Tetrahydrofuran → HCID 67055040, compound

Participants

Reaction Steps

4-cyano-2-fluorobenzoic acid (24.2 mg, 0.146 mmol, Alfa Aesar), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (51.7 mg, 0.136 mmol) and triethylamine (87.4 μL, 0.627 mmol) in THF (1.3 mL, 16 mmol) was stirred at RT for 15 min. Following this, 4-[2-(methoxymethyl)piperazin-1-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloric acid salt (0.061 g, 0.10 mmol, as a mixture of diastereomers from Step 4) was added. After 1 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, 0.1N NaOH and brine, dried over sodium sulfate, decanted and concentrated. The product was purified by preparative HPLC-MS, (C18 eluting with a gradient of H2O/MeCN/0.1% TFA. After removing solvent in vacuo, the residue was dissolved in saturated sodium bicarbonate and DCM. The aqueous phase was extracted with a further portion of DCM. The combined extracts were dried over sodium sulfate, decanted and concentrated under high vacuum to afford product as a mixture of diastereomers (55 mg, 80%). The diastereomers were partially separated using chiral HPLC (Phenomenex Lux Cellulose-1, 20×250 mm, 5 micron particle size, 30% ethanol in hexane, 20 mL/min, 8 mg/injection). Retention time of Peak 1: 32.84 min, retention time of peak 2: 37.30 min, retention time of peak 3: 45.74 min (contains two isomers).

Provenance & Evidence