Diisopropylethylamine → Nvp-tnks-656

To a solution of [4-(4-methoxy-benzoyl)-piperidin-1-yl]-acetic acid (0.071 g, 0.26 mmol, 1 eq.) and DIEA (0.089 mL, 0.51 mmol, 2 eq.) in 2 mL of DMF was added HATU (0.107 g, 0.281 mmol, 1.1 eq.). The resulting mixture was stirred at room temperature for 30 min. 2-[(Cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.06 g, 0.26 mmol, 1 eq.) in 1 mL of DMF was added and the mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was diluted with H2O (10 mL) and extracted with dichloromethane (3×50 mL). The combined organics were concentrated and purified by preparative HPLC (20-100% CH3CN/H2O over 10 min with 0.1% TFA, sun fire C18 OBD 50×50 mm column with flow rate of 60 mL/min) to give the title compound as a white solid (0.03 g, 24%). 1H NMR (400 MHz, MeOD) 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). HRMS calculated for C27H35N4O5 495.2607. found (ESI, [M+H]+) 495.2606. MS (ESI) m/z 495.3 (M+H)+. Retention time: 2.89 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).

1. stirringthe mixture was stirred at room temperature overnight
2. waitAfter 18 h
3. extractionextracted with dichloromethane (3×50 mL)
4. concentrationThe combined organics were concentrated
5. custompurified by preparative HPLC (20-100% CH3CN/H2O over 10 min with 0.1% TFA, sun fire C18 OBD 50×50 mm column with flow rate of 60 mL/min)

ORD record

ord-322882f235d740e5b662a0b38261fec1

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09181266B2