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26th September 2011 @ 07:45
===

Conversion of carboxylic acid PMY 8-2 to the acid chloride using thionyl chloride and its subsequent coupling with glycolamide to give TCMDC-123812.

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, mixture concentrated under reduced pressure, redissolved in toluene and concentrated twice more.

Residue dissolved in MeCN (5 mL). Glycolamide (37 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). Brown oil (40 mg, 31% of theory) consistent with expected product by 1H NMR and impurities. Also recovered mixture of SM and "anhydride" (46 mg). Recolumned (0-3% MeOH/DCM, careful) to obtain crystalline pale brown solid (27.3 mg).

m/z (ESI+) 313 [M+Na]+

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

TLC 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/glycolamide, glycolamide.

2nd Column TLC


NMR:
1H NMR
1H NMR recov \"SM\"


Repurified:
1H, 13C, 19F NMR.

IR spectra
IR JCAMP-DX


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 11-2)
Synthesis of TCMDC-123794 via acid chloride (PMY 11-1)

Identifiers:
InChi: InChI=1S/C15H15FN2O3/c1-9-7-13(15(20)21-8-14(17)19)10(2)18(9)12-5-3-11(16)4-6-12/h3-7H,8H2,1-2H3,(H2,17,19)
SMILES: Cc1cc(C(=O)OCC(N)=O)c(C)n1-c1ccc(F)cc1
Name: carbamoylmethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate
ChemDraw name: 2-amino-2-oxoethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate
Linked Posts
Attached Files
26th September 2011 @ 07:44
===

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
23rd September 2011 @ 03:21
===

Conversion of carboxylic acid PMY 8-1 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: 12.15 EST 23/09/11
PMY 8-1 (106 mg, 0.45 mmol, 1 equiv.) was dissolved in dry PhMe (5 mL). 1 drop DMF added followed by thionyl chloride (0.1 mL, 1.37 mmol, 3.0 equiv.). After 2.5 hours, reaction concentrated under reduced pressure to remove thionyl chloride. Dissolved in DCM (4 mL). Side chain (131 mg, 0.50 mmol, 1.1 equiv.) in DCM (1 mL) and triethylamine (0.1 mL) was added dropwise. After 21 hours, water added and stirred for 15 minutes. Extracted with DCM (3 × 10 mL). Emulsion. Organic layers washed with 10% NaHCO3 (2 × 10 mL), brine then dried (MgSO4) and concentrated under reduced pressure to a thick brown oil (142 mg). 1H NMR shows SM, new prod, EtOAc. Purified by chromatography on silica (0-25% EtOAc/petrol, then 15% MeOH/DCM flush).
First spot (trace mass). The flush (86 mg) appears promising by 1H NMR.

TLC (25% EtOAc/petrol) visualised with UV and vanillin:
TLC 4 hours

SM not necessarily consumed, note that mixed spot has a missing SM. Reacting on plate before TLC has run?

NMR:
Crude 1H NMR

PMY 11-1 flush


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 side-chain of TCMDC-123794 (PMY 9-1)
Linked Posts
Attached Files
23rd September 2011 @ 00:21
===

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
22nd September 2011 @ 08:07
Product obtained in 65% yield.

===

Scale-up of PMY 8-1 hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate to give the desired acid(1-(4-Fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid).

Reaction Scheme

Reaction start time: 16.45 EST 22/09/11
PMY 6-1 (1.05 g, 4.0 mmol, 1 equiv.) was dissolved in EtOH (approx 30 mL) and 20% NaOH (20 mL, approx 25 equiv.). Heated to reflux. After 15 hours, reaction was complete by TLC. Reaction allowed to cool to room temperature then in ice. Acidified (pH 2) with 2M HCl. Extracted with EtOAc (3 × 40 mL). Combined extracts washed with water (3 × 30 mL) and brine then dried (MgSO4) and concentrated under reduced pressure to a red/brown solid. Recrystallised (acetone/water) to give a white powder (608 mg, 65%). mpt: 241-242 °C.)

TLC (25% EtOAC/petrol) visualised with UV and vanillin:
TLC 30 minutes
TLC 15 hrs


NMR:
1H NMR
13C NMR

1H and 13C NMR


IR:
IR spectra
IR JCAMP-DX


Risk and Hazard Assessment:
As for Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-1)
Linked Posts
Attached Files