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1st November 2011 @ 00:44
===

Conversion of PMY 18-1 to its mesylate and then displacement by PMY 9-1 to form the ether analogue of TCMDC-123794.

Reaction Scheme

Reaction start time: 1400 01/11/11
PMY 18-1 (137 mg, 0.62 mmol, 1 equiv.) and triethylamine (87 μL, 0.62 mmol, 1 equiv.) were stirred in DCM (3 mL) at 0 °C. methanesulfonyl chloride (48 μL, 0.62 mmol, 1 equiv.) was added. After 20 minutes, TLC shows multiple products and SM. Water added and the mixture separated. The DCM layer was diluted (5 mL) and washed with 0.5M HCl (2 mL) then dried (MgSO4) and filtered. triethylamine (approx 0.1 mL, approx 0.72 mmol, 1.2 equiv.) was added followed by PMY 9-1 (163 mg, 0.62 mmol, 1 equiv.). Some "fizzing" observed. Earlier water and acid washes have turned bright blue within 15 minutes. TLC at 1800 (3 hours, 2nd step) shows 2 main new spots. TLC after overnight shows no change. Reaction concentrated under a stream of nitrogen.

1H NMR shows peaks similar to side-chain SM. No CH2O can be observed in significant quantity. No pyrrole type proton observed. Worth following up this reaction for another attempt.

TLC (25% EtOAc/hexane) visualised with UV and vanillin:
mesylate tlc

TLC 2nd step, 3 hours
TLC 2nd step, 17.5 hours


NMR:
1H NMR crude


Risk and Hazard Assessment:
As for Synthesis of ether-linked analogue of TCMDC-123794 (PMY 17-1)
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1st November 2011 @ 00:18
Product obtained.

===

Reduction of pyrrole-3-carbaldehyde, PMY 2-4, to the corresponding alcohol. See PMY 15-* for reduction of the ester to the alcohol.

Reaction Scheme

Reaction start time: 0920 01/11/11
PMY 2-4 (400 mg, 1.84 mmol, 1 equiv.) was dissolved in MeOH (approx 30 mL). Sodium borohydride (70 mg, 1.84 mmol, 4 hydride equiv.) was added. After 100 minutes, TLC, shows reaction almost complete. After a further 20 minutes, acetone (approx 5 mL) was added. Stirred for 5 minutes, then concentrated under reduced pressure. Water was added to the redidue and extracted with DCM (3 × 15 mL). The extracts were washed with brine then dried (MgSO4) and concentrated under reduced pressure to a white solid (424 mg, 105%). Stored at -20 °C under nitrogen.

Note: The product alcohol is not particularly stable, use very soon after preparation.

TLC (25% EtOAc/hexane) visualised with UV and vanillin:
TLC 100 mins

Left and right are both 100 minutes. Left plate spotted and eluted after 5 minutes. Right plate spotted and eluted immediately.

Risk and Hazard Assessment:
As for Reduction of pyrrole-3-ester PMY 6-1 using lithium aluminium hydride (PMY 15-2), except using the less hazardous sodium borohydride as the reductant.

See also:
Reduction of pyrrole-3-ester PMY 6-1 using lithium aluminium hydride (PMY 15-2)
Reduction of pyrrole-3-ester PMY 6-1 using lithium aluminium hydride (PMY 15-1)
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27th October 2011 @ 04:36
Product obtained in 55% 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: 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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26th October 2011 @ 06:54
Product obtained in 90% yield.

===

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 @ 04:42
===
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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