Trifluoroacetic acid → HCID 178494211, compound

HRID 1621861Notes

Reaction equation

HRID 1621861 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][CH2:20]3)[CH3:18])=[CH:13][C:12]=2[C:32]2[N:40]=[C:39]([CH3:41])[N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][N:36]3C2CCCCO2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O.F[C:56](F)(F)[S:57](O)(=[O:59])=[O:58].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:32]3[N:40]=[C:39]([CH3:41])[N:38]=[C:37]4[C:33]=3[N:34]=[CH:35][NH:36]4)=[CH:13][C:14]([C@H:17]([N:19]3[CH2:24][CH2:23][N:22]([S:57]([CH3:56])(=[O:59])=[O:58])[CH2:21][CH2:20]3)[CH3:18])=[CH:15][N:16]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 31297Methanesulfonyl chlorideHCID 62406Trifluoromethanesulfonic acidHCID 68515999Tert-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)piperazine-1-carboxylate

Product 1

HCID 178494211HCID 178494211, compoundYield 2.66%

Reagents, catalysts & solvents 3

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

Procedure

A mixture of 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)piperazine-1-carboxylate (0.450 g, 0.695 mmol) and trifluoroacetic acid (0.803 mL, 10.42 mmol) in DCM (25 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. The residue was diluted with DCM (10 mL), then sodium carbonate (2.50 g) was added to the mixture and allowed to stir 10 min. Then methanesulfonyl chloride (0.271 mL, 3.47 mmol) was added slowly via syringe into the mixture. The mixture was allowed to stir under inert atmosphere overnight. The mixture was diluted with dichloromethane (20 mL), water (20 mL) and brine solution (10 mL). The organic layer was extracted with dichloromethane (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 10 micron, C18(2), 100 Å, 250×50 mm, (Varian, 5-70% acetonitrile in water with trifluoroacetic acid additive 0.1% v/v in each solvent) and then further purified by normal phase silica-gel chromatography on an Interchim puriflash (25 g) column eluting with 10% methanol in dichloromethane to give N-(5-fluoro-6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((R)-1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-amine (0.010 g, 0.018 mmol, 2.66% yield) as a light-yellow solid. 1H NMR (400 MHz, CDCl3) δ 12.69 (s, 1H) 9.77 (d, J=1.96 Hz, 1H) 8.39 (dd, J=12.52, 2.15 Hz, 1H) 8.32 (d, J=2.15 Hz, 1H) 8.21 (s, 1H) 8.11 (d, J=2.15 Hz, 1H) 4.04 (s, 3H) 3.67-3.73 (m, 1H) 3.26 (t, J=4.69 Hz, 4H) 2.94 (s, 3H) 2.77 (s, 3H) 2.62-2.71 (m, 4H) 1.51 (d, J=6.65 Hz, 3H). m/z (ESI, +ve ion) 542.1 (M+H)+.

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. additionThe residue was diluted with DCM (10 mL)
  3. additionsodium carbonate (2.50 g) was added to the mixture
  4. stirringto stir 10 min
  5. stirringto stir under inert atmosphere overnight
  6. extractionThe organic layer was extracted with dichloromethane (3×15 mL)
  7. dry with materialThe combined organic extracts were dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe crude material was purified by reverse-phase preparative HPLC
  11. custom(Varian, 5-70% acetonitrile in water with trifluoroacetic acid additive 0.1% v/v in each solvent) and then further purified by normal phase silica-gel chromatography on an Interchim puriflash (25 g) column
  12. washeluting with 10% methanol in dichloromethane

Sources & evidence

ORD record
ord-110629c6d9034f0c8c5c0c430ba36418
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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