1-(4-Fluoro-2-(trifluoromethyl)phenyl)-3-methylpiperazine synthesis

Yield:946399-84-4 98%

Reaction Conditions:

with sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium⁽⁰⁾;2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl in toluene at 105; for 3.5 h;Inert atmosphere;

Steps:

1.1.1A

Step IA: A mixture of (R)-2-methyl-piperazine (25.0 g, 250 mmol), 2-bromo 5- fluoro benzotrifluoride (55.1 g, 227 mmol), tris(dibenzylidineacetone)dipalldium (0) (2.08g, 2.27 mmol), rac-2,2'-bis(diphenylphosphino)-l,r-binaphthyl (4.24 g, 6.81 mmol) and sodium tert-butoxide (27.3 g, 280 mmol) was mixed and purged with N₂. Anhydrous toluene (500 mL) was added and purged with N₂ again. The resulting mixture was heated in an oil bath at 105 ⁰C under N₂ for 3.5 hours. After cooling, the reaction mixture was concentrated and then filtered through a pad of Celite, washed with Et₂O. The organic layer was concentrated, diluted with Et₂O (500 mL), filtered through a pad of Celite again, and washed with IN aq. HCl (2 x 150 mL). The aqueous layer was basified with NaOH at 0 ⁰C (pH = -10) and then was extracted with Et₂O (3 x 200 mL). The combined organic layer was dried over MgSO₄ and concentrated under vacuum to give (3i?)-l-[4- fluoro-2-(trifluoromethyl)phenyl]-3-methylpiperazine as a brown oil (58.5 g, 98%), which was used without further purification.

References:

WO2010/141550,2010,A2 Location in patent:Page/Page column 48-49