Diisopropylamine → 2-(3-(3-((3-Methyloxetan-3-yl)ethynyl)pyrazin-2-yloxy)azetidin-1-yl)quinoline

Participants

Reaction Conditions

Reaction Steps

Tetrakis(triphenylphosphine)palladium (288 mg, 0.249 mmol), copper(i) iodide (190 mg, 0.998 mmol) and 2-(3-(3-chloropyrazin-2-yloxy)azetidin-1-yl)quinoline (see PREPARATION P2.6; 312 mg, 0.998 mmol) were combined in a microwave vial which was degassed and backfilled with nitrogen (procedure was repeated three times). DMF (1663 μL) was added followed by diisopropylamine (2097 μL, 14.96 mmol) and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (840 mg, 4.99 mmol). The tube was sealed and heated to 85° C. for 16 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with brine and water. The aqueous layer was back extracted with EtOAc (3×) and the combined organic phase was dried over Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide 2-(3-(3-((3-methyloxetan-3-yl)ethynyl)pyrazin-2-yloxy)azetidin-1-yl)quinoline (45 mg, 0.121 mmol, 12.11% yield) as orange powder. 1H NMR (400 MHz, chloroform-d) δ ppm 1.76 (s, 3H) 4.28 (dd, J=9.88, 4.21 Hz, 2H) 4.47 (d, J=5.48 Hz, 2H) 4.67 (dd, J=9.59, 6.65 Hz, 2H) 4.97 (d, J=5.48 Hz, 2H) 5.52-5.62 (m, 1H) 6.63 (d, J=8.80 Hz, 1H) 7.21-7.41 (m, 2H) 7.45-7.65 (m, 1H) 7.76 (d, J=8.22 Hz, 1H) 7.90 (d, J=8.80 Hz, 1H) 8.03 (d, J=2.74 Hz, 1H) 8.17 (d, J=2.54 Hz, 1H). ESI (M+1) 373.1; calc for C22H20N4O2 372. (PDE10 IC50=0.0446 nM).

Provenance & Evidence