Cesium carbonate → 5-Fluoro-4-(4-methylpiperazin-1-yl)pyridin-3-amine

HRID 524877Notes

Reaction equation

HRID 524877 reaction equation
C(=O)(OC(C)(C)C)[NH2:2].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl[C:58]1[CH:59]=[N:60][CH:61]=[C:62]([F:71])[C:63]=1[N:64]1[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:71][C:62]1[C:63]([N:64]2[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]2)=[C:58]([NH2:2])[CH:59]=[N:60][CH:61]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 77922tert-Butyl carbamate2×HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)2×HCID 867209331-(3-Chloro-5-fluoropyridin-4-yl)-4-methylpiperazine

Product 1

HCID 867209345-Fluoro-4-(4-methylpiperazin-1-yl)pyridin-3-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of tert-butyl carbamate (709.9 mg, 6.060 mmol), Cs2CO3 (3.291 g, 10.10 mmol), xantphos (146.1 mg, 0.2525 mmol), Pd2(dba)3 (231.2 mg, 0.2525 mmol) and 1-(3-chloro-5-fluoro-4-pyridyl)-4-methyl-piperazine (1.16 g, 5.050 mmol) in dioxane (11.60 mL) was heated at 110° C. for 1 h. At room temperature, tert-butyl carbamate (709.9 mg, 6.060 mmol), xantphos (146.1 mg, 0.2525 mmol) and Pd2(dba)3 (231.2 mg, 0.2525 mmol) was added and the mixture was further heated at 120° C. in the microwave for 1 h. The reaction mixture was then filtered through a celite pad and washed with methanol and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica, using the ISCO column companion system eluting with 0-10% MeOH/DCM. Product fractions were combined and concentrated in vacuo to yield 5-fluoro-4-(4-methylpiperazin-1-yl)pyridin-3-amine as a light brown viscous oil. (642 mg, 60%). MS (ES+) 211.1.

Workup

  1. temperaturethe mixture was further heated at 120° C. in the microwave for 1 h
  2. filtrationThe reaction mixture was then filtered through a celite pad
  3. washwashed with methanol
  4. concentrationthe filtrate concentrated in vacuo
  5. customThe residue was purified by column chromatography on silica
  6. washeluting with 0-10% MeOH/DCM
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-a2b81db8fc874db79f24908673f19b6f
Source dataset
uspto-grants-2016_05
Patent number
US09340546B2

Reaction notes

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