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18th September 2012 @ 01:45
This experiment aims to synthesise the hit from GSK that forms the centrepiece of our interest in the aminothienopyrimidine series.


Experiment start time: 11:00 am, 16/09/2012

1,4-Dioxane (6 mL) and water (4 mL) were degassed with nitrogen for 1.5 hr before 6-bromothieno[3,2-d]pyrimidin-4-amine (32.5 mg, 0.14 mmol, 1 equiv.), cesium fluoride (117 mg, 0.77 mmol, 5.5 equiv.), sodium bicarbonate (50.9 mg, 0.70 mmol, 5.0 equiv.) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (61.3 mg, 0.21 mmol, 1.5 equiv.) were dissolved in the stirring solution. Tetrakis(triphenylphosphine)palladium(0) (30 mg, 20 mol %) was added under inert atmospheric conditions. The resultant solution was heated to reflux undeer a blanket of argon for 48 hr. The reaction mixture was then allowed to cool to rt before being diluted with water (20 mL) and ethyl acetate (60 mL). This dilute solution was filtered over a pad of celite. The organic layer was extracted with water (2 x 20 mL) and brine (20 mL) before being dried over anhydrous magnesium sulfate. The residue was concentrated in vacuo to yield 78 mg as a tan solid.

1H-NMR shows the same aromatic pattern as has been observed in nearly all Suzuki-Miyura couplings thus far.

low res mass spec does not show the desired peaks.

Purified by flash chromatography using the standard solvent system (10% EtOAc/hex, 100% EtOAc, 5% MeOH, 10% MeOH). Three products eluted.

F2: Negligible mass
F3: 13 mg
NMR and mass spec show that this is likely the boronic ester starting material recovered.

Risk Assessment:
As for JRC 32-1, JRC 22-1, JRC 26-1, JRC 29-2, JRC 27-2, JRC 36-1
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