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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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19th June 2013 @ 03:27

See also: Deprotection of Boc-Gly-4-aminoantipyrine (PMY 30-3), no TFA used at outset as PMY found 4M HCl to be more effective.

Procedure:

Crude AEW 63-1 was dissolved in THF (6 mL). Yellow solution. HCl (4M in dioxane, 3 mL, 12 mmol) was added dropwise - reaction mixture turned red - stirred at room temperature for 3 hours. Still SM. Reaction mixture stirred overnight - still SM and a yellow slurry had formed which wasn't stirring properly. HCl (4M in dioxane, 2 mL, 8 mmol) was added and the reaction mixture stirred at room temperature for a further 4 hours. Reaction complete. Concentrated to a yellow solution and used directly in AEW 65-1.

 

Data:

TLC (10% MeOH in CH2Cl2) after 19 hours

AEW 64-1.png
 
AEW 64-1 (10% MeOH in DCM).png

 

AEW 64-1 after W.zip

Hazard and Risk Assessment:

See: Deprotection of Boc-Gly-4-aminoantipyrine (PMY 30-3)

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15th June 2013 @ 04:50

See also: Coupling of Boc-Gly-OH and 4-aminoantipyrine (PMY 29-2) but with EDCI and HOBt.

Procedure:
Boc-Gly-OH (200 mg, 1.14 mmol, 1 equiv.), EDCI (262 mg, 1.37 mmol, 1.2 equiv.) and HOBt (15 mg, 0.11 mmol, 0.1 equiv.) were stirred in CH2Cl2 (10 mL) and stirred at room temperature for 15 minutes. 4-Aminoantipyrine (255 mg, 1.26 mmol, 1.1 equiv.) was added and the reaction mixture stirred for 3 hours. A saturated aqueous solution of NaHCO3 was added and the the layers were separated and the aqueous layer was extracted with CH2Cl2. Combined organic layers were washed with water, brine and then dried (MgSO4) to give an orange foam (490 mg). Crude 1H NMR matched PMY 29-2 but with extra impurity, reaction TLC looks far worse than NMR. Used as crude in AEW 64-1.

Data:

TLC in 10% MeOH in CH2Cl2

AEW 63-1.jpg
AEW 63-1 crude 1H.pdf
AEW 63-1.zip

Hazard and Risk Assessment:

See Coupling of Boc-Gly-OH and 4-aminoantipyrine (PMY 29-2)

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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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13th June 2013 @ 01:04

Repeated to collect data for paper - see original experiment Resynthesis of N-(2-amino-2-oxoethyl)-1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxamide, OSM-S-19 (AEW 59-1) for failed attempt

Procedure:

AEW 10-2 (100 mg, 0.43 mmol, 1 equiv.) was dissolved in CH2Cl2 (4.3 mL) under Argon. 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. Glycinamide hydrochloride (52 mg, 0.47 mmol, 1.1 equiv.) was stirred in a separate flask in THF (0.22 mL) with DIPEA (66 mg, 0.09 mL, 0.51 mmol, 1.2 equiv.) and then transferred to the reaction mixture and stirred at room temperature overnight.

The reaction mixture was diluted in CH2Cland washed with a saturated aqueous solution of sodium hydrogen carbonate. Aqueous layers were extracted with CH2Cl(x 2) and then combined organic layers washed with brine, dried (MgSO4), filtered and evaporated to yield a crude yellow oil. 

The oil was purified by flash column chromatography over silica (0-20% MeOH in CH2Cl2) to give a yellow oil with some crystals within. MeOH (1.5 mL) was added and the mixture cooled to 0 and sonicated and then left in an ice bath for 30 mins. The off white crystals were filtered and washed with ice cold methanol to yield the desired product + impurities (23 mg, 0.08, 18 % yield).

Data:

 

AEW 59-2 cryst proton.pdf
AEW 59-2 crude.zip
AEW 59-2 cryst.zip
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