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18th November 2011 @ 01:13
===

Conversion of carboxylic acid PMY 8-3 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: 11.00 EST 18/11/11
PMY 8-3 (200 mg, 0.86 mmol, 1 equiv.) was dissolved in dry PhMe (10 mL). 1 drop DMF added followed by thionyl chloride (0.25 mL, 3.4 mmol, 4 equiv.). After 4 hours, 0.2 mL removed, concentrated and analysed by 1H NMR. Integrals of pyrrole-H indicate 65% conversion. not meticulously dry handling of mini work-up sample After 5 hours, reaction concentrated under reduced pressure. Then redissolved in DCM (10 mL) and freshly dried PMY 9-1 (224 mg, 0.86 mmol, 1 equiv.) added. 21/11/11 09.30 TLC shows formation of product along with side products. Concentrated under reduced pressure to a black solid. Purified by chromatography (0-1.5% MeOH/DCM). Column did not yield desired product, similar RF material appears to be SM by 1H NMR. Note different stain colour by vanillin after several hours. TLC does appear to show product (in comparison with PMY 11-3), but column TLC does not match.

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC 0930 21/11/11

Left plate: SM, M, RM, RM + PMY 9-1, PMY 9-1.
Right plate: SM, M, RM, RM + PMY 11-3, PMY 11-3.

Column TLC

Column TLC: Right plate is a repeat on overlap region.

NMR:
NMR at acid chloride stage
NMR of fractions 16-30
NMR of fractions 31-48


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

See also:
Synthesis of TCMDC-123794 using DIC/DMAP (PMY 11-3)
Synthesis of TCMDC-123794 via acid chloride (PMY 11-2)
Synthesis of TCMDC-123794 via acid chloride (PMY 11-1)
Synthesis of TCMDC-123812 via acid chloride (PMY 10-2)
Linked Posts
Attached Files
15th November 2011 @ 03:39
===

Coupling of acid PMY 8-3 and 4-aminoantipyrine for a analogue of TCMDC-123794 that does not contain the ester linker. Using EDC as coupling reagent.

Reaction Scheme

Reaction start time: 1500 15/11/11
EDC.HCl (181 mg, 0.94 mmol, 1.1 equiv.) was stirred in DCM (8 mL) at 0 °C. Triethylamine (0.13 mL, 0.94 mmol, 1.1 equiv.) was added, followed by PMY 8-3 (200 mg, 0.86 mmol, 1 equiv.) and 4-aminoantipyrine (192 mg, 0.94 mmol, 1.1 equiv.). After 19 hours, TLC shows new product. After a total of 22 hours, water added. 21/11/11 Diluted with further DCM (10 mL) and separated. The organic layer was washed with water (2 × 10 mL) and brine, then dried (MgSO4) and concentrated under reduced pressure to a brown oil. Purified by chromatography (0-3% then 10% MeOH/DCM). Not consistent with expected product by 1H NMR.

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC 1000 16/11/11


NMR:
1H NMR


Risk and Hazard Assessment:
See Synthesis of TCMDC-123794 Side-chain (PMY 5-1)
Linked Posts
Attached Files
14th November 2011 @ 06:36
===

Coupling of PMY 22-1 and Glycolamide using EDC and DMAP to obtain the N-p-trifluoromethyl-phenyl analogue of TCMDC-123812.

Reaction Scheme

Reaction start time: 1035 15/11/11
EDC.HCl (74 mg, 0.39 mmol, 1.1 equiv.) was stirred in DCM (5 mL) at 0 °C. Triethylamine (0.05 mL, 0.5 mmol, 1.1 equiv.) was added, followed by PMY 22-1 (100 mg, 0.35 mmol, 1 equiv.) and glycolamide (29 mg, 0.51 mmol, 1.1 equiv.). After 24 hours, TLC shows consumption of acid and new products. Water added at 26 hours. Separated and washed with water (2 × 5 mL) and brine then dried (MgSO4) and concentrated under reduced pressure to a pale brown solid (0.14 g). After Chromatography (MeOH/DCM), expected products were not observed by 1H NMR.

