Hydrazine → HCID 67232495, compound

Participants

Reaction Conditions

Reaction Steps

The starting material (3R,4R)-1-tert-butoxycarbonyl-3-(4-fluorophenyl)piperidine-4-carboxylic acid was prepared as an enantiomeric mixture according to the procedure disclosed in WO 2002/068387. The resulting enantiomers were separated via SFC (Instrument: Berger MG II preparative SFC; Column: ChiralPak AD-H, 250×30 mm I.D.; Mobile phase: CO2: Methanol (with 0.01% DEA), 95:5; Flow rate: 70 mL/min; Sample preparation: dissolved in Methanol, 20 mg/ml; Injection: 2 ml per injection.). The faster eluting enantiomer of (3R,4R)-1-tert-butoxycarbonyl-3-(4-fluorophenyl)piperidine-4-carboxylic acid (300 mg, 0.928 mmol) in THF (4.0 ml) was treated with CDT (165 mg, 1.021 mmol) and heated at 60° C. for 20 min. A solution of 4′-fluoroacetophenone (513 mg, 3.71 mmol) in a separate vial was treated at rt with solid lithium bis(trimethylsilyl)amide (621 mg, 3.71 mmol) and the mixture was stirred at rt for 10 min. This lithium mixture was then treated dropwise with the CDT-activated carboxylic acid solution. The combined mixture was stirred for 30 min at rt and then quenched with saturated aqueous NaHCO3. The mixture was diluted with water and extracted with MTBE. The combined organic layers were dried with anhydrous Na2SO4, and then filtered. The filtrate was concentrated to give a residue. The residue was dissolved in EtOH, and treated with hydrazine (0.25 ml, 7.97 mmol). The reaction was heated at 60° C. for 1 h, then cooled to rt and concentrated. Purification of the resulting residue by chromatography on SiO2 (0 to 10% MeOH/DCM) afforded tert-butyl (3R,4R)-3-(4-fluorophenyl)-4-[5-(4-fluorophenyl)-1H-pyrazol-3-yl]piperidine-1-carboxylate, which was dissolved in DCM (1 mL) and treated with TFA (1 mL), followed by stirring at rt for 12 h and concentrating under vacuum. Purification of the resulting residue by RP-HPLC(C18, 15% to 100% water/acetonitrile over 12 min, 0.1% TFA) afforded the title compound. HPLC/MS: 340.1 (M+1), R=1.45 min (LC-4 HPLC conditions). Racemic material can be obtained in a similar manner by using racemic starting material.

Provenance & Evidence