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4th March 2012 @ 22:18
Desired product isolated as an impure mixture. Reaction repeated (PMY 10-6) with meticulously dried starting materials.


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: 11.30 05/03/12
JRC 2-1 (500 mg, 2.14 mmol, 1 equiv.) was stirred in dry PhMe (3 mL). A drop of DMF was added followed by dropwise addition of thionyl chloride (0.31 mL, 4.29 mmol, 2 equiv.). Reaction stirred for 3 hours then concentrated under reduced pressure (twice from PhMe). Hexane (15 mL) was added to the residue and stirred for 15 minutes. Filtered and concentrated to a yellow solid (164 mg, 31%). The acid chloride was dissolved in THF (7 mL).

Glycolamide (177 mg, 2.36 mmol, 1.1 equiv.) and DIPEA (0.50 mL, 2.87 mmol, 1.3 equiv.) were stirred in DMF (1 mL) and THF (3 mL). The solution of acid chloride was added dropwise and the reaction heated to 60 °C. After approx 16 hours, the reaction was cooled. TLC inconclusive (probably due to DMF interfering with rf). Reaction was concentrated and purified using a short column (40-100% EtOAc/hexane then 5% MeOH/DCM). 3 fractions collected, middle fraction contains impure desired product.

B, product impure (19 mg)
C glycolamide? (86 mg)

Attempting trituration of 10-5-B with Et2O.

TLC (66% EtOAc/hexane) visualised with UV and vanillin:
TLC of fractions

Left to right: SM acid, 1/fraction A, 2/fraction B, 3/Fraction C, Product 10-2. By TLC fraction 3 is consistent with product, NMR shows product only in fraction B.

1H NMR fraction C
1H NMR fraction B
1H NMR fraction A

See also:
Synthesis of TCMDC-123794 via acid chloride, improved method (PMY 11-5)
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:
Synthesis of TCMDC-123812 via acid chloride (PMY 10-2)
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Attached Files
1H NMR fraction A
1H NMR fraction B
1H NMR fraction C
TLC of fractions