Methylamine → 1-(4-(4-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-methylurea

HRID 1093226Notes

Reaction equation

HRID 1093226 reaction equation
[CH:1]12[CH2:29][CH2:28][CH:4]([N:5]([C:7]3[N:12]=[C:11]([C:13]4[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=4)[N:10]=[C:9]4[N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:21]=[CH:22][C:8]=34)[CH2:6]1)[CH2:3][O:2]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CN.[N:44]([C:47]1C=CC(C2N=C3N(CC(F)(F)F)N=CC3=C(N3CC4CCC3CO4)N=2)=CC=1)=[C:45]=[O:46]>ClCCl.O1CCCC1.C(N(CC)CC)C>[CH:1]12[CH2:29][CH2:28][CH:4]([N:5]([C:7]3[N:12]=[C:11]([C:13]4[CH:14]=[CH:15][C:16]([NH:17][C:45]([NH:44][CH3:47])=[O:46])=[CH:18][CH:19]=4)[N:10]=[C:9]4[N:20]([CH2:23][C:24]([F:26])([F:27])[F:25])[N:21]=[CH:22][C:8]=34)[CH2:6]1)[CH2:3][O:2]2

Participants

8

Reactant 4

HCID 6329MethylamineHCID 94429TriphosgeneHCID 665890864-(4-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)anilineHCID 866293825-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.2]octane

Product 1

HCID 574246961-(4-(4-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-methylurea

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Procedure

A solution of 4-(4-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (50 mg, 0.12 mmol) in dichloromethane (2.5 mL) was treated triethylamine (160 μL), followed by triphosgene (27 mg, 0.09 mmol) as a solution in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 2.0 M methylamine solution in tetrahydrofuran (1.2 mL)—was added to the 5-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.2]octane (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 1-(4-(4-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-methylurea. MS (ES+): 462.3 (M+H)+

Workup

  1. concentrationThe reaction mixture was concentrated to dryness under reduced pressure
  2. customThe residue was purified by reverse-phase high performance liquid chromatography
  3. washa gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile

Sources & evidence

ORD record
ord-5b56f05f3b65451daf93cc5e6d35b0a0
Source dataset
uspto-grants-2012_03
Patent number
US08129371B2

Reaction notes

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