6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine → 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-2-methyl-4-pyrimidinamine

HRID 1621881Notes

Reaction equation

HRID 1621881 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[CH:18]=3)=[CH:15][C:14]([C@H:43]([N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]3)[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]>C(O)(C(F)(F)F)=O.OS(C(F)(F)F)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[CH:18]=3)=[CH:15][C:14]([C@H:43]([N:45]3[CH2:46][CH2:47][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:49][CH2:50]3)[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]

Participants

4

Reactant 1

HCID 666003246-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine

Product 1

HCID 595484516-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-2-methyl-4-pyrimidinamineYield 81%

Reagents, catalysts & solvents 2

HCID 62406Trifluoromethanesulfonic acidCatalystHCID 6422Trifluoroacetic acidSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.200 g, 0.264 mmol) in TFA (2 mL) at RT was treated with a few drops of triflic acid. The solution was heated to 80° C. for 90 minutes. The reaction mixture was allowed to cool to RT and was then concentrated. A few ice cubes were added and then saturated NaHCO3 (aq.) was added followed by CH2Cl2. The mixture was filtered and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of 0% to 3% MeOH in CH2Cl2, to provide 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-2-methyl-4-pyrimidinamine (0.110 g, 0.213 mmol, 81% yield) as a yellow solid. m/z (ESI, +ve) 517.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.17 (br. s, 1H); 8.35 (dd, J=13.01, 2.25 Hz, 1H); 8.22 (d, J=2.15 Hz, 1H); 8.17 (d, J=2.35 Hz, 1H); 7.95-7.98 (m, 1H); 7.04 (s, 2H); 6.80 (s, 1H); 3.94 (s, 3H); 3.61 (q, J=6.78 Hz, 1H); 3.11 (t, J=4.99 Hz, 4H); 2.87 (s, 3H); 2.53-2.58 (m, 5H); 2.43-2.50 (m, 2H); 1.38 (d, J=6.85 Hz, 3H).

Workup

  1. temperatureto cool to RT
  2. concentrationwas then concentrated
  3. additionA few ice cubes were added
  4. additionsaturated NaHCO3 (aq.) was added
  5. filtrationThe mixture was filtered
  6. customthe layers were separated
  7. extractionThe aqueous layer was extracted with CH2Cl2 (2×)
  8. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. custompurified by chromatography through a silica gel column (12 g)
  12. washeluting with a gradient of 0% to 3% MeOH in CH2Cl2

Sources & evidence

ORD record
ord-233fc97f0a9d4b0c9c4b5213b884b827
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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