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Trifluoromethanesulfonic acid → 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-2-methyl-4-pyrimidinamine

HRID 1812293
Notes
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Reaction equation

HRID 1812293 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][C@@H:46]3[CH3:55])[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].OS(C(F)(F)F)(=O)=O>C(O)(C(F)(F)F)=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[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][C@@H:46]3[CH3:55])[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

4

Reactant 2

HCID 62406Trifluoromethanesulfonic acidHCID 685177176-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine

Product 1

HCID 595483366-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-2-methyl-4-pyrimidinamineYield 29.2%

Reagents, catalysts & solvents 1

HCID 6422
Trifluoroacetic acid
Solvent

Conditions

Temperature
80 °C

Procedure

A mixture of 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.050 g, 0.065 mmol) in TFA (1 mL) was treated with triflic acid (5.76 μL, 0.065 mmol) and heated to 80° C. for 1 h. The reaction mixture was concentrated and then ice cubes were added to the brown residue. Saturated NaHCO3 (aq.) was added followed by CH2Cl2. The layers were separated and 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 (4 g), eluting with a gradient of 0% to 5% MeOH in CH2Cl2, to provide 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-2-methyl-4-pyrimidinamine (0.010 g, 0.019 mmol, 29.1% yield) as a brown solid. m/z (ESI, +ve) 531.2 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.14 (s, 1H); 8.36 (dd, J=12.91, 2.35 Hz, 1H); 8.22-8.25 (m, 1H); 8.16 (d, J=2.35 Hz, 1H); 7.95 (dd, J=1.96, 0.39 Hz, 1H); 7.04 (s, 2H); 6.79 (s, 1H); 4.02 (q, J=6.65 Hz, 1H); 3.94 (s, 3H); 3.05-3.20 (m, 2H); 2.77-2.95 (m, 5H); 2.53 (br. s., 3H); 2.45 (dd, J=11.35, 5.28 Hz, 1H); 1.40 (d, J=6.65 Hz, 3H); 1.10 (d, J=6.26 Hz, 3H).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. additionice cubes were added to the brown residue
  3. additionSaturated NaHCO3 (aq.) was added
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with CH2Cl2 (2×)
  6. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. custompurified by chromatography through a silica gel column (4 g)
  10. washeluting with a gradient of 0% to 5% MeOH in CH2Cl2

Sources & evidence

ORD record
ord-15e5c28c4c3742bfa9a40e633342950d
Source dataset
uspto-grants-2013_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08362241B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes