1-[(4-fluorophenyl)methyl]piperazine;dihydrochloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-fluorobenzylchlorine and piperazine was treated according to the general preparation 1 to obtain N-(4-fluorobenzyl) piperazine dihydrochloride (67%), mp, 282-284° C. The N1-(4-fluorobenzyl)-N4-phenacyl piperazine dihydrochloride could be preparated according to the general preparation 2, which was reduced with KHCO3 (0.65 g, 6.5 mmol) and KBH4 (0.59 g, 10.4 mmol) in methanol (40 ml) according to the general preparation 3 to obtain 0.72 g of the title compound as white solid. was treated according to the general preparation 1

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 4 mL vial was added 1-(4-fluoro-benzyl)-piperazine dihydrochloride (13) (51 mg, 0.22 mmol, 1.0 equiv), (6-chloro-2-oxo-benzooxazol-3-yl)-acetic acid (50 mg, 0.22 mmol, 1.00 equiv), DIEA (153 μL, 0.88 mmol, 4.0 equiv), HATU (100 mg, 0.26 mmol, 1.20 equiv) and 1.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at room temperature overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 6-chloro-3-{2-[4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (14): HPLC retention time, 1.05 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 403.8, found, 404.5. A stir bar was placed in the vial and the vial was then capped The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent)