Potassium Carbonate → 4-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-nitro-benzoic acid methyl ester

Participants

Reaction Conditions

Reaction Steps

Methyl 4-fluoro-3-nitrobenzoate Compound 3a (1.0 g, 5.02 mmol) (prepared as described in Nicolaou, et al., Bioorg. Med. Chem., 1998, 1185), 1-[bis(4-fluorophenyl)methyl]piperazine Compound 3b (1.59 g, 5.52 mmol) and potassium carbonate (0.76 g, 5.52 mmol) were dissolved in N,N-Dimethylformamide (15 mL) and heated to about 80° C. for about 5 h then cooled to rt. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (2×50 mL) and water (2×50 mL), then dried over Na2SO4, filtered and concentrated in vacuo to give 4-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-nitro-benzoic acid methyl ester Compound 3c (2.4 g) as a yellow foam. MS m/z 468 (M+H). A mixture of the nitro substituted methyl ester Compound 3c (2.4 g, 5.13 mmol) and tin (II) chloride dihydrate (11.60 g, 51.34 mmol) was stirred in DMF (50 mL) for about 1 h. The reaction was diluted with ethyl acetate (100 mL), washed with brine (2×100 mL) and water (3×150 mL), then dried over Na2SO4, filtered and concentrated in vacuo to give 3-amino-4-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-benzoic acid methyl ester Compound 3d (1.88 g) as a yellow foam. MS m/z 438 (M+H). A mixture of the amino substituted methyl ester Compound 3d (1.88 g, 4.30 mmol) and phenyl isocyanate Compound 3e (0.51 g, 4.30 mmol) was stirred in diethyl ether (50 mL) for about 18 h. The precipitate was collected by filtration, then washed with ether and hexane to provide Compound 11 (1.80 g) as an off-white solid. MS m/z 559 (M+H). A solution of Compound 11 (0.45 g, 0.81 mmol) and LiAlH4 in THF (1.0 M, 1 mL, 1.0 mmol) in THF (10 mL) was stirred for about 18 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×75 mL), dried over Na2SO4, filtered and concentrated in vacuo to give Compound 10 (0.31 g) as a white solid. MS m/z 529 (M+H).

Provenance & Evidence