-B(105 mg, 34%). 1H NMR consistent with pure expected product. Less polar spot, PMY 10-6-A, is a tan solid consistent with SM (trace mass).

TLC (66% EtOAc/hexane) visualised with UV and vanillin:
TLC 10 min (dilute)
TLC <5 min
Column TLC

Initial TLC, left to right: Acid chloride soln., mix, reaction mix.
Rxn mixture diluted for clearer TLC, left to right: SM (PMY 8-4), SM/reaction mix., RM, RM/Product (PMY 10-2)

1H NMR PMY 10-6-B product
1H NMR PMY 10-6-A

Mass Spec:
ESI mass spec

See also:
Synthesis of TCMDC-123812 via acid chloride (PMY 10-5)
Synthesis of TCMDC-123794 via acid chloride, improved method (PMY 11-5)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (JRC 2-1)
Coupling of pyrrole carboxylic acid PMY 8-4 and glycinamide derivative PMY30-3 (PMY 34-1)
Coupling of pyrrole acid chloride PMY 32-2 and glycinamide (PMY 31-5)

Risk and Hazard Assessment:
See: Synthesis of TCMDC-123812 via acid chloride (PMY 10-2)
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