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15th August 2012 @ 10:32
Synthesis of fluoro derivative of the pyrazole analogue core from ethyl acetoacetate, dimethylformamide dimethyl acetal and 4-fluorophenylhydrazine.

Reaction Scheme

Reaction Start Time 11:20 16/08/12
Dimethylformamide dimethyl acetal (910 μL, 7.21 mmol, 1.24 equiv.) was added with stirring to ethyl acetoacetate (919 μL, 7.21 mmol, 1.24 equiv.), the mixture turned yellow then heated to reflux at 100 °C. After 2 hours the mixture is a dark red oil and TLC showed consumption of ethyl acetoacetate.

NaOH (4 mL, 2M) was added to 4-fluorophenylhydrazine hydrochloride (1.00 g, 6.17 mmol, 1 equiv.) and the salt was dissolved with the aid of heating to give a clear solution. This was washed with ethyl acetate (3 x 10 mL) and once with brine (10 mL). The upper organic layer was then dried over MgSO4 and solvent removed under reduced pressure to give 4-fluorophenylhydrazine (733 mg) as a yellow oil.

4-fluorophenylhydrazine (733 mg, "5.8 mmol") was dissolved in ethanol (approx. 20 mL) and added dropwise to the enamine ketone, the reaction was then heated to reflux at 80 °C. After 1.5 hours TLC showed consumption of 4-fluorophenylhydrazine. The mixture was left overnight at room temperature with stirring. TLC showed that product had formed but some of the intermediate species remained. NMR analysis showed that the product had been formed but with an impurity of ethanol and some unidentifiable compounds of similar chemical shift to the product.

The reaction mixture was filtered through a silica pad using ethyl acetate / hexane (5%, 10%), a yellow layer was taken off, leaving a brown layer on the silica. TLC showed this gave several fractions: with minor impurities (1.41 g after concentration) and some pure fractions (54 mg after concentration) as shown by TLC.

TLC showed that the fractions were still not pure and a further column using 10% ethyl acetate / hexane was used to isolate cleaner fractions. These comprised the ester product as a yellow oil (0.842 g, 3.4 mmol, 64%) and one pure sample (113 mg, 0.455 mmol, a further 9% giving 73% yield in total) which after removing solvent was a yellow crystalline solid and will be used for characterisation. Melting point 45-46 ˚C.

TLC (20% EtOAc/hexane) visualised with UV and vanillin:
MJT2-1 TLC part i 2 hours.JPG
TLC after 1.5 hours after addition of 4-fluorophenylhydrazine
TLC 20 hours after addition of hydrazine


MJT 2-1 TLC of fractions from silica pad
MJT 2-1 TLC of fractions from silica pad (ii)


NMR:
MJT 2-1 pure fraction


IR:
IR 2-1


Reference
Synthesis of ethyl 5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (PMY 43-1)

Risk and Hazard Assessment
HIRAC updated 16-8-12
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13th August 2012 @ 07:53
Coupling of pyrazole carboxylic acid PMY 44-1 with serine methyl ester via the acid chloride.

2992.png

Reaction start time 1025 16/08/12
PMY 44-1 (250 mg, 1.24 mmol, 1 equiv.) was stirred in PhMe (2 mL) under a nitrogen atmosphere. Thionyl chloride (0.20 ml, 1.36 mmol, 2.2 equiv.) was added dropwise then DMF (5 drops, catalyst) was added and the reaction left at room temperature with stirring. After 4 hours the reaction mixture is a white slurry. After 5 hours the solvent (toluene) was removed under reduced pressure to leave the acid chloride as a white crystalline solid which was dissolved in THF and kept under a nitrogen atmosphere.

In a separate vessel DL-serine methyl ester hydrochloride (211 mg, 1.36 mmol, 1.1 equiv.) was dissolved in THF (10 mL), this solution was transferred in to the reaction vessel containing the acid chloride. DIPEA (0.6 mL, 3.09 mmol, 2.8 equiv.) was then added to the reaction vessel and a white vapour was emitted. The reaction was left overnight at room temperature with stirring. At 20 hours the reaction is a brown solution and TLC shows formation of a new product(s) and consumption of the carboxylic acid used initially. The solvent (THF) is removed under reduced pressure yielding a dark brown oil and white crystals appear on the sides of the reaction vessel. Reaction mixture left in fridge for 72 hours.

TLC showed presence of two compounds (one near to solvent front and one near to base line) and column purification was used to isolate the compound with higher Rf value, gradient elution with methanol / DCM (0.5%, 1%, 2%, 3%), desired compound eluted at 3%. TLC shows that 2 compounds are present in some fractions. All fractions containing product are collected and concentrated yielding a colourless oil.

TLC (5% MeOH/DCM) visualised with UV and vanillin:
MJT1-1 TLC 20 hours.JPG


TLC (10% MeOH/DCM) visualised with UV and vanillin:
1-1 TLC before column purification

MJT 1-1 column fractions TLC.JPG
MJT 1-1 column fractions TLC (ii).JPG


NMR:
NMR MJT1-1 impure, after first column


References
Coupling of pyrrole acid chloride and serine methyl ester (PMY 57-1)
Cyclodehydration of carboxamide PMY 57-1 (PMY 58-1)

Risk and Hazard Assessment
HIRAC updated 16-8-12 10AM
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