Aniline → N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamine

HRID 2193586Notes

Reaction equation

HRID 2193586 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.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCO.CO>[NH2:15][C:11]1[N:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1

Participants

5

Reactant 2

HCID 6115AnilineHCID 57708264N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine

Product 1

HCID 57708273N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamineYield 84.9%

Reagents, catalysts & solvents 2

HCID 2631-ButanolSolventHCID 887MethanolSolvent

Procedure

Step-1 A solution of N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine (1) (0.25 g, 1.1 mmol) and aniline (2) (0.16 g, 1.7 mmol) in n-BuOH (25 mL) was heated at 120° C. for 12 h in a pressure tube. The reaction mixture was cooled, was dissolved in methanol (10 mL) and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (35 mL) and was washed successively with 10% sodium bicarbonate solution (20 mL), water (20 mL), and saturated brine (20 mL). The ethyl acetate extract was dried over Na2SO4 and was concentrated under reduced pressure to give a residue, which was triturated with diethyl ether to give (260 mg, 83%) N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamine (3) as an off-white solid. Step-2 To a stirred solution of 3 (0.2 g, 0.7 mmol) in NMP (10 mL) was added acryloyl chloride (0.097 g, 1 mmol), drop wise at 0° C. The reaction mixture was allowed to stir at the same temperature for 20 min and then warmed to rt for 1.5 h. It was quenched with 10% sodium bicarbonate solution (4 mL) and was extracted with ethyl acetate (2×35 mL). The combined ethyl acetate layer was washed with water (20 mL), saturated brine (20 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was further purified by column chromatography (SiO2, 60-120, Petroleum ether/EtOAc: 90/10) to give N-6-(6-(phenylamino)pyrimidin-4-ylamino)pyridine-2-yl)acrylamide (I-72) as a brown solid. 1H NMR (DMSO-d6) δ ppm: 5.80 (dd, J=1.84 & 10.12 Hz, 1H), 6.31 (dd, J=1.8 & 16.96 Hz, 1H), 6.64 (dd, J=10.08 & 16.88 Hz, 1H), 6.96 (t, J=7.32 Hz, 1H), 7.15-7.20 (m, 1H), 7.28 (t, J=7.52 Hz, 2H), 7.34 (s, 1H), 7.60-7.70 (m, 4H), 8.30 (s, 1H), 9.08 (s, 1H), 9.66 (s, 1H), 10.06 (s, 1H); LCMS: m/e 332.6 (M+).

Workup

  1. temperatureThe reaction mixture was cooled
  2. concentrationwas concentrated under reduced pressure
  3. dissolutionThe residue was dissolved in ethyl acetate (35 mL)
  4. washwas washed successively with 10% sodium bicarbonate solution (20 mL), water (20 mL), and saturated brine (20 mL)
  5. extractionThe ethyl acetate extract
  6. dry with materialwas dried over Na2SO4
  7. concentrationwas concentrated under reduced pressure
  8. customto give a residue, which
  9. customwas triturated with diethyl ether

Sources & evidence

ORD record
ord-ae541a9e0010464bb128cc43fa6f9833
Source dataset
uspto-grants-2012_12
Patent number
US08329901B2

Reaction notes

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