Piperazine, 1-[(3-bromo-4-nitrophenyl)methyl]-4-methyl- synthesis

Yield:1094554-35-4 88%

Reaction Conditions:

Stage #1: 1-methyl-piperazine;3-bromo-4-nitrobenzaldehydewith acetic acid in toluene at 20; for 1 h;
Stage #2: with sodium tris(acetoxy)borohydride in toluene; for 4 h;
Stage #3: with sodium hydrogencarbonate in methanol;water;toluene;Product distribution / selectivity;

Steps:

N-methyl piperazine (0.95 ml_, 8.56 mmol) was added dropwise to a suspension of 3-bromo-4-nitrobenzaldehyde (0.985 g, 4.28 mmol) and acetic acid (0.29 ml_,5.14 mmol) in toluene (5.5 ml.) at room temperature. The reaction mixture was stirred for 1 h at room temperature before the addition of sodium triacetoxyborohydride (1.36 g, 6.42 mmol). The reaction mixture was stirred for 2 h. Further toluene (2.1 ml.) and sodium triacetoxyborohydride (0.18 g, 0.86 mmol) was added and the reaction mixture was stirred for 2 hours and then quenched by the addition of MeOH (0.99 ml_). The reaction mixture was stirred for 30 min, saturated aqueous NaHCO₃ (6.01 ml.) was then added and the reaction mixture was stirred overnight. The phases were separated and the aqueous layer was extracted with toluene (4.0 ml_). The combined organic extracts were concentrated under reduced pressure and purified by flash column chromatography (EtOAc:MeOH:NEt₃ 9:1 :0.1 ) to give the title compound (1.18 g, 88%) as a low melting point waxy brown solid. δ_H (400 MHz, CDCI₃) 7.81 (1 H, d, J 8.3, Ar H), 7.74 (1 H, d, J 1.5, Ar H), 7.42 (1 H, dd, J 1.7, 8.3, Ar H), 3.53 (2H, s, NCH₂Ar), 2.49 (8H, br s, 2 x NCH₂CH₂), 2.31 (3H, s, NCH₃).

References:

WO2009/2916,2008,A2 Location in patent:Page/Page column 27