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Trifluoroacetic acid → n-(5-Fluoro-6-methoxypyridin-3-yl)-5-((r)-1-((s)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)ethyl)-3-(2-methyl-9h-purin-6-yl)pyridin-2-amine

HRID 1621858
Notes
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Reaction equation

HRID 1621858 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C@H:17]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C@@H:20]3[CH3:32])[CH3:18])=[CH:13][C:12]=2[C:33]2[N:41]=[C:40]([CH3:42])[N:39]=[C:38]3[C:34]=2[N:35]=[CH:36][N:37]3C2CCCCO2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O.F[C:57](F)(F)[S:58](O)(=[O:60])=[O:59].CS(Cl)(=O)=O>C(Cl)Cl.O.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:12]([C:33]3[N:41]=[C:40]([CH3:42])[N:39]=[C:38]4[C:34]=3[N:35]=[CH:36][NH:37]4)=[CH:13][C:14]([C@H:17]([N:19]3[CH2:24][CH2:23][N:22]([S:58]([CH3:57])(=[O:60])=[O:59])[CH2:21][C@@H:20]3[CH3:32])[CH3:18])=[CH:15][N:16]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 31297Methanesulfonyl chlorideHCID 62406Trifluoromethanesulfonic acidHCID 68516009(3s)-Tert-butyl 4-((1r)-1-(6-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2h-pyran-2-yl)-9h-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate

Product 1

HCID 178494212
n-(5-Fluoro-6-methoxypyridin-3-yl)-5-((r)-1-((s)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)ethyl)-3-(2-methyl-9h-purin-6-yl)pyridin-2-amine
Yield 4.63%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 57417360Sodium chloride; waterSolvent

Procedure

A mixture of (3S)-tert-butyl 4-((1R)-1-(6-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (0.180 g, 0.272 mmol) and trifluoroacetic acid (0.314 mL, 4.08 mmol) in DCM (10 mL) was treated with trifluoromethanesulfonic acid (0.01 mL) and allowed to stir under inert atmosphere for 1 h. The mixture was concentrated in vacuo, then THF (10 mL) was added to the residue and stirred 5 min. Then sodium carbonate (0.500 g) was added to the mixture and allowed to stir under inert atmosphere an additional 5 min. Then methanesulfonyl chloride (0.064 mL, 0.816 mmol) was added slowly via syringe into the mixture. The mixture was allowed to stir under inert atmosphere overnight. The mixture was diluted with DCM (20 mL),water (20 mL) and brine solution (10 mL). The organic layer was extracted with DCM (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was recrystallized from methanol and dichloromethane to give N-(5-fluoro-6-methoxypyridin-3-yl)-5-((R)-1-((S)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)ethyl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (0.007 g, 0.013 mmol, 4.63% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 12.69 (s, 1H) 9.84 (s, 1H) 8.38 (dd, J=12.42, 2.05 Hz, 1H) 8.28 (d, J=2.15 Hz, 1H) 8.22 (s, 1H) 8.11 (d, J=2.15 Hz, 1H) 7.26 (s, 8H) 4.16 (dq, J=14.18, 6.94 Hz, 1H) 4.04 (s, 3H) 3.30 (s, 2H) 3.14-3.21 (m, 1H) 2.93-3.06 (m, 4H) 2.85 (dd, J=10.76, 7.24 Hz, 1H) 2.69-2.78 (m, 4H) 2.55-2.64 (m, 1H) 1.54 (d, J=6.85 Hz, 3H) 1.13-1.32 (m, 3H). m/z (ESI, +ve ion) 556.1 (M+H)+.

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. additionTHF (10 mL) was added to the residue
  3. stirringstirred 5 min
  4. additionThen sodium carbonate (0.500 g) was added to the mixture
  5. stirringto stir under inert atmosphere an additional 5 min
  6. stirringto stir under inert atmosphere overnight
  7. extractionThe organic layer was extracted with DCM (3×15 mL)
  8. dry with materialThe combined organic extracts were dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe crude material was recrystallized from methanol and dichloromethane

Sources & evidence

ORD record
ord-be53f35b877d40c589bc14d9ef0a7b04
Source dataset
uspto-grants-2014_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08772480B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes