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6th August 2013 @ 07:42

Repeat of Hydrolysis of MD 17-1 to give 2-((1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonyl)oxy)propanoic acid (MD 18-1) and Hydrolysis of MD 17-1 to give 2-((1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonyl)oxy)propanoic acid (MD 18-3) 

N.B No TLC data but need to monitor closely to prevent hydrolysis of both ester groups

AEW 71-1 (585 mg, 1.75 mmol) was dissolved in EtOH (27 mL), 20% NaOH (2.6 mL, 9 equiv.) and the mixture was stirred at room temperature for 1.5 h. No SM present by TLC.


(452 mg, 1.38 mmol, 79% yield)


Data:

400 MHZ

AEW 73-1 nmr13C.pdf
AEW 73-1 nmr1H.pdf
AEW 73-1 paper.zip


See also:
Hydrolysis of MD 17-1 to give 2-((1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonyl)oxy)propanoic acid (MD 18-1) and Hydrolysis of MD 17-1 to give 2-((1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonyl)oxy)propanoic acid (MD 18-3) 


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5th August 2013 @ 02:29

Coupling of Boc-protected glycine and 4-aminoantipyrine using T3P. Repeat of PMY 29-2. AEW63-1 (Resynthesis of tert-butyl (2-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino)-2-oxoethyl)carbamate, OSM-S-17 (AEW 63-1)) didn't proceed as well as Paul Ylioja's reaction.

Reaction Scheme

Procedure:
Boc-Gly-OH (500 mg, 2.85 mmol, 1 equiv.) and 4-aminoantipyrine (638 mg, 3.14 mmol, 1.1 equiv.) were dissolved in DMF (2.5 mL) and pyridine (1.30 mL, 16.14 mmol, 5.65 equiv.). The mixture was cooled in an ice/bath and T3P (50 wt.% in EtOAc, 3.1 mL, 4.9 mmol, 1.7 equiv.) was added. The mixture was allowed to warm to room temperature and the mixture stirred overnight. No SM present.

Water (30 mL) was added and the mixture stirred for 20 minutes. 10% NaHCO3 was added until pH 8 and then the mixture was extracted with EtOAc, water, brine then dried (MgSO4) and concentrated under reduced pressure to give a yellow/white solid (555 mg, ~1.54 mmol, ~54% yield), used directly in next step.

Data:

TLC (10% MeOH/DCM):

AEW 72-1.jpg

Mini-work up:Drop of reaction mixture quenched with water and partitioned with EtOAc. Potential for SM to have remained in aqueous.

NMR:

AEW 72-1 crude NMR.pdf
AEW 72-1.zip

Risk and Hazard Assessment:
As for, Synthesis of TCMDC-123812 using T3P (PMY 10-4)

See also:
Coupling of Boc-Gly-OH and 4-aminoantipyrine (PMY 29-1)
Hydrolysis of benzoyl protected glycinamide PMY 27-1 (PMY 28-2)
Hydrolysis of benzoyl protected glycinamide PMY 27-1 (PMY 28-1)
Coupling of hippuric acid and 4-aminoantipyrine using T3P (PMY 27-1)

InChI=1S/C18H24N4O4/c1-12-15(20-14(23)11-19-17(25)26-18(2,3)4)16(24)22(21(12)5)13-9-7-6-8-10-13/h6-10H,11H2,1-5H3,(H,19,25)(H,20,23)

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5th August 2013 @ 02:16

Repeat of Synthesis of 1-ethoxy-1-oxopropan-2-yl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate through ester synthesis (MD 17-1)

Procedure:

AEW 10-2  (500 mg, 2.14 mmol, 1 equiv.) was dissolved in DMF (8 mL) and oven-dried potassium carbonate (741 mg, 5.4 mmol, 2.5 equiv.) was added. The mixture was stirred at room temperature for 20 minutes, followed by addition of ethyl-2-bromopropionate (0.36 mL, 2.8 mmol, 1.3 equiv.). Reaction mixture stirred for 20 hours (meetings in afternoon, may have been complete before this time).

Work-up: Water added and then reaction mixture partitioned between EtOAc and water. Washed with water, brine and dried over MgSO4. Filtered and evaporated to give a dark orange oil - suspect DMF still present. Dissolved in toluene and applied to a column equilibrated with neat petroleum ether. Washed with ~250 mL of petroleum ether and then rapidly columned with a 2:1 mixture of petrol:EtOAc. Gave a paler yellow/orange oil. NMR confirms product and presence of residual EtOAC. Dried further at the high vac to give a viscous orange oil that slowly crystallised to a yellow semi-solid (680 mg, 2.04 mmol, 95%).

95 mg reserved for charac./testing

Data:

TLC (50% EtOAc in Hexane) ignore splattering from sampler.

AEW 71-1.jpg

1H NMR after column (+ residual EtOAc from column)

AEW 71-1 proton.pdf
AEW 71-1.zip

 

400 MHZ NMR proton, C and F

AEW 71-1.zip
AEW 71-1 proton.pdf
AEW 71-1 nmr13C.pdf

Hazard and Risk Assessment:

See Synthesis of 1-ethoxy-1-oxopropan-2-yl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate through ester synthesis (MD 17-1)

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20th June 2013 @ 07:52

See also See Coupling of pyrrole carboxylic acid PMY 8-4 and glycinamide derivative PMY30-3 (PMY 34-1) but this method uses coupling reagents rather than acid chloride.

Procedure:

AEW 10-2 (230 mg, 1 mmol, 1 equiv), EDCI (262 mg, 1.2 mmol, 1.2 equiv.) and HOBt (14 mg, 0.1 mmol, 0.1 equiv.) were stirred in CH2Cl2 (10 mL) and stirred at room temperature for 15 minutes. AEW 64-1 crude (~1.14 mmol) was added and the reaction mixture stirred at room temperature overnight. New spot on TLC. Aqueous work-up with saturated aqueous sodium hydrogen carbonate and CH2Cl2, brine, MgSO4 filtered and evaporated. 

Column: 1-20% MeOH in DCM.

First spot - recovered starting acid 90 mg

second spot - impure final product ~20 mg. 


Data:


Hazard and Risk Assessment:


See Coupling of pyrrole carboxylic acid PMY 8-4 and glycinamide derivative PMY30-3 (PMY 34-1)

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13th June 2013 @ 01:22

Repeat of Coupling of acid PMY 8-3 and 4-aminoantipyrine using T3P for a linker-less analogue of TCMDC-123794 (PMY 12-5) to collect data for the paper. Using EDCI and HOBt in attempt to enhance yield.

Procedure:

AEW 10-2 (100 mg, 0.43 mmol, 1 equiv.) was dissolved in CH2Cl2 (4.3 mL). EDC (100 mg, 0.51 mmol, 1.2 equiv.) and HOBt (6 mg, 0.04 mmol. 0.1 equiv.) were added and the yellow solution stirred at room temperature for 15 minutes under Argon. 4-Aminoantipyrine (96 mg, 0.47 mmol, 1.1 equiv.) was added and the reaction mixture stirred at rt. New product spots by TLC after 2 hours but still SM. Reaction mixture stirred o/n. Still SM. Reaction quenched by addition of a saturated aqueous soln of NaHCO3extracted into CH2Cl2, washed with water, brine, dried over MgSO4, filtered and evaporated to give an orange oil. Crude proton NMR looks pretty messy. Purification by flash column chromatography over silica (1 to 10% MeOH in DCM) gave the desired product as an orange oil - still not pure. Repurified with a slower gradient. Desired product not isolated cleanly - needs to be repeated.

Data:

AEW 62-1 (10% MeOH in DCM).jpg
 
AEW 62-1 col first spot.pdf
AEW 62-1 crude.zip
AEW 62-1 ck.zip

Hazard and Risk Assessment:


See Coupling of acid PMY 8-3 and 4-aminoantipyrine using T3P for a linker-less analogue of TCMDC-123794 (PMY 12-5) and

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