p-Toluenesulfonic acid → HCID 136248869, compound

HRID 922409Notes

Reaction equation

HRID 922409 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:5]=[C:6]([CH:8]=O)[CH:7]=1.[NH2:23][C:24]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:25]=1[C:26]([NH2:28])=[O:27].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+].FC(F)(F)C(O)=O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:28][C:26](=[O:27])[C:25]3[C:24](=[CH:32][C:31]([O:33][CH3:34])=[CH:30][C:29]=3[O:35][CH3:36])[N:23]=2)[CH:5]=[C:4]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH:3]=1

Participants

7

Reactant 5

HCID 6101p-Toluenesulfonic acidHCID 6422Trifluoroacetic acidHCID 203490162-Amino-4,6-dimethoxybenzamideHCID 23665763Sodium BisulfiteHCID 86719363tert-Butyl 4-(3-Chloro-5-formylphenyl)piperazine-1-carboxylate

Product 1

HCID 136248869HCID 136248869, compoundYield 29.3%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
110 °C

Procedure

A solution of tert-butyl 4-(3-chloro-5-formylphenyl)piperazine-1-carboxylate (3, 0.300 g, 0.918 mmol) and 2-amino-4,6-dimethoxybenzamide (4, 0.120 g, 0.612 mmol) in DMA (4 mL) was treated with p-TsOH (0.424 g, 1.46 mmol) and NaHSO3 (0.290 g, 1.84 mmol) and then heated at 110° C. for 16 h. The reaction mixture was cooled to room temperature, trifluoroacetic acid (5 mL) was added and the mixture was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-100% 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2. This material was further purified by reverse phase HPLC eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. The product fractions were concentrated and the residue was dissolved in acetonitrile and water. The mixture was basified with concentrated NH4OH and the precipitate filtered, washed with water, and dried under vacuum to afford the title compound (0.072 g, 29%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 7.60-7.70 (m, 2H), 7.08-7.12 (m, 1H), 6.78 (d, J=2.3 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.24 (t, J=5.2 Hz, 4H), 3.28 (t, J=5.2 Hz, 4H); ESI MS m/z 401 [M+H]+.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. temperaturethe mixture was heated at 70° C. for 1 h
  3. temperatureThe reaction mixture was cooled to room temperature
  4. concentrationconcentrated
  5. customThe residue was purified by silica gel chromatography
  6. washeluting with 0-100% 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2
  7. customThis material was further purified by reverse phase HPLC
  8. washeluting with 10% to 90% CH3CN in H2O with 0.1% TFA
  9. concentrationThe product fractions were concentrated
  10. dissolutionthe residue was dissolved in acetonitrile
  11. filtrationthe precipitate filtered
  12. washwashed with water
  13. customdried under vacuum

Sources & evidence

ORD record
ord-32b7e64efd874a3d855d2b21a0a6b634
Source dataset
uspto-grants-2016_03
Patent number
US09278940B2

Reaction notes

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