Acetonitrile → 5-(1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-6-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one

Participants

Reaction Steps

Trifluoroacetic acid (0.5 mL) was added to a stirred solution of 6-(4-oxo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (44 mg, 0.087 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 16 hours. The mixture was basified with a saturated solution of Na2CO3 and extracted with more DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 N solution of ammonia in MeOH in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo. The product was repurified by ion exchange chromatography using an ISOLUTE SCX2 cartridge and eluting with MeOH and 7 N solution of ammonia in MeOH. The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with DIPE and repurified by RP HPLC on (C18 XBridge 30×100 5 um). Mobile phase (Gradient from 80% 0.1% NH4CO3H/NH4OH pH 9 solution in H2O, 20% ACN to 0% 0.1% NH4CO3H/NH4OH pH 9 solution in H2O, 100% ACN) to yield 5-(1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (8 mg, 24% yield) as a white solid. 1H NMR (400 MHz, CDCl3d) δ ppm 1.66 (br. s., 1H), 1.70-1.83 (m, 2H), 1.89 (dd, J=12.0, 1.8 Hz, 2H), 2.76 (td, J=12.3, 2.8 Hz, 2H), 2.74-2.83 (m, 1H), 3.21 (dt, J=12.0, 2.8 Hz, 2H), 4.46-4.54 (m, 2H), 4.58-4.68 (m, 2H), 5.13 (s, 2H), 6.93-7.00 (m, 2H), 7.00-7.05 (m, 2H), 7.06 (s, 1H), 7.27-7.34 (m, 2H), 7.66 (t, J=8.0 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H).

Provenance & Evidence