M-Cresol → 2-[6-(3-Methylphenoxy)-pyrimidin-4-yl]amino-6-aminopyridine

HRID 404781Notes

Reaction equation

HRID 404781 reaction equation
Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[CH3:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1

Participants

6

Reactant 3

HCID 342M-CresolHCID 11430Potassium CarbonateHCID 57708264N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine

Product 1

HCID 577083532-[6-(3-Methylphenoxy)-pyrimidin-4-yl]amino-6-aminopyridineYield 75.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
145 °C

Procedure

A mixture of 2,6-diaminopyridine (1.530 g, 14.020 mmol) and 4,6-dichloropyrimidine (2.610 g, 17.519 mmol) in 15 mL of n-butanol in a sealed vial was heated at 100° C. for 72 h. The dark brown sample was cooled and was concentrated at reduced pressure to remove most of the n-butanol. The residue was then partitioned between EtOAc and saturated. NaHCO3 solution. An emulsion formed, the sample was filtered through a pad of Celite and the layers were separated. The organic extract was washed with sat. KH2PO4 and brine solutions, dried (MgSO4), filtered and concentrated to brown oily-solid. The sample was suspended into ˜50 mL of CH2Cl2, cooled and filtered to give 1.017 g (36%) of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine as yellow-orange solid. MS: m/z 222/224 (M+1, 100/63%). To a solution of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine (100 mg, 0.45 mmol) in DMF (1 mL) was added 3-methylphenol (88 mg, 0.8 mmol) and anhydrous K2CO3 (93 mg, 0.6 mmol). The reaction mixture was heated at 145° C. for 16 h. It was then cooled and DMF was removed under reduced pressure to get a yellow gummy residue. The residue was taken in EtOAc (20 mL), was washed sequentially with water (5 mL) and brine (5 mL) and was dried over Na2SO4. Filtration followed by concentration under reduced pressure afforded a yellow gum which was further purified by column chromatography (SiO2, 60-120, EtOAc/hexane, 5/5) to give 100 mg of 2-[6-(3-methylphenoxy)-pyrimidin-4-yl]amino-6-aminopyridine (IR-12) as a pale yellow solid. MS: m/z 294 (M+H)

Workup

  1. temperatureIt was then cooled
  2. customDMF was removed under reduced pressure
  3. customto get a yellow gummy residue
  4. washwas washed sequentially with water (5 mL) and brine (5 mL)
  5. dry with materialwas dried over Na2SO4
  6. filtrationFiltration
  7. concentrationfollowed by concentration under reduced pressure
  8. customafforded a yellow gum which
  9. customwas further purified by column chromatography (SiO2, 60-120, EtOAc/hexane, 5/5)

Sources & evidence

ORD record
ord-31beae943a084a5285effb83b07c43ba
Source dataset
uspto-grants-2014_06
Patent number
US08748606B2

Reaction notes

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