NVP-TNKS656

1419957-49-5

1419954-10-1

1419949-20-4

Example 5: Synthesis of N-cyclopropylmethyl-2-[4-(4-methoxybenzoyl)-piperidin-1-yl]-N-(4-oxo-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-acetamide. 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid (0.071 g, 0.26 mmol, 1 eq.) and N,N-diisopropylethylamine (DIEA, 0.089 mL, 0.51 mmol, 2 eq.) were dissolved in 2 mL of N,N-dimethylformamide (DMF), followed by addition of O-(7-azabenzotriazol-1-yl)-N ,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 0.107 g, 0.281 mmol, 1.1 eq.). The reaction mixture was stirred at room temperature for 30 minutes. Then, a 1 mL DMF solution of 2-[(cyclopropylmethylamino)methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.06 g, 0.26 mmol, 1 eq.) was added to the reaction mixture, and stirring was continued overnight at room temperature.After 18 h, the reaction mixture was diluted with 10 mL of water and dichloromethane (3 x 50 mL) was used for Extraction. The organic phases were combined, concentrated and purified by preparative high performance liquid chromatography (HPLC, 20-100% acetonitrile/water, 10 min, containing 0.1% trifluoroacetic acid, SunFire C18 OBD 50x50mm column at a flow rate of 60 mL/min) to afford the target compound N-(cyclopropylmethyl)-2-(4-(4-methoxybenzoyl)piperidin-1-yl)- N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)acetamide as a white solid (0.03 g, 24% yield).1H NMR (400 MHz, methanol-d4) δ ppm 7.94-8.07 (m, 2H), 6.98-7.10 (m, 2H), 4.64-4.70 (m, 1H), 4.54-4.60 (m, 1H), 4.44-4.52 (m, 2H), 4.28-4.37 (m, 1H), 3.94-3.99 (m, 1H), 3.91-3.95 (m, 2H), 3.88 (s, 3H), 3.67-3.80 (m, 2H), 3.40-3.61 (m, 1H). 3.33-3.40 (m, 2H), 3.09-3.27 (m, 2H), 2.50-2.72 (m, 2H), 1.92-2.26 (m, 4H), 0.83-1.15 (m, 1H), 0.12-0.67 (m, 4H). High resolution mass spectrometry (HRMS) calculated value C27H35N4O5 [M+H]+ 495.2607, measured value 495.2606. mass spectrometry (ESI) m/z 495.3 ([M+H]+). Retention time: 2.89 min (5-75% acetonitrile/water, 7.75 min with 0.1% formic acid, Inertsil ODS3 100x3mm C18 column, flow rate 1.0 mL/min).