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27th October 2011 @ 03:36
Product obtained in 55% yield.

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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: 14.30 EST 27/10/11
PMY 6-2 (3.05 g, 11.7 mmol, 1 equiv.) was dissolved in EtOH (approx 30 mL) and 20% NaOH (20 mL, approx 8.5 equiv.). Heated to reflux. After 17 hours, reaction was complete by TLC. Reaction allowed to cool to room temperature then in ice. Acidified (pH 1) with 6M HCl. Pale brown precipitate filtered and washed with water. Redissolved in hot acetone (approx 75 mL), cooled to room temperature and water (approx 25 mL) added, then cooled in ice. Brown powder filtered and dried under vacuum (1.49 g, 55%). Mother liquor still contains more mass.

TLC (25% EtOAC/petrol) visualised with UV and vanillin:
TLC



NMR:
1H NMR



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

See also:
Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-2)
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Attached Files
26th October 2011 @ 05:54
Product obtained in 90% yield.

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Synthesis of ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate from condensation of 4-fluoroaniline with ethyl 2-acetyl-4-oxopentanoate.

Reaction Scheme

Reaction Start Time: 1430 26/10/11
ethyl 2-acetyl-4-oxopentanoate LMW 7-1 (4.3 g, 23 mmol, 1 equiv.) and 4-fluoroaniline (2.2 mL, 23 mmol, 1 equiv.) were heated at 80 °C for 2 hours, then allowed to cool to room temp. Seeded with a couple of crystals of PMY 6-1. Upon crystallisation, water added with stirring. Solid filtered and redissolved in minimum ethanol. Attempted several recrystallisations (EtOH/water, Et2O or EtOH/hexane based), crytallised by very sticky and poorly crystalline (5.43 g, 90%). Used without further purification. Mpt 63-66 °C.

NMR:
1H NMR 6-2


Risk and Hazard Assessment:
See: Synthesis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 6-1)

See also:
Synthesis of ethyl 2-acetyl-4-oxopentanoate intermediate. (LMW 7-1)
Synthesis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 6-1)
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26th October 2011 @ 03:42
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Coupling of the acid chloride of PMY 8-2 and 4-aminoantipyrine for a analogue of TCMDC-123794 that does not contain the ester linker. Forming acid chloride to avoid acylurea by-product and to determine if the "anhydride is formed".

Reaction Scheme

Reaction Start Time: 1500 26/10/11
PMY 8-2 in DCM (4 mL) was cooled in an ice bath. 1 drop DMF was added followed by oxalyl chloride (0.05 mL, 0.59 mmol, 2.8 equiv.). After 10 minutes visible evolution of gas had stopped. Reaction allowed to warm to room temperature. After 2 hours, reaction was concentrated under reduced pressure, then redissolved in DCM (4 mL). 4-aminoantipyrine (48 mg, 0.24 mmol, 1.1 equiv.) dissolved in DCM (1 mL) and added to the reaction. After over night reaction, TLC shows disappearance of antipyrine (despite being in excess). Triethylamine (approx 0.5 mL) was added, a solid (NEt3.HCl) forms. Reaction diluted with DCM (10 mL) and washed with water (2 × 10 mL), 10% NaHCO (10 mL), water (2 × 10 mL), brine and dried (MgSO4) and concentrated under reduced pressure to a brown solid (116 mg). Purified by chromatography (0.5-10% MeOH/DCM).
12-2-A, top spot, yellow crystalline solid (26 mg), consistent with PMY 10-1 by 1H NMR.
12-2-B, 3 mixed spots (mid), brown oil.
12-2-C bottom spot (UV only), pale brown crystalline solid (35 mg), not desired product. Appears to be derived from 4-aminoantipyrine, 8.96 ppm (1H, s), 5 × ArH, 12 alkyl H?! DMF adduct?

TLC (10% MeOH/DCM) visualised with UV and vanillin:[b]
TLC
Column TLC


[b]NMR:

1H NMR 12-2-A
1H NMR 12-2-B
1H NMR 12-2-C


Risk and Hazard Assessment:
See: Coupling of acid PMY 8-2 and 4-aminoantipyrine for a linker-less analogue of TCMDC-123794 (PMY 12-1)
Replacing DCC and DMAP for oxalyl chloride (toxic, corrosive).
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25th October 2011 @ 00:40
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Conversion of PMY 15-2 to its mesylate and then displacement by PMY 9-1 to form the ether analogue of TCMDC-123794.

Reaction Scheme

Reaction start time: 12.00 25/10/11
PMY 15-2 (50 mg, 0.23 mmol, 1 equiv.) and triethylamine (0.03 mL, approx 0.23 mmol, 1 equiv.) were stirred in DCM (2 mL) at 0 °C. Methanesulfonyl chloride (18 μL, 0.23 mmol, 1 equiv.) was added. After 30 minutes, TLC does not shows SM to be impure (NMR confirms, see: Reduction of pyrrole-3-ester PMY 6-1 using lithium aluminium hydride (PMY 15-2)). PMY 9-1 (60 mg, 0.23 mmol, 1 equiv.) in DCM (1 mL) and triethylamine (0.03 mL, approx 0.23 mmol, 1 equiv.) was added. Reaction abandoned due to poor SM.

TLC (40% EtOAc/hexane) visualised with UV and vanillin:
TLC 30 minutes


Risk and Hazard Assessment:
Risk Assessment
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Attached Files
24th October 2011 @ 00:04
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Hydrolysis of PMY 14-1-C using NaOH in aqueous ethanol.

Reaction Scheme

Reaction Start Time: 1300 24/10/11
PMY 14-1-C (50 mg, 0.12 mmol, 1 equiv.) was dissolved in EtOH (1 mL). 2M NaOH (approx 1 mL) was added and the reaction stirred at room temperature. After 1 hour, reaction complete by TLC. 10% Citric acid (approx 3 mL) was added and a yellow precipitate formed (pH 5). Diluted with water (5 mL) and the yellow solid filtered and washed with further water then dried under reduced pressure (56 mg). The solid was dissolved in DCM (4 mL) and washed with water (2 × 3 mL), brine and dried (MgSO4) then concentrated under reduced pressure to a yellow solid (45 mg) containing product and grease by NMR. Sample in CDCl3 was precipitated by addition of hexane and the yellow solid filtered out and dried under high vacuum. Still contains grease/hexane. Resissolved in Ethanol and sodium hydroxide solution. Citric acid added (pH 5) to precipitate. Filtered onto celite. Cake washed with hexane. Then yellow solid washed from celite using EtOH and the concentrated under reduced pressure.

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


NMR:
1H, 19F NMR contains grease


Risk and Hazard Assessment:
Risk Assessment
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Attached Files