Potassium Phosphate, Tribasic → 2-(4-Methyl-piperazin-1-yl)-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine

HRID 1481582Notes

Reaction equation

HRID 1481582 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([NH2:18])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>O1CCOCC1.O.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([NH2:18])[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28]([F:39])([F:38])[F:27])[N:7]=2)[CH2:9][CH2:10]1

Participants

8

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27343872-(Trifluoromethyl)benzeneboronic acidHCID 866574286-Chloro-2-(4-methyl-piperazin-1-yl)-3-nitro-pyridin-4-ylamine

Product 1

HCID 674108042-(4-Methyl-piperazin-1-yl)-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 12976736Bis(ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane);iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 6-chloro-2-(4-methyl-piperazin-1-yl)-3-nitro-pyridin-4-ylamine (578 mg, 2.13 mmol, prepared as described in the previous step) in 1,4-dioxane (20 mL) was treated with K3PO4 (2.03 g, 9.58 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene (101 mg, 0.213 mmol), and 2-trifluoromethylphenylboronic acid (910 mg, 4.79 mmol). The resulting mixture was degassed via sonication, Pd(OAc)2 (47.8 mg, 0.213 mmol) was added, and the mixture was heated to 80° C. for 18 h. The cooled mixture was diluted with water (50 mL) and extracted twice with EtOAc (60 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 40-g SEPRA Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 3:1 v/v for 5 min, then 3:1 to 1:0 v/v over 40 min) to yield 2-(4-methyl-piperazin-1-yl)-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine as an orange solid. 1H-NMR (400 MHz, CDCl3) δ: 7.74 (d, J=7.6 Hz, 1H), 7.55-7.61 (m, 1H), 7.45-7.54 (m, 2H), 6.13 (s, 1H), 6.02 (br. s., 2H), 3.46-3.52 (m, 4H), 2.44-2.50 (m, 4H), 2.32 (s, 3H). Mass Spectrum (LCMS, APCI pos.): Calculated for C17H18F3N5O2: 382.1 (M+H). Measured: 382.1.

Workup

  1. additionwas added
  2. extractionextracted twice with EtOAc (60 mL)
  3. dry with materialThe combined extracts were dried over MgSO4
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified on a 40-g SEPRA Si 50 SPE column (Isco system

Sources & evidence

ORD record
ord-f5123e15308240468dd0359a283f3a90
Source dataset
uspto-grants-2016_08
Patent number
US09409915B2

Reaction notes

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