Potassium trimethylsilanolate → 2-[4-(4-{4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl}phenyl)bicyclo[2.2.2]octan-1-yl]propanoic acid

Participants

Reaction Conditions

Reaction Steps

A mixture of methyl 2-{4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]bicyclo[2.2.2]oct-1-yl}propanoate (Intermediate 18; 220 mg, 0.49 mmol) and potassium trimethylsilanolate (315 mg, 2.45 mmol) in THF (5 mL) was heated in a microwave for 35 mins at 100° C. and was then stirred at ambient temperature for 2 days. The solvent was removed under reduced pressure and the residue partitioned between 2M HCl (20 mL) and EtOAc (50 mL) and the aqueous phase was further extracted with EtOAc (50 mL). The organic extracts were combined, dried (MgSO4) and concentrated to leave a gum. This was dissolved in DMSO/MeCN/H2O (7:2:1) and separated by reverse phase chromatography eluting 5-95% water-acetonitrile 0.2% TFA, providing the title compound (45 mg, 0.104 mmol, 21%) as a white solid; 1H NMR δ 1.01 (d, 3H), 1.49-1.55 (m, 3H), 1.62 (s, 6H), 1.64-1.69 (m, 3H), 1.78-1.81 (m, 6H), 2.12 (q, 1H), 7.05 (s, 1H), 7.40 (d, 2H), 7.65 (d, 2H), 7.99 (s, 1H); MS m/e MH+ 435.

Provenance & Evidence