Potassium Phosphate, Tribasic → HCID 86701071, compound

HRID 334495Notes

Reaction equation

HRID 334495 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:49]1[CH:50]=[N:51][CH:52]=[C:53]([N+:56]([O-:58])=[O:57])[C:54]=1[NH2:55]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CN(C=O)C>[F:16][C:14]1[CH:15]=[C:2]([C:49]2[CH:50]=[N:51][CH:52]=[C:53]([N+:56]([O-:58])=[O:57])[C:54]=2[NH2:55])[CH:3]=[C:4]([CH2:5][N:6]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[CH:13]=1

Participants

10

Reactant 5

HCID 62657Potassium Phosphate, TribasicHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 49975884-Amino-3-bromo-5-nitropyridineHCID 79673114HCID 79673114, compound

Product 1

HCID 86701071HCID 86701071, compoundYield 42%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

A solution of 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) (528 mg, 1.84 mmol), bis(pinacolato)diboron (560 mg, 2.21 mmol), KOAc (541 mg, 5.51 mmol) and dry DMF (26 mL) was purged with argon. PdCl2(dppf)2 (90 mg, 0.11 mmol) was added to the reaction and purged again with argon. The solution was heated at 90° C. for 2 h. Once TLC showed the disappearance of (CII), the solution was cooled to room temperature. To this solution was added K3PO4 (588 mg, 2.76 mmol), 3-bromo-5-nitropyridin-4-amine (LXIX) (400 mg, 1.84 mmol), Pd(PPh3)4 (106 mg, 0.09 mmol) and water (5 mL). The solution was purged with argon and heated at 90° C. for 4 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned between CHCl3 and water. The aqueous phase was separated and washed 2×CHCl3. The combined organic phases were washed with brine, dried over MgSO4, filtered and then evaporated under vacuum. The residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3) to give 3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)-5-nitropyridin-4-amine (CIV) as a yellow amorphous solid (419 mg, 1.21 mmol, 42% yield for 2 steps). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.27-2.41 (m, 8H), 3.52 (s, 2H), 7.16-7.22 (m, 3H), 7.42 (brs, 2H), 8.11 (s, 1H), 9.04 (s, 1H); ESIMS found for C17H20FN5O2 m/z 346.0 (M+H).

Workup

  1. custompurged again with argon
  2. temperaturethe solution was cooled to room temperature
  3. customThe solution was purged with argon
  4. temperatureheated at 90° C. for 4 h
  5. temperatureThe solution was cooled to room temperature
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was partitioned between CHCl3 and water
  8. customThe aqueous phase was separated
  9. washwashed 2×CHCl3
  10. washThe combined organic phases were washed with brine
  11. dry with materialdried over MgSO4
  12. filtrationfiltered
  13. customevaporated under vacuum
  14. customThe residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3)

Sources & evidence

ORD record
ord-938088b0427449c48fac724195c68ffa
Source dataset
uspto-grants-2014_11
Patent number
US08883822B2

Reaction notes

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