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12th September 2012 @ 05:29
Conversion of carboxylic acid MJT to the acid chloride and subsequent coupling with serinamide hydrochloride.

3155.png

reaction start time 0900AM 17-09-2012

The carboxylic acid (256 mg, 1.16 mmol, 1 equiv.) was stirred in PhMe (3 mL) under nitrogen. Insoluble, the mixture is a white slurry. Thionyl chloride (0.19 mL, 25.6 mmol, 2.2 equiv.) then DMF (0.1 mL, catalyst) were added, on adding DMF a white gas appeared to exit the syringe. The reaction was left to stir at room temperature for 4 hours. The reaction is now a cream slurry. The solvent is removed to give a white solid, the acid chloride, which is dissolved in the minimum amount (1.5 mL) of THF to give a yellow solution.

In a separate vessel, serinamide hydrochloride (0.164 g, 1.16 mmol, 1 equiv.) is stirred with THF (10 mL), no dissolution despite heating and sonication of the mixture. This mixture is added dropwise to the acid chloride solution using a wide mouthed pipette (nitrogen atmosphere briefly disrupted). Subsequently diisopropylethylamine (0.68 mL, 3.84 mmol, 3.3 equiv.) is added dropwise and the mixture left to stir at room temperature over night, the serinamide is now dissolved (only a few rocks remain) and the reaction is a yellow solution. After 16 hours reaction concentrated under reduced pressure, saturated NaHCO3(aq) and water (1:1) were added to the residue and extracted with DCM (3 × 15 mL). The extracts were then washed with brine and dried over MgSO4 before being concentrated.
TLC

see also
Coupling of pyrazole PMY 44-1 with serine methyl ester (MJT 1-1), Coupling of pyrrole acid chloride and serine methyl ester (PMY 57-1)

Risk and Hazard Assessment:
HIRAC
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11th September 2012 @ 06:10
Hydrolysis of the pyrazole core ester to carboxylic acid under basic conditions.

3124.png

Reaction Start Time: 18.45 11/09/12
MJT 2-1 (0.842 g, 3.4 mmol, 1 equiv.), an orange oil, was dissolved in ethanol (4.5 mL) and sodium hydroxide (4.8 mL, 5M, 24 mmol, 7 equiv.) was added, the reaction mixture was left stirring over night at room temperature. After 14 hours stirring at room temperature TLC showed no reaction. 915am The mixture was set to reflux at 100˚C, after 1 hour TLC showed product formation and consumption of starting material. The reaction (yellow mixture) was left to cool at room temperature for 1 hour then cooled in ice and acidified with 6M HCl (pH1). The cream precipitate was then isolated and dried by filtration under reduced pressure. This crude solid (1.442 g) was recrystallised from diethyl ether (15 mL), some (estimate: a third) was lost due to bumping.
First crop gave the carboxylic acid (0.160 g, 0.73 mmol, 22%) as white needles which will be used for characterisation.
TLC showed that the aqueous run off contained no product.
The solvent was removed from the mother liquor and recrystallised from ether again. Not much solid precipitated out so solvent was removed and the solid recrystallised from the minimum amount of ethanol (~2 mL) to give a second crop of cream coloured powder (144 mg, 0.66 mmol, a further 20% making 42% in total).
A melting point of the pure sample gave 168-169 ˚C.

TLC (30% EtOAc/hexane) visualised with UV and vanillin:
TLC after 10 minutes of reflux
TLC after 1 hour of reflux
TLC 3-1 showing no product in aq layer
TLC of first crop of (pure) 3-1 showing it contains no starting material


IR:
IR 3-1


Reference
Hydrolysis of ethyl 5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (PMY 44-1)

Risk and Hazard Assessment:
HIRAC MJT 3-1
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