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

HRID 855532Notes

Reaction equation

HRID 855532 reaction equation
F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:26]2[CH2:25][CH2:24][N:23]([CH:22]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[CH2:28][CH2:27]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 1529321-(Bis(4-fluorophenyl)methyl)piperazineHCID 5219721Methyl 4-fluoro-3-nitrobenzoate

Product 1

HCID 589357284-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-nitro-benzoic acid methyl ester

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

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).

Workup

  1. temperaturethen cooled to rt
  2. washwashed with brine (2×50 mL) and water (2×50 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-606d68c8e12843a987021795cca94ac0
Source dataset
uspto-grants-2007_08
Patent number
US07262197B2

Reaction notes

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