反应详情

Step 1—Synthesis of (S)-1-(2-chloro-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2,2-difluoroethanone (yi): A solution of (S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylmorpholine hydrochloride (yh) (300 mg, 1.0 mmol), difluoroacetic acid (192 mg, 2.0 mmol), DIPEA (1 mL) and HATU (500 mg, 1.3 mmol) in THF (5 ml) was stirred at r.t. overnight. LC-MS indicated the reaction was completed and the mixture was poured into water, and extracted with EtOAc. The EtOAc layer was dried over anhydrous Na2SO4 and concentrated to give the crude, which was purified by reverse-phase HPLC to give the desired product (280 mg, 85%). 1H NMR (CDCl3, 400 MHz): δ6.23-5.95 (m, 1H), 4.70-4.54 (m, 2H), 4.06-4.04 (m, 1H), 3.90-3.80 (m, 2H), 3.67-3.56 (m, 5H), 3.49-3.35 (m, 1H), 2.66-2.61 (m, 2H), 1.31 (d, J=9.6, 3H). LC-MS: m/z=+496 (M+H)+.

1. extractionextracted with EtOAc
2. dry with materialThe EtOAc layer was dried over anhydrous Na2SO4
3. concentrationconcentrated
4. customto give the crude, which
5. customwas purified by reverse-phase HPLC