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

TLC (10% MeOH/DCM) visualised with vanillin and UV:
TLC 1 hour
TLC 1000 16/11/11

TLC of reactions PMY 23-1, 24-1 and 25-1. Mixed spots with respective acids.

NMR:
1H NMR PMY 25-1-A
1H NMR PMY 25-1-A2
1H NMR PMY 25-1-B


See also:
Synthesis of N-p-tolyl analogue of TCMDC-123812 (PMY 24-1)
Synthesis of N-Phenyl analogue of TCMDC-123812 (PMY 23-1)
Synthesis of TCMDC-123812 via acid chloride (PMY 10-2)
Hydrolysis of Ethyl 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate (PMY 20-1)
Linked Posts
Attached Files
14th November 2011 @ 06:33
Trace product obtained.

===

Coupling of PMY 21-1 and Glycolamide using EDC and DMAP to obtain the em>N-p-tolyl analogue of TCMDC-123812.

Reaction Scheme

Reaction start time: 1035 15/11/11
EDC.HCl (92 mg, 0.48 mmol, 1.1 equiv.) was stirred in DCM (5 mL) at 0 °C. Triethylamine (0.07 mL, 0.51 mmol, 1.2 equiv.) was added, followed by PMY 21-1 (100 mg, 0.44 mmol, 1 equiv.) and glycolamide (36 mg, 0.48 mmol, 1.1 equiv.). After 24 hours, TLC shows consumption of acid and new products. Water added at 26 hours. Separated and washed with water (2 × 5 mL) and brine then dried (MgSO4) and concentrated under reduced pressure to a brown oil (0.22 g). Purified by chromatography (0,0.25,0.5,1,1.5% MeOH/DCM) to obtain 24-1-anhydride, pale yellow solid (57 mg) and 24-1-A SM acid (trace), 24-1-B (trace) consistent with expected product by 1H NMR.

TLC (10% MeOH/DCM) visualised with vanillin and UV:
TLC 1 hour
TLC 1000 16/11/11

TLC of reactions PMY 23-1, 24-1 and 25-1. Mixed spots with respective acids.

NMR:
1H NMR, recov SM, 24-1-A


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

See also:
Synthesis of N-Phenyl analogue of TCMDC-123812 (PMY 23-1)
Synthesis of TCMDC-123812 via acid chloride (PMY 10-2)
Hydrolysis of Ethyl 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate (PMY 20-1)
Linked Posts
Attached Files
14th November 2011 @ 06:28
===

Coupling of PMY 20-1 and Glycolamide using EDC and DMAP to obtain the N-phenyl analogue of TCMDC-123812.

Reaction Scheme

Reaction start time: 1035 15/11/11
EDC.HCl (98 mg, 0.51 mmol, 1.1 equiv.) was stirred in DCM (5 mL) at 0 °C. Triethylamine (0.07 mL, 0.51 mmol, 1.1. equiv.) was added, followed by PMY 20-1 (100 mg, 0.46 mmol, 1 equiv.) and glycolamide (38 mg, 0.51 mmol, 1.1 equiv.). After 24 hours, TLC shows consumption of acid and new products. Water added at 26 hours. Reaction left for another 24 hours. Separated and washed with water (2 × 5 mL) and brine then dried (MgSO4) and concentrated under reduced pressure to a brown oil (0.22 g). Purified by chromatography (0,0.25,0.5,1,1.5% MeOH/DCM) to obtain 23-1-A (early product "anhydride", yellow oil (5 mg) and 23-1-B, consistent with expected product by 1H NMR, brown oil (4 mg). really poor mass balance going on here.


TLC (10% MeOH/DCM) visualised with vanillin and UV:
TLC 1 hour
TLC 1000 16/11/11

TLC of reactions PMY 23-1, 24-1 and 25-1. Mixed spots with respective acids.

NMR:
1H NMR PMY 23-1-A
1H NMR PMY 23-1-B


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

See also:
Synthesis of TCMDC-123812 via acid chloride (PMY 10-2)
Hydrolysis of Ethyl 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate (PMY 20-1)
Linked Posts
Attached Files