Sodium Carbonate → 5-(4-morpholinospiro[6H-[1,4]dioxino[2,3-d]pyrimidine-7,1'-cyclopropane]-2-yl)pyrimidin-2-amine

Temperature

120 °C

A mixture of 2-chloro-7-cyclopropyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (98 mg, 0.34 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (144 mg, 0.65 mmol), Pd(PPh3)2Cl2 (25 mg, 0.035 mmol) and sodium carbonate (1.0 mL, 1.0 mmol, 1M aqueous solution) in acetonitrile (4 mL) was degassed then heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 106 as a white solid (41 mg, 35%). LCMS: RT=3.24 min, [M+H]+=343. 1H NMR (400 MHz, CDCl3): δ 9.12 (2H, s), 5.20 (2H, broad s), 4.16 (2H, s), 3.82 (8H, s), 1.29 (2H, t, J=6.89 Hz), 0.88 (2H, t, J=6.88 Hz).

1. customwas degassed
2. custommicrowave irradiation
3. washwas washed with methanol
4. washthe product eluted with 2M ammonia in methanol
5. concentrationconcentrated in vacuo
6. customThe resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%)

ORD record

ord-1208f11cab76467f9fa291a27b30a35b

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09346817B2